N-(3-fluorobenzyl)-1h-indazole-5-amine derivative and use thereof

Abstract

The present invention belongs to the field of medicinal chemistry, and particularly relates to an N-(3-fluorobenzyl)-1H-indazole-5-amine derivative having a structure as shown in general formula (I), and the preparation and the use thereof. The N-(3-fluorobenzyl)-1H-indazole-5-amine derivative having a structure as shown in general formula (I), and a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof provided in the present invention have an activity as a protein kinase inhibitor, particularly an inhibitory activity against tropomyosin receptor kinase (TRK).

Description

N-(3-fluorobenzyl)-1H-indazol-5-amine derivatives and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims the benefit of Chinese Application No. 2024106059089, filed May 15, 2024. The application number 2024106059089 is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present invention belongs to the field of medicinal chemistry, in particular to a kind of N-(3-fluorobenzyl)-1H-indazol-5-amine derivatives and uses. BACKGROUND

[0004] NTRK is a gene that encodes TRK proteins, with three homologues, NTRK1, NTRK2 and NTRK3. These three genes encode three proteins of the TRK receptor family: TRKA, TRKB and TRKC. TRK, the full name of which is tropomyosin receptor kinase, is a transmembrane protein. TRKA, TRKB and TRKC are highly homologous in structure, all of which have an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. The extracellular domain contains three leucine-rich 24-repeat sequences (LRR1-3), two cysteine-rich clusters (C1 and C2) and two immunoglobulin-like domains (Ig1 and Ig2). The LRR1-3 motif is specific to TRK proteins and is not found in other receptor tyrosine kinases. TRK receptors are activated by four protein families known as neurotrophins. Neurotrophins were originally thought to be survival molecules for sensory and sympathetic neurons, but are now known to play many roles in the development and function of the nervous system. The four neurotrophins are all specific for a particular TRK and bind to it with high affinity. Nerve growth factor (NGF) binds to TRKA, brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) bind to TRKB, and neurotrophin 3 (NT-3) binds to TRKC. NT-3 can bind to all three TRK receptors, but has the highest affinity for TRKC and is its only ligand. After binding to the endogenous ligand, TRK leads to dimerization and autophosphorylation of intracellular tyrosine residues. Autophosphorylation of three amino acids located in the activation loop of the kinase domain is necessary for full activation of the kinase. Two tyrosines located on either side of the kinase domain, which can serve as binding sites for adaptor proteins such as SHC1, PLCy, GAB1, Dok5 and Dok6 after phosphorylation. These adaptor proteins activate downstream signaling pathways such as SHC / RAS / MAPK, PI3K / AKT and PLC-y / PKC, which control cell cycle progression, proliferation, apoptosis and survival. The TRK pathway is involved in the pathogenesis of many cancer types. Chromosomal rearrangements leading to oncogenic fusions, protein overexpression and single nucleotide variations are the most common changes associated with the NTRK family. They have been found in colorectal cancer, lung cancer, large cell neuroendocrine carcinoma and non-small cell lung cancer (NSCLC), melanoma, acute myeloid leukemia breast cancer, skin cancer (such as basal cell carcinoma) and lung cancer, neuroblastoma, cylindroma and other tumors. NTRK gene fusions have the highest probability of being oncogenic. In NTRK gene fusions, the 3' end of the NTRK gene is combined with the 5' end of a partner gene through intrachromosomal or interchromosomal rearrangement. The resulting fusion gene encodes a protein that contains the N-terminal of the fusion partner connected to the C-terminal of the TRK protein. The C-terminal of the TRK protein includes the catalytic tyrosine kinase domain.The 5' partner gene sequence of most NTRK gene fusions can encode one or more dimerization domains. These domains mediate the corresponding tyrosine kinase activity, thereby conferring ligand-independent oncogenic potential by uninterrupted downstream signaling, promoting cell proliferation and survival. Studies have shown that inhibiting the kinase catalytic action of TRK can treat cancer patients carrying NTRK gene fusions. The first generation of TRK inhibitors represented by larotrectinib and entrectinib, for example, can show strong efficacy for NTRK gene fusion patients regardless of cancer type. Although these first-generation TRK inhibitors have achieved clinical success, their effectiveness is limited due to the inevitable emergence of acquired resistance.

[0005] Therefore, it is necessary to design new TRK inhibitors to maintain efficacy against drug-resistant mutations. SUMMARY

[0006] The purpose of the present application is to provide a new N-(3-fluorobenzyl)-1H-indazole-5-amine derivative and its use in the preparation of therapeutic agents, particularly TRK inhibitors.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0008] In a first aspect, the present application provides an N-(3-fluorobenzyl)-1H-indazole-5-amine derivative, which is a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof;

[0009] wherein R1 is selected from -CONH-R a , cyano or

[0010] R a is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl or C1-C6 alkoxy; X, Y, Z are selected from C or N, wherein when the X atom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by R b ; R b is selected from H, halogen or C1-C6 haloalkyl;

[0011] R2 is selected from C1-C6 alkoxy, C1-C6 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkyl-substituted phosphonyl or C1-C6 alkyl-substituted sulfonyl;

[0012] R3 is selected from H or C1-C6 alkyl;

[0013] Preferably, the N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative is a 3- fluorobenzylamine substituted indazole compound having the general structure of Formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof;

[0014] wherein R1is selected from -CONH-R a or

[0015] R a is selected from H, methyl, haloethyl, halocyclopentyl or hydroxycyclopentyl; X, Y, Z are selected from C or N, wherein, when the X atom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by R b is selected from H, halogen or halomethyl; b

[0016] R2is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, halomethoxy, haloethoxy, dimethylphosphato or methylsulfonyl;

[0017] R3is selected from H or methyl;

[0018] Preferably, the N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative is a 3- fluorobenzylamine substituted indazole compound having the general structure of Formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof;

[0019] wherein R1is selected from -CONH-R a or

[0020] R a is selected from H, methyl, 2,2-difluoroethyl, 3,3-difluoropyrrolidin-1-yl or hydroxycyclopentyl; X, Y, Z are selected from C or N, wherein, when the X atom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by R b is selected from H, halogen or halomethyl; b

[0021] R2is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, 2,2-difluoromethoxy, 2,2-difluoroethoxy, dimethylphosphato or methylsulfonyl;

[0022] R3is selected from H or methyl;

[0023] ​​Still further preferred, the N-(3-fluorobenzyl)-1H-indazole-5-amine derivative is a 3-fluorobenzylamine substituted indazole compound having the structure of Formula (I), or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;

[0024] wherein R1is selected from -CONH-R a 、

[0025] R a is selected from H, methyl, 2,2-difluoroethyl, 3,3-difluoropyrrolidin-1-yl or hydroxycyclopentyl; R b is selected from H, fluorine or trifluoromethyl;

[0026] R2is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, 2,2-difluoromethoxy, 2,2-difluoroethoxy, dimethylphosphato or methylsulfonyl;

[0027] R3is selected from H or methyl;

[0028] More preferred, the N-(3-fluorobenzyl)-1H-indazole-5-amine derivative is a compound represented by the following structures, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:

[0029] N-(5-fluoro-2-methoxybenzyl)-3-(1H-pyrazol-1-yl)-1H-indazole-5-amine

[0030] 3-(4-fluoro-1H-pyrazol-1-yl)-N-(5-fluoro-2-methoxybenzyl)-1H-indazole-5-amine

[0031] N-(5-fluoro-2-methoxybenzyl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-indazole-5-amine

[0032] N-(5-fluoro-2-methoxybenzyl)-3-(4-(trifluoromethyl)-1H-imidazol-1-yl)-1H-indazole-5-amine

[0033] 5-((5-fluoro-2-methoxybenzyl)amino)-N-hydroxy-1H-indazole-3-carboxamide

[0034] 6-((5-fluoro-2-methoxybenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0035] N-cyclopropyl-5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazole-3-carboxamide

[0036] N-(2,2-difluoroethyl)-5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazole-3-carboxamide

[0037] (3,3-difluoropyrrolidin-1-yl)(5-((5-fluoro-2-methoxybenzyl(amino)-1H-indazol-3-yl)methanone

[0038] (5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazol-3-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0039] 5-((2-(dimethylphosphoryl)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0040] 5-((5-fluoro-2-isopropoxybenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0041] 5-((5-fluoro-2-((tetrahydrofuran-3-yl)oxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0042] 5-((5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0043] 5-((5-fluoro-2-(2-hydroxyethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0044] 5-((2-(difluoromethoxy)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0045] 5-((5-fluoro-2-(2-fluoroethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0046] 5-((2-(2,2-difluoroethoxy)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0047] 5-((5-fluoro-2-(2,2,2-trifluoroethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0048] 5-((5-fluoro-2-(methylsulfonyl)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0049] N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(1H-1,2,4-triazol-1-yl)-1H-indazol-5-amine

[0050] N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(1H-1,2,3-triazol-1-yl)-1H-indazol-5- amine

[0051] (S)-N-(1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethyl)-3-(1H-1,2,4-triazol-1-yl)-1H- indazol-5-amine

[0052] (R)-N-(1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethyl)-3-(1H-1,2,4-triazol-1-yl)-1H- indazol-5-amine.

[0053] The following first explains some terms involved in the present application:

[0054] Halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl: straight chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl or t-butyl. Cycloalkyl: substituted or unsubstituted cyclic alkyl, such as cyclopropyl, cyclopentyl or cyclohexyl. Substituents such as methyl, halogen, etc. Haloalkyl: straight chain or branched alkyl, the hydrogen atoms on these alkyl groups can be partially or completely replaced by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc. Alkoxy: straight chain or branched alkyl, the hydrogen atoms of the hydroxyl group can be replaced by these straight chain or branched alkyl, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, etc. Haloalkoxy: straight chain or branched alkyl, the hydrogen atoms of the hydroxyl group can be replaced by these straight chain or branched alkyl, the hydrogen atoms on these alkyl groups can be partially or completely replaced by halogen atoms, such as difluoromethyloxy, difluoroethyloxy, trifluoroethyloxy, etc.

[0055] In the second aspect, the present application provides a preparation method of the N-(3- fluorobenzyl)-1H-indazol-5-amine derivative represented by the general formula (I) or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug described in the first aspect above:

[0056] (1) When the target derivative has a structure as shown in general formula 7 or a similar structure, it is prepared according to the method shown in route 1, that is, 6-nitroindazole is used as the starting material, radical substitution with NIS to obtain intermediate 2, THP protection is performed on 2 to obtain intermediate 3, different substituted azoles of intermediate 3 are subjected to Ullmann coupling reaction to obtain intermediate 4, intermediate 4 is reduced to obtain intermediate 5, intermediate 5 is subjected to reductive amination with different substituted 5-fluorobenzaldehyde to obtain intermediate 6, and intermediate 6 is subjected to acid deprotection to obtain the target compound 7;

[0057] R in the above preparation process flow 1selected from methoxy, 2,2-difluoroethoxy, X, Y, Z are selected from C or N.

