Novel heterocyclic histone deacetylase inhibitors and pharmaceutical compositions containing the same

Abstract

The present invention relates to a novel heterocyclic histone deacetylase inhibitor, a new therapeutic agent for histone deacetylase-associated diseases, and a pharmaceutical composition containing the same. More specifically, the compound according to the present invention exhibits more selective and effective HDAC6 inhibitory activity against HDAC6 among histone deacetylases (HDACs), and can therefore be usefully used as a therapeutic agent for various diseases such as HDAC6-associated diseases, for example, cancer diseases, inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases.

Description

[Technical Field]

[0001] The present invention relates to novel heterocyclic compounds having histone deacetylase inhibitory activity and medical uses thereof, and in particular to HDAC6 inhibitors that are more selective and effective against HDAC6 among histone deacetylases (HDACs), and to the treatment of histone deacetylase-related diseases. [Background technology]

[0002] Histone deacetylases (HDACs) play an important role in gene expression, differentiation, and cellular homeostasis by facilitating the removal of acetate groups from acetylated 3-aminolysine residues in histones and non-histone proteins. HDACs are divided into four classes and 18 subtypes: class I (HDACs 1, 2, 3, and 8), class II (HDACs 4, 5, 7, 9, 6, and 10), class III (SIRT1-7), and class IV (HDAC11). HDACs belonging to classes I, II, and IV are involved in the regulation of Zn 2+ Class III HDACs are characterized as nicotinamide adenine dinucleotide (NAD)-dependent enzymes, while Class III HDACs are characterized as nicotinamide adenine dinucleotide (NAD)-dependent enzymes.

[0003] Among these HDACs, HDAC6 consists of 1215 amino acid residues, including CD1 and CD2 catalytic domains at the N-terminus and central region, respectively. The C-terminus contains a zinc finger ubiquitin-binding domain that promotes interaction between the ubiquitin proteasome and aggresome pathways. In addition to histone deacetylation, HDAC6 also induces deacetylation of non-histone proteins, such as α-tubulin, cortactin, tau, peroxiredoxin, and heat shock protein 90 (HSP90).

[0004] Numerous reports have shown that HDAC6 is involved in various physiological processes such as cell migration, autophagy, endocytosis, protein transport, apoptosis, and degradation. These important physiological functions make HDAC6 an effective therapeutic target for various human diseases such as cancer, inflammation, and immune disorders.

[0005] Currently, various HDAC inhibitors have been developed, and five FDA-approved HDAC inhibitor anticancer drugs are currently in use. However, these drugs are non-selective HDAC inhibitors, and the development of selective inhibitors that target specific isoforms with reduced side effects is needed. Due to the high similarity between HDAC types, finding a selective inhibitor is not an easy task, and there is a strong demand for the development of more selective and effective HDAC6 inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide novel HDAC6 inhibitors.

[0007] Another object of the present invention is to provide a method for inhibiting HDAC6 using the novel HDAC6 inhibitor.

[0008] A further object of the present invention is to provide a therapeutic agent for HDAC6-related diseases through the discovery of novel HDAC6 inhibitors.

[0009] Another object of the present invention is to provide a method for treating an HDAC6-related disease, comprising administering a novel HDAC6 inhibitor to a subject in need of such treatment. [Means for solving the problem]

[0010] The present invention provides a compound selected from the group consisting of compounds represented by the following Chemical Formula 1 or pharmaceutically acceptable salts thereof:

[0011] [ka]

[0012] In the above Chemical Formula 1,

[0013] X is selected from hydrogen, fluorine, chlorine or bromine;

[0014] A is selected from substituted or unsubstituted phenyl, naphthyl, or heterocyclic compounds;

[0015] The substitution is with one or more substituents selected from (C1-C10) alkyl, (C1-C10) alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy;

[0016] the heterocyclic compound is a 5- or 6-ring heteroaryl compound,

[0017] n is an integer of 1 to 3.

[0018] The present invention also provides a pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-related disease, comprising a compound selected from the compounds represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof.

[0019] The present invention also provides a health functional food for improving or preventing histone deacetylase 6 (HDAC6)-related diseases, comprising a compound selected from the group consisting of compounds represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof.

[0020] The present invention also provides a composition for inhibiting histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof.

[0021] The present invention also provides a method for inhibiting histone deacetylase 6 (HDAC6), comprising treating a compound selected from the compounds represented by Formula 1 or pharmaceutically acceptable salts thereof.

[0022] The present invention also provides a method for treating a histone deacetylase 6 (HDAC6)-related disease, comprising administering a compound selected from the compounds represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof to a subject suffering from the histone deacetylase 6 (HDAC6)-related disease. [Effects of the Invention]

[0023] The present invention relates to novel heterocyclic histone deacetylase inhibitors, and in particular, by providing an HDAC6 inhibitor that is more selective and effective against HDAC6 among histone deacetylases (HDACs), it is possible to develop therapeutic agents for various diseases such as HDAC6-related diseases, such as cancer diseases, inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention will now be described in more detail.

[0025] The present inventors have made extensive efforts to develop more effective HDAC6 inhibitors, and as a result, have synthesized novel indazole-based HDAC6 inhibitors and confirmed their excellent HDAC6 inhibitory activity, thereby completing the present invention.

[0026] Accordingly, the present invention provides a compound selected from the group consisting of compounds represented by the following Chemical Formula 1 or pharmaceutically acceptable salts thereof:

[0027] [ka]

[0028] In the above Chemical Formula 1,

[0029] X is selected from hydrogen, fluorine, chlorine or bromine;

[0030] A is selected from substituted or unsubstituted phenyl, naphthyl, or heterocyclic compounds;

[0031] The substitution is with one or more substituents selected from (C1-C10) alkyl, (C1-C10) alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy;

[0032] the heterocyclic compound is a 5- or 6-ring heteroaryl compound,

[0033] n is an integer of 1 to 3.

