An indazole derivative and its use in medicine

Abstract

The present invention belongs to the field of medicinal chemistry and relates to indazole derivatives and their use as therapeutic agents, in particular as PLK4 inhibitors. The derivatives are compounds of general formula I or general formula II, and geometric isomers, enantiomers or pharmaceutically acceptable salts thereof; preferred compounds have activity as protein kinase inhibitors, in particular as PLK4 kinase inhibitors.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to an indazole derivative and its use as a therapeutic agent, particularly as a PLK4 inhibitor. Background Technology

[0002] Malignant tumors have always been a major disease troubling the world. Treatment methods for tumors are gradually shifting from the use of traditional, non-selective chemotherapy drugs to highly selective targeted therapies. With the emergence of the concept of precision medicine, targeting abnormally expressed protein kinases in tumor cells has gradually become an important research direction in the field of anti-tumor therapy. In recent years, therapies that inhibit the unlimited proliferation of tumor cells by controlling centrosome expansion are considered a promising strategy for tumor treatment.

[0003] Polo-like kinase 4 (PLK4) is a member of the Polo-like protein kinase family and belongs to the highly conserved serine / threonine protein kinases. It is primarily expressed in actively dividing tissues and cells. A series of biological studies have shown that PLK4 is closely related to centrosome replication during the cell cycle. As a key regulatory protein of intracellular centrosome replication, it plays an important role in centrosome replication and mitosis, participating in various biological processes such as tumor cell proliferation, migration, invasion, and apoptosis. Studies have shown that PLK4 is abnormally expressed in most human tumors, such as liver cancer, gastric cancer, lung cancer, breast cancer, melanoma, and hematological malignancies.

[0004] Small-molecule ATP-competitive inhibitors of PLK4 are an important approach for treating tumors induced by centrosome error replication, and PLK4 inhibitors can achieve precise treatment of tumors containing TRIM37 gene amplification. To date, no PLK4 inhibitors have been marketed; only two molecules are in clinical trials: CFI-400945, in Phase II clinical trials for myeloid leukemia; and RP-1664, in Phase I clinical trials for solid tumors with high TRIM37 amplification, including breast cancer and neuroblastoma.

[0005] Therefore, developing novel and highly efficient PLK4 inhibitors for the treatment of diseases related to the expression or activity of PLK4 kinase, especially malignant tumors related to the expression or activity of PLK4 kinase, particularly tumors with high TRIM37 gene amplification, such as neuroblastoma and breast cancer, has significant scientific value and application prospects. Summary of the Invention

[0006] The purpose of this invention is to provide a novel indazole derivative, its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, as well as a method for their preparation and their use as therapeutic agents, particularly as PLK4 inhibitors.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] An indazole derivative, wherein the derivative is a compound of general formula I or general formula II, and its geometric isomers, enantiomers or pharmaceutically acceptable salts thereof.

[0009] The compounds represented by general formula I or general formula II are as follows:

[0010]

[0011] L1 is selected from -C≡C-, -CH=CH-, or bonds;

[0012] X1 is selected from -(NR) a )-、O、S、 Where R a Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, or C1-C4 haloalkyl;

[0013] X2 is selected from N, O, and S;

[0014] L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, or C1-C4 haloalkyl; R c Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl,

[0015] A1, A2, and A3 are the same or different, and are selected from C or N;

[0016] R1 is selected from hydrogen, halogen, C1-C4 alkyl-substituted sulfonyl group, unsubstituted or amino group substituted with 1-2 C1-C4 alkyl groups, C3-C7 aliphatic ring containing 1-2 heteroatoms, -CH2R d , where R d The components are selected from hydrogen, C1-C4 alkyl-substituted sulfonyl groups, unsubstituted or 1-2 C1-C4 alkyl-substituted amino groups, and C3-C7 aliphatic rings containing 1-2 heteroatoms; the heteroatoms are selected from N, O, or S, and when the heteroatom is N, it may be further substituted with C1-C4 alkyl groups, and when the heteroatom is S, it may be further oxidized to sulfoxides and sulfones;

[0017] R2, R3, and R6, which may be the same or different, are selected from hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, unsubstituted or modified by at least one Re Substituted aryl; R e Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy;

[0018] When X2 is selected from O, either R2 or R3 exists in general formula I (that is, O connects to R2 or O connects to R3, and either R2 or R3 exists).

[0019] R4 and R5, whether identical or different, are selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C3-C7 cycloalkyl, unsubstituted or modified by at least one R. f Substituted aryl; R f Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy.

[0020] Preferably, the derivative is a compound represented by general formula I or general formula II, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug.

[0021] L1 is selected from -C≡C-, -CH=CH-, or bonds;

[0022] X1 is selected from -(NR) a )-、O、S、 Where R a Selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C2 haloalkyl;

[0023] X2 is selected from N, O, and S;

[0024] L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl; R c Selected from hydrogen, C1-C2 alkyl,

[0025] A1, A2, and A3 are the same or different, and are selected from C or N;

[0026] R1 is selected from hydrogen, halogen, C1-C3 alkyl-substituted sulfonyl group, unsubstituted or amino group substituted with 1-2 C1-C4 alkyl groups, C3-C6 aliphatic ring containing 1-2 heteroatoms, -CH2R d , where R dThe group is selected from hydrogen, C1-C4 alkyl-substituted sulfonyl groups, unsubstituted or substituted amino groups with 1-2 C1-C4 alkyl groups, and C3-C6 aliphatic rings containing 1-2 heteroatoms; the heteroatoms are selected from N, O, or S, and when the heteroatom is N, it may be further substituted with C1-C2 alkyl groups, and when the heteroatom is S, it may be further oxidized to sulfoxides and sulfones;

[0027] R2, R3, and R6, whether identical or different, are selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, unsubstituted or modified by at least one R. e Substituted phenyl, pyridyl, or pyrimidinyl; R e Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy;

[0028] When X2 is selected from O, R2 or R3 exists in general formula I;

[0029] R4 and R5, whether identical or different, are selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, unsubstituted or modified by at least one R. f Substituted phenyl, pyridyl, or pyrimidinyl; R f Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy.

[0030] Further preferably, the derivative is a compound represented by general formula I or general formula II, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug.

[0031] L1 is selected from -C≡C-, -CH=CH-, or bonds;

[0032] X1 is selected from -(NR) a )-、S、 Where R a Selected from hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl;

[0033] X2 is selected from N and O;

[0034] L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl; R c Selected from H,

[0035] A1, A2, and A3 are the same or different, and are selected from C or N;

[0036] R1 is selected from hydrogen, C1-C3 alkyl-substituted sulfonyl group, unsubstituted or amino group substituted with 1-2 C1-C4 alkyl groups, C3-C6 aliphatic ring containing 1-2 heteroatoms, or -CH2R. d , where R d The group is selected from hydrogen, C1-C2 alkyl-substituted sulfonyl groups, unsubstituted or 1-2 C1-C2 alkyl-substituted amino groups, and C3-C6 aliphatic rings containing 1-2 heteroatoms; the heteroatoms are selected from N, O or S, and when the heteroatom is N, it may be further substituted with C1-C2 alkyl groups, and when the heteroatom is S, it may be further oxidized to sulfoxides and sulfones;

[0037] R2, R3, and R6 may be the same or different and selected from hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, unsubstituted or modified by at least one R e Substituted phenyl, pyridyl, or pyrimidinyl, R e Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy;

[0038] When X2 is selected from O, R2 or R3 exists in general formula I;

[0039] R4 and R5 may be the same or different and selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, unsubstituted or modified by at least one R. f Substituted phenyl, pyridyl, or pyrimidinyl, wherein R f Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy.

[0040] Further preferably, the derivative is a compound represented by general formula I or general formula II, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug.

[0041] L1 is selected from -C≡C- or -CH=CH-;

[0042] X1 is selected from -(NR) a )-、S or Where R a Selected from hydrogen and C1-C2 alkyl groups;

[0043] X2 is selected from N and O;

[0044] L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C2 alkyl; Rc Selected from H,

[0045] A1, A2, and A3 are the same or different, and are selected from C or N;

[0046] R1 is selected from hydrogen, methanesulfonyl, dimethylamino, morpholinyl, piperazine, or -CH2R. d , where R d Selected from hydrogen, methanesulfonyl, dimethylamino, morpholinyl, and piperazine;

[0047] R2, R3, and R6 may be the same or different and selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, unsubstituted, or modified by at least one R. e Substituted phenyl, pyridyl, or pyrimidinyl, wherein R e Derived from hydrogen, halogen, hydroxyl, amino, dimethylamino, methyl, ethyl, isopropyl, trifluoromethyl, difluoroethoxy, methoxy, or trifluoromethoxy;

[0048] When X2 is selected from O, R2 or R3 exists in general formula I;

[0049] R4 and R5 may be the same or different and selected from hydrogen, deuterium, fluorine, methyl, unsubstituted, or by at least one R. f Substituted phenyl, pyridyl, or pyrimidinyl, wherein R f Derived from hydrogen, fluorine, hydroxyl, amino, dimethylamino, methyl, ethyl, trifluoromethyl, difluoroethoxy, methoxy, or trifluoromethoxy;

[0050] More preferably, the derivative is the following compound, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate or prodrug, 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)ethyl acetate;

[0051] 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0052] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0053] N-Ethyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0054] N-Phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0055] N-Methyl-N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0056] N-(4-Fluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0057] N-(4-Chlorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0058] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(p-tolyl)acetamide;

[0059] N-(4-methoxyphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0060] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(4-(trifluoromethyl)phenyl)acetamide;

[0061] N-(3-Fluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0062] N-(3-Chlorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0063] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(m-tolyl)acetamide;

[0064] N-(3-methoxyphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0065] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(3-(trifluoromethyl)phenyl)acetamide;

[0066] N-(3,5-Difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0067] N-(3,4-Difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0068] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(3,4,5-trifluorophenyl)acetamide;

[0069] N-Ethyl-N-(3-fluorophenyl)-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0070] N-(3-Fluorophenyl)-N-isopropyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0071] N-(3-Fluorophenyl)-N-methyl-2-((3-(phenylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0072] N-(3-Fluorophenyl)-N-methyl-2-((3-((4-(morpholinomethyl)phenyl)ethynyl)-1H-indazol-6-yl)thio)acetamide;

[0073] N-(3-Fluorophenyl)-N-methyl-2-((3-(pyridin-2-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0074] N-(3-Fluorophenyl)-N-methyl-2-((3-(pyrimidin-5-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0075] N-(3-Fluorophenyl)-N-methyl-2-((3-(((2-morpholinidin-5-yl)ethynyl)-1H-indazol-6-yl)thio)acetamide;

[0076] N-(3,5-Difluorophenyl)-N-ethyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0077] N-(2,4-Difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0078] N-Ethyl-2-((3-((4-(morpholinomethyl)phenyl)ethynyl)-1H-indazol-6-yl)thio)-N-phenylacetamide;

[0079] N-Isopropyl-N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0080] N-(3-fluoro-5-methylphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0081] N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(4-(trifluoromethoxy)phenyl)acetamide;

[0082] N-Ethyl-N-(4-methoxyphenyl)-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thioacetamide;

[0083] (3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)glycine ethyl ester;

[0084] N-(4-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0085] N-(3-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0086] (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)thio)acetamide;

[0087] (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide;

[0088] (E)-N-methyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide;

[0089] (E)-N-methyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide;

[0090] (E)-N-ethyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide;

[0091] N-Ethyl-2-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide;

[0092] N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0093] 4-Methyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0094] 4-Ethyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0095] 4-Chloro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0096] 4-Bromo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0097] 3-Bromo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0098] N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)-3-(trifluoromethyl)benzenesulfonamide;

[0099] 4-Methoxy-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0100] 4-Hydroxy-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0101] 4-(isopropyl)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0102] 4-Fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0103] 4-Iodo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0104] 3-Methyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0105] 3-Fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0106] 3-Fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0107] N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)-4-(trifluoromethyl)benzenesulfonamide;

[0108] 4-(dimethylamino)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0109] 4-Amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0110] 4-Amino-N-(3-(pyrimidin-5-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0111] 4-Amino-N-(3-((2-(1,4-oxazacyclohexyl-4-yl)pyrimidin-5-yl)ethynyl)-1H-indazole-6-yl)benzenesulfonamide;

[0112] 4-Amino-N-(3-((6-(1,4-oxazacyclohexyl-4-yl)pyridin-3-yl)ethynyl)-1H-indazole-6-yl)benzenesulfonamide;

[0113] 3-Amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide;

[0114] (E)-4-amino-N-(3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-yl)benzenesulfonamide.

[0115] Methods for preparing the indazole derivatives or their stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs shown in Formula I or Formula II:

[0116]

[0117] (1) The target derivative has a structure or analogue as shown in general formula 7 and is prepared according to the method shown in route 1:

[0118] Step a: Using 6-bromoindazole as starting material 1, an iodination reaction is carried out with N-iodosuccinimide to obtain intermediate 2;

[0119] Step b: Intermediate 2 reacts with 3,4-dihydro-2H-pyran under acid catalysis to give tetrahydropyran-protected intermediate 3;

[0120] Step c: Intermediate 3 undergoes a Sonogashira coupling reaction with different alkynes to obtain intermediate 4;

[0121] Step d: Intermediate 4 undergoes a coupling reaction with 2-ethylhexyl 3-mercaptopropionic acid to obtain intermediate 5;

[0122] Step e: Under alkaline conditions, intermediate 5 is deprotected and then directly added to a haloalkane in a one-pot process to undergo a substitution reaction to obtain intermediate 6;

[0123] Step f: Intermediate 6 is deprotected from tetrahydropyran under acidic conditions to obtain the target compound shown in general formula 7.

[0124] The preferred conditions are as follows:

[0125] In step a, 6-bromoindazole (1) is dissolved in N,N-dimethylformamide, and N-iodosuccinimide is added. The mixture is stirred at room temperature for 3 hours, and the reaction is monitored by TLC until complete. The reaction solution is poured into water, filtered, and the filter cake is washed with methanol and dried to obtain intermediate 2. The reaction solvent can be polar solvents such as acetonitrile, methanol, ethanol, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide, with N,N-dimethylformamide being preferred. The reaction temperature can range from 0℃ to 100℃, with room temperature being preferred.

[0126] In step b, intermediate 2 and a catalytic amount of p-toluenesulfonic acid are dissolved in dichloromethane. A dichloromethane solution of 3,4-dihydro-2H-pyran is added dropwise at 0°C. After the addition is complete, the mixture is transferred to room temperature and stirred for 2 hours. The reaction is monitored by TLC until complete. The reaction solution is washed with saturated sodium bicarbonate solution, the organic phase is concentrated under reduced pressure, washed with methanol, and dried to obtain intermediate 3. The reaction solvent can be a polar solvent such as dichloromethane, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide, with dichloromethane being preferred. The reaction temperature can range from 0°C to 100°C, with room temperature being preferred.

[0127] In step c, intermediate 3 was mixed with different alkynes and dissolved in anhydrous triethylamine. Cuprous iodide and Pd(PPh3)4 were added under an Ar atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 4. The reaction solvent can be a polar solvent such as triethylamine, N,N-diisopropylethylamine, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or toluene, with triethylamine being preferred. The base in the reaction can be an organic base such as triethylamine or N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, or sodium bicarbonate, with triethylamine being preferred. The copper catalyst in the reaction can be cuprous iodide, copper sulfate, cuprous bromide, etc., with cuprous iodide being preferred. The palladium catalyst in the reaction can be Pd(PPh3)4, Pd(PPh2)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, etc., with Pd(PPh3)4 being preferred.

[0128] In step d, intermediate 4, N,N-diisopropylethylamine, and 2-ethylhexyl 3-mercaptopropionic acid were dissolved in anhydrous toluene. XantPhos and Pd2(dba)3 were added under an Ar atmosphere, and the mixture was stirred at 110 °C for 12 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 5. The reaction solvent can be anhydrous 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, or other polar solvents, with anhydrous toluene being preferred; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, or other bases, with N,N-diisopropylethylamine being preferred; the palladium catalyst in the reaction can be Pd(PPh3)4, Pd(PPh2)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, or other bases, with Pd2(dba)3 being preferred.