[0058] Further, 6-nitroindazole is used as the starting material, and a radical substitution reaction with NIS is carried out under high temperature to obtain intermediate 2, the reaction temperature is 30-90°C, preferably 60°C, and the reaction solvent can be acetonitrile, DMA, DMF, DMF, preferably DMF; intermediate 2 is reacted with DHP under low-temperature acidic conditions to obtain intermediate 3, the reaction solvent can be acetonitrile, tetrahydrofuran, dichloromethane, preferably dichloromethane, the reaction temperature is 0-30°C, preferably 30°C, and the acid in the reaction can be acetic acid, trifluoroacetic acid, 4N HCl / 1,4-dioxane, etc., methanesulfonic acid, p-toluenesulfonic acid, preferably p-toluenesulfonic acid; intermediate 3 is subjected to an Ullmann coupling reaction to obtain the final product 4, the base can be cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, etc., preferably cesium carbonate, the reaction temperature is 80-120°C, preferably 110°C, the reaction solvent can be DMSO, DMF, acetonitrile, tert-butanol, sec-butanol, etc., preferably acetonitrile, and the catalyst can be cuprous oxide, cuprous iodide, preferably cuprous oxide; the starting material 4 is subjected to a reduction reaction to obtain intermediate 5, the reduction conditions can be Fe / NH4Cl, H2 and Pd / C, hydrazine hydrate, etc., preferably Fe / NH4Cl, the reaction solvent can be methanol, ethanol, acetonitrile, etc., preferably ethanol, and the reaction temperature is 50-120°C, preferably 80°C; intermediate 5 is subjected to a reductive amination reaction with the corresponding aromatic aldehyde under low-temperature conditions to obtain intermediate 6, the low-temperature reaction temperature is 0-30°C, preferably 30°C, and the reaction solvent can be acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably methanol, and the reduction conditions can be sodium borohydride, sodium cyanoborohydride, H2 and Pd / C, preferably sodium cyanoborohydride; intermediate 6 is subjected to acid deprotection to obtain the final product 7, the acid can be trifluoroacetic acid, 4N HCl / EA, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably 4N HCl / EA, and the reaction temperature is 0-30°C, preferably 30°C.

[0059] (2) When the target derivative has a structure as shown in general formula 15 or 18 or a similar structure, it is prepared according to the method shown in route 2, i.e., starting from 3-carboxyindazole 2, nitration occurs under acidic conditions to obtain intermediate 9, esterification of intermediate 9 with thionyl chloride in methanol obtains intermediate 10, THP protection of intermediate 10 obtains intermediate 11, hydrogenation reduction of intermediate 11 obtains intermediate 12, reductive amination of intermediate 12 with 5-fluoro-2-methoxybenzaldehyde obtains intermediate 13, reaction of intermediate 13 with aqueous hydroxylamine solution obtains intermediate 14, acid deprotection of intermediate 14 obtains target compound 15; hydrolysis of intermediate 13 under basic conditions obtains intermediate 16, condensation of intermediate 16 with different amines obtains intermediate 17; deprotection of intermediate 17 under acidic conditions obtains target compound 18;

[0060] R in the above preparation process flow 1 is selected from H, methyl, 2,2-difluoroethyl, 3,3-difluoropyrrolidin-1-yl, hydroxycyclopentyl.

[0061] Further, 3-carboxyindazole is used as the starting material, nitration reaction is carried out at low temperature to obtain intermediate 9, the reaction temperature is 0-30°C, preferably 30°C; esterification reaction of intermediate 9 with thionyl chloride is carried out at high temperature in methanol to obtain intermediate 10, the reaction temperature is 50-90°C, preferably 65°C; intermediate 10 reacts with DHP under low temperature and acidic conditions to obtain intermediate 11, the reaction solvent can be acetonitrile, tetrahydrofuran, dichloromethane, preferably dichloromethane, the reaction temperature is 0-30°C, preferably 30°C, the acid in the reaction can be acetic acid, trifluoroacetic acid, 4N HCl / 1,4-dioxane, etc., methanesulfonic acid, p-toluenesulfonic acid, preferably p-toluenesulfonic acid; intermediate 11 is subjected to reduction reaction to obtain intermediate 12, the reduction conditions can be Fe / NH4Cl, H2 and Pd / C, H2 and Raney-Ni, hydrazine hydrate, etc., preferably H2 and Raney-Ni, the reaction solvent can be methanol, ethanol, acetonitrile, etc., preferably methanol, the reaction temperature is 0-50°C, preferably 30°C; intermediate 12 is subjected to reductive amination reaction with the corresponding aromatic aldehyde under low temperature conditions to obtain intermediate 13, the low temperature reaction temperature is 0-30°C, preferably 30°C, the reaction solvent can be acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably methanol, the reduction condition can be sodium borohydride, sodium cyanoborohydride, H2 and Pd / C, preferably sodium cyanoborohydride; intermediate 13 reacts with aqueous hydroxylamine under alkaline conditions to obtain intermediate 14, the base can be NaOH, KOH, LiOH, etc., preferably NaOH; intermediate 14 is subjected to acid deprotection to obtain the final product 7, the acid can be trifluoroacetic acid, 4N HCl / EA, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably 4N HCl / EA, the reaction temperature is 0-30°C, preferably 30°C; intermediate 13 is subjected to hydrolysis under alkaline conditions to obtain intermediate 16, the base can be NaOH, KOH, LiOH, etc., preferably LiOH; the reaction solvent can be acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably 1,4-dioxane, the reaction temperature is 30-80°C, preferably 45°C; intermediate 16 is subjected to condensation reaction with different amines to obtain intermediate 17, the condensing agent used in the reaction can be thionyl chloride, oxalyl chloride, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluron hexafluorophosphate, O-benzotriazol-tetramethyluron hexafluorophosphate, dicyclohexyl carbodiimide, 1-hydroxybenzotriazole, (1-ethyl-3(3-dimethylpropylamine) carbodiimide), etc., preferably 1-hydroxybenzotriazole and (1-ethyl-3(3-dimethylpropylamine) carbodiimide), the base in the reaction can be cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropyl ethylamine, etc., preferably N,N-diisopropyl ethylamine;The intermediate 17 is deprotected under acidic conditions to obtain the target compound 18, the acid can be trifluoroacetic acid, 4N HCl / EA, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably 4N HCl / EA, the reaction temperature is 0-30°C, preferably 30°C.

[0062] (3) when the target derivative has the structure as shown in general formula 24 or 26 or similar structure, it is prepared according to the method shown in route 3, i.e. the intermediate 9 is protected by THP to obtain the intermediate 19, the intermediate 19 is condensed with methylamine hydrochloride to obtain the intermediate 20, the intermediate 20 is subjected to reduction to obtain the intermediate 21, the intermediate 21 is subjected to reductive amination with 5-fluoro-2-iodobenzaldehyde to obtain the intermediate 22, the intermediate 22 is coupled with dimethyl phosphine oxide to obtain the intermediate 23, and the intermediate 23 is deprotected by acid to obtain the target compound 24; the intermediate 21 is subjected to reductive amination with 5-fluorobenzaldehyde with different substitution to obtain the intermediate 25, and the intermediate 25 is deprotected by acid to obtain the target compound 24;

[0063] R in the above preparation process flow 4 is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, 2,2-difluoromethoxy, 2,2-difluoroethoxy, dimethyl phosphoric acid group, methylsulfonyl.

[0064] Further, intermediate 9 reacts with DHP under acidic condition at low temperature to obtain intermediate 19, the reaction solvent can be acetonitrile, tetrahydrofuran, dichloromethane, preferably dichloromethane, the reaction temperature is 0-30°C, preferably 30°C, the acid in the reaction can be acetic acid, trifluoroacetic acid, 4N HCl / 1,4-dioxane, etc., methanesulfonic acid, p-toluenesulfonic acid, preferably p-toluenesulfonic acid; intermediate 19 condenses with methylamine hydrochloride to obtain intermediate 20, the condensing agent used in the reaction can be thionyl chloride, oxalyl chloride, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazol-tetramethyluronium hexafluorophosphate, dicyclohexyl carbodiimide, 1-hydroxybenzotriazole, (1-ethyl-3(3-dimethylpropylamine) carbodiimide), etc., preferably 1-hydroxybenzotriazole and (1-ethyl-3(3-dimethylpropylamine) carbodiimide), the base in the reaction can be cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropyl ethylamine, etc., preferably N,N-diisopropyl ethylamine; intermediate 20 is reduced by hydrazine hydrate to obtain intermediate 21, intermediate 21 undergoes reductive amination with 5-fluoro-2-iodobenzaldehyde to obtain intermediate 22, the low-temperature reaction temperature is 0-30°C, preferably 30°C, the reaction solvent can be acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably methanol, the reduction condition can be sodium borohydride, sodium cyanoborohydride, H2 and Pd / C, preferably sodium cyanoborohydride; intermediate 22 is coupled with dimethyl phosphine oxide to obtain intermediate 23, the base can be potassium phosphate, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, etc., preferably potassium phosphate, the reaction temperature is 80-120°C, preferably 100°C, the reaction solvent can be DMSO, DMF, acetonitrile, tert-butanol, sec-butanol, 1,4-dioxane, etc., preferably 1,4-dioxane, the catalyst can be Pd(OAc)2, Pd2(dba)3, preferably Pd(OAc)2; intermediate 23 is deprotected under acidic condition to obtain target compound 24, the acid can be trifluoroacetic acid, 4N HCl / EA, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably 4N HCl / EA, the reaction temperature is 0-30°C, preferably 30°C; intermediate 21 undergoes reductive amination with the corresponding aromatic aldehyde under low-temperature condition to obtain intermediate 25, the low-temperature reaction temperature is 0-30°C, preferably 30°C, the reaction solvent can be acetonitrile, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably methanol, the reduction condition can be sodium borohydride, sodium cyanoborohydride, H2 and Pd / C, preferably sodium cyanoborohydride; intermediate 25 is deprotected under acidic condition to obtain target compound 26, the acid can be trifluoroacetic acid, 4N HCl / EA, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably 4N HCl / EA, the reaction temperature is 0-30°C, preferably 30°C.

[0065] (4) When the target derivative has a structure as shown in general formula 34 or a similar structure, it is prepared according to the method shown in route 4, that is, 4-bromo-3-nitrotoluene is used as the starting material 27, 27 is subjected to bromination with NBS to obtain the intermediate 28, the intermediate 28 is subjected to substitution reaction with different azoles under alkaline conditions to obtain the intermediate 29, the intermediate 29 is subjected to reduction reaction to obtain the intermediate 30, the intermediate 30 is subjected to cyclization reaction under acidic conditions to obtain the intermediate 31, the intermediate 31 is subjected to substitution reaction with chloromethyltriphenylphosphonium under alkaline conditions to obtain the intermediate 32, the intermediate 32 is subjected to Buchwald coupling reaction with different amines to obtain the intermediate 33, and the intermediate 33 is subjected to acid deprotection to obtain the target compound 34;

[0066] R in the above preparation process flow 3 is selected from H, methyl; X, Y, Z are selected from C or N.