[0034] The heterocyclic compound may be selected from the group consisting of, but is not limited to, thiophene, furan, pyrrozole, pyridine, pyran, oxazine, thiazine, pyrimidine, and piperazine.

[0035] Preferably, the compound is a compound represented by the following formula 1-1:

[0036] [ka]

[0037] In the above Chemical Formula 1-1,

[0038] X is hydrogen or fluorine;

[0039] A is selected from phenyl, naphthyl or pyrimidyl;

[0040] R 1 and R 2are the same or different and are selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy;

[0041] n is an integer of 1 to 3.

[0042] More preferably, the compound has the structure: i) A is selected from phenyl, naphthyl, or pyrimidyl; R 1 is selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy; R 2 is selected from hydrogen, (C1-C4)alkoxy or halo, and n is an integer from 1 to 2.

[0043] In one embodiment, the compound is 2-benzyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 50); 2-(4-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 51); 2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 52); 2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 53); hydroxyamide (Compound 53); 2-(4-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 54); 2-(4-Bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 55); 2-(3-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 56); 2-(4-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 57);2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 58); 2-Phenethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 59); 2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 60); 2-(3,5-Difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 61). hydroxyamide (Compound 61); 2-(4-Difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 62); 2-Biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (Compound 63); 2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 64); 2-(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 65);2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 66); 2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 67); 2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 68); 2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 69). hydroxyamide (Compound 69); 2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 70); 2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 71); 2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 72); 2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 73);The compound may be selected from the group consisting of 2-pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 76); 2-benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 88); 2-(3-chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 89); and 2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 90).

[0044] The compounds according to the present invention can more selectively inhibit histone deacetylase 6 (HDAC6).

[0045] The "pharmaceutically acceptable salt" can be used in the form of any one of a pharmaceutically acceptable basic salt or acid salt. The basic salt can be used in the form of any one of an organic basic salt or an inorganic basic salt, such as, but not limited to, sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt, and pyridinium salt.

[0046] Furthermore, acid salts formed with free acids are useful. The free acids may include inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, and phosphoric acid. Examples of organic acids include citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, and aspartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

[0047] Furthermore, the compounds according to the present invention may include not only pharmaceutically acceptable salts, but also any salts, hydrates and solvates that can be produced by conventional methods.

[0048] The addition salts according to the present invention can be prepared by a conventional method, for example, by dissolving the compound in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of an organic base or an aqueous solution of an inorganic base, followed by precipitation or crystallization. Alternatively, the solvent or excess base can be evaporated from the mixture, followed by drying to obtain the addition salt, or the precipitated salt can be filtered off with suction.

[0049] The present invention also provides a pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-related disease, comprising a compound selected from the compounds represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof.

[0050] The present invention also provides a method for treating a histone deacetylase 6 (HDAC6)-related disease, comprising administering a compound selected from the compounds represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof to a subject suffering from the histone deacetylase 6 (HDAC6)-related disease.

[0051] The histone deacetylase 6 (HDAC6)-associated disease may be selected from the group consisting of cancer diseases, inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases.

[0052] The cancer disease may be selected from the group consisting of colon cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, peritoneal metastatic cancer, skin cancer, prostate cancer, osteosarcoma, fibrous tumor, brain tumor, acute lymphocytic leukemia, acute myeloid leukemia, lymphoma, and neuroblastoma, but is not limited thereto.

[0053] The inflammatory disease or autoimmune disease includes osteoarthritis, rheumatoid arthritis, dermatitis, allergy, atopy, asthma, psoriasis, conjunctivitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, inflammatory bowel disease, lupus, hepatitis, cystitis, interstitial cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, Hashimoto thyroiditis, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection disease, autoimmune diabetes, and the like. The cause may be selected from the group consisting of, but not limited to, diabetes, diabetic retinopathy, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), Graves' disease, and acute and chronic inflammatory diseases.

[0054] The fibrotic disease may be selected from the group consisting of, but is not limited to, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, liver fibrosis, scleroderma, skeletal muscle fibrosis and diabetic fibrosis.

[0055] The liver fibrosis may also include, but is not limited to, non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

[0056] The degenerative disease is a degenerative neurological disease selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, and Lou Gehrig's disease, but is not limited to these.

[0057] The pharmaceutical composition may be provided in one or more dosage forms selected from the group consisting of gel, emulsion, injection, powder, granule, aerosol, paste, transdermal absorption agent and patch by a conventional method, but is not limited thereto.

[0058] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, glidants, flavoring agents, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders, and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0059] Specifically, carriers, excipients, and diluents that can be used include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginic acid, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid formulations can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Oral liquid formulations include suspensions, oral solutions, emulsions, syrups, etc., and in addition to the commonly used simple diluents of water and liquid paraffin, they contain various excipients such as humectants, sweeteners, flavorings, and preservatives. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Examples of suppository bases include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, and glycerogelatin.

[0060] The pharmaceutical compositions can be administered to a subject in the usual manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes.

[0061] The desired dosage of the compound varies depending on the condition and weight of the subject, the type and severity of the disease, the drug form, the route and duration of administration, and can be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dosage is, but is not limited to, 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg. The dosage may be administered once a day or in several divided doses, and the scope of the present invention is not limited thereto.

[0062] In the present invention, the "subject" is a mammal, including a human, but is not limited to these examples.