[0129] In step e, intermediate 5 and potassium tert-butoxide are dissolved in tert-butanol and stirred at room temperature for 1 h. The reaction is monitored by TLC until complete. The mixture is concentrated under reduced pressure, and the reaction system is dissolved in tetrahydrofuran. Tetrahydrofuran solutions of substituted halogenated hydrocarbons are added to the reaction solution, and stirring continues for 2 h. The reaction is monitored by TLC until complete. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic phase is concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 6. The reaction solvent can be a polar solvent such as water, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, or tetrahydrofuran. Tert-butanol is preferred for the deprotection reaction, and tetrahydrofuran is preferred for the substitution reaction. The base in the reaction can be a strong inorganic base such as potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, or lithium hydroxide, with potassium tert-butoxide being preferred. The reaction temperature can be 0℃-100℃, with room temperature being preferred.

[0130] In step f, intermediate 6 was dissolved in trifluoroacetic acid, and the mixture was stirred at 50°C for 1 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, the pH of the system was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by pre-thin-layer chromatography to obtain the target compound shown in general formula 7.

[0131]

[0132] (2) The target derivative has a structure or analogue as shown in general formula 10 and is prepared according to the method shown in route 2:

[0133] Step g: Intermediate 4 undergoes a Buchwald coupling reaction with different amino fragments to obtain intermediate 8;

[0134] Step h: Intermediate 8 is deprotected under acidic conditions to obtain intermediate 9;

[0135] Step i: Intermediate 9 undergoes a substitution reaction with different haloalkanes under alkaline conditions to obtain intermediate 10.

[0136] The preferred conditions are as follows:

[0137] In step g, intermediate 4 and the corresponding amino fragment were dissolved in anhydrous 1,4-dioxane, cesium carbonate was added, and Pd2(dba)3 and Xantphos were added under an Ar atmosphere. The reaction was carried out at 100°C with stirring for 7 h, and the reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 8. The reaction solvent can be anhydrous 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, or other polar solvents, with anhydrous 1,4-dioxane being preferred. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, sodium hydroxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate, or other solvents, with cesium carbonate being preferred. The palladium catalyst in the reaction can be Pd(PPh3)4, Pd(PPh2)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, or other solvents, with Pd2(dba)3 being preferred.

[0138] In step h, intermediate 8 is dissolved in a mixture of V(methanol):V(water) = 3:0.5, and p-toluenesulfonic acid (10 eq) is added. The mixture is heated to 80°C and reacted for 3 hours, with TLC monitoring to ensure complete reaction. Saturated sodium bicarbonate solution is added to adjust the pH to 8, followed by extraction with ethyl acetate. The organic phase is concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 9. The acid used in the reaction can be p-toluenesulfonic acid, hydrochloric acid, or trifluoroacetic acid, with p-toluenesulfonic acid being preferred. The reaction solvent can be dichloromethane, methanol, ethanol, or water, with a mixed solvent of methanol and water being preferred. The reaction temperature can range from 0°C to 100°C, with 80°C being preferred.

[0139] In step i, intermediate 9 and the haloalkane were dissolved in anhydrous N,N-dimethylformamide, potassium carbonate was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target compound shown in general formula 10.

[0140]

[0141] (3) The target derivative has a structure or analogue as shown in general formula 14 and is prepared according to the method shown in route 3:

[0142] Step j: Intermediate 3 undergoes Heck coupling reaction with different olefins to obtain intermediate 11;

[0143] Step k: Intermediate 11 undergoes a coupling reaction with 2-ethylhexyl 3-mercaptopropionic acid to obtain intermediate 12;

[0144] Step 1: Under alkaline conditions, intermediate 12 is deprotected and then directly added to a haloalkane in a one-pot process to undergo a substitution reaction to obtain intermediate 13;

[0145] Step m: Intermediate 13 is deprotected from tetrahydropyran under acidic conditions to obtain the target compound shown in general formula 14.

[0146] The preferred conditions are as follows:

[0147] In step j, intermediate 3 and N,N-diisopropylethylamine were dissolved in anhydrous N,N-dimethylformamide. Under an Ar atmosphere, the corresponding olefin, tris(o-methylphenyl)phosphine, and Pd(OAc)₂ were added, and the reaction was carried out at 100°C for 4 hours. TLC monitoring showed the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography to obtain intermediate 11. The reaction solvent can be anhydrous 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, or other polar solvents, with anhydrous N,N-dimethylformamide being preferred. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, N,N'-dimethylethylenediamine, cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate, or other solvents, with N,N-diisopropylethylamine being preferred. The palladium catalyst in the reaction can be Pd(PPh3)4, Pd(PPh2)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, or other solvents, with Pd(OAc)2 being preferred.

[0148] Step k is the same as step d.

[0149] Step 1 is the same as step e.

[0150] Step m is the same as step f.

[0151]

[0152] (4) When the derivative has the structure shown in intermediate 15 or similar, wherein R1'-R5' are nitro-containing segments, the compound of general formula 17 is prepared according to the method shown in route 4, wherein R1-R5 are amino groups:

[0153] Step n: Intermediate 15 undergoes a nitro reduction reaction to obtain intermediate 16;

[0154] Step o: Remove THP protection from intermediate 16 to obtain the compound shown in formula 17.

[0155] The preferred conditions are as follows:

[0156] In step n, the compound of general formula 15 is dissolved in a mixed solvent of V(methanol):V(tetrahydrofuran) = 2:1. Iron powder and glacial acetic acid are added under an Ar atmosphere, and the mixture is heated to 60°C and stirred vigorously for 6 hours. The reaction is monitored by TLC until complete. The mixture is filtered, and the filtrate is concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 16. The reaction solvent can be a polar solvent such as tetrahydrofuran, dichloromethane, methanol, or ethanol, preferably a mixed solvent of methanol and tetrahydrofuran. The reducing agent in the reaction can be iron powder-hydrochloric acid, iron powder-ammonium chloride, iron powder-glacial acetic acid, etc. Iron powder can be replaced with zinc powder, and iron powder / glacial acetic acid is preferred as the reducing agent.

[0157] Step o is the same as step f.

[0158]

[0159] (5) The target derivative has a structure as shown in general formula 20 or similar, and is prepared according to the method shown in route 5:

[0160] Step p: Methyl phenyl acetate with different substitutions undergoes free radical halogenation to give the intermediate shown in general formula M2;

[0161] Step q: Intermediate 5 undergoes deprotection and substitution reactions under alkaline conditions to obtain intermediate 18;

[0162] Step r: Intermediate 18 undergoes an amide condensation reaction to give intermediate 19;

[0163] Step s: Intermediate 19 was deprotected from THP under acidic conditions to give the compound shown in general formula 20.

[0164] The preferred conditions are as follows:

[0165] In step p, methyl phenylacetate is dissolved in chloroform, and N-bromosuccinimide and azobisisobutyronitrile are added. The mixture is refluxed for 6 hours, and the reaction is monitored by TLC until it is complete. The reaction solution is concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate M2. The reaction solvent can be dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc., with chloroform being preferred. The brominating reagent can be N-bromosuccinimide, liquid bromine, etc., with N-bromosuccinimide being preferred.

[0166] Step q is the same as step e.

[0167] In step r, intermediate 18 is dissolved in anhydrous N,N-dimethylformamide, HATU is added, and N,N-diisopropylethylamine is added at 0°C. The mixture is stirred for 0.5 h, followed by the addition of the corresponding amino fragment, and stirring is continued for another 0.5 h. The reaction is monitored by TLC until complete. The reaction solution is poured into water and extracted with ethyl acetate. The organic phase is washed with saturated ammonium chloride aqueous solution, concentrated under reduced pressure, and purified by pre-thickness thin-layer chromatography to obtain intermediate 19. The reaction solvent can be N,N-dimethylformamide, tetrahydrofuran, dichloromethane, etc., preferably anhydrous N,N-dimethylformamide. The condensing agent used in the reaction can be HATU, HBTU, PyBOP, HOBt, etc., preferably HATU. The base in the reaction can be an organic base such as N,N-diisopropylethylamine or triethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, etc., preferably N,N-diisopropylethylamine. The reaction temperature can be 0°C-60°C, preferably room temperature.

[0168]

[0169] (6) The target derivative has a structure or analogue as shown in general formula 22 and is prepared according to the method shown in route 6:

[0170] Step t: Intermediate 4 undergoes a coupling reaction with different sulfonamides to obtain intermediate 21;

[0171] Step u: Intermediate 21 is deprotected from THP under acidic conditions to obtain the compound shown in general formula 22.

[0172] The preferred conditions are as follows:

[0173] In step t, intermediate 4 is dissolved in anhydrous acetonitrile, benzenesulfonamide and potassium carbonate are added, cuprous iodide and DMEDA are added under an Ar atmosphere, and the reaction is carried out at 100°C with stirring for 10 h. The reaction is monitored by TLC until complete. The reaction solution is concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 21. The reaction solvent can be anhydrous 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, or other polar solvents, preferably anhydrous acetonitrile; the base in the reaction can be triethylamine, N,N-diisopropylethylamine, sodium hydroxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate, etc., preferably potassium carbonate; the copper catalyst in the reaction can be cuprous iodide, copper sulfate, cuprous bromide, etc., preferably cuprous iodide.

[0174] Step u is the same as step e.

[0175]

[0176] (7) The target derivative has a structure or analogue as shown in general formula 24 and is prepared according to the method shown in route 7, wherein the preparation method of intermediate 23 is the same as that of intermediate 9:

[0177] Step v: Intermediate 23 undergoes acylation reaction with different sulfonyl chlorides to give the compound shown in general formula 24.

[0178] The preferred conditions are as follows:

[0179] In step v, intermediate 23 is dissolved in anhydrous pyridine, 4-dimethylaminopyridine is added, and different sulfonyl chlorides are added at 0°C. The mixture is then transferred to room temperature and reacted for 5 hours. The reaction is monitored by TLC until complete. Most of the solvent is removed by vacuum concentration, followed by extraction with ethyl acetate. The organic phase is concentrated and purified by silica gel column chromatography to obtain the compound of general formula 24. The reaction solvent can be anhydrous 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, dichloromethane, pyridine, or other polar solvents, preferably anhydrous pyridine. The base in the reaction can be triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate, etc., preferably 4-dimethylaminopyridine.

[0180]

[0181] (8) The target derivative has a structure as shown in general formula 28 or similar, and is prepared according to the method shown in route 8:

[0182] Step w: Intermediate 25 undergoes a coupling reaction with different benzenesulfonamides to obtain intermediate 26;

[0183] Step x: Intermediate 26 undergoes a nitro reduction reaction to obtain intermediate 27;

[0184] Step y: Intermediate 27 is deprotected from THP under acidic conditions to obtain the compound shown in general formula 28.

[0185] The preferred conditions are as follows:

[0186] Step w is the same as step t;

[0187] Step x is the same as step n;

[0188] Step y is the same as step e.

[0189] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the indazole derivative or stereoisomer thereof described in the first aspect above, a pharmaceutically acceptable salt, hydrate, solvate or prodrug, and a pharmaceutically acceptable carrier or excipient.

[0190] The use of indazole derivatives, compounds of general formula I or general formula II, their geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, in the preparation of medicaments for the prevention or treatment of diseases related to the expression or activity of PLK4 kinase.

[0191] The use of the compounds represented by general formula I or general formula II, their geometric isomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof in the preparation of medicaments for the prevention or treatment of tumors associated with the expression or activity of PLK4 kinase.

[0192] A pharmaceutical composition comprising a compound of formula I or formula II and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs as an active ingredient and pharmaceutically acceptable excipients.

[0193] The composition is used in the preparation of medicaments for the prevention or treatment of diseases related to the expression or activity of PLK4 kinase.

[0194] The composition is used in the preparation of medicaments for the prevention or treatment of tumors associated with the expression or activity of PLK4 kinase.

[0195] Preferably, the disease is a tumor caused by centrosome abnormalities, especially a tumor caused by abnormal expression of PLK4, and particularly a tumor with high amplification of the TRIM37 gene.

[0196] In the definitions of compounds of general formula I and general formula II given above, the terms used in the compilation are generally defined as follows:

[0197] Halogen: Refers to fluorine, chlorine, bromine, or iodine. Alkyl: Straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, or tert-butyl. Cycloalkyl: Substituted or unsubstituted cyclic alkyl, such as cyclopropyl, cyclobutane, cyclopentyl, or cyclohexyl. Halogenated alkyl: Straight-chain or branched alkyl, where the hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc. Alkoxy: Straight-chain or branched alkyl, where the hydrogen atoms of the hydroxyl group may be replaced by these straight-chain or branched alkyl groups, such as methoxy, ethoxy, isopropyloxy, etc. Halogenated alkoxy: Straight-chain or branched alkyl, where the hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms, and the hydrogen atoms of the hydroxyl group may be replaced by these straight-chain or branched alkyl groups, such as trifluoromethoxy, difluoroethoxy, etc. Aliphatic rings containing 1-2 heteroatoms, including N, O, and S, such as tetrahydrofuranyl, morpholinyl, piperidinyl, piperazineyl, etc.

[0198] Advantages of this invention:

[0199] This invention focuses on tumors caused by centrosome abnormalities, designs compounds having the structure shown in general formula I or general formula II, and finds that compounds with such structures exhibit good PLK4 inhibitory activity for the treatment of diseases related to abnormal PLK4 expression.

[0200] The compounds of general formula I or general formula II of this invention are not limited to their specific isomers, and all exhibit good inhibitory activity against PLK4, and can be used to treat tumors associated with abnormal PLK4 expression, especially tumors with high amplification of the TRIM37 gene, such as neuroblastoma and breast cancer. Detailed Implementation

[0201] The examples are intended to illustrate, and not limit, the scope of the invention. The proton and carbon NMR spectra of the compounds were determined using a Bruker ARX-600 or Bruker ARX-400; all reagents used were analytically or chemically pure.

[0202] The specific implementation structure is as follows:

[0203] Example 1

[0204] Synthesis of ethyl 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)ethyl acetate:

[0205]

[0206] 1) Preparation of 6-bromo-3-iodo-1H-indazole (1-2)

[0207] 6-Bromo-1H-indazole (1-1, 5.0 g, 25.4 mmol) was dissolved in 10 mL of anhydrous N,N-dimethylformamide, and N-iodosuccinimide (38.1 mmol) was added. The mixture was stirred at room temperature for 5 h. The reaction was monitored by TLC until complete. The reaction solution was poured into water, and a brown solid precipitated. The solid was filtered, washed with water, and dried to obtain a brownish-red powder. Yield: 94.5%.

[0208] 2) Preparation of 6-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1-3)

[0209] 6-Bromo-3-iodo-1H-indazole (1-2, 5.0 g, 15.5 mmol) was dissolved in 30 mL of anhydrous dichloromethane, and p-toluenesulfonic acid (1.6 mmol) was added. Then, a solution of 3,4-dihydro-2H-pyran (46.4 mmol) in anhydrous dichloromethane (10 mL) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was transferred to room temperature and the reaction was continued for 4 h. The reaction was monitored by TLC until complete. The reaction solution was washed with water, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white powdery solid, yield: 95.3%.