[0067] (5) Further, 4-bromo-3-nitrotoluene 27 was used as the starting material, 27 was subjected to bromination with NBS to obtain intermediate 28, the reaction temperature was 60-120 °C, preferably 110 °C, the reaction solvent could be acetonitrile, chloroform, carbon tetrachloride, preferably acetonitrile; intermediate 28 was subjected to substitution reaction with different azoles under basic conditions to obtain intermediate 29, the base could be potassium phosphate, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, preferably cesium carbonate, the reaction temperature was 0-100 °C, preferably 30 °C, the reaction solvent could be DMSO, DMF, acetonitrile, tert-butanol, sec-butanol, 1,4-dioxane, preferably DMF; intermediate 29 was subjected to reduction to obtain intermediate 30, the reduction conditions could be Fe / NH4Cl, H2 and Pd / C, hydrazine hydrate, preferably Fe / NH4Cl, the reaction solvent could be methanol, ethanol, acetonitrile, preferably ethanol, the reaction temperature was 50-120 °C, preferably 80 °C; intermediate 30 was subjected to cyclization under acidic conditions to obtain intermediate 31, the acid in the reaction could be acetic acid, trifluoroacetic acid, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably acetic acid; intermediate 31 was subjected to substitution reaction with chloromethyltriphenylphosphonium under basic conditions to obtain intermediate 32, the base could be potassium phosphate, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, preferably cesium carbonate, the reaction temperature was 0-100 °C, preferably 30 °C, the reaction solvent could be DMSO, DMF, acetonitrile, tert-butanol, sec-butanol, 1,4-dioxane, preferably DMF; intermediate 32 was subjected to Buchwald coupling reaction with different amines to obtain intermediate 33, the base could be potassium phosphate, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, preferably sodium tert-butoxide, the reaction temperature was 30-90 °C, preferably 60 °C, the reaction solvent could be DMSO, DMF, acetonitrile, tetrahydrofuran, tert-butanol, sec-butanol, 1,4-dioxane, preferably tetrahydrofuran, the catalyst could be Pd(OAc)2, Pd2(dba)3, tBuXphos-Pd-G3, Ruphos-Pd-G1, preferably tBuXphos-Pd-G3; intermediate 33 was subjected to acid deprotection to obtain the target compound 34, the acid could be trifluoroacetic acid, 4N HCl / EA, 4N HCl / 1,4-dioxane, methanesulfonic acid, p-toluenesulfonic acid, preferably trifluoroacetic acid, the reaction temperature was 0-30 °C, preferably 30 °C.

[0068] In a third aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the N-(3-fluorobenzyl)-1H-indazole-5-amine derivative of the first aspect described above, which is a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0069] In a fourth aspect, the present application provides use of the N-(3-fluorobenzyl)-1H-indazol-5-amine derivative of the first aspect above, or the pharmaceutical composition of the third aspect above, in the manufacture of a medicament for preventing or treating a disease associated with the expression or activity of TRK kinase, wherein the derivative is a 3-fluorobenzylamine-substituted indazole compound having the general structure of Formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof.

[0070] Optionally, in the above use, the medicament is for preventing or treating a tumor, a cancer or severe pain caused by different reasons.

[0071] In a fifth aspect, the present application provides use of the N-(3-fluorobenzyl)-1H-indazol-5-amine derivative of the first aspect above, or the pharmaceutical composition of the third aspect above, in the manufacture of a medicament for preventing or treating a tumor, wherein the derivative is a 3-fluorobenzylamine-substituted indazole compound having the general structure of Formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof.

[0072] Optionally, in the above use, the tumor is selected from one or more of the following: non-small cell lung cancer, melanoma, glioblastoma, astrocytoma and other tumors carrying NTRK gene fusion.

[0073] The present application has the following advantages over the prior art:

[0074] The present application focuses on NTRK gene fusion tumors, and a series of novel N-(3-fluorobenzyl)-1H-indazol-5-amine derivatives are designed, and it is found that compounds having such a structure exhibit good inhibitory activity on wild-type and various mutant TRK kinases, and can be used to treat tumors caused by NTRK gene fusion, overcome drug resistance caused by TRK mutations in the clinic, or other diseases associated with abnormal TRK expression. DETAILED DESCRIPTION

[0075] The present application will be further described below with reference to specific examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the scope of the present application. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-600; the reagents used are all analytical pure or chemical pure.

[0076] If a specific technique or condition is not specified in the examples, it is performed according to the technique or condition described in the literature in the art, or according to the product instructions. If the manufacturer of the reagent or instrument is not specified, it is a conventional product that can be purchased through a regular channel.

[0077] The experimental methods in the following examples are all conventional methods unless otherwise specified. The experimental materials used in the following examples are all commercially available unless otherwise specified.

[0078] The preparation route of Example 1 is shown as follows:

[0079] The specific synthesis steps are as follows:

[0080] Synthesis of 3-iodo-5-nitro-lH-indazole (2)

[0081] Dissolve 5-nitro-lH-indazole (2.0 g, 12.3 mmol) in 20 mL of DMF, slowly add NIS (3.0 mL, 13.5 mmol) under stirring. Warm the reaction solution to 60°C, stir for 9 hours. Monitor the reaction completion by TLC, cool the reaction mixture to room temperature and pour into 200 mL of water, precipitate brown solid. Filter and dry the solid to obtain 3.4 g of intermediate 2, with a yield of 95.8%.

[0082] Synthesis of 3-iodo-5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (3)

[0083] Dissolve 2 (2.0 g, 6.92 mmol) and p-TSA (120 mg, 0.69 mmol) in 20 mL of DCM solution, slowly drop DHP (1.7 g, 20.76 mmol) into it at 0°C. After the dropwise addition is completed, stir at room temperature for 4 hours. Monitor the reaction completion by TLC, dilute the reaction solution with 100 mL of DCM and wash twice with saturated aqueous sodium chloride solution (60 mL x 2). Collect the organic phase, remove the solvent by rotary evaporation. Add 20 mL of cyclohexane and stir at room temperature for 2 hours, precipitate solid. Filter and dry to obtain 1.98 g of yellow intermediate 3, with a yield of 76.8%.

[0084] Synthesis of 5-nitro-3-(lH-pyrazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (4)

[0085] Intermediate 3 (0.6 g, 1.6 mmol), pyrazole (0.13 g, 2.0 mmol), salicylhydroxamic acid (0.04 g, 0.32 mmol eq) and CS2CO3 (1.3 g, 4.0 mmol) were sequentially placed in a 120 mL sealed tube with 20 mL of anhydrous acetonitrile as solvent. After argon gas was bubbled through, Cu2O (0.024 g, 0.16 mmol) was added. The reaction was heated to 120 °C and stirred for 12 h. After cooling to room temperature, TLC monitoring showed that the starting material was almost consumed. The reaction was poured into 60 mL of saturated aqueous NaCl solution and extracted with EtOAc (60 mL x 3). The organic layer was collected and the solvent was removed. Purification by column chromatography (5% EtOAc / PE) gave 0.15 g of yellow solid 4 with a yield of 30.5%.

[0086] Synthesis of 3-(1H-pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (5)

[0087] Intermediate 4 (0.15 g, 0.48 mmol) was dissolved in 18 mL of EtOH / NH2NH2-H2O = 8:1 (volume ratio) mixed solvent. 15.0 mg of Pd / C was added with stirring. The reaction was heated to 60 °C and stirred for 3 h. TLC monitoring showed that the starting material was consumed. The reaction was cooled to room temperature, filtered to remove Pd / C, and the filtrate was concentrated. The reaction was diluted with 50 mL of EtOAc, washed with water (30 mL x 2), and saturated aqueous NaCl (30 mL x 2). The organic phase was collected and the solvent was removed to give 0.12 g of red solid 5 with a yield of 89.5%.

[0088] Synthesis of N-(5-fluoro-2-methoxybenzyl)-3-(1H-pyrazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (6)

[0089] Intermediate 5 (0.1 g, 0.35 mmol) was dissolved in 10 mL of MeOH. 100 μL of AcOH and 5-fluoro-2-methoxybenzaldehyde (0.06 g, 0.39 mmol) were sequentially added at 0 °C. The reaction was stirred at room temperature for 1 h, and yellow solid precipitated. (42 μL, 0.7 mmol) and NaBH3CN (22.0 mg, 0.35 mmol) were added to the reaction. The stirring was continued at room temperature for 1 h. TLC monitoring showed that the starting material was consumed. The reaction was quenched by adding 1 mL of saturated aqueous NH4Cl. The solvent was removed, and the reaction was diluted with 50 mL of EtOAc and washed with saturated aqueous Na2CO3 (30 mL x 2). The organic phase was collected and the solvent was removed to give 0.07 g of yellow solid 6 with a yield of 48.5%.

[0090] N-(5-fluoro-2-methoxybenzyl)-3-(1 H-pyrazol-1 -yl)-1 H-indazol-5-amine

[0091] To intermediate 6 (0.07 g, 0.17 mmol) was added 10 mL of 4N HCI / EA. The reaction was stirred at room temperature for 4 hours. TLC monitoring showed the reaction was complete. The solvent was removed, and 30 mL of H2O was added. The aqueous solution was cooled to 0 °C, and the pH was adjusted to 9-10 with 1 N NaOH (aq). The mixture was extracted with EtOAc three times (30 mL x 5), and the organic phase was collected and the solvent was removed. Purification by column chromatography (2% MeOH / CH2Cl2) gave 0.03 g of Example 1 as a white solid in 52.9% yield. 1 H NMR (600 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 9.1, 2.5 Hz, 1H), 7.05 - 6.95 (m, 4H), 6.52 (t, J = 2.1 Hz, 1H), 6.11 (t, J = 6.2 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 156.90 (d, J = 234.3 Hz), 153.70, 143.88, 141.11, 140.79, 136.70, 130.35 (d, J = 6.5 Hz), 128.28, 119.68, 114.97, 114.88 (d, J = 24.7 Hz), 113.90 (d, J = 22.3 Hz), 112.21 (d, J = 7.9 Hz), 111.60, 107.14, 97.78, 56.46, 41.71. HRMS (ESI, m / z) calcd for C 18 H 16 FN5O[M+Na] + ,360.1237; found 360.1245.

[0092] 3-(4-fluoro-1 H-pyrazol-1 -yl)-N-(5-fluoro-2-methoxybenzyl)-1 H-indazol-5-amine

[0093] Following the procedure for the preparation of Example 1, the pyrazole starting material in step c was replaced with 4-fluoro-1 H-pyrazole in equal proportion to give Example 2. 1H NMR (600 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.44 (dd, J = 4.6, 0.9 Hz, 1H), 7.88 - 7.85 (m, 1H), 7.35 - 7.31 (m, 1H), 7.10 (dd, J = 9.2, 2.8 Hz, 1H), 7.03 - 6.97 (m, 4H), 6.15 (t, J = 6.2 Hz, 1H), 4.24 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 156.90 (d, J = 235.3 Hz), 153.71, 150.51 (d, J = 244.6 Hz), 144.06, 140.48, 136.73, 130.28 (d, J = 6.6 Hz), 128.56, 128.46, 119.80, 114.89 (d, J = 22.2 Hz), 114.79, 113.93 (d, J = 22.2 Hz), 112.20 (d, J = 8.7 Hz), 111.72, 97.36, 56.46, 41.64. HRMS (ESI, m / z) calcd for C 18 H 15 F2N5O [M+H] + , 356.1213; found 356.1329.