[0063] The present invention also provides a health functional food for improving or preventing histone deacetylase 6 (HDAC6)-related diseases, comprising a compound selected from the group consisting of compounds represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof.

[0064] The term "health functional food" refers to food manufactured and processed using raw materials or ingredients that have functional properties beneficial to the human body as defined by the Health Functional Food Act, and "functional" refers to food that is ingested for the purpose of adjusting nutrients to the structure and function of the human body or obtaining beneficial effects for health purposes such as physiological effects.

[0065] The functional health food may contain ordinary food additives, and unless otherwise specified, the suitability of a substance as a "food additive" shall be determined in accordance with the specifications and standards for the item in question, such as the general provisions and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety.

[0066] Examples of items listed in the "Food Additives Code" include chemically synthesized substances such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as indigo dye, licorice extract, crystalline cellulose, sorghum pigment, and guar gum; and mixed preparations such as monosodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0067] The effective dose of the active ingredient contained in the health functional food can be used in accordance with the effective dose of the therapeutic agent, but in the case of long-term intake for the purpose of health and hygiene or health regulation, it is below the above range, and it is certain that the active ingredient can be used in an amount greater than the above range because there are no safety issues.

[0068] The types of the health functional foods are not particularly limited, and examples include meats, sausages, bread, chocolates, candies, snacks, sweets, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, drinking water, tea, energy drinks, alcoholic beverages, and vitamin complexes.

[0069] The present invention also provides a composition for inhibiting histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds represented by Chemical Formula 1 or pharmaceutically acceptable salts thereof.

[0070] The present invention also provides a method for inhibiting histone deacetylase 6 (HDAC6), comprising treating a compound selected from the compounds represented by Formula 1 or pharmaceutically acceptable salts thereof.

[0071] The description of the compound is the same as that given above, so a repeated description will be omitted.

[0072] The composition can be used as a pharmaceutical composition, a health functional food, a reagent composition, etc.

[0073] The present invention will be described in more detail with reference to the following examples. It will be obvious to those skilled in the art that these examples are merely for the purpose of explaining the present invention in more detail, and that the scope of the present invention is not limited by these examples according to the gist of the present invention.

[0074] Example: Synthesis of indazole derivatives as HDAC6 inhibitors

[0075] Indazole derivatives as HDAC6 inhibitors were synthesized by the general process shown in the following Reaction Scheme 1, 2, or 3. The specific synthesis process will be described in detail below for each compound.

[0076] [Anti 1] JPEG0007823945000004.jpg74166

[0077] (a) Alkyl bromide / chloride, Cs2CO3, DMF, 100℃, 4-8 hours;

[0078] (b) 2N NaOH, MeOH, room temperature (rt), 6-12 h;

[0079] (c) NH2OH, BOP, DIPEA, DMSO, room temperature (rt), 6-8 hours.

[0080] [Anti 2] JPEG0007823945000005.jpg77166

[0081] (a) Alkyl bromide / chloride, Cs2CO3, DMF, 100℃, 4-8 hours;

[0082] (b) 2N NaOH, MeOH, room temperature (rt), 6-12 h;

[0083] (c) NH2OH, BOP, DIPEA, DMSO, room temperature (rt), 6-8 hours.

[0084] [Anti 3] JPEG0007823945000006.jpg79166

[0085] (a) H2SO4, HNO3, 0℃, 3 hours;

[0086] (b) H2SO4, MeOH, 65 °C, 20 h;

[0087] (c) Pd / C, H2, EtOAc, room temperature (rt), 2 h;

[0088] (d) KOAc, AcOH, isoamyl nitrate, CHCl3, room temperature (rt), 3 h;

[0089] (e) Alkyl bromide / chloride, Cs2CO3, DMF, room temperature (rt), 2 h;

[0090] (f) 2N NaOH, MeOH, THF, room temperature (rt), 2 h;

[0091] (g) NH2OH, BOP, DIPEA, DMSO, room temperature (rt), 6-8 hours.

[0092] 1. Synthesis of N2-substituted 2H-indazole-6-carboxylic acid methyl ester compounds (Compounds 2, 25, and 74)

[0093] A mixture of indazole (1; 5.02 mmol), alkyl bromide / chloride (5.52 mmol), and CsCO (5.52 mmol) in DMF (15 mL) was heated at 100 °C for 4-8 hours. After completion of the reaction, the reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The N-substituted indazole derivatives (2-25, 74) were isolated by column chromatography using hexane:ethyl acetate (80:20) as the eluent.

[0094] 1) 2-Benzyl-2H-indazole-6-carboxylic acid methyl ester [2-Benzyl-2H-indazole-6-carboxylic acid methyl ester; Compound 2]

[0095] White solid; 45% yield 1 H NMR (500MHz, DMSO-d6) δ8.62(s, 1H), 8.30(s, 1H), 7.84(d, J=8.7Hz, 1H), 7.57(d, J=8.7Hz, 1H), 7.42-7.29(m, 5H), 5.72(s, 2H), 3.88(s, 3H).

[0096] 2) 2-(4-Methoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [2-(4-Methoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; Compound 3]

[0097] White solid; 42% yield 1 H NMR (500MHz, DMSO) δ8.56(s, 1H), 8.29(s, 1H), 7.82(d, J=8.8Hz, 1H), 7.56(d, J=8.8Hz, 1 H), 7.35(d, J=8.6Hz, 2H), 6.93(d, J=8.6Hz, 2H), 5.63(s, 2H), 3.88(s, 3H), 3.73(s, 3H).