[0210] 3) Preparation of 6-bromo-3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1-4)

[0211] Intermediate 1-3 (2.0 g, 4.9 mmol) was dissolved in 40 mL of triethylamine, and 3-alkynylpyridine (5.9 mmol) was added. Cuprous iodide (0.098 mmol) and Pd(PPh3)4 (0.049 mmol) were added under an Ar atmosphere. The mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, concentrated under reduced pressure, washed with methanol, filtered, and the filter cake was dried to give a white powdery solid. Yield: 71.2%. 1 H NMR(600MHz,DMSO-d6)δ8.90(s,1H),8.65(d,J=4.1Hz,1H),8.19(d,J=1.1Hz,1H),8.13 (dt,J=7.9,1.8Hz,1H),7.89(d,J=8.5Hz,1H),7.52(dd,J=7.8,4.9Hz,1H),7.48(dd,J= 8.5,1.5Hz,1H),5.98(dd,J=9.4,2.2Hz,1H),3.88(d,J=11.5Hz,1H),3.82-3.77(m,1H) ,2.40-2.32(m,1H),2.05-1.99(m,2H),1.77-1.70(m,1H),1.60(dd,J=7.3,3.7Hz,2H).

[0212] 4) Preparation of 2-ethylhexyl 3-((3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)propionate (1-5)

[0213] Intermediate 1-4 (1.0 g, 2.6 mmol) was dissolved in anhydrous toluene, and N,N-diisopropylethylamine (5.2 mmol) was added. Under an Ar atmosphere, Pd₂(dba)₃ (0.13 mmol), Xantphos (0.26 mmol), and 2-ethylhexyl 3-mercaptopropionate (4.8 mmol) were added. The mixture was heated to 110 °C and reacted for 3 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a yellow oily substance in 89.7% yield.

[0214] 5) Preparation of ethyl acetate (1-6) of 2-((3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)

[0215] Intermediate 1-5 (0.40 g, 0.77 mmol) was dissolved in tert-butanol, and potassium tert-butoxide (7.7 mmol) was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, dissolved in 1 mL of anhydrous tetrahydrofuran, and then added with stirring in 1 mL of anhydrous tetrahydrofuran solution containing 1.0 mmol of ethyl chloroacetate. The reaction was stirred at room temperature for 0.5 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a white powdery solid in 51.6% yield.

[0216] 6) Synthesis of 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)ethyl acetate (Example 1)

[0217] Intermediate 1-6 (40 mg, 0.095 mmol) was dissolved in 4N hydrochloric acid / ethyl acetate solution and reacted with stirring at room temperature for 1 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the pH of the system was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. Thin-layer chromatography was performed to obtain a white powdery solid, yield: 65.6%. mp 202.2-202.9℃. 1 H NMR (600MHz, DMSO-d6) δ13.60(s,1H),8.88(d,J=2.2Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.10(dt,J=7.9,2.0Hz,1H),7.83(d,J=8.5Hz,1H),7.55(d,J =1.5Hz,1H),7.51(dd,J=7.9,4.8Hz,1H),7.23(dd,J=8.4,1.6Hz,1H),4.10(q,J=7.1Hz,2H),4.01(s,2H),1.15(t,J=7.1Hz,3H).HRMS(ESI,m / z)calcd for C 18 H 15 N3NaO2S[M+Na] + ,360.0777; found360.0772.

[0218] Example 2

[0219] Synthesis of 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide

[0220] The synthesis in Example 2 was similar to that in Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloroethylamide. It is a yellow powdery solid. mp 211.4-212.8℃. 1H NMR (600MHz, DMSO-d6) δ13.57(s,1H),8.87(d,J=1.1Hz,1H),8.63(dt,J=5.0,1.4Hz,1H),8.10(d,J=7.7Hz,1H) ,7.80(d,J=8.4Hz,1H),7.62(s,1H),7.54(s,1H),7.51(dd,J=7.9,4.8Hz,1H),7.21-7.19(m,2H),3.73(s,2H). 13 C NMR(151MHz,DMSO)δ170.32,151.90,149.44,141.13,139.49,136.64,127.73,124.34 ,122.80,122.69,120.36,119.68,108.77,89.68,85.08,36.71.HRMS(ESI,m / z)calcd for C 16 H 11 N4OS[MH] - ,307.0659; found 307.0693.

[0221] Example 3

[0222] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis in Example 3 was similar to that in Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methylacetamide. It is a yellow powdery solid. mp 183.7-184.5℃. 1 H NMR (600MHz, DMSO-d6) δ13.56(s,1H),8.87(d,J=2.4Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.13-8.09(m,2H),7.80(d,J=8.4Hz,1H),7. 55(d,J=1.8Hz,1H),7.51(dd,J=7.9,4.8Hz,1H),7.20(dd,J=8.5,1.6Hz,1H),3.74(s,2H),2.61(d,J=4.6Hz,3H).HRMS(ESI,m / z)calcd for C 17 H 14 N4NaOS[M+Na] + ,345.0781; found 345.0785.

[0223] Example 4

[0224] Synthesis of N-ethyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 4 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-ethylacetamide. It is a yellow powdery solid. mp 159.0-159.7℃. 1 H NMR (600MHz, DMSO-d6) δ13.58(s,1H),8.90(s,1H),8.65(dd,J=5.0,1.8Hz,1H),8.17-8.13(m,2H),7.81(d,J=8.6Hz,1H),7.56- 7.54(m,2H),7.21(dd,J=8.4,1.7Hz,1H),3.72(s,2H),3.09(qd,J=7.2,5.3Hz,2H),0.99(t,J=7.2Hz,3H).HRMS(ESI,m / z)calcd for C 18 H 16 N4NaOS[M+Na] + ,359.0937; found 359.0933.

[0225] Example 5

[0226] Synthesis of N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 5 was similar to that of Example 1, except that ethyl chloroacetanilide was replaced proportionally with 2-chloroacetanilide. It is a pale yellow powdery solid. The mp value is 157.4-158.1℃. 1 H NMR (600MHz, DMSO-d6) δ13.59 (s, 1H), 10.29 (s, 1H), 8.87 (d, J = 2.6Hz, 1H), 8.63 (dd,J=4.9,1.7Hz,1H),8.10(dt,J=7.9,2.0Hz,1H),7.82(d,J=8.4Hz,1H),7.63( d,J=1.7Hz,1H),7.57(d,J=7.3Hz,2H),7.50(dd,J=7.9,4.8Hz,1H),7.31(dd,J= 8.4,7.3Hz,2H),7.26(dd,J=8.4,1.7Hz,1H),7.06(t,J=7.3Hz,1H),3.98(s,2H). 13C NMR(151MHz,DMSO)δ167.22,151.52,149.00,141.10,140.00,139.30,136.18,129.30(2C),127.69,124.50 ,124.05,123.00,122.97,120.45,119.83,119.68(2C),109.41,89.54,85.26,38.02.HRMS(ESI,m / z)calcd for C 22 H 16 N4NaOS[M+Na] + ,407.0937; found 407.0940.

[0227] Example 6

[0228] Synthesis of N-methyl-N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis in Example 6 was similar to that in Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methyl-N-phenylacetamide. It is a pale yellow powder. The mp value is 99.5-100.7℃. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(d,J=3.1Hz,1H),8.63(dd,J=4.8,1.7Hz,1H),8.09(dt,J=7.9,2.0Hz,1H),7.77(d,J=8.4 Hz,1H),7.51(ddd,J=8.1,4.9,1.0Hz,1H),7.47(d,J=7.9Hz,2H),7.43-7.40(m,4H),7.10(d,J=8.3Hz,1H),3.73(s,2H),3.21(s,2H). 13 C NMR(151MHz,DMSO)δ166.52,151.09,148.64,142.55,139.91,138.09,135.03,129.23(2C),127.44,126.75,12 6.71,123.10(2C),121.95,121.85,119.32,118.46,108.31,88.70,83.85,36.71,35.56.HRMS(ESI,m / z)calcd for C 23 H 18 N4NaOS[M+Na] + ,421.1093; found421.1130.

[0229] Example 7

[0230] Synthesis of N-(4-fluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 7 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(4-fluorophenyl)-N-methylacetamide. It was a white powdery solid. mp 160.2 -161.6℃. 1 HNMR(600MHz,DMSO-d6)δ13.53(s,1H),8.87(d,J=2.4Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.09(dt,J=7.9,2.0Hz,1H),7.7 7(d,J=8.4Hz,1H),7.52-7.48(m,3H),7.41(s,1H),7.30(t,J=8.7Hz,2H),7.10(d,J=8.6Hz,1H),3.73(s,2H),3.18(s,3H). 13 C NMR (151MHz, DMSO) δ 167.70, 161.64 (d, J = 245.4Hz), 152.14, 149.71, 140.98, 139.89, 139.17, 136.05, 130.12 (d, J = 8.4Hz, 2C), 127 .80,124.19,123.02,122.92,120.40,119.53,117.04(d,J=23.0Hz,2C),109.39,89.78,84.92,37.85,36.66.HRMS(ESI,m / z)calcd for C 23 H 17 FN4NaOS[M+Na] + ,439.0999; found 439.1006.

[0231] Example 8

[0232] Synthesis of N-(4-chlorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 8 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(4-chlorophenyl)-N-methylacetamide. It was a white powdery solid. The mp value was 167.9-168.4 °C. 1H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.3Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.10(dt,J=7.9,2.0Hz,1H),7.78(d,J=8.5Hz ,1H),7.53-7.52(m,1H),7.51(d,J=3.1Hz,2H),7.50-7.48(m,1H),7.46-7.42(m,2H),7.11(d,J=8.5Hz,1H),3.77(s,2H),3.19(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.50,151.10,148.63,141.42,139.92,138.10,134.91,131.81,129.14,128.73(2C), 126.72,123.10(2C),121.94,121.88,119.31,118.48,108.38,88.70,83.89,36.67,35.64.HRMS(ESI,m / z)calcd for C 23 H 17 ClN4NaOS[M+Na] + ,455.0704; found 455.0715.

[0233] Example 9

[0234] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(p-tolyl)acetamide The synthesis of Example 9 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(4-methylphenyl)-N-methylacetamide. It was a white powdery solid. The mp values ​​were 128.9-129.4 °C. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(d,J=2.4Hz,1H),8.63(dd,J=4.9,1.9Hz,1H),8.09(dt,J=7.9,2.0Hz,1H),7.77(d,J=8.5H z,1H),7.51(dd,J=7.9,4.9Hz,1H),7.41(s,1H),7.27(q,J=8.0Hz,4H),7.10(d,J=8.5Hz,1H),3.71(s,2H),3.18(s,3H),2.32(s,3H). 13C NMR(151MHz,DMSO-d6)δ167.71,152.14,149.70,141.05,140.98,139.17,137.94,136.13,130.75(2C),127.80,127 .54(2C),124.19,123.07,122.93,120.39,119.54,109.44,89.78,84.93,37.79,36.59,21.06.HRMS(ESI,m / z)calcd for C 24 H 20 N4NaOS[M+Na] + ,435.1250; found 435.1247.

[0235] Example 10

[0236] Synthesis of N-(4-methoxyphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 10 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(4-methoxyphenyl)-N-methylacetamide. It was a white powdery solid. mp 155.4 -156.3℃. 1 H NMR (600MHz, DMSO-d6) δ13.53(s,1H),8.86(d,J=2.2Hz,1H),8.63(dd,J=4.8,1.7 Hz,1H),8.09(dt,J=8.0,2.0Hz,1H),7.77(d,J=8.5Hz,1H),7.51(dd,J=7.9,4.8Hz ,1H),7.41(d,J=1.5Hz,1H),7.33(d,J=8.9Hz,2H),7.10(dd,J=8.4,1.5Hz,1H),6 .99(d,J=8.9Hz,2H),3.77(s,3H),3.71(s,2H),3.16(s,3H).HRMS(ESI,m / z)calcd forC 24 H 20 N4NaO2S[M+Na] + ,451.1199; found 451.1207.

[0237] Example 11

[0238] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(4-(trifluoromethyl)phenyl)acetamide The synthesis of Example 11 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methyl-N-(4-(trifluoromethyl)phenyl)acetamide. It was a white powdery solid. The mp temperature was 99.5-100.1℃. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.3Hz,1H),8.63(dd,J=4.8,1.7Hz,1H),8.09(dt,J=7.9,1.9Hz,1H),7.80(d,J=8.1H z,2H),7.78(d,J=8.8Hz,1H),7.63(s,2H),7.52-7.50(m,2H),7.15(s,1H),4.11-3.64(m,2H),3.30-3.10(m,3H).HRMS(ESI,m / z)calcd for C 24 H 17 F3N4NaOS[M+Na] + 489.0967; found 489.0977.

[0239] Example 12

[0240] Synthesis of N-(3-fluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 12 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3-fluorophenyl)-N-methylacetamide. It was a white powdery solid. The mp value was 154.1-154.8 °C. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(dd,J=2.1,1.0Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.09(dt,J=7.9,1.9Hz,1H),7.78(d, J=8.5Hz,1H),7.52-7.50(m,2H),7.43-7.36(m,2H),7.28-7.24(m,2H),7.12(s,1H),3.80(s,2H),3.21(s,3H).HRMS(ESI,m / z)calcd forC 23 H 17 FN4NaOS[M+Na] + ,439.0999; found 439.0993.

[0241] Example 13

[0242] Synthesis of N-(3-chlorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 13 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3-chlorophenyl)-N-methylacetamide. It was a white powdery solid. The mp value was 155.0-155.9 °C. 1 HNMR(600MHz,DMSO-d6)δ13.56(s,1H),8.87(s,1H),8.63(d,J=4.9Hz,1H),8.10(d,J=7.9 Hz,1H),7.79(d,J=8.5Hz,1H),7.52-7.46(m,6H),7.13(s,1H),3.78(s,2H),3.21(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.63,152.08,149.64,144.99,140.99,139.25,135.80,134.20,131.73,128.53,127.95, 127.79,126.73,124.22,123.29,123.02,120.41,119.57,109.89,89.77,84.95,37.74,36.82.HRMS(ESI,m / z)calcd for C 23 H 17 ClN4NaOS[M+Na] + ,455.0704; found 455.0718.

[0243] Example 14

[0244] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(m-tolyl)acetamide The synthesis of Example 14 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methyl-N-(m-tolyl)acetamide. It was a white powdery solid. The mp value was 98.5-99.7°C. 1 H NMR(600MHz,DMSO-d6)δ13.56(s,1H),8.87(s,1H),8.63(s,1H),8.10(s,1H),7.78(s,1H), 7.51-7.43(m,2H),7.34(s,1H),7.19-7.11(m,4H),3.72(s,2H),3.19(s,3H),2.30(s,3H). 13C NMR(151MHz,DMSO-d6)δ167.66,152.12,149.67,143.55,140.98,139.92,139.22,136.02,130.03,129.09,128.17,127 .80,124.69,124.20,123.26,122.99,120.39,119.55,109.75,89.78,84.93,37.73,36.64,21.23.HRMS(ESI,m / z)calcd for C 24 H 21 N4OS[M+Na] + ,413.1431; found 413.1429.

[0245] Example 15

[0246] Synthesis of N-(3-methoxyphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 15 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3-methoxyphenyl)-N-methylacetamide. It was a white powdery solid. The mp value was 156.7-157.4 °C. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(dd,J=2.1,1.0Hz,1H),8.63(dd,J=4.8,1.7Hz,1H),8.09(dt,J=7.9,1.9Hz,1H),7.77(d,J=8.5Hz,1H),7. 51(ddd,J=7.9,4.9,0.9Hz,1H),7.43(s,1H),7.37(t,J=8.1Hz,1H),7.11( d,J=8.5Hz,1H),6.99(s,1H),6.97-6.94(m,2H),3.76(s,5H),3.20(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.62,160.59,152.06,149.61,144.75,141.01,139.29,136.13,131.02,127.77,124.23,123 .10,122.95,120.39,119.73,119.58,114.23,113.45,109.53,89.76,84.97,55.80,37.68,36.65.HRMS(ESI,m / z)calcd for C 24 H 20N4NaO2S[M+Na] + ,451.1199; found 451.1200.