[0094] N-(5-Fluoro-2-methoxybenzyl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-indazol-5- amine

[0095] Reference to the method of Preparation Example 1, the pyrazole raw material in step c is replaced with 4-(trifluoromethyl)-1H-pyrazole in equal proportion, to obtain Example 3. 1 H NMR (600 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.44 (dd, J = 4.6, 0.9 Hz, 1H), 7.88 - 7.85 (m, 1H), 7.35 - 7.31 (m, 1H), 7.10 (dd, J = 9.2, 2.8 Hz, 1H), 7.03 - 6.97 (m, 4H), 6.15 (t, J = 6.2 Hz, 1H), 4.24 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 156.88 (d, J = 235.5 Hz), 153.73, 139.64, 138.62, 136.74, 130.00, 128.78 (d, J = 4.5 Hz), 124.19, 122.43, 120.07, 115.14, 114.99 (d, J = 23.9 Hz), 114.05 (d, J = 22.9 Hz), 113.52, 113.27, 112.25 (d, J = 8.7 Hz), 111.92, 56.46, 41.76. HRMS (ESI, m / z) calcd for C 19 H 15 F4N5O [M+H] + ,406.1291; found 406.1280.

[0096] N-(5-Fluoro-2-methoxybenzyl)-3-(4-(trifluoromethyl)-1H-imidazol-1-yl)-1H-indazol-5- amine

[0097] Following the procedure of Preparation Example 1, the pyrazole starting material in step c was replaced with 4-(trifluoromethyl)-1H-imidazole in equal proportion to give Example 4. 1 H NMR (600 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.28 (q, J = 1.4 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 9.4, 3.0 Hz, 1H), 7.04 - 6.97 (m, 3H), 6.59 (d, J = 2.0 Hz, 1H), 6.19 (t, J = 6.2 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), 3.80 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 156.88 (d, J = 235.5 Hz), 153.73, 139.64, 138.62, 136.74, 130.00, 128.78 (d, J = 4.5 Hz), 124.19, 122.43, 120.07, 115.14, 114.99 (d, J = 23.9 Hz), 114.05 (d, J = 22.9 Hz), 113.52, 113.27, 112.25 (d, J = 8.7 Hz), 111.92, 56.46, 41.76. HRMS (ESI, m / z) calcd for C 19 H 15 F4N5O [M+H]+ 406.1291; found 406.1282.

[0098] The preparation route of Example 5 is shown below:

[0099] The specific synthesis steps are as follows:

[0100] Synthesis of 5-nitro-lH-indazole-3-carboxylic acid (9)

[0101] Add 12 mL of concentrated H2SO4 to lH-indazole-3-carboxylic acid (1.0 g, 6.17 mmol) at 0 °C, continue to stir the reaction solution at 0 °C for 20 min, and add KNO3 (0.63 g, 6.17 mmol). Stir at room temperature for 4 h. TLC monitoring shows that the reaction is complete. Pour the reaction mixture into 120 mL of water, and a white transparent solid is precipitated. Filter and dry the solid to obtain 2.3 g of white solid 9, with a yield of 87.6%.

[0102] Synthesis of methyl 5-nitro-lH-indazole-3-carboxylate (10)

[0103] Dissolve intermediate 9 (0.5 g, 2.41 mmol) in 10 mL of MeOH, and slowly drop in SOCl2 (350 μL, 4.82 mmol) with stirring. Warm the reaction solution to 65 °C, and stir for 5 h, during which time a solid is precipitated. TLC monitoring shows that the reaction is complete. Cool the reaction solution to room temperature. Filter and rinse with methanol, collect the filter cake, and dry to obtain 0.51 g of white solid 10, with a yield of 95.0%.

[0104] Synthesis of methyl 5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxylate (11)

[0105] Dissolve intermediate 10 (0.5 g, 2.26 mmol) and p-TSA (39 mg, 0.23 mmol) in 20 mL of DCM, and drop in DHP (0.57 g, 6.78 mmol) at 0 °C. After the dropwise addition is complete, stir the reaction solution at room temperature for 4 h. TLC monitoring shows that the reaction is complete. Dilute the solvent with 50 mL of DCM, and wash twice with saturated aqueous NaCl solution (30 mL x 2). Collect the organic phase, and remove the solvent by rotary evaporation. Add 10 mL of cyclohexane, and stir at room temperature for 2 h, during which time a solid is precipitated. Filter and dry the solid to obtain 0.52 g of yellow solid 11, with a yield of 75.3%.

[0106] Synthesis of methyl 5-amino-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxylate (12)

[0107] Intermediate 11 (0.5 g, 1.63 mmol) and NH4CI (0.26 g, 4.91 mmol) were dissolved in 20 mL EtOH / H2O = 9:1 (volume ratio), and iron powder (0.46 g, 8.15 mmol) was added under vigorous stirring. The reaction was heated to 80 °C and stirred for 4 h. TLC monitoring showed that the starting material was consumed. The reaction was cooled to room temperature and filtered through celite. The filtrate was collected and the solvent was removed by rotary evaporation. The residue was diluted with 100 mL EtOAc and washed with water twice (50 mL x 2) and saturated aqueous NaCI solution twice (50 mL x 2). The organic phase was collected and concentrated under reduced pressure to give 0.3 g of orange solid 12 in 66.9% yield.

[0108] Synthesis of methyl 5-((5-fluoro-2-methoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole-3-carboxylate (13)

[0109] Intermediate 12 (0.3 g, 1.09 mmol) was dissolved in 10 mL MeOH and cooled to 0 °C. 5-Fluoro-2-methoxybenzaldehyde (0.19 g, 1.2 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1 h. AcOH (124 μL, 2.19 mmol) and NaBH3CN (0.07 g, 1.09 mmol) were added and stirring was continued at room temperature for 1 h. TLC monitoring showed that the starting material was consumed. The reaction was quenched with 1 mL saturated NH4CI solution. The solvent was removed by rotary evaporation and the residue was taken up in 50 mL EtOAc and washed with saturated Na2CO3 solution (2 x 30 mL). The organic phase was collected and the solvent was removed by rotary evaporation to give 0.4 g of yellow oily liquid 13 in 88.9% yield.

[0110] Synthesis of methyl 5-((5-fluoro-2-methoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole-3-carboxylate (13)

[0111] Intermediate 13 (40 mg, 0.09 mmol) was dissolved in 5 mL MeOH and 1 mL 50% aqueous NH2OH solution and 1 mL 1 N aqueous NaOH solution were added. The reaction was stirred at room temperature for 1 h. TLC monitoring showed that the starting material was consumed. The solvent was removed by rotary evaporation and the residue was taken up in 10 mL H2O and cooled to 0 °C. The pH was adjusted to 6-7 with 1 N HCI solution and a solid precipitated. The solid was filtered and dried to give 36 mg of yellow solid 14 in 92.3% yield.

[0112] 5-((5-Fluoro-2-methoxybenzyl)amino)-N-hydroxy-1H-indazole-3-carboxamide

[0113] To intermediate 14 (36 mg, 0.08 mmol) was added 10 mL of 4N HCI / EtOAc. The reaction was stirred at room temperature for 4 h. TLC monitoring showed the reaction was complete. The solvent was removed, and 30 mL of H20 was added. The aqueous solution was cooled to 0 °C, and the pH was adjusted to 9-10 with 1 N NaOH solution. The organic phase was collected, and the solvent was removed. Purification by column chromatography (2% MeOH / CH2Cl2) gave 12 mg of Example 5 as a yellow-green solid in 42.8% yield. 1 H NMR (600 MHz, DMSO-d6) δ 13.32 (d, J = 5.6 Hz, 1H), 10.85 (s, 1H), 8.83 (s, 1H), 7.36 (d, J = 9.7 Hz, 1H), 7.06 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.97 - 6.93 (m, 2H), 6.22 (s, 1H), 4.24 (s, 2H), 3.87 (d, J = 2.5 Hz, 3H). HRMS (ESI, m / z) calcd for C 16 H 15 FN4O3[M+Na] + , 353.1026; found 353.1023.

[0114] The preparation route of Example 6 is shown below:

[0115] The specific synthesis steps are as follows:

[0116] Synthesis of 5-((5-fluoro-2-methoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole-3-carboxylic acid (16)

[0117] Intermediate 13 (0.30 g, 0.73 mmol) was dissolved in 10 mL of a mixture of 1,4- dioxane / H20 (V 1,4-dioxane :V H2O = 3:1) and LiOH (0.05 g, 2.19 mmol) was added. The reaction was heated to 45 °C and stirred for 4 h. TLC monitoring showed the reaction was complete. The reaction was cooled to 0 °C, and the pH was adjusted to 4-5 with 1 N HCI (aq). The aqueous layer was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected. The organic phase was washed with saturated NaCI (50 mL x 2), and the organic phase was collected. The solvent was removed, and the product was purified by column chromatography (4% methanol / dichloromethane) to give 0.21 g of yellow solid 16 in 72.2% yield.

[0118] Synthesis of 5-((5-fluoro-2-methoxybenzyl)amino)-N-methyl-1 -(tetrahydro- 2H-pyran-2-yl)-1 H-indazole-3-carboxamide (17)

[0119] Methylamine hydrochloride (16 mg, 0.24 mmol) was dissolved in 5 mL of DMF, DIPEA (102 μL, 0.6 mmol) was added. The reaction was stirred at room temperature for 20 min, 16 (0.05 g, 0.12 mmol) and HATU (55 mg, 0.14 mmol) were added. The reaction was stirred at room temperature for 4 hours. TLC monitoring showed the reaction was complete. The reaction mixture was poured into 50 mL of H2O, a solid precipitated, which was filtered and dried to give 45 mg of intermediate 17, yield 92.0%.

[0120] 5-((5-Fluoro-2-methoxybenzyl)amino)-N-methyl-1 H-indazole-3-carboxamide

[0121] 10 mL of 4N HC1 / EtOAc was added to intermediate 17 (45 mg, 0.11 mmol). The reaction was stirred at room temperature for 4 hours. TLC monitoring showed the reaction was complete. The solvent was removed, 30 mL of H2O was added. The aqueous solution was cooled to 0 °C and the pH was adjusted to 9-10 with 1 N NaOH solution. It was extracted with EtOAc three times (30 mL x 5), the organic phase was collected and the solvent was removed. Column chromatography (2% MeOH / CH2Cl2) gave 23 mg of Example 6 as a white solid, yield 63.8%. 1 H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.08 (q, J = 4.7 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.07 - 6.98 (m, 4H), 6.95 (dd, J = 9.0, 2.2 Hz, 1H), 6.14 (t, J = 6.2 Hz, 1H), 4.25 (d, J = 5.3 Hz, 2H), 3.87 (s, 3H), 2.75 (d, J = 4.7 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 163.76, 156.91 (d, J = 235.1 Hz), 153.61, 144.57, 137.08, 136.07, 130.27 (d, J = 6.5 Hz), 123.31, 118.67, 114.49 (d, J = 23.7 Hz), 113.73 (d, J = 23.0 Hz), 112.13 (d, J = 8.0 Hz), 111.57, 98.34, 56.39, 42.00, 25.86. HRMS (ESI, m / z) calcd for C 17 H17 FN4O2[M+Na] + ,351.1233; found 351.1237.