[0098] 3) 2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 4]

[0099] White solid; 40% yield 1 H NMR (500MHz, DMSO-d6) δ8.58(s, 1H), 8.29(s, 1H), 7.83(d, J=8.7Hz, 1H), 7.57(d, J=8.7Hz , 1H), 7.27(d, J=7.6Hz, 2H), 7.17(d, J=7.6Hz, 2H), 5.66(s, 2H), 3.88(s, 3H), 2.28(s, 3H).

[0100] 4) 2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 5]

[0101] White solid; 38% yield 1H NMR (500MHz, DMSO-d6) δ8.62 (s, 1H), 8.29 (s, 1H), 7.84 (d, J=8.7Hz, 1H), 7.57 (d , J=8.7Hz, 1H), 7.49-7.40(m, 2H), 7.23-7.17(m, 2H), 5.71(s, 2H), 3.88(s, 3H).

[0102] 5)2-(4-Chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; compound 6]

[0103] White solid; yield 41%, 1 H NMR (500MHz, DMSO-d6) δ8.63 (s, 1H), 8.29 (s, 1H), 7.84 (d, J=9.5Hz, 1H), 7.58 (d, J= 9.5Hz, 1H), 7.44 (d, J=8.5Hz, 2H), 7.38 (d, J=8.5Hz, 2H), 5.73 (s, 2H), 3.88 (s, 3H).

[0104] 6)2-(4-Bromobenzyl)-2H-indazole-5-carboxylic acid methyl ester; compound 7]

[0105] White solid; yield 39%, 1 H NMR (500MHz, MeOD-d4) δ8.41 (s, 1H), 8.39 (s, 1H), 7.80 (d, J=8.7Hz, 1H), 7.69 (d, J= 8.7Hz, 1H), 7.54 (d, J=7.5Hz, 2H), 7.27 (d, J=7.5Hz, 2H), 5.68 (s, 2H), 3.95 (s, 3H).

[0106] 7) 2-(3-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [2-(3-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; Compound 8]

[0107] 8) 2-(4-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [2-(4-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; Compound 9]

[0108] White solid; 40% yield 1 H NMR (500MHz, DMSO-d6) δ8.65(s, 1H), 8.31(s, 1H), 7.86-7.27(m, 6H), 5.77(s, 2H), 3.88(s, 3H).

[0109] 9) 2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid methyl ester [2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid methyl ester; Compound 10]

[0110] White solid; 45% yield 1 H NMR (500MHz, DMSO-d6) δ8.68(s, 1H), 8.30(s, 1H), 7.93-7.89(m, 4H), 7.85(d, J=8.8Hz, 1H), 7.61-7.47(m, 4H), 3.88(s, 3H).

[0111] 10) 2-Phenethyl-2H-indazole-5-carboxylic acid methyl ester [2-Phenethyl-2H-indazole-5-carboxylic acid methyl ester; Compound 11]

[0112] White solid; 41% yield 1H NMR (500MHz, DMSO-d6) δ8.39 (s, 1H), 8.31 (s, 1H), 7.79 (d, J=9.4Hz, 1H), 7.55 (d, J=9. 4Hz, 1H), 7.25-7.18 (m, 5H), 4.75 (t, J=7.3Hz, 2H), 3.89 (s, 3H), 3.29 (t, J=7.3Hz, 2H).

[0113] 11)2-(2-4-メトキシフェニルエチル)-2H-インダゾール-5-カルボンメチルエステル[2 -(2-4-Methoxyphenylethyl)-2H-indazole-5-carboxylic acid methyl ester; compound 12]

[0114] White solid; yield 42%, 1 H NMR (500MHz, DMSO-d6) δ8.37 (s, 1H), 8.33 (s, 1H), 7.78 (d, J=8.7Hz, 1H), 7.56 (d, J=8.7Hz, 1H), 7.09 (d, J= 8.6Hz, 2H), 6.81 (d, J=8.6Hz, 2H), 4.69 (t, J=7.3Hz, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 3.22 (t, J=7.3Hz, 2H).

[0115] [ 2-(3,5-Difluorobenzyl)-2H-indazole-5-carboxylic acid methyl ester; compound 13]

[0116] White solid; yield 38%, 1 H NMR (500MHz, DMSO-d6) δ8.66 (s, 1H), 8.31 (s, 1H), 7.86 (d, J=9.4Hz, 1H), 7.59 (d, J=9. 4Hz, 1H), 7.21 (tt, J=8.9Hz, 2.3Hz, 1H), 7.11-7.05 (m, 2H), 5.76 (s, 2H), 3.88 (s, 3H).

[0117] 13) 2-(4-Difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [2-(4-Difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; Compound 14]

[0118] White solid; 39% yield 1 H NMR (500MHz, DMSO-d6) δ8.63(s, 1H), 8.29(s, 1H), 7.84(d, J=8.8Hz, 1H), 7.57(d, J=8.8Hz, 1H), 7.44(d, J=8.6Hz, 2H), 7.36(t, J=74.0, 1H), 7.18(d, J=8.6), 5.72(s, 2H), 3.88(s, 3H).

[0119] 14) 2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid methyl ester [2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid methyl ester; Compound 15]

[0120] White solid; 42% yield 1 H NMR (500MHz, DMSO-d6) δ8.66(s, 1H), 8.31(s, 1H), 7.85(d, J=8.7Hz, 1H), 7.71-7.61(m, 4H) , 7.58(d, J=8.7Hz, 1H), 7.47-7.43(m, 4H), 7.37(t, J=7.3Hz, 1H), 5.77(s, 2H), 3.88(s, 3H).