[0247] Example 16

[0248] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(3-(trifluoromethyl)phenyl)acetamide The synthesis of Example 16 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methyl-N-(3-(trifluoromethyl)phenyl)acetamide. It was a white powdery solid. The mp value was 153.9-154.1 °C. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.8,1.7Hz,1H),8.09(dt,J=7.9,2.0Hz,1H),7.84-7.78 (m,2H),7.77-7.69(m,3H),7.51(dd,J=7.9,4.9Hz,1H),7.45(s,1H),7.11(s,1H),3.77(s,2H),3.24(s,3H).HRMS(ESI,m / z)calcd for C 24 H 17 F3N4NaOS[M+Na] + ,489.0967; found 489.0998.

[0249] Example 17

[0250] Synthesis of N-(3,5-difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 17 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3,5-difluorophenyl)-N-methylacetamide. It was a white powdery solid. The mp values ​​were 182.3-182.8 °C. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.8,1.6Hz,1H),8.09(dt,J=7.9,2.0Hz, 1H),7.78(d,J=8.5Hz,1H),7.51-7.48(m,2H),7.31-7.24(m,3H),7.16(d,J=8.2Hz,1H),3.92(s,2H),3.24(s,3H).13 C NMR(151MHz, DMSO-d6)δ166.65,161.83(dd,J=246.8,15.1Hz,2C),151.10,148.62,144.93(d,J=12.7Hz),139.93,138.11,134.75 ,126.74,123.11,122.15,121.94,119.31,118.50,110.65(2C),108.71,102.88,88.70,83.90,36.67,35.93.HRMS(ESI,m / z)calcd for C 23 H 16 F₂N₄NaOS[M+Na] + ,457.0905; found 457.0916.

[0251] Example 18

[0252] Synthesis of N-(3,4-difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 18 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3,4-difluorophenyl)-N-methylacetamide. It was a white powdery solid. mp 154.1 -155.3℃. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.8,1.7Hz,1H),8.09(dt,J=7.9,2.0Hz,1H),7.78( d,J=8.5Hz,1H),7.64(s,1H),7.53-7.50(m,2H),7.43(s,1H),7.33(s,1H),7.12(d,J=8.4Hz,1H),3.80(s,2H),3.18(s,3H). 13 C NMR (151MHz, DMSO) δ166.59, 151.09, 148.53 (dd, J=241.6, 63.2Hz, 2C), 148.64, 139.91, 139.18, 138.07, 134.85, 126.72, 124.24, 12 3.10,122.01,121.88,119.29,118.47,117.19(dd,J=130.5,17.5Hz,2C),108.46,88.70,83.86,36.68,35.70.HRMS(ESI,m / z)calcd forC 23H 16 F₂N₄NaOS[M+Na] + ,457.0905; found 457.0922.

[0253] Example 19

[0254] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(3,4,5-trifluorophenyl)acetamide The synthesis of Example 19 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methyl-N-(3,4,5-trifluorophenyl)acetamide. It was a white powdery solid. The mp temperature was 187.8-189.5 °C. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(d,J=2.3Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.09(dt, J=7.8,2.0Hz,1H),7.78(d,J=8.5Hz,1H),7.54-7.46(m,4H),7.15(s,1H),3.88(s,2H),3.18(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.68,151.09,150.42(2C),148.65,139.92,138.37,138.11,137.16,134.73,126.75, 123.15,122.15,121.93,119.29,118.52,112.70(2C),108.72,88.71,83.89,36.62,35.83.HRMS(ESI,m / z)calcd forC 23 H 15 F3N4NaOS[M+Na] + ,475.0811; found475.0811.

[0255] Example 20

[0256] Synthesis of N-ethyl-N-(3-fluorophenyl)-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 20 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-ethyl-N-(3-fluorophenyl)acetamide. It was a white powdery solid. The mp value was 166.5-166.9 °C. 1H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.8,1.7Hz,1H),8.09(dt,J=7.9,1.9Hz,1H),7.78(d,J=8.5Hz,1H),7.53-7 .49(m,2H),7.41(s,1H),7.32(d,J=9.4Hz,1H),7.28-7.24(m,2H),7.11(d ,J=8.5Hz,1H),3.73(s,2H),3.69(d,J=7.0Hz,2H),1.02(t,J=7.2Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ167.02,162.76(d,J=245.9Hz),152.09,149.63,1 43.41(d,J=10.2Hz),140.99,139.25,135.96,131.73,127.78,125.16,124 .21,123.16,122.96,120.40,119.57,116.17(d,J=21.5Hz),115.70(d,J= 20.8Hz),109.59,89.76,84.96,44.39,37.07,13.17.HRMS(ESI,m / z)calcd forC 24 H 19 FN4NaOS[M+Na] + ,453.1156; found 453.1174.

[0257] Example 21

[0258] Synthesis of N-(3-fluorophenyl)-N-isopropyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 21 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3-fluorophenyl)-N-isopropylacetamide. It was a white powdery solid. mp 154.1 -154.7℃. 1HNMR(600MHz,DMSO-d6)δ13.56(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.9,1.7Hz,1H), 8.09(dt,J=7.9,2.0Hz,1H),7.78(d,J=8.5Hz,1H),7.55-7.54(m,1H),7.51(dd,J=8.1,4.8 Hz,1H),7.38(s,1H),7.33(td,J=8.6,2.5Hz,1H),7.23(dt,J=9.9,2.3Hz,1H),7.18(d,J=8 .8Hz,1H),7.10(d,J=7.1Hz,1H),4.79(p,J=6.8Hz,1H),3.58(s,2H),1.01(d,J=6.8Hz,6H). 13 CNMR(151MHz,DMSO)δ165.66,161.43(d,J=246.0Hz),151.12,148.65,139.9 1,138.71(d,J=9.4Hz),138.07,134.99,130.28(d,J=9.4Hz),126.72,123.09 ,122.08,121.88,119.33,118.47,117.11(d,J=21.0Hz),115.21(d,J=20.4H z),108.55,108.40,88.71,83.87,45.82,36.69,19.96.HRMS(ESI,m / z)calcd for C 25 H 21 FN4NaOS[M+Na] + ,467.1312; found 467.1325.

[0259] Example 22

[0260] Synthesis of N-(3-fluorophenyl)-N-methyl-2-((3-(phenylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 22 was similar to that of Example 1, except that 3-ethynylpyridine was replaced with ethynylbenzene in equal proportions, and ethyl chloroacetate was replaced with 2-chloro-N-(3-fluorophenyl)-N-methylacetamide in equal proportions. It was a white powdery solid. The mp temperature was 184.1-185.7℃. 1HNMR(600MHz,DMSO-d6)δ13.47(s,1H),7.74(d,J=8.4Hz,1H),7.67(d,J=4.1Hz,1H),7.66(d,J=2.2Hz,1H),7.52-7.49(m,1H),7.48 (d,J=1.8Hz,1H),7.47(d,J=2.2Hz,2H),7.43(s,1H),7.38-7.34(m,1H),7.29-7.24(m,2H),7.11(s,1H),3.80(s,2H),3.22(s,3H). 13 C NMR (151MHz, DMSO) δ166.54, 161.67 (d, J = 245.7Hz), 144.17, 139.92, 134.73, 130.88 (2C), 130.69, 129.06, 128.50, 128.26 (2C),127.21,123.06,121.93,121.87,121.29,119.31,114.31,108.54,91.78,80.84,36.64,35.80.HRMS(ESI,m / z)calcd for C 24 H 18 FN3NaOS[M+Na] + ,438.1047; found 438.1064.

[0261] Example 23

[0262] Synthesis of N-(3-fluorophenyl)-N-methyl-2-((3-((4-(morpholinomethyl)phenyl)ethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 23 was similar to that of Example 1, except that 3-ethynylpyridine was replaced by 4-(4-ethynylbenzyl)morpholine in equal proportion, and ethyl chloroacetate was replaced by 2-chloro-N-(3-fluorophenyl)-N-methylacetamide in equal proportion. It was a white powdery solid. The mp values ​​were 164.1-165.9 °C. 1 H NMR (600MHz, DMSO-d6) δ13.45(s,1H),7.73(d,J=8.5Hz,1H),7.62(d,J=7.9Hz ,2H),7.50-7.49(m,1H),7.43(s,1H),7.40(d,J=7.9Hz,2H),7.36(s,1H),7.28 -7.24(m,2H),7.11(s,1H),3.79(s,2H),3.60-3.58(m,4H),3.51(s,2H),3.22(s,3H),2.37(s,4H). 13C NMR(151MHz, DMSO)δ166.53,161.66(d,J=246.5Hz),144.15,139.92,138.61,134.70,130.89,130.76(2C),129.05,128.65(2C),127.27,1 23.05,121.90,121.85,119.85,119.29,114.29,108.52,91.80,80.59,65.60(2C),61.41,52.57(2C),36.64,35.79.HRMS(ESI,m / z)calcd for C 29 H 27 FN4NaO2S[M+Na] + ,537.1731; found 537.1747.

[0263] Example 24

[0264] Synthesis of N-(3-fluorophenyl)-N-methyl-2-((3-(pyridin-2-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 24 was similar to that of Example 1, except that 3-ethynylpyridine was replaced with 2-ethynylpyridine in equal proportions, and ethyl chloroacetate was replaced with 2-chloro-N-(3-fluorophenyl)-N-methylacetamide in equal proportions. It was a white powdery solid. The mp value was 153.9-154.5 °C. 1 H NMR (600MHz, DMSO-d6) δ13.60(s,1H),8.66(dt,J=4.9,1.5Hz,1H),7.90(td,J=7.7,1.8Hz,1H),7.77(dt,J=7.8,1.2Hz,1H),7.74(d,J=8.5Hz ,1H),7.50(dd,J=4.8,1.2Hz,1H),7.46(ddd,J=7.6,4.9,1.2Hz,2H),7.37(s,1H),7.29-7.24(m,2H),7.14(s,1H),3.81(s,2H),3.22(s,3H). 13C NMR(151MHz,DMSO-d6)δ167.11,162.25(d,J=244.8Hz),150.29,144.74,142.01,140.55,136.91,135.51,131.28,127.46 ,127.05,123.78(2C),123.64,122.81,122.58,119.74,114.86,109.21,92.00,80.60,37.25,36.35.HRMS(ESI,m / z)calcd for C 23 H17FN4NaOS[M+Na] + ,439.0999; found439.0997.

[0265] Example 25

[0266] Synthesis of N-(3-fluorophenyl)-N-methyl-2-((3-(pyrimidin-5-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 25 was similar to that of Example 1, except that 3-ethynylpyridine was replaced with 5-ethynylpyrimidine in equal proportions, and ethyl chloroacetate was replaced with 2-chloro-N-(3-fluorophenyl)-N-methylacetamide in equal proportions. It was a white powdery solid. mp 99.7-101.2℃. 1 H NMR(600MHz,Chloroform-d)δ11.61(s,1H),9.18(s,1H),8.95(s,2H),7.73(s,1H),7.70(d,J=8.4Hz,1H),7.42(d,J=7.5Hz ,1H),7.18(d,J=8.3Hz,1H),7.11(t,J=8.2Hz,1H),7.05(d,J=7.7Hz,1H),6.97(d,J=9.1Hz,1H),3.64(s,2H),3.32(s,3H). 13 C NMR (151MHz, CDCl3) δ168.97,163.11(d,J=250.1Hz),158.79(2C),156.94,144.52(d,J=9.1Hz),140.69,135.39,131.33(d,J=9.2Hz),128.57,1 24.29,123.43,123.28,120.38,119.51,115.76(d,J=20.6Hz),114.99(d,J=22.1Hz),111.55,87.96,86.03,38.04,36.90.HRMS(ESI,m / z)calcd for C 22 H16 FN5NaOS[M+Na] + ,440.0950; found 440.0955.

[0267] Example 26

[0268] Synthesis of N-(3-fluorophenyl)-N-methyl-2-((3-((2-morpholinidin-5-yl)ethynyl)-1H-indazole-6-yl)thio)acetamide The synthesis of Example 26 was similar to that of Example 1, except that 3-ethynylpyridine was replaced by 4-(5-ethynylpyrimidin-2-yl)morpholine in equal proportion, and ethyl chloroacetate was replaced by 2-chloro-N-(3-fluorophenyl)-N-methylacetamide in equal proportion. It was a white powdery solid. mp 135.2-135.9℃. 1 H NMR (600MHz, DMSO-d6) δ13.38(s,1H),8.42(d,J=2.3Hz,1H),7.79(dd,J=8.8,2.4Hz,1H),7.72(d,J=8.5Hz,1H),7.49(d,J=7.8Hz,1H),7 .40-7.36(m,2H),7.28-7.23(m,2H),7.09(s,1H),6.90(d,J=8.9Hz,1H),3.79(s,2H),3.71-3.70(m,4H),3.56-3.54(m,4H),3.21(s,3H). 13 C NMR (151MHz, DMSO) δ166.54, 161.64 (d, J = 244.5Hz), 157.38, 150.18, 144.15, 139.89, 139.42 (2C), 134.62, 130.68, 127.62, 123.0 5,121.72,119.39,114.27,108.45,106.52,105.93(2C),90.08,81.22,65.27(2C),44.06(2C),36.63,35.78.HRMS(ESI,m / z)calcd forC 27 H 24 FN5NaO2S[M+Na] + ,524.1527; found 524.1517.

[0269] Example 27

[0270] Synthesis of N-(3,5-difluorophenyl)-N-ethyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 27 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3,5-difluorophenyl)-N-ethylacetamide. It was a white powdery solid. The mp value was 168.8-169.5 °C. 1 H NMR (600MHz, DMSO-d6) δ13.55 (s, 1H), 8.87 (d, J = 2.2Hz, 1H), 8.63 (dd, J = 4.9 ,1.7Hz,1H),8.09(dt,J=7.9,1.9Hz,1H),7.78(d,J=8.4Hz,1H),7.51(dd,J=7 .9,4.8Hz,1H),7.44(s,1H),7.31(s,1H),7.23-7.21(m,2H),7.14(d,J=9.0H z,1H),3.82(s,2H),3.70(s,2H),1.02(t,J=7.1Hz,3H).HRMS(ESI,m / z)calcd for C 24 H 17 F2N4OS[MH] - ,447.1097; found 447.1103.

[0271] Example 28

[0272] Synthesis of N-(2,4-difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 28 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(2,4-difluorophenyl)-N-methylacetamide. It was a white powdery solid. The mp value was 158.4-159.5 °C. 1 H NMR (600MHz, DMSO-d6) δ13.55 (s, 1H), 8.87 (d, J = 2.2Hz, 1H), 8.63 (dd, J = 4. 8,1.6Hz,1H),8.09(dt,J=7.8,2.0Hz,1H),7.77(d,J=8.5Hz,1H),7.68-7.64 (m,1H),7.51(ddd,J=7.9,4.9,1.0Hz,1H),7.49-7.45(m,2H),7.20(td,J=8 .7,3.3Hz,1H),7.12(dd,J=8.5,1.5Hz,1H),3.77-3.70(m,2H),3.14(s,3H). 13C NMR(151MHz,DMSO)δ168.23,162.14(dd,J=248.4,11.7Hz),158.11(dd,J=249.9,13 .8Hz),152.15,149.70,140.94,139.19,135.63,131.87(d,J=9.9Hz),127.80,127. 32(d,J=9.2Hz),124.19,123.15,123.02,120.42,119.53,113.05(dd,J=22.2,3.8H z),109.80,105.95(t,J=25.4Hz),89.78,84.91,37.05,36.30.HRMS(ESI,m / z)calcd for C 23 H 16 F₂N₄NaOS[M+Na] + ,457.0905; found457.0922.