[0122] N-Cyclopropyl-5-((5-Fluoro-2-methoxybenzyl)amino)-1H-Indazole-3-carboxamide

[0123]

[0124] Referring to the method of preparation Example 6, the methylamine hydrochloride raw material in step b was replaced with cyclopropylamine in an equal proportion to obtain Example 7. 1 H NMR (600MHz, DMSO-d6) δ13.14(s,1H),8.12(d,J=4.4Hz,1H),7.35(d,J=8.9Hz,1H),7.06–7.00(m,4H),6.95(dd,J=9.0,2.2Hz,1H),6.15(t, J=6.1Hz,1H),4.25(d,J=6.0Hz,2H),3.87(s,3H),2.80(tt,J=7.3,3.8Hz,1H),0.64(ddt,J=7.3,5.3,2.8Hz,2H),0.60(q,J=3.0,2.1Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ164.48,156.91(d,J=235.3Hz),153.62,144.53,136.92,136.11,130.17,123.34,118.74,114.50(d,J =24.2Hz),113.77(d,J=22.2Hz),112.14(d,J=8.6Hz),111.61,98.39,56.39,42.07,22.75,6.24(s,2C).HRMS(ESI,m / z)calcd for C 19 H 19 FN4O2[M+H] + ,355.1570;found 355.1575;[M+Na] + ,377.1390; found 377.1395.

[0125] N-(2,2-Difluoroethyl)-5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazole-3-carboxamide

[0126] Referring to the method of Preparation Example 1, the methylamine hydrochloride raw material in step b was replaced with 2,2-difluoroethylamine in an equal proportion to obtain Example 8. 1H NMR (600MHz, DMSO-d6) δ13.30(s,1H),8.45(t,J=6.1Hz,1H),7.39(d,J=8.9Hz,1H),7.06–7.00(m,4H),6.97( dd,J=8.9,2.2Hz,1H),6.23–6.00(m,2H),4.28–4.21(m,2H),3.87(s,3H),3.64(tdd,J=15.2,6.1,4.3Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ163.70,156.89(d,J=234.8Hz),153.63,144.70,136.19(d,J=6.4Hz),130.06,123.45,118.92,116.85,115.26,1 14.54(d,J=23.8Hz),113.82(d,J=22.5Hz),112.14(d,J=8.5Hz),111.80,98.11,56.38,42.04,41.22(t,J=26.8Hz).HRMS(ESI,m / z)calcd for C 18 H 17 F3N4O2[M+Na] + ,401.1201; found 401.1206.

[0127] (3,3-Difluoropyrrolidone-1-yl)(5-((5-fluoro-2-methoxybenzyl(amino)-1H-indazol-3-yl)methyl ketone)

[0128] Referring to the method of Preparation Example 1, the methylamine hydrochloride raw material in step b was replaced with 3,3-difluoropyrrolidine in an equal proportion to obtain Example 9. 1 H NMR (600MHz, DMSO-d6) δ13.30(s,1H),7.38(d,J=8.9Hz,1H),7.05–6.99(m,4H),6.97(dd,J=9.0,2.2Hz,1H),6.18(t,J=6.1Hz,1H),4.38(t,J=1 3.1Hz, 1H), 4.24 (d, J = 6.1Hz, 2H), 4.20 (t, J = 7.4Hz, 1H), 3.92 (t, J = 13.4Hz, 1H), 3.86 (s, 3H), 3.74 (t, J = 7.5Hz, 1H), 2.53 (m, 1H), 2.44 (m, 1H). 13C NMR(151MHz,DMSO-d6)δ162.78,156.90(d,J=234.4Hz),153.61,144.82,137 .06,136.88,135.36,130.21(d,J=6.5Hz),124.97,118.93J,114.50(d,J=24 .2Hz),113.75(d,J=22.4Hz),112.14(d,J=8.5Hz),111.55,98.59,56.38,55 .23(t,J=31.6Hz),53.04(t,J=31.9Hz),44.19,41.96.HRMS(ESI,m / z)calcd for C 20 H 19 F3N4O2[M+H] + ,405.1538;found 405.1541;[M+Na] + ,427.1358; found 427.1360.

[0129] (5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazol-3-yl)(3-hydroxypyrrolidone-1-yl)methyl ketone

[0130] Referring to the method of Preparation Example 1, the methylamine hydrochloride raw material in step b was replaced with pyrrolidine-3-ol in an equal proportion to obtain Example 10. 1 H NMR(600MHz,DMSO-d6)δ13.14(d,J=2.5Hz,1H),7.36(d,J=8.9Hz,1H),7.03(dd t,J=17.1,8.9,3.3Hz,4H),6.95(dd,J=8.9,2.2Hz,1H),6.10(t,J=6.1Hz,1H),4 .92(dd,J=11.2,3.4Hz,1H),δ4.34–4.27(m,1H),4.24(d,J=6.0Hz,2H),3.91(dd d,J=26.8,12.3,8.5Hz,2H),3.86(s,3H),3.60–3.43(m,2H),1.96–1.74(m,2H). 13C NMR (151 MHz, DMSO-d6) δ 162.71, 156.88 (d, J = 235.4 Hz), 153.62, 144.15, 138.18, 135.44, 130.13, 124.82 (d, J = 5.2 Hz), 118.77, 115.39 (d, J = 7.8 Hz), 114.62 (d, J = 23.9 Hz), 113.82 (d, J = 22.4 Hz), 112.13 (d, J = 7.9 Hz), 111.39, 70.27, 67.83, 57.27, 56.37, 42.22, 34.90. HRMS (ESI, m / z) calcd for C 20 H 21 FN4O3[M+H] + , 385.1676; found 385.1679; [M+Na] + , 407.1495; found 407.1498.

[0131] The route for the preparation of Example 11 is shown below:

[0132] The specific synthesis steps are as follows:

[0133] Synthesis of 5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxylic acid (19)

[0134] Intermediate 9 (11.0 g, 53.0 mmol) and p-TSA (0.91 g, 5.3 mmol) were dissolved in 200 mL DCM, cooled to 0 °C, and DHP (14.5 mL, 159.0 mmol) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 4 hours. TLC monitoring showed that the starting material was consumed. 500 mL DCM was added, and the mixture was washed twice with saturated NaCl (2 x 400 mL). The organic phase was collected, and the solvent was removed by rotary evaporation. Purification by column chromatography (4% MeOH / CH2Cl2) gave 12 g of 19 as a white solid in 77.8% yield.

[0135] Synthesis of N-methyl-5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxamide (20)

[0136] Methanamine hydrochloride (2.3 g, 34.3 mmol) was dissolved in 20 mL of DMF, DIPEA (19 mL, 110.0 mmol) was added and stirred for 20 min, 19 (2.0 g, 6.88 mmol) and HATU (3.9 g, 10.3 mmol) were added. The reaction was stirred at room temperature for 4 h. TLC monitoring, the raw material was reacted completely. The reaction was poured into 200 mL of H2O, a solid was precipitated, filtered and dried to give 1.57 g of white solid of intermediate 20, yield 75.2%.

[0137] Synthesis of 5-amino-N-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-3- carboxamide (21 )

[0138] Intermediate 20 (1.57 g, 5.17 mmol) was dissolved in 20 mL of EtOH / NH2NH2H2O = 8:1 (volume ratio), Pd / C (0.16 g) was added. The reaction was warmed to 60 °C and stirred for 3 h. TLC monitoring, the raw material was reacted completely. The reaction was cooled to room temperature, filtered with diatomite, the filtrate was collected, the solvent was removed by rotary evaporation, 200 mL of EtOA was added, washed twice with saturated NaCl (2 x 400 mL). The organic phase was collected and the solvent was removed by rotary evaporation to give 1.21 g of white solid of 21, yield 85.2%.

[0139] Synthesis of 5-((5-fluoro-2-iodobenzyl)amino)-N-methyl-1 -(tetrahydro-2H-pyran-2- yl)-1 H-indazole-3-carboxamide (22)

[0140] Intermediate 21 (0.2 g, 0.73 mmol) was dissolved in 10 mL of MeOH, cooled to 0 °C, 100 μL of AcOH, 5-fluoro-2-iodobenzaldehyde (0.2 g, 0.8 mmol) was added, stirred at room temperature for 1 h, AcOH (84 μL, 1.46 mmol) and NaBH3CN (0.05 g, 0.73 mmol) were added. The reaction was stirred at room temperature for 1 h. TLC monitoring, the raw material was reacted completely. The reaction was quenched with 1 mL of saturated NH4Cl solution. The solvent was removed by rotary evaporation, 50 mL of EtOAc was added, and washed with saturated Na2CO3 solution (2 x 30 mL). The organic phase was collected and concentrated under reduced pressure to give 0.27 g of yellow oil 22, yield 73.8%.

[0141] Synthesis of 5-((2-(dimethylphosphoryl)-5-fluorobenzyl)amino)-N-methyl-1 -(tetrahydro- 2H-pyran-2-yl)-1 H-indazole-3-carboxamide (23)

[0142] Intermediate 22 (85.0 mg, 0.17 mmol), dimethyl phosphine oxide (0.16 g, 2.0 mmol), Xantphos (20 mg, 0.034 mmol) and K3PO4(0.11 g, 0.5 mmol) were dissolved in 5 mL of anhydrous 1.4-dioxane, Ar was bubbled three times, Pd(OAc)2(5.0 mg, 0.017 mmol) was added. The reaction was warmed to 100 °C and stirred for 3 h. TLC monitoring, a little of starting material remained. The reaction was cooled to room temperature, the solvent was removed, added to 50 mL EtOAc, washed with saturated NaCl twice (2 x 30 mL). The organic phase was collected, the solvent was removed, purified by column chromatography (4% MeOH / CH2Cl2) to give 0.06 g of green oil of intermediate 23, yield 77.9%.

[0143] 5-((2-(dimethylphosphoryl)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0144] 10 mL of 4N HC1 / EtOAc was added to intermediate 23 (74 mg, 0.16 mmol). The reaction was stirred at room temperature for 4 h. TLC monitoring, the reaction was complete. The solvent was removed, 30 mL of H2O was added. The aqueous solution was cooled to 0 °C and the pH was adjusted to 9-10 with 1 M NaOH solution. EtOAc was extracted three times (30 mL x 5), the organic phase was collected, the solvent was removed. Purified by column chromatography (2% MeOH / CH2Cl2) to give 25 mg of white solid of example 11, yield 42.0%. 1 H NMR (600 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.07 (q, J = 4.7 Hz, 1H), 7.75 (ddd, J = 12.6, 8.6, 6.0 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.24 - 7.17 (m, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 9.0, 2.2 Hz, 1H), 6.33 (t, J = 6.1 Hz, 1H), 4.70 (d, J = 5.9 Hz, 2H), 2.75 (d, J = 4.7 Hz, 3H), 1.81 (d, J = 13.2 Hz, 6H). 13C NMR (151 MHz, DMSO-d6) δ 163.69, 146.20 (d, J = 618.8 Hz), 137.12, 136.18, 134.28 (dd, J = 13.2, 8.5 Hz), 130.32, 130.13, 129.70, 123.21, 118.56, 115.49 (dd, J = 21.8, 10.5 Hz), 114.01 (dd, J = 21.0, 12.5 Hz), 111.67, 99.09, 45.89, 25.89, 19.23, 18.76. HRMS (ESI, m / z) calcd for C 18 H 20 FN4O2P[M+Na] + ,397.1206; found 397.1209.