[0121] 15) 2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 16]

[0122] White solid; 36% yield 1H NMR (500MHz, CDCl3) δ8.52 (s, 1H), 7.90 (s, 1H), 7.70 (dd, J=8.8, 1.3Hz, 1H), 7.64 (dd, J=8.8, 0.8Hz , 1H), 7.25-7.20 (m, 4H), 5.59 (s, 2H), 3.95 (s, 3H), 2.90 (hept, J=6.9Hz, 1H), 1.23 (d, J=6.9Hz, 6H).

[0123] 16)2-(2-(4-フルオロフェニル)エチル)-2H-インダゾール-6-カルボンメチルエステル[2 -(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid methyl ester; compound 17]

[0124] White solid; yield 20%, 1 H NMR (500MHz, CDCl3) δ8.52 (s, 1H), 7.70 (dd, J=8.6, 1.1Hz, 2H), 7.62 (dd, J=8.6, 0.6Hz, 1H), 7. 06-6.97 (m, 2H), 6.97-6.87 (m, 2H), 4.63 (t, J=7.1Hz, 2H), 3.96 (s, 3H), 3.31 (t, J=7.1Hz, 2H).

[0125] 17)2-(3-フルオロベンジル)-2H-インダゾール-6-カルボンメチルエステル[ 2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; compound 18]

[0126] White solid; yield 39%, 1 H NMR (500MHz, CDCl3) δ8.52 (d, J=1.3Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J=8.8, 1.4Hz, 1H), 7.64 (d, J=8. 8Hz, 1H), 7.30 (q, J=8.0Hz, 1H), 7.11-6.97 (m, 2H), 6.95 (d, J=9.5Hz, 1H), 5.58 (s, 2H), 3.93 (s, 3H); 13C NMR (125MHz, CDCl3) δ167.5, 163.0, 148.3, 137.8, 130.6, 128.1, 124.2, 123.5, 123.3, 121.6, 121.4, 120.3, 115.5, 114.93, 57.2, 52.2.

[0127] 18) 2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 19]

[0128] White solid; 39% yield 1 H NMR (500MHz, CDCl3) δ8.52(s, 1H), 7.95(s, 1H), 7.72(dd, J=8.8, 1.3Hz, 1H), 7.67(dd, J=8.8, 0.7Hz, 1H), 7.34-7.28(m, 3H), 7.17(d, J=7.0Hz, 1H), 5.60(s, 2H), 3.95(s, 3H).

[0129] 19) 2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 20]

[0130] White solid; 36% yield 1 H NMR (500MHz, CDCl3) δ8.52(q, J=1.1Hz, 1H), 7.97(d, J=1.1Hz, 1H), 7.73(dd, J=8.7, 1.4Hz, 1H), 7.67(dd, J=8.7, 1.0Hz, 1H), 7.60(d, J=7.4Hz, 1H), 7.59-7.57(m, 1H), 7.52-7.41(m, 2H), 5.68(s, 2H), 3.95(s, 3H); 13C NMR (125MHz, CDCl3) δ167.5, 148.4, 136.4, 131.3, 131.3, 129.6, 128.2, 125.5, 124.7, 123.8, 124.3, 123.2, 121.8, 121.5, 120.2, 57.3, 52.2.

[0131] 20) 2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 21]

[0132] White solid; 37% yield 1 H NMR (500MHz, CDCl3) δ8.52(d, J=1.1Hz, 1H), 7.97(d, J=1.1Hz, 1H), 7.72(dd, J=8.8, 1.4Hz, 1H), 7. 66(dd, J=8.8, 1.0Hz, 1H), 7.60(d, J=8.1Hz, 2H), 7.37(d, J=8.1Hz, 2H), 5.67(s, 2H), 3.94(s, 3H).

[0133] 21) 2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 22]

[0134] White solid; 39% yield 1 H NMR (500MHz, CDCl3) δ8.52(d, J=0.9Hz, 1H), 7.91(d, J=0.9Hz, 1H), 7.70(dd, J=8.8, 1.3Hz, 1H), 7.64(dd, J=8.8, 0 .6Hz, 1H), 7.27(t, J=7.9Hz, 1H), 6.91-6.85(m, 2H), 6.83(d, J=1.7Hz, 1H), 5.58(s, 2H), 3.94(s, 3H), 3.76(s, 3H); 13C NMR (125MHz, CDCl3) δ167.6, 160.1, 148.1, 136.7, 130.1, 127.9, 124.2, 123.1, 121.5, 121.4, 120.3, 120.2, 114.0, 113.8, 57.9, 55.3, 52.2.

[0135] 22) 2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 23]

[0136] White solid; 42% yield 1 H NMR (500MHz, CDCl3) δ8.52(d, J=1.1Hz, 1H), 7.89(d, J=1.1Hz, 1H), 7.71(dd, J=8.8, 1.4Hz, 1H), 7.65(dd, J=8. 8, 0.9Hz, 1H), 7.39-7.27(m, 6H), 6.96-6.94(m, 1H), 6.92-6.84(m, 2H), 5.59(s, 2H), 5.02(s, 2H), 3.95(s, 3H); 13 C NMR (125MHz, CDCl3) δ167.6, 159.2, 148.1, 136.8, 136.6, 130.1, 128.6, 128.1, 127. 9, 127.5, 124.2, 123.2, 121.5, 121.4, 120.6, 120.3, 115.0, 114.7, 70.0, 57.8, 52.2.

[0137] 23) 2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 24]

[0138] White solid; 40% yield 1H NMR (500MHz, CDCl3) δ8.51 (d, J=1.1Hz, 1H), 7.92 (d, J=1.1Hz, 1H), 7.69 (dt, J=8.8, 1.4Hz, 1H), 7.6 5-7.63(m, 1H), 6.46-6.37(m, 3H), 5.54-5.52(m, 2H), 3.94(q, J=1.4Hz, 3H), 3.74(q, J=1.4Hz, 6H); 13 C NMR (125MHz, CDCl3) δ167.6, 161.3, 148.1, 137.4, 127.9, 124.2, 123.2, 121.5, 121.4, 120.3, 106.2, 100.3, 58.0, 55.4, 52.2.