[0273] Example 29

[0274] Synthesis of N-ethyl-2-((3-((4-(morpholinomethyl)phenyl)ethynyl)-1H-indazol-6-yl)thio)-N-phenylacetamide The synthesis of Example 29 was similar to that of Example 1, except that 3-ethynylpyridine was replaced by 4-(4-ethynylbenzyl)morpholine in equal proportions, and ethyl chloroacetate was replaced by 2-chloro-N-ethyl-N-phenylacetamide in equal proportions. mp 174.3-175.9℃. 1 H NMR (600MHz, DMSO-d6) δ13.45(s,1H),7.71(d,J=8.5Hz,1H),7.61(d,J=7.8Hz,2H),7.48(t,J=7.6Hz,2H),7.42-7.36(m,6H),7 .08(d,J=8.5Hz,1H),3.70-3.67(m,2H),3.66(s,2H),3.60-3.58(m,4H),3.51(s,2H),2.38-2.36(m,4H),1.03(t,J=7.1Hz,3H). 13C NMR(151MHz,DMSO)δ167.07,141.82,140.96,139.61,135.92,131.83(2C),130.28(2C),129.77(2C),128.82(2C),128.69,128.33 ,122.96,122.88,120.90,120.38,109.46,92.90,81.63,66.63(2C),62.45,53.60(2C),44.37,37.00,13.19.HRMS(ESI,m / z)calcd for C 30 H 30 N4NaO2S[M+Na] + ,533.1982; found533.1990.

[0275] Example 30

[0276] Synthesis of N-isopropyl-N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 30 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-isopropyl-N-phenylacetamide. It is a pale yellow powder. The mp value is 161.2-162.2℃. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.9,1.7H z,1H),8.09(dt,J=7.9,1.9Hz,1H),7.77(d,J=8.4Hz,1H),7.52-7.49(m,2H),7.47- 7.44(m,2H),7.37(d,J=1.6Hz,1H),7.31-7.30(m,2H),7.09(dd,J=8.4,1.6Hz,1H), 4.81(hept,J=6.7Hz,1H),3.53(s,2H),1.00(d,J=6.8Hz,6H).HRMS(ESI,m / z)calcd for C 25 H 22 N4NaOS[M+Na] + ,449.1407; found 449.1415.

[0277] Example 31

[0278] Synthesis of N-(3-fluoro-5-methylphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 31 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-(3-fluoro-5-methylphenyl)-N-methylacetamide. It was a white powdery solid. The mp value was 149.0-149.9 °C. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),9.25(s,1H),8.14(d,J=7.6Hz,1H),7.78(d,J=8.5Hz,1H),7.68 (s,1H),7.45(s,1H),7.13-7.04(m,5H),3.79(s,2H),3.19(s,3H),2.30(s,3H).HRMS(ESI,m / z)calcd for C 24 H 19 FN4NaOS[M+Na] + ,453.1156; found453.1179.

[0279] Example 32

[0280] Synthesis of N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(4-(trifluoromethoxy)phenyl)acetamide The synthesis of Example 32 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-methyl-N-(4-(trifluoromethoxy)phenyl)acetamide. It was a white powdery solid. The mp value was 128.2-129.0 °C. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),8.87(d,J=2.1Hz,1H),8.63(dd,J=4.9,1.7Hz,1H),8.09(dt,J=7.9,2.0Hz,1H),7.77(d,J =8.3Hz,1H),7.57(s,2H),7.51(dd,J=7.9,4.9Hz,1H),7.45(s,3H),7.11(s,1H),3.76(s,2H),3.21(s,3H).HRMS(ESI,m / z)calcd for C 24 H 17 F3N4NaO2S[M+Na] + ,505.0917; found 505.0931.

[0281] Example 33

[0282] Synthesis of N-ethyl-N-(4-methoxyphenyl)-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thioacetamide The synthesis of Example 33 was similar to that of Example 1, except that ethyl chloroacetate was replaced proportionally with 2-chloro-N-ethyl-N-(4-methoxyphenyl)acetamide. It was a white powdery solid. The mp values ​​were 137.1-138.6 °C. 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.8,1.7Hz,1H ),8.09(dt,J=8.0,2.0Hz,1H),7.77(d,J=8.4Hz,1H),7.51(dd,J=8.0,4.9Hz,1H),7.40 (s,1H),7.28(d,J=8.8Hz,2H),7.10(dd,J=8.4,1.5Hz,1H),7.00(d,J=8.7Hz,2H),3.78 (s,3H),3.66(s,2H),3.63(d,J=7.1Hz,2H),1.01(t,J=7.1Hz,3H).HRMS(ESI,m / z)calcd for C 25 H 22 N4NaO2S[M+Na] + ,465.1356; found 465.1373.

[0283] Example 34

[0284] Synthesis of (3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)glycine ethyl ester:

[0285]

[0286] 1) Preparation of tert-butyl carbamate (2-1) (pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)carbamate

[0287] Intermediate 1-4 (0.50 g, 1.3 mmol), tert-butyl carbamate (2.0 mmol), and cesium carbonate (3.9 mmol) were dissolved in anhydrous 1,4-dioxane. Pd₂(dba)₃ (0.13 mmol) and XantPhos (0.26 mmol) were added under Ar atmosphere. The reaction was carried out at 100 °C for 8 h under Ar protection, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white powder solid, yield: 93.0%.

[0288] 2) Preparation of 3-(pyridin-3-ylethynyl)-1H-indazole-6-amine (2-2)

[0289] Intermediate 2-1 (0.30 g, 0.72 mmol) was dissolved in a solution of methanol:water = 3:0.5, and p-toluenesulfonic acid (7.2 mmol) was added. The mixture was refluxed at 80 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was purified by silica gel column chromatography to give a pale yellow powder solid in 83.5% yield.

[0290] 3) Synthesis of ethyl glycine (3-(pyridin-3-ylethynyl)-1H-indazole-6-yl)glycine (Example 34)

[0291] Intermediate 2-2 (60 mg, 0.056 mmol) was dissolved in anhydrous N,N-dimethylformamide, and ethyl chloroformamide (0.31 mmol) and potassium carbonate (0.77 mmol) were added. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give a white powdery solid in 51.1% yield. mp 135.1–136.7 °C. 1 H NMR (600MHz, DMSO-d6) δ8.89(s,1H),8.67(s,1H),8.06(d,J=7.8Hz,1H),7.52-7.51(m,2H),6.68(dd,J=8.6,1.8Hz,1H) ,6.51(d,J=1.8Hz,1H),5.60(s,1H),5.21(s,2H),4.16(q,J=7.1Hz,2H),1.22(t,J=7.1Hz,3H).HRMS(ESI,m / z)calcdfor C 18 H 16 N4NaO2[M+Na] + ,343.1165; found 343.1168.

[0292] Example 35

[0293] Synthesis of N-(4-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide

[0294] 1) Preparation of N-methyl-N-(4-nitrophenyl)-2-((3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)acetamide (3-1)

[0295] Intermediate 1-5 (0.10 g, 0.19 mmol) was dissolved in tert-butanol, and potassium tert-butoxide (0.57 mmol) was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, dissolved in 1 mL of anhydrous tetrahydrofuran, and 1 mL of anhydrous tetrahydrofuran solution of 0.29 mmol of 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide was added with stirring. The reaction was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a white oily substance in 35.3% yield.

[0296] 2) Preparation of N-(4-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)acetamide (3-2)

[0297] Intermediate 3-1 (50 mg, 0.087 mmol) was dissolved in a mixture of ethanol and water at a ratio of 2:0.5. Iron powder (0.87 mmol) and concentrated hydrochloric acid (1 drop) were added. The mixture was stirred at room temperature for 36 h under Ar protection, and the reaction was monitored by TLC until complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the pH of the system was adjusted to 8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by silica gel column chromatography to give a yellow oily substance with a yield of 43.9%. 3) Synthesis of N-(4-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazole-6-yl)thio)acetamide (Example 35)

[0298] Intermediate 3-2 (19 mg, 0.040 mmol) was dissolved in a mixture of ethanol and water at a ratio of 3:0.5, and p-toluenesulfonic acid (0.60 mmol) was added. The mixture was refluxed at 80 °C for 7 h, and the reaction was monitored by TLC until complete. The pH of the reaction solution was adjusted to 8, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by preparative thin-layer chromatography to give a white powdery solid in 36.1% yield. mp 167.7–168.5 °C. 1H NMR (600MHz, DMSO-d6) δ13.53(s,1H),8.87(d,J=2.2Hz,1H),8.63(dd,J=4.9,1.6 Hz,1H),8.09(dt,J=7.9,1.9Hz,1H),7.77(d,J=8.5Hz,1H),7.51(dd,J=7.9,4.8Hz ,1H),7.41(d,J=1.6Hz,1H),7.10(dd,J=8.5,1.6Hz,1H),7.01(d,J=8.6Hz,2H),6 .59(d,J=8.6Hz,2H),5.31(s,2H),3.70(s,2H),3.12(s,3H).HRMS(ESI,m / z)calcd forC 23 H 19 N5NaOS[M+Na] + ,436.1203; found 436.1205.

[0299] Example 36

[0300] Synthesis of N-(3-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 36 was similar to that of Example 35, except that 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide was replaced by 2-chloro-N-methyl-N-(3-nitrophenyl)acetamide in equal proportions. It is a pale yellow powder. The mp value is 144.5-145.1℃. 1 H NMR(600MHz,Chloroform-d)δ8.83(s,1H),8.57(d,J=5.0Hz,1H),7.88(dt,J=7.9,1 .9Hz,1H),7.67(d,J=8.4Hz,1H),7.58(s,1H),7.30(dd,J=7.9,4.9Hz,1H),7.17(t,J =7.9Hz,1H),7.14(dd,J=8.4,1.5Hz,1H),6.67(dd,J=8.1,2.4Hz,1H),6.58(dd,J=7. 7,2.0Hz,1H),6.49(d,J=2.2Hz,1H),3.67(s,2H),3.28(s,3H).HRMS(ESI,m / z)calcd for C 23 H 19 N5NaOS[M+Na] + ,436.1203; found 436.1220.

[0301] Example 37

[0302] Synthesis of (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-yl)thio)acetamide

[0303] 1) Preparation of (E)-6-bromo-3-(2-(pyridin-3-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4-1)

[0304] Intermediate 1-4 (1.0 g, 2.3 mmol), 3-vinylpyridine (3.2 mmol), and N,N-diisopropylethylamine (7.4 mmol) were dissolved in anhydrous N,N-dimethylformamide. Pd₂(OAc)₂ (0.12 mmol) and tris(o-methylphenyl)phosphine (0.25 mmol) were added under Ar atmosphere, and the reaction was carried out at 100 °C for 4 h under Ar protection. The reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white powder solid, yield: 17.6%.

[0305] 2) Preparation of 2-ethylhexyl (4-2) of (E)-3-((3-(2-(pyridin-3-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)propionate

[0306] Intermediate 4-1 (0.15 g, 0.40 mmol) was dissolved in anhydrous toluene, and N,N-diisopropylethylamine (0.80 mmol) was added. Under an Ar atmosphere, Pd₂(dba)₃ (0.040 mmol), Xantphos (0.080 mmol), and 2-ethylhexyl 3-mercaptopropionate (0.72 mmol) were added. The mixture was heated to 110 °C and reacted for 9 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a yellow oily substance in 85.0% yield.

[0307] 3) Preparation of (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-3-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)acetamide (4-3)

[0308] Intermediate 4-2 (0.25 g, 0.29 mmol) was dissolved in tert-butanol, and potassium tert-butoxide (0.86 mmol) was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, dissolved in 1 mL of anhydrous tetrahydrofuran, and 1 mL of anhydrous tetrahydrofuran solution of 0.43 mmol of 2-chloro-N-(3-fluorophenyl)-N-methylacetamide was added with stirring. The reaction was stirred at room temperature for 0.5 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a yellow oily substance, yield: 16.7%.

[0309] 4. Synthesis of (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)thio)acetamide (Example 37)

[0310] Intermediate 4-3 (22 mg, 0.044 mmol) was dissolved in 4N hydrochloric acid / ethyl acetate solution and stirred at room temperature for 1 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the pH of the system was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by silica gel column chromatography to give a white powdery solid, yield: 74.2%. mp 149.4–150.3 °C. 1 H NMR(600MHz,Chloroform-d)δ11.12(s,1H),8.77(s,1H),8.51(s,1H),7.88(dt,J= 8.0,1.9Hz,1H),7.84(d,J=8.5Hz,1H),7.63(s,1H),7.47-7.38(m,2H),7.38-7.37 (m,1H),7.30(dd,J=7.9,4.7Hz,1H),7.16(d,J=8.4Hz,1H),7.09(t,J=9.0Hz,1H), 7.03(dd,J=7.8,2.0Hz,1H),6.94(dt,J=9.2,2.3Hz,1H),3.62(s,2H),3.30(s,3H). 13C NMR (151MHz, CDCl3) δ168.81,163.05(d,J=249.7Hz),148.44,148.28,144.66,144.60,143.14,141.92,134.48,133.04,132.78,131.22(d,J=9. 0Hz),127.00,123.75,123.26,122.30,120.82,120.02,115.61(d,J=20.8Hz),114.95(d,J=22.0Hz),111.55,37.90,37.02.HRMS(ESI,m / z)calcd for C 23 H 19 FN4NaOS[M+Na] + ,441.1156; found 441.1166.

[0311] Example 38

[0312] Synthesis of (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 38 was similar to that of Example 37, except that 3-vinylpyridine was replaced by 2-vinylpyridine in equal proportions. It is a white powdery solid. mp 184.1-185.7℃. 1 H NMR (600MHz, DMSO-d6) δ13.23(s,1H),8.60(dd,J=4.9,1.8Hz,1H),8.08(d,J=8.6Hz,1H),7.91(d,J=16.4Hz,1H),7.81(td,J=7.6,1.9Hz,1H),7.6 6(d,J=7.8Hz,1H),7.54(d,J=16.3Hz,1H),7.49(s,1H),7.40-7.36(m,2H ),7.28-7.24(m,1H),7.23(s,1H),7.09(s,1H),3.78(s,2H),3.22(s,3H). 13C NMR(151MHz,DMSO-d6)δ166.62,161.66(d,J=246.2Hz),154.35,148.95,144.19,141.28,141.21,136.27,133.84,130.68, 128.45,123.25,123.06,122.01,121.85,121.59,120.40,118.63,114.29(2C),108.68,36.64,35.96.HRMS(ESI,m / z)calcd forC 23 H 19 FN4NaOS[M+Na] + ,441.1156; found 441.1173.

[0313] Example 39

[0314] Synthesis of (E)-N-methyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 39 was similar to that of Example 37, except that 3-vinylpyridine was replaced with 2-vinylpyridine in equal proportions, and 2-chloro-N-(3-fluorophenyl)-N-methylacetamide was replaced with 2-chloro-N-methyl-N-phenylacetamide in equal proportions. White powdery solid. mp 191.0-191.6℃. 1 H NMR (600MHz, DMSO-d6) δ13.23(s,1H),8.60(d,J=4.7Hz,1H),8.08(d,J=8.6Hz,1H),7.91(d,J=16.4Hz,1H),7.81(td,J=7.6,1.8Hz,1H),7.66(d,J=7. 8Hz,1H),7.54(d,J=16.4Hz,1H),7.49-7.46(m,2H),7.42-7.37(m,4H),7. 27(dd,J=7.5,4.7Hz,1H),7.07(d,J=8.5Hz,1H),3.72(s,2H),3.21(s,3H). 13CNMR(151MHz,DMSO)δ167.70,155.30,149.91,143.66,142.31,142.26,137.50,135.06,130.30(2C),129.39,12 8.51,127.81(2C),124.38,123.10,122.99,122.60,121.46,119.63,109.58,37.77,36.84.HRMS(ESI,m / z)calcd for C 23 H 20 N4NaOS[M+Na] + ,423.1250; found 423.1259.