[0145] The route for the preparation of Example 12 is shown below:

[0146] The specific synthesis steps are as follows:

[0147] Synthesis of 5-((5-fluoro-2-isopropoxybenzyl)amino)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (25)

[0148] Intermediate 21 (0.1 g, 0.36 mmol) was dissolved in 5 mL MeOH, cooled to 0 °C, 50 μL AcOH, 5-fluoro-2-isopropoxybenzaldehyde (0.078 g, 0.43 mmol) was added, stirred at room temperature for 1 h, AcOH (42 μL, 0.73 mmol) and NaBH3CN (25 mg, 0.36 mmol) were added. The reaction was stirred at room temperature for 1 h. TLC monitoring, the starting material was consumed. The reaction was quenched with 1 mL saturated NH4Cl solution. The solvent was removed by rotary evaporation, 50 mL EtOAc was added, and washed with saturated Na2CO3 solution (2 x 30 mL). The organic phase was collected and concentrated under reduced pressure to give 0.12 g of yellow oil 25, 76.0% yield.

[0149] 5-((5-Fluoro-2-isopropoxybenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0150] To intermediate 25 (80 mg, 0.18 mmol) was added 10 mL of 4N HC1 / EtOAc. The reaction was stirred at room temperature for 4 hours. TLC monitoring showed the reaction was complete. The solvent was removed, and 30 mL of H20 was added. The aqueous solution was cooled to 0 °C, and the pH was adjusted to 9-10 with 1 N NaOH solution. The organic phase was collected, and the solvent was removed. Purification by column chromatography (2% MeOH / CH2Cl2) gave 27 mg of Example 12 as a white solid, 42.1% yield. 1 H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.07 (q, J = 4.7 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.05 - 7.01 (m, 3H), 6.98 (td, J = 8.5, 3.3 Hz, 1H), 6.94 (dd, J = 9.0, 2.3 Hz, 1H), 6.09 (t, J = 6.2 Hz, 1H), 4.62 (p, J = 6.1 Hz, 1H), 4.23 (d, J = 6.1 Hz, 2H), 2.75 (d, J = 4.8 Hz, 3H), 1.33 (d, J = 6.0 Hz, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 163.76, 156.82 (d, J = 235.4 Hz), 151.89, 144.61, 137.08, 136.08, 131.64 (d, J = 6.5 Hz), 123.30, 118.59, 115.27 (d, J = 8.4 Hz), 114.54 (d, J = 23.5 Hz), 113.80 (d, J = 23.1 Hz), 111.57, 98.44, 71.13, 42.20, 25.86, 22.46. HRMS (ESI, m / z) calcd for C 19 H 21 FN4O2[M+Na] + , 379.1546; found 379.1553.

[0151] 5-((5-Fluoro-2-((tetrahydrofuran-3-yl)oxy)benzyl)amino)-N-methyl-1H-indazole-3- carboxamide

[0152] Following the procedure for the preparation of Example 12, Example 13 was obtained by replacing 5-fluoro-2-isopropoxybenzaldehyde in step a with 5-fluoro-2- (tetrahydrofuran-3-yl)oxybenzaldehyde in equal proportion. 1H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.08 (q, J = 4.7 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.06 - 6.98 (m, 4H), 6.93 (dd, J = 9.0, 2.2 Hz, 1H), 6.10 (t, J = 6.2 Hz, 1H), 5.10 (ddt, J = 6.4, 4.3, 1.8 Hz, 1H), 4.23 (d, J = 6.1 Hz, 2H), 3.95 - 3.88 (m, 2H), 3.86 (dt, J = 10.2, 1.3 Hz, 1H), 3.79 (td, J = 8.3, 4.3 Hz, 1H), 2.75 (d, J = 4.7 Hz, 3H), 2.23 (dtd, J = 13.2, 8.3, 6.1 Hz, 1H), 2.09 - 2.02 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 163.74, 157.04 (d, J = 235.6 Hz), 151.53, 144.57, 137.09, 136.08, 131.41 (d, J = 6.4 Hz), 123.31, 118.54, 114.79 (d, J = 23.6 Hz), 114.48 (d, J = 7.9 Hz), 113.83 (d, J = 22.4 Hz), 111.57, 98.50, 78.50, 72.83, 67.00, 42.14, 33.09, 25.85. HRMS (ESI, m / z) calcd for C 20 H 21 FN4O3[M + Na] + , 407.1495; found 407.1503.

[0153] 5-((5-Fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)amino)-N-methyl-1H- indazole-3-carboxamide

[0154] Following the procedure of Reference Preparation Example 12, Example 14 was prepared by replacing 5-fluoro-2-isopropoxybenzaldehyde in step a with 5-fluoro-2-(tetrahydro-2H-pyran-4-yl)oxybenzaldehyde in an equimolar ratio. 1H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.07 (q, J = 4.7 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 9.0, 4.5 Hz, 1H), 7.04 (dd, J = 9.5, 3.2 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.95 (dd, J = 9.0, 2.2 Hz, 1H), 6.13 (t, J = 6.1 Hz, 1H), 4.62 (tt, J = 8.1, 3.9 Hz, 1H), 4.28 (d, J = 6.0 Hz, 2H), 3.87 (ddd, J = 11.6, 5.6, 4.0 Hz, 2H), 3.51 (ddd, J = 11.6, 8.7, 3.1 Hz, 2H), 2.75 (d, J = 4.7 Hz, 3H), 2.05 - 1.98 (m, 2H), 1.69 (dtd, J = 12.6, 8.5, 3.9 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 163.74, 157.03 (d, J = 236.5 Hz), 151.26, 144.57, 137.09, 136.07, 131.85 (d, J = 6.5 Hz), 123.31, 118.62, 115.60 (d, J = 7.8 Hz), 114.61 (d, J = 23.6 Hz), 113.85 (d, J = 22.7 Hz), 111.58, 98.40, 72.75, 64.90 (s, 2C), 42.22, 32.22, 27.29, 25.82. HRMS (ESI, m / z) calcd for C 21 H 23 FN4O3[M+H] + , 399.1382; found 399.1837; [M+Na] + , 421.1652; found 421.1657.

[0155] 5-((5-Fluoro-2-(2-hydroxyethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0156] Following the procedure of Reference Preparation Example 12, Example 15 was obtained by replacing 5-fluoro-2-isopropoxybenzaldehyde in step a with 5-fluoro-2- hydroxyethoxybenzaldehyde in equal proportions. 1H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.10 (q, J = 4.7 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.07 - 6.97 (m, 4H), 6.95 (dd, J = 8.9, 2.2 Hz, 1H), 6.13 (t, J = 6.2 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.08 (t, J = 5.0 Hz, 2H), 3.78 (q, J = 5.2 Hz, 2H), 2.76 (d, J = 4.7 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 163.80, 156.91 (d, J = 235.4 Hz), 153.17, 144.64, 137.05, 136.08, 130.89 (d, J = 6.5 Hz), 123.32, 118.64, 114.64 (d, J = 23.5 Hz), 113.76 (d, J = 22.8 Hz), 113.62 (d, J = 8.1 Hz), 111.55, 98.55, 71.09, 60.21, 42.20, 25.86. HRMS (ESI, m / z) calcd for C 18 H 19 FN4O3[M+Na] + , 381.1339; found 381.1345.

[0157] 5-((2-(Difluoromethoxy)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0158] Referring to the method of Preparation Example 12, the 5-fluoro-2- isopropoxybenzaldehyde in step a is replaced by 5-fluoro-2-difluoromethoxybenzaldehyde in equal proportion to obtain Example 16. 1 H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.10 (q, J = 4.7 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.07 - 6.97 (m, 4H), 6.95 (dd, J = 8.9, 2.2 Hz, 1H), 6.13 (t, J = 6.2 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.08 (t, J = 5.0 Hz, 2H), 3.78 (q, J = 5.2 Hz, 2H), 2.76 (d, J = 4.7 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.75, 159.89 (d, J = 241.4 Hz), 145.32, 144.18, 137.12, 136.19, 134.73 (d, J = 6.8 Hz), 123.23, 121.50 (d, J = 8.9 Hz), 118.54, 117.24, 115.44 (d, J = 24.7 Hz), 114.95 (d, J = 23.5 Hz), 111.72, 98.66, 42.02, 25.87. HRMS (ESI, m / z) calcd for C 17 H 15 F3N4O2[M+H] + ,365.1225; found 365.1230; [M+Na] + ,387.1045; found 387.1048.

[0159] 5-((5-Fluoro-2-(2-fluoroethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0160] Following the procedure for Preparation Example 12, Example 17 was prepared by replacing 5-fluoro-2-isopropoxybenzaldehyde in step a with 5-fluoro-2- fluoroethoxybenzaldehyde in an equimolar ratio. 1 H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.09 (q, J = 4.6 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.08 - 6.99 (m, 4H), 6.94 (dd, J = 9.0, 2.2 Hz, 1H), 6.14 (t, J = 6.2 Hz, 1H), 4.88 - 4.83 (m, 1H), 4.80 - 4.76 (m, 1H), 4.37 - 4.34 (m, 1H), 4.32 - 4.30 (m, 1H), 4.28 (d, J = 5.9 Hz, 2H), 2.75 (d, J = 4.7 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.75, 157.21 (d, J = 235.5 Hz), 152.63, 144.52, 137.10, 136.12, 130.97, 130.13, 123.30, 118.62, 114.69 (d, J = 24.5 Hz), 113.95 (d, J = 11.7 Hz), 113.84 (d, J = 3.4 Hz), 98.51, 82.81 (d, J = 166.5 Hz), 68.68 (d, J = 19.4 Hz), 41.97, 25.85. HRMS (ESI, m / z) calcd for C 18 H 18 F2N4O2[M+H] + ,361.1476; found 361.1477; [M+Na] + ,383.1296; found 383.1297.

[0161] 5-((2-(2,2-Difluoroethoxy)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0162]

[0163] Reference to the method of Preparation Example 12, 5-fluoro-2- isopropoxybenzaldehyde in step a was replaced by 2-(2,2-difluoroethoxy)-5- fluorobenzaldehyde in equal proportion, to obtain Example 18. 1 H NMR (600 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.09 (q, J = 4.6 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 8.9, 4.4 Hz, 1H), 7.09 - 7.02 (m, 3H), 6.93 (dd, J = 8.9, 2.2 Hz, 1H), 6.50 (tt, J = 54.7, 3.7 Hz, 1H), 6.17 (t, J = 6.1 Hz, 1H), 4.42 (td, J = 14.4, 3.7 Hz, 2H), 4.28 (d, J = 6.2 Hz, 2H), 2.75 (d, J = 4.7 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.77, 157.53 (d, J = 236.7 Hz), 152.08, 144.36, 137.10, 136.14, 131.11, 123.29, 118.63, 116.40, 114.83 (t, J = 11.9 Hz), 114.27 (d, J = 8.0 Hz), 114.08 (d, J = 23.2 Hz), 111.62, 98.58, 67.97 (t, J = 27.2 Hz), 41.80, 25.83. HRMS (ESI, m / z) calcd for C 18 H 17 F3N4O2[M + Na] + , 401.1201; found 401.1207.