[0139] 24) 2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; Compound 25]

[0140] White solid; 32% yield 1 H NMR (500MHz, CDCl3) δ8.51(d, J=1.1Hz, 1H), 7.92(d, J=1.1Hz, 1H), 7.70(dd, J=8.8, 1.4Hz, 1H), 7.64(dd, J=8.8, 0 .9Hz, 1H), 7.31-7.27(m, 3H), 7.14-7.06(m, 1H), 7.02-6.96(m, 3H), 6.96-6.90(m, 2H), 5.57(s, 2H), 3.93(s, 3H); 13 C NMR (125MHz, CDCl3) δ167.5, 158.0, 156.6, 148.2, 137.3, 130.4, 129.9, 128.0, 12 4.2, 123.7, 123.2, 122.5, 121.5, 121.4, 120.2, 119.2, 118.5, 118.2, 57.6, 52.2.

[0141] 25) 2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid methyl ester [2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid methyl ester; Compound 74]

[0142] White solid; 51% yield 1 H NMR (500MHz, CDCl3) δ8.72-8.55(m, 2H), 8.51(d, J=1.0Hz, 1H), 7.98(d, J=0.6Hz, 1H), 7.72(dd, J=8.8, 1. 3Hz, 1H), 7.67(dd, J=8.8, 0.8Hz, 1H), 7.61(d, J=7.9Hz, 1H), 7.33-7.27(m, 1H), 5.65(s, 2H), 3.95(s, 3H).

[0143] 2. Synthesis of N-substituted 2H-indazole-6-carboxylic acids (compounds 26, 49, and 75)

[0144] N-substituted 2H-indazole-6-carboxylic acid methyl esters (Compounds 2, 25, and 74, 1 mmol) were dissolved in methanol (5-10 ml), and 2N NaOH solution (1-2 ml) was slowly added. The reaction mixture was stirred at room temperature for 6-12 hours, then poured into water and neutralized with 2N HCl. The precipitate was filtered and dried to obtain the carboxylic acid derivatives (Compounds 26, 49, and 75).

[0145] 1) 2-Benzyl-2H-indazole-5-carboxylic acid [2-Benzyl-2H-indazole-5-carboxylic acid; Compound 26]

[0146] White solid; 75% yield 1 H NMR (500MHz, DMSO-d6) δ12.88(s, 1H), 8.60(s, 1H), 8.27(s, 1H), 7.80(d, J=8.8Hz, 1H), 7.57(d, J=8.8Hz, 1H), 7.41-7.28(m, 5H), 5.71(s, 2H).

[0147] 2) 2-(4-Methoxybenzyl)-2H-indazole-5-carboxylic acid [2-(4-Methoxybenzyl)-2H-indazole-5-carboxylic acid; Compound 27]

[0148] White solid; yield 64%, 1 H NMR (500MHz, DMSO-d6) δ12.87 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.79 (d, J=8.7Hz, 1H), 7.5 6 (d, J=8.7Hz, 1H), 7.35 (d, J=8.2Hz, 2H), 6.93 (d, J=8.2Hz, 2H), 5.62 (s, 2H), 3.73 (s, 3H).

[0149] 3) 2-(4-Methylbenzyl)-2H-インダゾール-5-カルボン acid [2-(4-Methylbenzyl)-2H-indazole-5-carboxylic acid; Compound 28]

[0150] White solid; yield 69%, 1 H NMR (500MHz, DMSO-d6) δ12.88 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.79 (d, J=8.7Hz, 1H), 7.5 6 (d, J=8.7Hz, 1H), 7.26 (d, J=7.9Hz, 2H), 7.17 (d, J=7.9Hz, 2H), 5.65 (s, 2H), 2.27 (s, 3H).

[0151] 4) 2-(4-Fluorobenzyl)-2H-インダゾール-5-カルボン acid [2-(4-Fluorobenzyl)-2H-indazole-5-carboxylic acid; Compound 29]

[0152] White solid; yield 77%, 1 H NMR (500MHz, DMSO-d6) δ12.89 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.80 (d, J=8.5Hz, 1H), 7.57(d, J=8.5Hz, 1H), 7.45-7.41(m, 2H), 7.20(t, J=8.9Hz, 2H), 5.70(s, 2H).

[0153] 5) 2-(4-クロロベンジル)-2H-インダゾール-5-カルボン acid [2-(4-Chlorobenzyl)-2H-indazole-5-carboxylic acid; Compound 30]

[0154] Color solid; yield 71%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 7.81 (d, J=9.4Hz, 1 H), 7.57(d, J=9.4Hz, 1H), 7.44(d, J=8.5Hz, 2H), 7.37(d, J=8.5Hz, 2H), 5.72(s, 2H).

[0155] 6) 2-(4-Bromobenzyl)-2H-インダゾール-5-カルボン acid [2-(4-Bromobenzyl)-2H-indazole-5-carboxylic acid; Compound 31]

[0156] White solid; yield 73%, 1 H NMR (500MHz, DMSO-d6) δ12.88 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.81 (d, J=8.5Hz, 1H), 7.58-7.56 (m, 3H), 7.31 (d, J=8.4Hz, 2H), 5.70 (s, 2H).