[0315] Example 40

[0316] Synthesis of (E)-N-methyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 40 was similar to that of Example 37, except that 3-vinylpyridine was replaced with 2-vinylpyridine in equal proportions, and 2-chloro-N-(3-fluorophenyl)-N-methylacetamide was replaced with 2-chloro-N-(4-fluorophenyl)-N-methylacetamide in equal proportions. It was a white powdery solid. The mp temperature was 188.5-189.3℃. 1 H NMR (600MHz, DMSO-d6) δ13.23(s,1H),8.60(dd,J=4.9,1.7Hz,1H),8.08(d,J=8.5Hz,1H),7.92(d,J=16.3Hz,1H),7.81(td,J=7.7,1.9Hz,1H),7.66(d ,J=7.8Hz,1H),7.54(d,J=16.4Hz,1H),7.49(dd,J=8.6,4.9Hz,2H),7.38( s,1H),7.32-7.26(m,3H),7.08(d,J=8.5Hz,1H),3.72(s,2H),3.19(s,3H). 13C NMR (151MHz, DMSO) δ167.78,161.63(d,J=245.4Hz),155.34,149.97,142.32,142.26,139.93,137.43,135.01,130.13(d,J=8.9Hz,2 C),129.47,124.32,123.08,122.97,122.56,121.47,119.63,117.03(d,J=22.9Hz,2C),109.55,37.84,36.85.HRMS(ESI,m / z)calcd for C 23 H 19 FN4NaOS[M+Na] + ,441.1156; found441.1171.

[0317] Example 41

[0318] Synthesis of (E)-N-ethyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide The synthesis of Example 41 was similar to that of Example 37, except that 3-vinylpyridine was replaced with 2-vinylpyridine in equal proportions, and 2-chloro-N-(3-fluorophenyl)-N-methylacetamide was replaced with 2-chloro-N-ethyl-N-phenylacetamide in equal proportions. White powdery solid. mp 146.9-147.7℃. 1 H NMR (600MHz, DMSO-d6) δ13.24(s,1H),8.60(dd,J=4.9,1.8Hz,1H),8.08(d,J=8.5Hz,1H),7.91(d, J=16.3Hz,1H),7.81(td,J=7.6,1.9Hz,1H),7.66(d,J=7.8Hz,1H),7.54(d,J=16.3Hz,1H),7.48(t, J=7.6Hz,2H),7.41(t,J=7.4Hz,1H),7.38-7.36(m,3H),7.27(ddd,J=7.5,4.7,1.1Hz,1H),7.07(d, J=8.5Hz,1H),3.68(q,J=8.1,7.6Hz,2H),3.66(s,2H),1.03(t,J=7.1Hz,3H).HRMS(ESI,m / z)calcd for C 24 H 22 N4NaOS[M+Na] + ,437.1407; found 437.1436.

[0319] Example 42

[0320] Synthesis of N-ethyl-2-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide

[0321]

[0322] 1) Preparation of 2-phenyl-2-((3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)acetic acid (5-1)

[0323] Intermediate 1-5 (0.28 g, 0.54 mmol) was dissolved in tert-butanol, and potassium tert-butoxide (2.7 mmol) was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until complete. Methyl 2-bromo-2-phenylacetate (1.1 mmol) was added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at room temperature for another 0.5 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, the pH of the system was adjusted to 4 with 2N hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and separated by thin-layer chromatography to obtain a pale yellow powder solid, with a yield of 86.8%.

[0324] 2) Synthesis of N-ethyl-2-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide (Example 42)

[0325] Intermediate 5-1 (40 mg, 0.085 mmol) was dissolved in anhydrous N,N-dimethylformamide, and HATU (0.17 mmol) was added. N,N-diisopropylethylamine (0.26 mmol) was added at 0 °C, and the mixture was stirred for 0.5 h. Ethylamine (0.17 mmol) was then added, and the mixture was stirred for another 0.5 h. The reaction was monitored by TLC until complete. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride aqueous solution, concentrated under reduced pressure, and purified by pre-thickness thin-layer chromatography. The purified product was dissolved in 4N hydrochloric acid / ethyl acetate, and the mixture was stirred at room temperature for 10 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, the pH of the system was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by pre-thickness thin-layer chromatography to obtain a pale yellow powdery solid, with a yield of 37.1%. 1H NMR (600MHz, DMSO-d6) δ13.60 (s, 1H), 8.87 (d, J = 2.2Hz, 1H), 8.63 (dd, J = 4.9 ,1.7Hz,1H),8.37(t,J=5.5Hz,1H),8.10(dt,J=7.9,2.0Hz,1H),7.82(d,J=8. 4Hz,1H),7.53-7.49(m,4H),7.34(t,J=7.5Hz,2H),7.30-7.27(m,1H),7.21( dd,J=8.4,1.5Hz,1H),5.20(s,1H),3.14-2.98(m,2H),0.94(t,J=7.2Hz,3H).

[0326] Example 43

[0327] Synthesis of N-(3-(pyridin-3-ylethynyl)-1H-indazole-6-yl)benzenesulfonamide

[0328]

[0329] 1) Preparation of N-(3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)benzenesulfonamide (6-1)

[0330] Intermediate 1-4 (0.15 g, 0.39 mmol) was dissolved in anhydrous acetonitrile, and benzenesulfonamide (0.51 mmol) and potassium carbonate (1.2 mmol) were added. Cuprous iodide (0.20 mmol) and DMEDA (0.39 mmol) were added under an Ar atmosphere. The reaction was carried out at 100 °C with stirring for 10 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white powder solid in 80.1% yield.

[0331] 2) Synthesis of N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide (Example 43)

[0332] Intermediate 6-1 (0.30 g, 0.72 mmol) was dissolved in a mixture of methanol and water at a ratio of 3:0.5. P-Toluenesulfonic acid (7.2 mmol) was added, and the mixture was refluxed at 80 °C for 3 h. The reaction was monitored by TLC until complete. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give a pale yellow powder, yield: 76.2%. mp 229.5–230.4 °C. 1H NMR (600MHz, DMSO-d6) δ13.38(s,1H),10.56(s,1H),8.83(d,J=1.5Hz,1H),8.61( dd,J=4.8,1.5Hz,1H),8.05(d,J=7.9Hz,1H),7.74(d,J=8.8Hz,1H),7.72(d,J=8.4 Hz,2H),7.48(dd,J=7.5,4.9Hz,1H),7.41(d,J=8.4Hz,2H),7.35(d,J=1.1Hz,1H) ,7.05(dd,J=8.7,1.7Hz,1H),2.90(dt,J=13.7,6.9Hz,1H),1.14(d,J=6.9Hz,6H). 13 C NMR(151MHz,DMSO)δ152.13,149.69,140.82,139.68,139.11,137.45,133.54,129.81(2C),127.73 ,127.10(2C),124.15,121.46,121.04,119.50,116.57,100.79,89.70,84.88.HRMS(ESI,m / z)calcd for C 20 H 14 N4NaO2S[M+Na] + ,397.0730; found 397.0754.

[0333] Example 44

[0334] Synthesis of 4-methyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 44 was similar to that of Example 43, except that benzenesulfonamide was replaced by 4-methylbenzenesulfonamide in equal proportion. It is a white powdery solid. mp 238.1-239.0℃. 1 H NMR (600MHz, DMSO-d6) δ13.37(s,1H),10.50(s,1H),8.84(d,J=1.4Hz,1H),8.62(dd,J=4.8,1.6Hz,1H),8.07-8.05(m,1H),7.73(d,J=8.7Hz,1 H),7.67(d,J=8.3Hz,2H),7.50(dd,J=7.5,4.5Hz,1H),7.34(d,J=8.1Hz,2H),7.31(d,J=1.2Hz,1H),7.03(dd,J=8.7,1.7Hz,1H),2.31(s,3H). 13C NMR(151MHz,DMSO)δ152.15,149.70,143.92,140.84,139.10,137.60,136.85,130.23(2C),127.71,12 7.17(2C),124.14,121.39,121.00,119.51,116.44,100.53,89.68,84.92,21.41.HRMS(ESI,m / z)calcd for C 21 H 16 N4NaO2S[M+Na] + ,411.0994; found411.0917.

[0335] Example 45

[0336] Synthesis of 4-ethyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 45 was similar to that of Example 43, except that benzenesulfonamide was replaced by 4-ethylbenzenesulfonamide in equal proportion. It is a white powdery solid. mp 222.5-223.7℃. 1 H NMR(600MHz,DMSO-d6)δ13.37(s,1H),10.52(s,1H),8.83(d,J=1.6Hz,1H),8.6 1(dd,J=4.8,1.4Hz,1H),8.05(dt,J=7.9,1.7Hz,1H),7.73(d,J=8.7Hz,1H),7. 69(d,J=8.3Hz,2H),7.49(dd,J=7.8,4.9Hz,1H),7.37(d,J=8.3Hz,2H),7.32(s ,1H),7.03(dd,J=8.7,1.5Hz,1H),2.61(q,J=7.6Hz,3H),1.13(t,J=7.6Hz,4H). 13 C NMR(151MHz,DMSO)δ152.15,149.83,149.70,140.85,139.10,137.61,137.15,129.10(2C),127.71,127.2 4(2C),124.14,121.35,121.02,119.51,116.35,100.38,89.67,84.92,28.38,15.34.HRMS(ESI,m / z)calcd forC 22 H 18 N4NaO2S[M+Na] + ,425.1043; found 425.1075.

[0337] Example 46

[0338] Synthesis of 4-chloro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 46 was similar to that of Example 43, except that benzenesulfonamide was replaced by 4-chlorobenzenesulfonamide in equal proportion. It is a white powdery solid. mp 232.5-233.1℃. 1 HNMR (600MHz, DMSO-d6) δ13.42(s,1H),10.63(s,1H),8.84(d,J=1.4Hz,1H),8.62(dd,J=4.8,1.6Hz,1H),8.06(dt,J=7.9,1.9Hz, 1H),7.76(d,J=8.7Hz,3H),7.63(d,J=8.7Hz,2H),7.50(dd,J=7.9,4.9Hz,1H),7.32(d,J=1.1Hz,1H),7.02(dd,J=8.7,1.7Hz,1H). 13 C NMR(151MHz,DMSO)δ152.16,149.70,140.79,139.10,138.51,138.44,137.09,129.99(2C),129.05 (2C),127.77,124.13,121.69,121.15,119.49,116.74,101.35,89.74,84.86.HRMS(ESI,m / z)calcd forC 20 H 14 ClN4O2S[M+H] + ,409.0521; found 409.0550.

[0339] Example 47

[0340] Synthesis of 4-bromo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 47 was similar to that of Example 43, except that benzenesulfonamide was replaced by 4-bromobenzenesulfonamide in equal proportion. It is a white powdery solid. mp 208.1-209.7℃. 1 HNMR(600MHz,DMSO-d6)δ13.41(s,1H),10.62(s,1H),8.84(s,1H),8.62(s,1H),8.06-7.94(m,1H),7.79-7.46(m,6H),7.31(s,1H),7.02(s,1H). 13C NMR(151MHz,DMSO)δ152.15,149.69,140.79,139.26,139.15,138.72(2C),137.11,128.96(2C),12 7.77,124.17,121.62,121.16,119.49,116.68,101.88,101.19,89.74,84.85.HRMS(ESI,m / z)calcd for C 20 H 14 BrN4O2S[M+H] + ,453.0015; found,453.0039.

[0341] Example 48

[0342] Synthesis of 3-bromo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 48 was similar to that of Example 43, except that benzenesulfonamide was replaced by 3-bromobenzenesulfonamide in equal proportion. It is a white powdery solid. mp 215.0-215.8℃. 1 H NMR(600MHz,DMSO-d6)δ13.42(s,1H),10.62(s,1H),8.84(s,1H),8.62(s,1H),8.08(d,J=16.7Hz,1 H),7.84-7.72(m,3H),7.63-7.47(m,3H),7.32(s,1H),7.03(d,J=7.6Hz,1H).HRMS(ESI,m / z)calcd for HRMS(ESI,m / z)calcd for C 20 H 12 BrN4O2S[MH] - ,450.9923;found,450.9922.

[0343] Example 49

[0344] Synthesis of N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)-3-(trifluoromethyl)benzenesulfonamide The synthesis of Example 49 was similar to that of Example 43, except that benzenesulfonamide was replaced by 3-(trifluoromethyl)benzenesulfonamide in equal proportion. It is a white powdery solid. mp 134.7-135.4℃. 1H NMR (600MHz, DMSO-d6) δ13.43(s,1H),10.71(s,1H),8.84(d,J=1.4Hz,1H),8.61(d,J=4.7Hz,1H),8.06(d,J=7.8Hz,2 H),8.01(s,2H),7.80(d,J=7.9Hz,1H),7.77(d,J=8.5Hz,1H),7.50-7.47(m,1H),7.34(s,1H),7.02(d,J=8.6Hz,1H). 13 C NMR (151MHz, DMSO) δ152.12, 149.70, 140.72 (d, J = 4.4Hz), 139.13, 136.76, 131.52, 131.16, 130.35 (q, J = 32.7Hz), 130.31 (d, J = 2.9Hz), 127.7 9,124.15,123.71(q,J=272.8Hz),123.63(d,J=3.7Hz),123.60,121.82,121.26,119.46,116.91,101.81,89.77,84.76.HRMS(ESI,m / z)calcd for C 21 H 14 F3N4O2S[M+H] + ,443.0821;found,443.0822.

[0345] Example 50

[0346] Synthesis of 4-methoxy-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 50 was similar to that of Example 43, except that benzenesulfonamide was replaced by 4-methoxybenzenesulfonamide in equal proportion. White powdery solid. mp 121.0-121.8℃. 1 H NMR (600MHz, DMSO-d6) δ13.37(s,1H),10.42(s,1H),8.83(s,1H),8.61(d,J=3.4Hz,1H),8.06(d,J=7.5Hz,1H),7.73 (s,1H),7.70(d,J=8.6Hz,2H),7.50(d,J=4.9Hz,1H),7.31(s,1H),7.05(d,J=8.7Hz,2H),7.02(s,1H),3.77(s,3H). 13C NMR(151MHz,DMSO)δ162.98,152.06,149.62,140.88,139.19,137.70,131.25,129.36(2C),127.69,12 4.20,121.35,120.98,119.55,116.50,114.91(2C),100.52,89.67,84.94,56.07.HRMS(ESI,m / z)calcd for C 21 H 16 N4NaO3S[M+Na] + ,427.0835; found 427.0866.

[0347] Example 51

[0348] Synthesis of 4-hydroxy-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 51 was similar to that of Example 43, except that benzenesulfonamide was replaced by 4-hydroxybenzenesulfonamide in equal proportion. It is a light gray powdery solid. The mp value is 260.5-261.4℃. 1 H NMR (600MHz, DMSO-d6) δ13.67(s,1H),8.87(s,1H),8.64(d,J=2.8Hz,1H),8.39(d,J=8.7Hz,2H),8.09(d,J=7.9Hz,1H ),7.85(d,J=8.6Hz,1H),7.79(d,J=8.7Hz,2H),7.51(dd,J=7.6,5.0Hz,1H),7.40(s,1H),6.98(dd,J=8.7,1.3Hz,1H). 13 C NMR (151MHz, DMSO) δ161.85,151.73,149.20,140.91,139.66,137.88,129.58,129.56,128.53,127.60 ,125.97,124.36,121.28,120.89,119.73,116.49,116.09,100.38,89.49,85.20.HRMS(ESI,m / z)calcd for C 20 H 14 N4NaO3S[M+Na] + ,413.0701; found 413.0710.