[0164] 5-((5-Fluoro-2-(2,2,2-trifluoroethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0165] Following the procedure for Preparation Example 12, Example 19 was obtained by replacing 5-fluoro-2-isopropoxybenzaldehyde in step a with 2-(2,2,2-trifluoroethoxy)-5-fluorobenzaldehyde in equal proportion. 1 H NMR (600 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.09 (q, J = 4.7 Hz, 1H), 7.36 (dd, J = 9.0, 5.6 Hz, 1H), 7.19 (dd, J = 10.0, 4.4 Hz, 1H), 7.11 - 7.06 (m, 2H), 7.03 (s, 1H), 6.94 (dd, J = 8.9, 2.2 Hz, 1H), 6.19 (s, 1H), 4.88 (q, J = 8.8 Hz, 2H), 4.28 (s, 2H), 2.75 (d, J = 4.7 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 163.70, 157.88 (d, J = 236.9 Hz), 151.49, 137.15, 136.24, 131.29, 130.13, 125.45, 123.61, 123.23, 118.62, 115.07, 114.89 (d, J = 24.1 Hz), 114.26 (d, J = 22.9 Hz), 111.68, 66.24 (d, J = 34.0 Hz), 41.95, 25.85. HRMS (ESI, m / z) calcd for C 18 H 16 F4N4O2[M + Na] +, 419.1107; found 419.1110.

[0166] 5-((5-Fluoro-2-(methylsulfonyl)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide

[0167] Referring to the method of Preparation Example 12, 5-fluoro-2- isopropoxybenzaldehyde in step a was replaced by 2-methylsulfonyl-5- fluorobenzaldehyde in an equal proportion to obtain Example 20. 1 H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.09 (q, J = 4.6 Hz, 1H), 8.06 (dd, J = 8.8, 5.6 Hz, 1H), 7.44 (dd, J = 10.3, 2.7 Hz, 1H), 7.39 (dd, J = 9.7, 6.0 Hz, 2H), 7.05 (d, J = 2.3 Hz, 1H), 6.97 (dd, J = 9.0, 2.3 Hz, 1H), 6.38 (t, J = 6.1 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H), 3.40 - 3.38 (s, 3H), 2.74 (d, J = 4.7 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 165.54 (d, J = 252.2 Hz), 163.68, 144.55 (d, J = 7.8 Hz), 143.95, 137.16, 136.27, 135.39, 133.16 (d, J = 9.9 Hz), 123.21, 118.41, 116.26 (d, J = 24.4 Hz), 115.08 (d, J = 22.2 Hz), 111.83, 99.07, 63.27, 44.66, 25.87. HRMS (ESI, m / z) calcd for C 17 H 17 FN4O3S [M + Na] + , 399.0903; found 399.0910.

[0168] The preparation route of Example 21 is shown below:

[0169] The specific synthesis steps are as follows:

[0170] Synthesis of 4-bromo-2-(bromomethyl)-1-nitrobenzene (28)

[0171] Place 4-bromo-2-methyl-l-nitrobenzene (2.0 g, 9.26 mmol), NBS (2.0 g, 11.1 mmol) and AIBN (0.16 g, 0.93 mmol) in a 350 mL sealed tube, add 30 mL of anhydrous acetonitrile as solvent, purge with argon, heat to 110 °C, stir for 12 h. Cool to room temperature, check by TLC, the starting material is completely reacted. Remove the solvent, add to 100 mL of EtOAc, wash twice with saturated NaCl (30 mL x 2). Collect the organic phase, remove the solvent, without purification, directly proceed to the next step.

[0172] Synthesis of l-(5-bromo-2-nitrobenzyl)-lH-l,2,4-triazole (29)

[0173] Dissolve intermediate 28 in 20 mL of DMF, add CsCO3(3.0 g, 9.26 mmol) and lH-l,2,4-triazole (0.64 g, 9.26 mmol). Stir at room temperature for 1 h. Check by TLC, the starting material is completely reacted. Pour the reaction into 200 mL of water, extract with EtOAc (100 mL x 3), wash with saturated NaCl (200 mL x 2). Collect the organic phase, remove the solvent, purify by column chromatography (0.5% MeOH / CH2Cl2) to give 0.93 g of white solid 29, 35.4% yield for two steps.

[0174] Synthesis of 2-((lH-l,2,4-triazol-l-yl)methyl)-4-bromoaniline (30)

[0175] Dissolve intermediate 29 (0.9 g, 3.18 mmol) in 100 mL of EtOH, add 20 mL of saturated NH4Cl solution, add iron powder (0.9 g, 16 mmol) with vigorous stirring. Heat to 80 °C, stir for 1 h. Cool to room temperature, check by TLC, the starting material is completely reacted. Filter off the insoluble material on celite, rinse with EtOH, collect the filtrate, remove the solvent, add to 100 mL of EtOAc, wash twice with water (50 mL x 2) and twice with saturated NaCl (50 mL x 2). Collect the organic phase, remove the solvent to give 0.72 g of yellow solid 30, 89.0% yield.

[0176] Synthesis of 5-bromo-3-(lH-l,2,4-triazol-l-yl)-lH-indazole (31)

[0177] Intermediate 30 (0.7 g, 2.76 mmol) was dissolved in 10 mL of AcOH, and isoamyl nitrite (0.42 g, 3.59 mmol) was added. The mixture was stirred at room temperature for 2 h, and a solid precipitated; the temperature was raised to 50 °C, and the mixture was stirred for 2 h; then the temperature was raised to 70 °C, and the mixture was stirred for 0.5 h, and the solid dissolved. The mixture was cooled to room temperature, and TLC indicated that the reaction was complete. The insoluble material was filtered off on celite, rinsed with EtOH, and the filtrate was collected and the solvent was removed. The residue was dissolved in 100 mL of EtOAc, washed twice with water (50 mL x 2), and twice with saturated NaCl (50 mL x 2). The organic phase was collected, and the solvent was removed to give 0.72 g of a yellow solid, 89.0% yield.

[0178] Synthesis of 5-bromo-3-(lH-l,2,4-triazol-l-yl)-l-trityl-lH-indazole (32)

[0179] Intermediate 31 (0.7 g, 2.65 mmol) was dissolved in 5 mL of DMF, and CsCO3(1.7 g, 5.3 mmol) and triphenylmethyl chloride (0.81 g, 2.91 mmol) were added. The mixture was stirred at room temperature for 1 h. TLC indicated that the reaction was complete. The reaction mixture was poured into 50 mL of water, and a white solid precipitated, which was filtered off and dried to give 1.1 g of a white solid, 32, 82.2% yield.

[0180] Synthesis of N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(lH-l,2,4-triazol-l-yl)-l- trityl-lH-indazol-5-amine (33)

[0181] Intermediate 32 (0.2 g, 0.40 mmol), (2-(2,2-difluoroethoxy)-5-fluorophenyl)methanamine (0.11 g, 0.52 mmol), and NaOtBu (0.1 g, 0.99 mmol) were dissolved in dry 10 mL of THF, and the mixture was purged with argon. t-Busphos Pd-G3 (32 mg, 0.039 mmol) was added, and the mixture was stirred at 60 °C for 2 h. TLC indicated that the reaction was complete. The solvent was removed, and the residue was dissolved in 100 mL of EtOAc, washed twice with water (50 mL x 2), and twice with saturated NaCl (50 mL x 2). The organic phase was collected, and the solvent was removed. The residue was purified by column chromatography (1% MeOH / CH2Cl2) to give 0.1 g of a white solid, 33, 39.5% yield.

[0182] N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(lH-l,2,4-triazol-l-yl)-lH-indazol-5-amine

[0183] Intermediate 33 (100 mg, 0.16 mmol) was placed in a sealed tube, 5 mL DCM and 10 mL TFA were added. The reaction was warmed to 70 °C and stirred for 12 h. TLC monitoring, a little of starting material remained. The solvent was evaporated, added to 50 mL EtOAc, washed twice with saturated Na2C03(30 mL x 2). The organic phase was collected, the solvent was evaporated, purified by column chromatography (3% MeOH / CH2Cl2) to give 35 mg white solid, Example 21. Yield 56.4%. 1 H NMR (600 MHz, DMSO-d6) δ 12.98 (s, 1H), 9.10 (s, 1H), 8.26 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.11 (dt, J = 9.1, 4.6 Hz, 2H), 7.03 (td, J = 8.9, 2.7 Hz, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.43 (tt, J = 54.5, 3.5 Hz, 1H), 6.22 (t, J = 6.2 Hz, 1H), 4.39 (td, J = 14.6, 3.6 Hz, 2H), 4.28 (d, J = 6.1 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 157.55 (d, J = 237.4 Hz), 152.77, 152.19, 144.33, 143.01, 137.64, 136.48, 131.14 (d, J = 6.7 Hz), 119.94, 115.41, 115.01 (d, J = 24.5 Hz), 114.64 (d, J = 24.2 Hz), 114.30, 111.99, 96.31, 68.13 (t, J = 26.7 Hz), 46.06, 41.64. HRMS (ESI, m / z) calcd for C 18 H 15 F3N6O [M+H] + , 389.1338; found 389.1344.

[0184] N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(1H-1,2,3-triazol-1-yl)-1H-indazol-5- amine

[0185] Reference to the method of Preparation Example 21, replace 1H-1,2,4-triazole with 1H-1,2,3-triazole in equal proportion in step b, Example 22 was obtained. 1H NMR (600 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.67 (s, 1H), 7.97 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.12 (dt, J = 9.2, 3.4 Hz, 2H), 7.04 (td, J = 8.6, 2.9 Hz, 2H), 6.91 (d, J = 2.2 Hz, 1H), 6.46 (tt, J = 54.6, 3.7 Hz, 1H), 6.30 (t, J = 6.2 Hz, 1H), 4.42 (td, J = 14.4, 3.7 Hz, 2H), 4.30 (d, J = 6.1 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 157.53 (d, J = 236.4 Hz), 152.14, 144.60, 137.70, 136.62, 133.95, 131.01 (d, J = 6.6 Hz), 123.37, 120.08, 116.32, 115.17 (d, J = 33.0 Hz), 114.82 (d, J = 25.7 Hz), 114.38 (d, J = 8.0 Hz), 113.15, 112.07, 96.52, 67.99 (t, J = 27.1 Hz), 41.53. HRMS (ESI, m / z) calcd for C 18 H 15 F3N6O [M+H] + , 389.1338; found 389.1343; [M+Na] + , 411.1157; found 411.1162.

[0186] (S)-N-(1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethyl)-3-(1H-1,2,4-triazol-1-yl)-1H-indazol-5- amine

[0187] Referring to the method of Preparation Example 21, the (2-(2,2-difluoroethoxy)-5-fluorophenyl)methanamine in step f was replaced by (S)-1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethan-1-amine in equal proportion to obtain Example 23. 1HNMR (600 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.05 (s, 1H), 8.22 (s, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.14 (dd, J = 9.6, 3.2 Hz, 1H), 7.10 (dd, J = 9.0, 4.4 Hz, 1H), 6.97 (ddt, J = 8.0, 5.6, 3.3 Hz, 2H), 6.71 (d, J = 2.1 Hz, 1H), 6.47 (tt, J = 54.4, 3.5 Hz, 1H), 6.26 (d, J = 7.8 Hz, 1H), 4.84 (p, J = 6.8 Hz, 1H), 4.48 (tdd, J = 14.5, 11.4, 3.6 Hz, 1H), 4.39 (tdd, J = 14.9, 11.4, 3.4 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 157.86 (d, J = 237.2 Hz), 152.59, 151.88, 143.37, 142.88, 137.61, 137.07 (d, J = 6.5 Hz), 136.34, 119.99, 116.25, 115.36, 114.69 (d, J = 4.7 Hz), 114.11 (d, J = 23.4 Hz), 112.89 (d, J = 23.8 Hz), 111.78, 97.33, 68.20 (t, J = 26.6 Hz), 46.41, 23.02. HRMS (ESI, m / z) calcd for C 19 H 17 F3N6O [M+H] + , 403.1494; found 403.1497; [M+Na] + , 425.1314; found 425.1317.