[0157] 7) 2-(3-Torotronic acid)-2H-indazole-5-carboxylic acid [2-(3-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid] acid; compound 32]

[0158] White solid; yield 79%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.80 (d, J=9.5Hz, 1H), 7.71 ( d, J=9.5Hz, 1H), 7.48 (t, J=7.8Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 7.29-7.25 (m, 2H), 5.76 (s, 3H).

[0159] 8) 2-(4-Torotronic acid [2-(4-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid)-2H-インダゾール-5-カルボン acid acid; compound 33]

[0160] White solid; yield 69%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.81 (d, J=9.4Hz, 1 H), 7.57(d, J=9.4Hz, 1H), 7.48(d, J=8.7Hz, 2H), 7.37(d, J=8.7Hz, 2H), 5.76(s, 2H).

[0161] 9) 2-Naphthalen-2-ylmethyl-2H-インダゾール-5-carboxylic acid [2-Naphthalen-2-ylmethyl-2H-indazole-5-carboxylic acid; Compound 34]

[0162] White solid; yield 71%, 1 H NMR (500MHz, DMSO-d6) δ12.89 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 7.92-7.90 (m, 4H), 7.82 (d, J=8.7Hz, 1H), 7.64-7.45 (m, 4H), 5.88 (s, 2H).

[0163] 10) 2-Phenethyl-2H-indazole-5-carboxylic acid [2-Phenethyl-2H-indazole-5-carboxylic acid]

[0164] White solid; yield 79%, 1 H NMR (500MHz, DMSO-d6) δ12.88 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.75 (d, J=9.2Hz, 1H), 7.55 (d, J =9.2Hz, 1H), 7.30-7.22(m, 2H), 7.21-7.19(m, 3H), 4.74(t, J=7.3Hz, 2H), 3.29(t, J=7.3Hz, 2H).

[0165] 11) 2-[2-(4-Methoxyphenylethyl)]-2H-indazole-5-carboxylic acid; Compound 36

[0166] White solid; 82% yield 1 H NMR (500MHz, DMSO-d6) δ12.90(s, 1H), 8.36(s, 1H), 8.29(s, 1H), 7.75(d, J=8.7Hz, 1H), 7.55(d, J=8.7Hz, 1 H), 7.09(d, J=8.6Hz, 2H), 6.81(d, J=8.6Hz, 2H), 4.68(t, J=7.3Hz, 2H), 3.69(s, 3H), 3.22(t, J=7.3Hz, 2H).

[0167] 12) 2-(3,5-Difluorobenzyl)-2H-indazole-5-carboxylic acid [2-(3,5-Difluorobenzyl)-2H-indazole-5-carboxylic acid; Compound 37]

[0168] White solid; 68% yield 1 H NMR (500MHz, DMSO-d6) δ12.96(s, 1H), 8.65(s, 1H), 8.28(s, 1H), 7.83(d, J=8.7Hz, 1H) , 7.58(d, J=8.7Hz, 1H), 7.23(tt, J=8.9Hz, 2.3Hz, 1H), 7.09-7.05(m, 2H), 5.75(s, 2H).

[0169] 13) 2-(4-Difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid [2-(4-Difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid; Compound 38]

[0170] White solid; 60% yield 1H NMR (500MHz, DMSO-d6) δ12.89 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.81 (d, J=8.7Hz, 1H), 7.57 ( d, J=8.7Hz, 1H), 7.44 (d, J=8.6Hz, 2H), 7.22 (t, J=74.0), 7.20 (d, J=8.6Hz, 2H), 5.71 (s, 2H).

[0171] 14) 2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid [2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid]

[0172] White solid; yield 71%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 7.82 (d, J=8.7Hz, 1H), 7.67 -7.62 (m, 4H), 7.58 (d, J=9.9Hz, 1H), 7.48-7.44 (m, 4H), 7.36 (t, J=7.4Hz, 1H), 5.76 (s, 2H).

[0173] 15) 2-(4-イソプロピルベンジル)-2H-インダゾール-6-カルボン acid [2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid; compound 40]

[0174] White solid; yield 96%, 1 H NMR (500MHz, DMSO-d6) δ12.85 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=8.7Hz, 1H), 7.55 (d, J=8.7Hz, 1H), 7.28(d, J=8.1Hz, 2H), 7.22(d, J=8.1Hz, 2H), 5.64(s, 2H), 2.90-2.81(m, 1H), 1.16(d, J=6.9Hz, 6H).

[0175] 16)2-[2-(4-フルオロフェニルエチル)]-2H-インダゾール-6-カルボン acid [2-[2-(4-Fluorophenylethyl)]-2H-indazole-6-carboxylic acid; compound 41]

[0176] White solid; yield 61%, 1 H NMR (500MHz, DMSO-d6) δ12.88 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.75 (d, J=8.7Hz, 1H), 7.55 (d, J=8.7H z, 1H), 7.21 (dd, J=8.3, 5.7Hz, 2H), 7.07 (t, J=8.3Hz, 2H), 4.72 (t, J=7.2Hz, 2H), 3.28 (t, J=7.2Hz, 2H).

[0177] 17) 2-(3-Fluorobenzyl)-2H-インダゾール-6-カルボン acid [2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid; compound 42]

[0178] White solid; yield 83%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 7.81 (d, J=8.7Hz, 1H), 7.57(d, J=8.7Hz, 1H), 7.40(q, J=7.5Hz, 1H), 7.27-7.05(m, 3H), 5.73(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.2, 162.6, 148.0, 139.8, 131.2, 128.8, 125.4, 124.5, 124.0, 121.4, 121.2, 120.5, 115.4, 115.2, 56.4.