[0349] Example 52

[0350] Synthesis of 4-(isopropyl)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide

[0351]

[0352] 1) Synthesis of 4-(isopropyl)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide

[0353] Intermediate 2-2 (50 mg, 0.21 mmol) was dissolved in anhydrous pyridine, and 4-dimethylaminopyridine (0.23 mmol) was added. 4-Isopropylbenzenesulfonyl chloride (0.32 mmol) was added at 0 °C, and the mixture was transferred to room temperature and reacted for 5 h. The reaction was monitored by TLC until complete. Most of the solvent was removed by vacuum concentration, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography to give a white powdery solid, yield: 61.5%. mp 211.5–212.3 °C. 1 HNMR(600MHz,DMSO-d6)δ13.38(s,1H),10.56(s,1H),8.83(d,J=1.5Hz,1H),8.6 1(dd,J=4.8,1.5Hz,1H),8.05(dt,J=7.9,1.8Hz,1H),7.74(d,J=8.8Hz,1H),7.72 (d,J=8.4Hz,2H),7.48(dd,J=7.5,4.9Hz,1H),7.41(d,J=8.4Hz,2H),7.35(d,J=1 .1Hz,1H),7.05(dd,J=8.7,1.7Hz,1H),2.93-2.87(m,1H),1.14(d,J=6.9Hz,6H). 13 C NMR (151MHz, DMSO) δ154.29,152.15,149.69,140.88,139.09,137.64,137.37,127.75,127.72(2C),127.26( 2C),124.14,121.32,121.04,119.51,116.24,100.21,89.67,84.93,33.76,23.80(2C).HRMS(ESI,m / z)calcd forC 23 H 20 N4NaO2S[M+Na] + ,439.1200; found 439.1228.

[0354] Example 53

[0355] Synthesis of 4-fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 53 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced by 4-fluorobenzenesulfonamide in equal proportion. It is a white powdery solid. mp 238.1-239.0℃. 1 H NMR (600MHz, DMSO-d6) δ13.40(s,1H),10.57(s,1H),8.83(s,1H),8.62(d,J=4.7Hz,1H),8.06(d,J=7.9Hz,1H),7.85-7 .80(m,2H),7.75(d,J=8.7Hz,1H),7.49(dd,J=7.8,4.9Hz,1H),7.41-7.37(m,2H),7.31(s,1H),7.01(d,J=8.7Hz,1H). 13 C NMR (151MHz, DMSO) δ164.84(d,J=251.4Hz),152.10,149.67,140.80,139.16,137.22,136.00(d,J=2.5Hz),130.19(d,J=9.9Hz ,2C),127.75,124.19,121.61,121.11,119.51,117.04(d,J=23.0Hz,2C),116.73,101.22,89.72,84.85.HRMS(ESI,m / z)calcd for C 20 H 13 FN4NaO2S[M+Na] + ,415.0639; found415.0621.

[0356] Example 54

[0357] Synthesis of 4-iodo-N-(3-(pyridin-3-ylethynyl)-1H-indazole-6-yl)benzenesulfonamide. The synthesis of Example 54 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced with 4-iodobenzenesulfonyl chloride in equal proportion. It is a white powdery solid. mp 263.7-264.4℃. 1H NMR (600MHz, DMSO-d6) δ13.40(s,1H),10.61(s,1H),8.83(d,J=2.1,0.7Hz,1H),8.61(dd,J=4.8,1.6Hz,1H),8.06(dt,J=7.9,1.9Hz,1H) ,7.93(d,J=8.6Hz,2H),7.75(d,J=8.7Hz,1H),7.52-7.49(m,2H),7.49-7.47(m,1H),7.31(d,J=1.3Hz,1H),7.01(dd,J=8.7,1.7Hz,1H). 13 C NMR(151MHz,DMSO)δ152.12,149.69,140.79,139.26,139.15,138.72(2C),137.11,128.76(2C),12 7.77,124.17,121.62,121.16,119.49,116.68,101.88,101.19,89.74,84.85.HRMS(ESI,m / z)calcd for C 20 H 14 IN4O2S[M+H] + ,500.9877; found 500.9901.

[0358] Example 55

[0359] Synthesis of 3-methyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 55 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced by 3-methylbenzenesulfonyl chloride in equal proportions. It is a white powdery solid. mp 255.7-256.5℃. 1 H NMR(600MHz,DMSO-d6)δ13.37(s,1H),10.54(s,1H),8.83(d,J=1.4Hz,1H), 8.61(dd,J=4.8,1.6Hz,1H),8.06(dt,J=7.9,1.9Hz,1H),7.74(d,J=8.7Hz,1 H),7.62(s,1H),7.56(d,J=3.7Hz,1H),7.49(dd,J=7.9,5.5Hz,1H),7.43-7 .41(m,2H),7.31(d,J=1.3Hz,1H),7.03(dd,J=8.7,1.7Hz,1H),2.33(s,3H). 13CNMR(151MHz,DMSO)δ152.15,149.69,140.84,139.73,139.52,139.10,137.52,134.16,129.64,127.72,12 7.31,124.29,124.14,121.40,121.02,119.51,116.43,100.55,89.68,84.93,21.29.HRMS(ESI,m / z)calcd for C 21 H 16 N4NaO2S[M+Na] + ,411.0911; found 411.0921.

[0360] Example 56

[0361] Synthesis of 3-fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 56 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced by 3-fluorobenzenesulfonyl chloride in equal proportions. It is a white powdery solid. mp 225.3.1-226.0℃. 1 H NMR (600MHz, DMSO-d6) δ13.40(s,1H),10.67(s,1H),8.84(d,J=1.4Hz,1H),8.62(dd,J=4.8,1.6Hz,1H),8.06(dt,1H),7.76(d, J=8.7Hz,1H),7.61-7.59(m,2H),7.57(d,J=8.1Hz,1H),7.51-7.47(m,2H),7.33(d,J=1.2Hz,1H),7.03(dd,J=8.7,1.7Hz,1H). 13 C NMR (151MHz, DMSO) δ162.09 (d, J = 248.7Hz), 152.14, 149.70, 141.67 (d, J = 6.5Hz), 140.78, 139.12, 136.99, 132.33, 127.78, 124.15 ,123.46(d,J=2.3Hz),121.69,121.17,120.74,119.48,116.72,114.14(d,J=24.5Hz),101.35,89.75,84.83.HRMS(ESI,m / z)calcd for C 20 H 14 FN4O2S[M+H] + ,393.0816; found393.0843.

[0362] Example 57

[0363] Synthesis of 3-chloro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 57 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced by 3-chlorobenzenesulfonyl chloride in equal proportion. It is a white powdery solid. mp 243.1-244.0℃. 1 H NMR(600MHz,DMSO-d6)δ13.41(s,1H),10.67(s,1H),8.84(d,J=1.4Hz,1H),8 .62(dd,J=4.8,1.6Hz,1H),8.06(dt,J=7.9,1.9Hz,1H),7.79(t,J=1.9Hz,1H ),7.77(d,J=8.7Hz,1H),7.71(s,1H),7.69(s,1H),7.58(t,J=8.0Hz,1H),7. 49(dd,J=7.9,4.9Hz,1H),7.32(d,J=1.5Hz,1H),7.03(dd,J=8.7,1.6Hz,1H). 13 C NMR (151MHz, DMSO) δ152.15,149.71,141.48,140.77,139.11,136.94,134.36,133.58,131.93,127.79 ,126.67,125.87,124.14,121.72,121.22,119.48,116.73,101.40,89.76,84.83.HRMS(ESI,m / z)calcd for C 20 H 14 ClN4O2S[M+H] + ,409.0521; found 409.0549.

[0364] Example 58

[0365] Synthesis of N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)-4-(trifluoromethyl)benzenesulfonamide The synthesis of Example 58 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced by 4-trifluoromethylbenzenesulfonyl chloride in equal proportion. It is a white powdery solid. mp 197.5-198.2℃. 1H NMR (600MHz, DMSO-d6) δ13.42(s,1H),10.78(s,1H),8.83(d,J=1.1Hz,1H),8.61(dd,J=4.7,1.2Hz,1H),8.05(dt,J=7.9,1.9Hz ,1H),7.97-7.94(m,4H),7.76(d,J=8.7Hz,1H),7.49(dd,J=7.6,4.6Hz,1H),7.34(d,J=1.2Hz,1H),7.02(dd,J=8.7,1.7Hz,1H). 13 C NMR (151MHz, DMSO) δ152.13,149.71,143.56,140.77,139.12,136.81,133.14(q,J=32.4Hz),128.11,127.80(2C),127.11(d ,J=3.6Hz,2C),124.16,123.77(q,J=273.0Hz),121.78,121.25,119.47,116.77,101.57,89.76,84.79.HRMS(ESI,m / z)calcd for C 21 H 13 F3N4O2S[M+H] + ,443.0800; found 443.0801.

[0366] Example 59

[0367] Synthesis of 4-(dimethylamino)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 59 was similar to that of Example 52, except that 4-isopropylbenzenesulfonyl chloride was replaced by 4-(dimethylamino)benzenesulfonyl chloride in equal proportions. It is a white powdery solid. mp 214.5-215.2℃. 1 H NMR (600MHz, DMSO-d6) δ13.34(s,1H),10.23(s,1H),8.83(d,J=1.4Hz,1H),8.61(dd,J=4.8,1.5Hz,1H),8.05(dt,J=7.9,1.8Hz,1H),7.70(d,J= 8.7Hz,1H),7.56(s,1H),7.54(s,1H),7.49(dd,J=7.8,4.9Hz,1H),7.30(s,1H),7.03(dd,J=8.7,1.4Hz,1H),6.68(d,J=9.1Hz,2H),2.92(s,6H). 13C NMR (151MHz, DMSO) δ153.06,152.11,149.66,140.95,139.12(2C),138.25,128.86,127.65,124.52,124. 16,121.06,120.80,119.54(2C),116.25,111.26,99.74,89.61,85.02,39.98(2C).HRMS(ESI,m / z)calcd for C 22 H 19 N5NaO2S[M+Na] + ,440.1152; found 440.1177.

[0368] Example 60

[0369] Synthesis of 4-amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide

[0370]

[0371] 1) Preparation of 4-nitro-N-(3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)benzenesulfonamide (7-1)

[0372] Intermediate 1-4 (0.15 g, 0.39 mmol) was dissolved in anhydrous acetonitrile, and 4-nitrobenzenesulfonamide (0.51 mmol) and potassium carbonate (1.2 mmol) were added. Cuprous iodide (0.20 mmol) and DMEDA (0.39 mmol) were added under an Ar atmosphere. The reaction was carried out at 100 °C with stirring for 10 h, and the reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white powder solid in 80.2% yield.

[0373] 2) Preparation of 4-amino-N-(3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)benzenesulfonamide (7-2)

[0374] Intermediate 7-1 (0.10 g, 0.20 mmol) was dissolved in a mixture of methanol and tetrahydrofuran at a ratio of 2:1. Iron powder (1.3 mmol) and glacial acetic acid (150 μL) were added under an Ar atmosphere, and the reaction was carried out at 60 °C for 5 h. The reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a yellow powdery solid in 85.9% yield.

[0375] 3) Synthesis of 4-amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide (Example 60)

[0376] The reaction conditions were the same as in step b of Example 43. Yield: 74.3%. Pale yellow powdery solid. mp 245.6-246.2℃. 1 H NMR (600MHz, DMSO-d6) δ13.33(s,1H),10.15(s,1H),8.84(d,J=2.0Hz,1H),8.62(dd,J=4.8,1.4Hz,1H),8.06(dt,J=7.9,1.7Hz,1H),7.70(d,J =8.7Hz,1H),7.49(dd,J=7.9,4.9Hz,1H),7.41(d,J=8.7Hz,2H),7.27(s,1H),7.01(dd,J=8.7,1.5Hz,1H),6.52(d,J=8.7Hz,2H),5.98(s,2H). 13 C NMR(151MHz,DMSO)δ153.45,152.15,149.66,140.95,139.09,138.31,129.20(2C),127.65,124.45 ,124.13,121.02,120.73,119.57,116.29,113.04(2C),99.76,89.58,85.08.HRMS(ESI,m / z)calcd for C 20 H 15 N5NaO2S[M+Na] + ,412.0839; found 412.0866.

[0377] Example 61

[0378] Synthesis of 4-amino-N-(3-(pyrimidin-5-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 61 was similar to that of Example 60, except that 3-ethynylpyridine was replaced by 5-ethynylpyrimidine in equal proportion. It is a white powdery solid. mp 281.5-282.2℃. 1 H NMR(600MHz,DMSO-d6)δ13.41(s,1H),10.16(s,1H),9.22(s,1H),9.10(s,2H),7.73(d,J=8.7Hz,1 H),7.42(d,J=8.5Hz,2H),7.29(s,1H),7.02(d,J=8.7Hz,1H),6.52(d,J=8.6Hz,2H),5.98(s,2H). 13C NMR(151MHz,DMSO)δ159.23(2C),157.44,153.45,140.97,138.39,129.21(2C),127.22,124. 43,121.08,120.72,119.11,116.42,113.04(2C),99.76,88.48,86.43.HRMS(ESI,m / z)calcd for C 19 H 14 N6NaO2S[M+Na] + ,413.0801; found413.0815.

[0379] Example 62

[0380] Synthesis of 4-amino-N-(3-((2-(1,4-oxazacyclohexyl-4-yl)pyrimidin-5-yl)ethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 62 was similar to that of Example 60, except that 3-ethynylpyridine was replaced by 5-ethynyl-2-(1,4-oxazacyclohexyl-4-yl)pyrimidine in equal proportion. It is a pale yellow powder. The mp value is 198.5-199.7℃. 1 H NMR (600MHz, DMSO-d6) δ13.21(s,1H),10.12(s,1H),8.65(s,2H),7.65(d,J=8.7Hz,1H),7.40(d,J=8.8Hz,2H),7.24(d ,J=1.1Hz,1H),6.98(dd,J=8.7,1.7Hz,1H),6.51(d,J=8.8Hz,2H),5.97(s,2H),3.78-3.76(m,4H),3.68-3.66(m,4H). 13 CNMR(151MHz,DMSO)δ160.61(2C),159.74,153.42,140.92,138.20,129.19(2C),128.22,124.48,120.85 ,120.75,116.05,113.03(2C),106.19,99.73,88.03,84.85,66.35(2C),44.34(2C).HRMS(ESI,m / z)calcd for C 23 H 21 N7NaO3S[M+Na] + ,498.1319; found 498.1359.

[0381] Example 63

[0382] Synthesis of 4-amino-N-(3-((6-(1,4-oxazacyclohexyl-4-yl)pyridin-3-yl)ethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 63 was similar to that of Example 60, except that 3-ethynylpyridine was replaced proportionally with 4-(5-ethynylpyridin-2-yl)-1,4-oxazacyclohexane. It is a pale yellow powder. The mp value is 199.7-200.4 °C. 1 H NMR (600MHz, DMSO-d6) δ13.16(s,1H),10.11(s,1H),8.39(d,J=2.0Hz,1H),7.76(dd,J=8.9,2.3Hz,1H),7.64(d,J=8.7Hz,1H),7.41(d,J=8.8Hz ,2H),7.24(s,1H),6.98(dd,J=8.7,1.6Hz,1H),6.89(d,J=8.9Hz,1H),6 .52(d,J=8.8Hz,2H),5.98(s,2H),3.71-3.68(m,4H),3.55-3.53(m,4H). 13 C NMR(151MHz,DMSO)δ158.40,153.42,151.17,140.91,140.45,138.15,129.18(2C),128.52,124.50,120.86,12 0.77,115.97,113.03(2C),107.64,107.00,99.73,90.93,82.41,66.33(2C),45.13(2C).HRMS(ESI,m / z)calcd for C 24 H 22 N6NaO3S[M+Na] + ,497.1366; found497.1398.

[0383] Example 64

[0384] Synthesis of 3-amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide The synthesis of Example 63 was similar to that of Example 60, except that 4-nitrobenzenesulfonamide was replaced by 3-nitrobenzenesulfonamide in equal proportion. It is a pale yellow powder. The mp value is 252.8-253.6℃. 1H NMR (600MHz, DMSO-d6) δ13.39 (s, 1H), 10.42 (s, 1H), 8.84 (d, J = 1.4Hz, 1H), 8.6 1(dd,J=4.8,1.3Hz,1H),8.07-8.04(m,1H),7.73(d,J=8.7Hz,1H),7.49(dd,J= 7.8,4.9Hz,1H),7.29(s,1H),7.13(t,J=7.9Hz,1H),7.04(dd,J=8.7,1.5Hz,1H ),6.97(s,1H),6.88(d,J=7.8Hz,1H),6.70(dd,J=8.0,1.6Hz,1H),5.58(s,2H). 13 C NMR (151MHz, DMSO) δ151.08,148.81,148.61,139.81,139.35,138.02,136.77,128.98,126.62,123.06 ,120.18,119.78,118.47,117.10,115.31,112.62,110.35,99.16,88.56,83.94.HRMS(ESI,m / z)calcd for C 20 H 15 N5NaO2S[M+Na] + ,412.0839; found 412.0844.