[0188] (R)-N-(1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethyl)-3-(1H-1,2,4-triazol-1-yl)-1H-indazol-5- amine

[0189] Reference the method of Preparation Example 21, replace (2-(2,2-difluoroethoxy)-5-fluorophenyl)methanamine in step f with (R)-1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethan-1-amine in equal proportion to obtain Example 24. 1HNMR (600 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.05 (s, 1H), 8.21 (s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.14 (dd, J = 9.6, 3.3 Hz, 1H), 7.10 (dd, J = 9.0, 4.4 Hz, 1H), 6.97 (ddd, J = 8.7, 6.7, 4.4 Hz, 2H), 6.71 (d, J = 2.1 Hz, 1H), 6.47 (tt, J = 54.4, 3.5 Hz, 1H), 6.25 (d, J = 7.8 Hz, 1H), 4.84 (p, J = 6.9 Hz, 1H), 4.48 (tdd, J = 14.5, 11.4, 3.6 Hz, 1H), 4.39 (tdd, J = 14.9, 11.4, 3.4 Hz, 1H), 1.40 (d, J = 6.7 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 157.86 (d, J = 237.2 Hz), 152.59, 151.88, 143.37, 142.89, 137.61, 137.07 (d, J = 6.2 Hz), 136.34, 119.99, 116.25, 115.36, 114.69 (d, J = 4.7 Hz), 114.11 (d, J = 23.4 Hz), 112.89 (d, J = 23.8 Hz), 111.78, 97.33, 68.20 (t, J = 26.6 Hz), 46.41, 23.02. HRMS (ESI, m / z) calcd for C 19 H 17 F3N6O[M+Na] + , 425.1314; found 425.1322.

[0190] Example 25: In vitro enzyme inhibitory activity of N-(3-fluorobenzyl)-1H- indazol-5-amine derivatives of the application

[0191] Experimental materials:

[0192] Tecan F500 microplate reader.

[0193] KinEASE™-STK kit (containing biotinylated polypeptide substrate S2, Eu 3+ labeled monoclonal antibody specific for the specific phosphorylation site, Sa-XL665 labeled streptavidin, kinase reaction buffer solution (KinEASE enzyme reaction buffer), 384-well plate, TRKA G595R full-length protein.

[0194] TRKA G595R Protein concentration 0.111 ng / μl, MgCl2, Ethylenediaminetetraacetic acid (EDTA), DL-Dithiothreitol (DTT), DMSO.

[0195] Experimental method:

[0196] First step: Kinase reaction:

[0197] First, the compound sample prepared in the above example was dissolved in DMSO to make a 20 mM solution, and then diluted with a kinase reaction buffer solution to make a 100 μM, 10 μM, 1 μM, etc. concentration as required for testing. Then, TRKA kinase (concentration of 0.111 ng / μL), ATP (4 μM), biotin-labeled polypeptide substrate TK (1 μM), and compound sample (4 μL) were added to 10 μL of kinase reaction buffer solution (containing MgCl25 mM and DTT 1 mM) and incubated at room temperature for 30 minutes, and the kinase phosphorylated the substrate TK. Then, 10 μL of detection reagent containing EDTA (kit provided) was added to detect the phosphorylation product.

[0198] Second step: Detection of phosphorylation product:

[0199] Rare earth element europium (Eu 3+ ) labeled antibody recognizes the phosphorylated substrate, and XL665 labeled streptavidin binds to the biotin on the substrate. Eu3 + is the fluorescence donor, and XL665 is the fluorescence acceptor. When Eu 3+ is close to XL665, Eu 3+ transfers energy to XL665, generating an HTRF signal.

[0200] Result evaluation method: The fluorescence signal is generated by the 620 nm fluorescence absorption signal of Eu 3+ and the 665 nm fluorescence absorption signal of XL665. Therefore, the HTRF signal (665 / 620) ratio of each well plate reaction is calculated. The results are characterized as Delta F (DF %):

[0201] Calculate the inhibition rate (activity %): The DF % of the kinase activity without adding the compound sample is defined as 100%. When the compound sample is added, the kinase activity rate:

[0202] Calculate IC 50 : The DF % of the kinase activity with the addition of the compound is plotted on the Y-axis, and the logarithmic value of the concentration of the compound is plotted on the X-axis. The IC 50 value is obtained by fitting the data into an S-shaped dose-response curve.

[0203] Table 1: IC50values of N-(3-fluorobenzyl)-1H-indazol-5-amine derivatives of the application against TRKA kinase 50 Values

[0204] The above test results show that the above examples all have good inhibitory effect on TRKA G595R kinase, and the IC50values of most examples are in the nM range. 50

[0205] Table 2: IC50values of some N-(3-fluorobenzyl)-1H-indazol-5-amine derivatives of the application against TRKA kinase 50 Values

[0206] The above test results show that the above examples all have good inhibitory effect on various mutants of TRKA kinase, and the IC50values of most examples are in the nM range. 50

[0207] It will be apparent to those skilled in the art that various modifications and variations can be made to the present application without departing from the spirit or scope of the application. Thus, it is intended that the present application cover modifications and variations of this application provided they come within the scope of the appended claims and their equivalents.​​

Claims

1. An N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative, characterized by: The derivative is a 3-fluorobenzylamine substituted indazole compound having a structure according to Formula (I), or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; wherein R1is selected from -CONH-R a , cyano or R a is selected from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-halocycloalkyl, C1-C6-alkoxy; X, Y, Z are selected from C or N, wherein, when the X atom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by R b ; R b is selected from H, halogen or C1-C6-haloalkyl; R2 is selected from C1-C6 alkoxy, C1-C6 cycloalkoxy, C1-C6 haloalkoxy, C1-C6 alkyl-substituted phosphonoyl or C1-C6 alkyl-substituted sulfonyl; R3 is selected from H or C1-C6 alkyl groups.

2. The N-(3-fluorobenzyl)-1 H-indazole-5-amine derivative according to claim 1, characterized by The derivative is a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug; wherein R1is selected from -CONH-R a or R a is selected from H, methyl, halogenethyl, halogencyclopentyl or hydroxycyclopentyl; X, Y, Z are selected from C or N, wherein, when the X atom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by R b is selected from H, halogen or halogenmethyl; and b is selected from H, halogen or halogenmethyl. R2 is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, halomethoxy, haloethoxy, dimethylphosphate or methylsulfonyl; R3 is selected from H or methyl.

3. The N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative according to claim 2, characterized by: The derivative is a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug; wherein R1is selected from -CONH-R a or R a is selected from H, methyl, 2,2-difluoroethyl, 3,3-difluoropyrrolidin-1-yl or hydroxycyclopentyl; X, Y, Z are selected from C or N, wherein, when the X atom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by R b ; R b is selected from H, fluorine or trifluoromethyl; R2 is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, 2,2-difluoromethoxy, 2,2-difluoroethoxy, dimethylphosphate or methylsulfonyl. R3 is selected from H or methyl.

4. The N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative according to claim 3, characterized by: The derivative is a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug; wherein R1is selected from -CONH-R a 、 R a is selected from H, methyl, 2,2-difluoroethyl, 3,3-difluoropyrrolidin-1-yl or hydroxycyclopentyl; R b is selected from H, fluorine or trifluoromethyl; R2 is selected from methoxy, isopropoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, 2-hydroxyethoxy, 2,2-difluoromethoxy, 2,2-difluoroethoxy, dimethylphosphate or methylsulfonyl. R3 is selected from H or methyl.

5. The N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative according to claim 4, characterized by: The derivative is an indazole compound, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug, as shown below. N-(5-fluoro-2-methoxybenzyl)-3-(1H-pyrazol-1-yl)-1H-indazole-5-amine; 3-(4-Fluoro-1H-pyrazol-1-yl)-N-(5-Fluoro-2-methoxybenzyl)-1H-indazole-5-amine; N-(5-fluoro-2-methoxybenzyl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-indazole-5-amine; N-(5-fluoro-2-methoxybenzyl)-3-(4-(trifluoromethyl)-1H-imidazol-1-yl)-1H-indazole-5-amine; 6-((5-fluoro-2-methoxybenzyl)amino)-N-hydroxy-1H-indazole-3-carboxamide; 6-((5-fluoro-2-methoxybenzyl)amino)-N-methyl-1H-indazole-3-carboxamide; N-Cyclopropyl-5-((5-Fluoro-2-methoxybenzyl)amino)-1H-indazole-3-carboxamide; N-(2,2-difluoroethyl)-5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazole-3-carboxamide; (3,3-Difluoropyrrolidone-1-yl)(5-((5-fluoro-2-methoxybenzyl(amino)-1H-indazol-3-yl)methyl ketone; (5-((5-fluoro-2-methoxybenzyl)amino)-1H-indazol-3-yl)(3-hydroxypyrrolidone-1-yl)methyl ketone; 6-((2-(dimethylphosphoryl)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-isopropoxybenzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-((tetrahydrofuran-3-yl)oxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-(2-hydroxyethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((2-(difluoromethoxy)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-(2-fluoroethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((2-(2,2-difluoroethoxy)-5-fluorobenzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-(2,2,2-trifluoroethoxy)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide; 5-((5-fluoro-2-(methylsulfonyl)benzyl)amino)-N-methyl-1H-indazole-3-carboxamide; N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(1H-1,2,4-triazol-1-yl)-1H-indazol-5-amine; N-(2-(2,2-difluoroethoxy)-5-fluorobenzyl)-3-(1H-1,2,3-triazol-1-yl)-1H-indazol-5-amine; (S)-N-(1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethyl)-3-(1H-1,2,4-triazol-1-yl)-1H-indazol-5-amine; or (R)-N-(1-(2-(2,2-difluoroethoxy)-5-fluorophenyl)ethyl)-3-(1H-1,2,4-triazol-1-yl)-1H-indazole-5-amine.

6. A pharmaceutical composition, characterized by: The pharmaceutical composition comprises a therapeutically effective amount of any one of claims 1-5 of an N-(3-fluorobenzyl)-1H-indazole-5-amine derivative and a pharmaceutically acceptable carrier or excipient, said derivative being a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug.

7. Use of an N-(3-fluorobenzyl)-1 H-indazol-5-amine derivative according to any one of claims 1 to 5 or of a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the prophylaxis or treatment of a disease which is associated with the expression or activity of a TRK kinase, characterized in that: The derivative is a 3-fluorobenzylamine-substituted indazole compound having the structure shown in general formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug.

8. Use according to claim 7, characterized in that: The drug is used to prevent or treat tumors, cancer, or severe pain caused by various reasons.

9. Use of N-(3-fluorobenzyl)-1 H-indazol-5-amine derivatives according to any one of claims 1 to 5 or of pharmaceutical compositions according to claim 6 for the manufacture of a medicament for the prophylaxis or treatment of tumors, characterized in that: The derivative is a 3-fluorobenzylamine-substituted indazole compound having a structure shown in general formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof.

10. Use according to claim 9, characterized in that: The tumor is selected from one or more of the following: non-small cell lung cancer, melanoma, glioblastoma, astrocytoma and other tumors carrying NTRK gene fusion.

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