[0385] Example 65

[0386] Synthesis of (E)-4-amino-N-(3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-yl)benzenesulfonamide The synthesis of Example 65 was similar to that of Example 60, except that the starting material was replaced by (E)-6-bromo-3-(pyridin-3-ylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1-4) in equal proportions. The product was a pale yellow powder. The mp value was 212.8-213.7 °C. 1H NMR (600MHz, DMSO-d6) δ12.98(s,1H),10.06(s,1H),8.84(d,J=1.7Hz,1H),8.45(dd,J=4.7,1.4Hz,1H),8.13(d,J=8.0Hz,1H),8.03(d,J=8.7Hz ,1H),7.58(d,J=16.8Hz,1H),7.45(d,J=16.8Hz,1H),7.42-7.39(m,3H) ,7.22(s,1H),6.97(d,J=8.7Hz,1H),6.51(d,J=8.1Hz,2H),5.96(s,2H). 13 C NMR(151MHz,DMSO)δ153.38,148.83,148.79,142.41,142.19,137.66,133.36,133.05,129.18(2C), 126.35,124.61,124.23,123.07,121.82,117.59,115.49,113.02(2C),99.80.HRMS(ESI,m / z)calcd forC 20 H 17 N5NaO2S[M+Na] + ,414.0995; found 414.1026.

[0387] Example 66: In vitro enzyme inhibitory activity study of some products of the present invention

[0388] Experimental materials:

[0389] Distilled water, DMSO, 384 shallow well plate, Tecan F500 ELISA reader, Eu KinaseBinding Assay Kit: Contains Kinase Tracer 236 (Thermo Scientific: PV5592), Eu-Anti-GST Antibody (Thermo Scientific: PV5594), Kinase Buffer (Thermo Scientific: PV6135), and Recombinant Human PLK4 Protein (Thermo Scientific: PV6395).

[0390] Experimental methods:

[0391] First, the 5X kinase buffer solution was diluted with distilled water to prepare a 1X kinase buffer solution. The compound sample prepared in the above example was prepared into a 4 mM solution with DMSO, and then serially diluted with 1X kinase buffer solution according to the test requirements. Then, the compound sample (4 μL) was added to a 384-well plate, followed by 8 μL of kinase buffer solution containing recombinant human PLK4 kinase (concentration of 50 ng / μL) and Eu-Anti-GSTAntibody, and 4 μL of kinase buffer solution containing Tracer 236. The plate was incubated at room temperature for 60 minutes and the readings were taken.

[0392] Results Evaluation Method: Kinase "tracer" binding was detected by adding Eu-labeled antibodies. Binding of the tracer and antibody to the kinase resulted in high FRET, while using a kinase inhibitor instead of the tracer caused FRET loss. The europium donor was excited by a 340nm excitation filter with a 30nm grating, using a filter centered at 665nm with a 10nm bandpass to detect the energy transferred to the Alexa Fluor 647 tracer. This signal was then replaced with the peak excitation of europium, which was performed using a 615nm filter with a 10nm bandpass. The "emission ratio" was calculated by dividing the 665nm signal by the 615nm signal. Therefore, the HTRF signal (665 / 615) ratio for each well plate reaction was calculated. The results were characterized as Delta F (DF%).

[0393]

[0394] Calculation of inhibition rate (% activity): The DF% of kinase activity without the addition of a compound sample is defined as 100%. When the compound sample is added, the kinase activity rate is:

[0395]

[0396] Computing IC 50 With the addition of the compound, the DF% of kinase activity was plotted on the Y-axis, and the logarithm of the compound concentration was plotted on the X-axis. IC 50 The values ​​were obtained by fitting the data to an S-type stoichiometric curve. Centrinone was used as a positive control in the experiment, and its IC50 value was tested. 50 The value is 0.003 μM.

[0397] Table 1 Examples of Compound IC 50 value

[0398] Example IC 50 (μM) Example IC 50 (μM) Example 1 0.307 Example 2 0.101 Example 3 0.480 Example 4 0.550 Example 5 0.235 Example 6 0.070 Example 7 0.036 Example 8 0.062 Example 9 0.120 Example 10 0.729 Example 11 0.798 Example 12 0.0056 Example 13 0.120 Example 14 0.041 Example 15 0.062 Example 16 0.124 Example 17 0.056 Example 18 0.089 Example 19 0.049 Example 20 0.074 Example 21 0.070 Example 22 0.264 Example 23 0.027 Example 24 0.0059 Example 25 0.059 Example 26 0.026 Example 27 0.159 Example 28 0.054 Example 29 0.051 Example 30 0.031 Example 31 0.127 Example 32 0.711 Example 33 0.266 Example 34 19.00 Example 35 0.025 Example 36 0.032 Example 37 0.0001 Example 38 0.008 Example 39 0.009 Example 40 0.298 Example 41 0.0007 Example 42 0.065 Example 43 0.098 Example 44 0.012 Example 45 0.103 Example 46 0.067 Example 47 0.023 Example 48 0.011 Example 49 0.818 Example 50 0.032 Example 51 0.004 Example 52 0.240 Example 53 0.184 Example 54 0.067 Example 55 0.180 Example 56 0.012 Example 57 0.021 Example 58 0.501 Example 59 0.118 Example 60 0.00003 Example 61 0.184 Example 62 0.156 Example 63 0.0009 Example 64 0.020 Example 65 0.0001 Centrinone 0.003

[0399] The above test results show that all the above embodiments have a good inhibitory effect on PLK4 kinase, and the IC50 of most embodiments is [missing information].50 The value is in the range of nM.

[0400] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. An indazole derivative, characterized in that: Derivatives are compounds of general formula I or general formula II, their geometric isomers, enantiomers or pharmaceutically acceptable salts thereof; The compounds represented by general formula I or general formula II are as follows: L1 is selected from -C≡C-, -CH=CH-, or bonds; X1 is selected from -(NR) a )-、O、S、 Where R a Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, or C1-C4 haloalkyl; X2 is selected from N, O, and S; L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, or C1-C4 haloalkyl; R c Selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, A1, A2, and A3 are the same or different, and are selected from C or N; R1 is selected from hydrogen, halogen, C1-C4 alkyl-substituted sulfonyl group, unsubstituted or amino group substituted with 1-2 C1-C4 alkyl groups, C3-C7 aliphatic ring containing 1-2 heteroatoms, -CH2R d , where R d The components are selected from hydrogen, C1-C4 alkyl-substituted sulfonyl groups, unsubstituted or 1-2 C1-C4 alkyl-substituted amino groups, and C3-C7 aliphatic rings containing 1-2 heteroatoms; the heteroatoms are selected from N, O, or S, and when the heteroatom is N, it may be further substituted with C1-C4 alkyl groups, and when the heteroatom is S, it may be further oxidized to sulfoxides and sulfones; R2, R3, and R6, which may be the same or different, are selected from hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, unsubstituted or modified by at least one R e Substituted aryl; R e Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy; When X2 is selected from O, R2 or R3 exists in general formula I; R4 and R5, whether identical or different, are selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C3-C7 cycloalkyl, unsubstituted or modified by at least one R. f Substituted aryl; R f Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy.

2. The indazole derivative according to claim 1, characterized in that, The derivative is a compound of general formula I or general formula II, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug. L1 is selected from -C≡C-, -CH=CH-, or bonds; X1 is selected from -(NR) a )-、O、S、 Where R a Selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C2 haloalkyl; X2 is selected from N, O, and S; L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl; R c Selected from hydrogen, C1-C2 alkyl, A1, A2, and A3 are the same or different, and are selected from C or N; R1 is selected from hydrogen, halogen, C1-C3 alkyl-substituted sulfonyl group, unsubstituted or amino group substituted with 1-2 C1-C4 alkyl groups, C3-C6 aliphatic ring containing 1-2 heteroatoms, -CH2R d , where R d The group is selected from hydrogen, C1-C4 alkyl-substituted sulfonyl groups, unsubstituted or substituted amino groups with 1-2 C1-C4 alkyl groups, and C3-C6 aliphatic rings containing 1-2 heteroatoms; the heteroatoms are selected from N, O, or S, and when the heteroatom is N, it may be further substituted with C1-C2 alkyl groups, and when the heteroatom is S, it may be further oxidized to sulfoxides and sulfones; R2, R3, and R6, whether identical or different, are selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, unsubstituted or modified by at least one R. e Substituted phenyl, pyridyl, or pyrimidinyl; R e Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy; When X2 is selected from O, R2 or R3 exists in general formula I; R4 and R5, whether identical or different, are selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, unsubstituted or modified by at least one R. f Substituted phenyl, pyridyl, or pyrimidinyl; R f Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy.

3. The indazole derivative according to claim 2, characterized in that, The derivative is a compound of general formula I or general formula II, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug. L1 is selected from -C≡C-, -CH=CH-, or bonds; X1 is selected from -(NR) a )-、S、 Where R a Selected from hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl; X2 is selected from N and O; L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl; R c Selected from H, A1, A2, and A3 are the same or different, and are selected from C or N; R1 is selected from hydrogen, C1-C3 alkyl-substituted sulfonyl group, unsubstituted or amino group substituted with 1-2 C1-C4 alkyl groups, C3-C6 aliphatic ring containing 1-2 heteroatoms, or -CH2R. d , where R d The group is selected from hydrogen, C1-C2 alkyl-substituted sulfonyl groups, unsubstituted or 1-2 C1-C2 alkyl-substituted amino groups, and C3-C6 aliphatic rings containing 1-2 heteroatoms; the heteroatoms are selected from N, O or S, and when the heteroatom is N, it may be further substituted with C1-C2 alkyl groups, and when the heteroatom is S, it may be further oxidized to sulfoxides and sulfones; R2, R3, and R6 may be the same or different and selected from hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, unsubstituted or modified by at least one R e Substituted phenyl, pyridyl, or pyrimidinyl, R e Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy; When X2 is selected from O, R2 or R3 exists in general formula I; R4 and R5 may be the same or different and selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, unsubstituted or modified by at least one R. f Substituted phenyl, pyridyl, or pyrimidinyl, wherein R f Derived from hydrogen, halogen, hydroxyl, unsubstituted or substituted amino, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy.

4. The indazole derivative according to claim 3, characterized in that, The derivative is a compound of general formula I or general formula II, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug. L1 is selected from -C≡C- or -CH=CH-; X1 is selected from -(NR) a )-、S or Where R a Selected from hydrogen and C1-C2 alkyl groups; X2 is selected from N and O; L2 is selected from -(NR) b R c )-, where R b Selected from hydrogen, C1-C2 alkyl; R c Selected from H, A1, A2, and A3 are the same or different, and are selected from C or N; R1 is selected from hydrogen, methanesulfonyl, dimethylamino, morpholinyl, piperazine, or -CH2R. d , where R d Selected from hydrogen, methanesulfonyl, dimethylamino, morpholinyl, and piperazine; R2, R3, and R6 may be the same or different and selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, unsubstituted, or modified by at least one R. e Substituted phenyl, pyridyl, or pyrimidinyl, wherein R e Derived from hydrogen, halogen, hydroxyl, amino, dimethylamino, methyl, ethyl, isopropyl, trifluoromethyl, difluoroethoxy, methoxy, or trifluoromethoxy; When X2 is selected from O, R2 or R3 exists in general formula I; R4 and R5 may be the same or different and selected from hydrogen, deuterium, fluorine, methyl, unsubstituted, or by at least one R. f Substituted phenyl, pyridyl, or pyrimidinyl, wherein R f Derived from hydrogen, fluorine, hydroxyl, amino, dimethylamino, methyl, ethyl, trifluoromethyl, difluoroethoxy, methoxy, or trifluoromethoxy.

5. The indazole derivative according to claim 4, characterized in that, The derivative is a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug. 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)ethyl acetate; 2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Ethyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(4-Fluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(4-Chlorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(p-tolyl)acetamide; N-(4-methoxyphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(4-(trifluoromethyl)phenyl)acetamide; N-(3-Fluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Chlorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(m-tolyl)acetamide; N-(3-methoxyphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(3-(trifluoromethyl)phenyl)acetamide; N-(3,5-Difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3,4-Difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(3,4,5-trifluorophenyl)acetamide; N-Ethyl-N-(3-fluorophenyl)-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Fluorophenyl)-N-isopropyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Fluorophenyl)-N-methyl-2-((3-(phenylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Fluorophenyl)-N-methyl-2-((3-((4-(morpholinomethyl)phenyl)ethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Fluorophenyl)-N-methyl-2-((3-(pyridin-2-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Fluorophenyl)-N-methyl-2-((3-(pyrimidin-5-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-Fluorophenyl)-N-methyl-2-((3-(((2-morpholinidin-5-yl)ethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3,5-Difluorophenyl)-N-ethyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(2,4-Difluorophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Ethyl-2-((3-((4-(morpholinomethyl)phenyl)ethynyl)-1H-indazol-6-yl)thio)-N-phenylacetamide; N-Isopropyl-N-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-fluoro-5-methylphenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-Methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)-N-(4-(trifluoromethoxy)phenyl)acetamide; N-ethyl-N-(4-methoxyphenyl)-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thioacetamide; (3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)glycine ethyl ester; N-(4-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-aminophenyl)-N-methyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)thio)acetamide; (E)-N-(3-fluorophenyl)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide; (E)-N-methyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide; (E)-N-methyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide; (E)-N-ethyl-N-phenyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)acetamide; N-Ethyl-2-phenyl-2-((3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)thio)acetamide; N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Methyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Ethyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Chloro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Bromo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 3-Bromo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)-3-(trifluoromethyl)benzenesulfonamide; 4-Methoxy-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Hydroxy-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-(isopropyl)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Iodo-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 3-Methyl-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 3-Fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 3-Fluoro-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)-4-(trifluoromethyl)benzenesulfonamide; 4-(dimethylamino)-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Amino-N-(3-(pyrimidin-5-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; 4-Amino-N-(3-((2-(1,4-oxazacyclohexyl-4-yl)pyrimidin-5-yl)ethynyl)-1H-indazole-6-yl)benzenesulfonamide; 4-Amino-N-(3-((6-(1,4-oxazacyclohexyl-4-yl)pyridin-3-yl)ethynyl)-1H-indazole-6-yl)benzenesulfonamide; 3-Amino-N-(3-(pyridin-3-ylethynyl)-1H-indazol-6-yl)benzenesulfonamide; (E)-4-amino-N-(3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-yl)benzenesulfonamide.

6. The use of the indazole derivative according to any one of claims 1-5, characterized in that: The use of the compounds represented by general formula I or general formula II, their geometric isomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof in the preparation of medicaments for the prevention or treatment of diseases related to the expression or activity of PLK4 kinase.

7. The use of the indazole derivative according to any one of claims 1-5, characterized in that: The use of the compounds represented by general formula I or general formula II, their geometric isomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof in the preparation of medicaments for the prevention or treatment of tumors associated with the expression or activity of PLK4 kinase.

8. A pharmaceutical composition, characterized in that: The active ingredient comprises a compound of general formula I or general formula II of any one of claims 1-5, or a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug as a pharmaceutically acceptable excipient.

9. The use of the pharmaceutical composition according to claim 8, characterized in that: The composition is used in the preparation of medicaments for the prevention or treatment of diseases related to the expression or activity of PLK4 kinase.

10. The use of the pharmaceutical composition according to claim 8, characterized in that: The composition is used in the preparation of medicaments for the prevention or treatment of tumors associated with the expression or activity of PLK4 kinase.

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