[0179] 18) 2-(3-Chlorobenzyl)-2H-インダゾール-6-カルボン acid [2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid; Compound 43]

[0180] White solid; yield 92%, 1H NMR (500MHz, DMSO-d6) δ12.90(s, 1H), 8.63(s, 1H), 8.26(s, 1H), 7.81(d, J=8.8Hz, 1H), 7. 56(dd, J=8.8, 1.2Hz, 1H), 7.42(s, 1H), 7.41-7.33(m, 2H), 7.33-7.25(m, 1H), 5.72(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.2, 148.0, 139.4, 133.6, 131.1, 128.7, 128.5, 128.3, 127.2, 125.4, 124.0, 121.5, 121.2, 120.5, 98.7, 56.3.

[0181] 19) 2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid [2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid; Compound 44]

[0182] White solid; 97% yield 1 H NMR (500MHz, DMSO-d6) δ12.90(s, 1H), 8.66(s, 1H), 8.26(s, 1H), 7.82(d, J= 8.7Hz, 1H), 7.77(s, 1H), 7.72-7.68(m, 1H), 7.64-7.53(m, 3H), 5.83(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.2, 148.1, 141.3, 138.5, 132.7, 130.3, 129.7, 128.8, 125.6, 125.3, 125.1, 124.0, 121.5, 121.2, 120.5, 56.3.

[0183] 20) 2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid [2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid; Compound 45]

[0184] White solid; 93% yield 1H NMR (500MHz, DMSO-d6) δ12.91 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.82 (d, J=8.8Hz, 1H), 7.73(d, J=8.2Hz, 2H), 7.57(dd, J=8.8, 1.2Hz, 1H), 7.51(d, J=8.1Hz, 2H), 5.83(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.2, 148.1, 141.8, 141.8, 129.1, 128.8, 126.0, 125.6, 124.0, 121.6, 121.5, 121.2, 120.5, 56.4.

[0185] 21) 2-(3-Methoxybenzyl)-2H-インダゾール-6-カルボン acid [2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid; Compound 46]

[0186] White solid; yield 67%, 1 H NMR (500MHz, DMSO-d6) δ12.86 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.79 (d, J=8.6Hz, 1H), 7 .56(d, J=8.6Hz, 1H), 7.27(t, J=7.6Hz, 1H), 6.98-6.83(m, 3H), 5.66(s, 2H), 3.73(s, 3H); 13 C NMR (125MHz, DMSO-d6) δ159.9, 147.9, 138.5, 130.3, 125.2, 125.1, 124.0, 121.4, 121.1, 121.1, 120.6, 120.5, 117.5, 114.3, 113.8, 57.0, 55.6.

[0187] 22) 2-(3-Benzyloxybenzyl)-2H-インダゾール-6-カルボン acid [2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid; Compound 47]

[0188] White solid; yield 98%, 1H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.80 (d, J=8.5Hz, 1H), 7.57 (d, J=8 .5Hz, 1H), 7.45-7.18(m, 6H), 7.01(s, 1H), 6.93(dd, J=24.9, 7.7Hz, 2H), 5.66(s, 2H), 5.06(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.3, 158.9, 147.9, 138.5, 137.3, 130.3, 128.9, 128. 3. 128.2, 125.2, 124.0, 121.4, 121.1, 120.8, 120.6, 115.2, 114.6, 69.7, 57.0.

[0189] 23) 2-(3,5-ジメトキシベンジル)-2H-インダゾール-6-carboxylic acid [2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid; compound 48]

[0190] White solid; yield 87%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.79 (d, J=8.7Hz, 1H), 7 .62-7.51(m, 1H), 6.51(d, J=2.1Hz, 2H), 6.45(t, J=2.1Hz, 1H), 5.61(s, 2H), 3.70(s, 6H); 13 C NMR (125MHz, DMSO-d6) δ168.3, 161.1, 147.9, 139.1, 128.6, 125.2, 124.0, 121.4, 121.1, 120.6, 106.7, 99.9, 57.1, 55.7.

[0191] 24) 2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid [2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid; Compound 49]

[0192] White solid; yield 99%, 1H NMR (500MHz, DMSO-d6) δ12.91 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 7.79 (d, J=8.7Hz, 1H), 7.56 (d, J=8.7Hz, 1H), 7.43-7 .30 (m, 3H), 7.14 (t, J=7.4Hz, 1H), 7.07 (d, J=7.7Hz, 1H), 7.05-6.94 (m, 3H), 6.92 (dd, J=8.1, 2.0Hz, 1H), 5.70 (s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.3, 157.3, 156.7, 148.0, 139.3, 130.8, 130.6, 125. 3. 124.2, 124.0, 123.3, 121.4, 121.2, 121.1, 120.5, 119.3, 118.5, 118.3, 56.6.

[0193] 25) 2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid [2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid]

[0194] White solid; yield 80%, 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 9.02 (s, 1H), 8.88 (d, J=5.4Hz, 1H), 8.77 (s, 1H), 8.46 (d, J=8.1H z, 1H), 8.25 (s, 1H), 8.03-7.98 (m, 1H), 7.84 (d, J=8.8Hz, 1H), 7.57 (dd, J=8.8, 1.2Hz, 1H), 6.00 (s, 2H); 13 C NMR (125MHz, DMSO-d6) δ168.1, 148.3, 145.1, 142.6, 142.3, 136.4, 129.0, 127.5, 126.2, 123.9, 121.7, 121.4, 120.5, 53.3.

[0195] 3.Synthesis of N2-substituted された2H-インダゾール-6-カルボン acid ヒドロキシアミド inducer (compound 50-compound 73, compound 76)

[0196] A mixture of carboxylic acid derivatives (compounds 26-49 and 75; 1 mmol), hydroxyamine hydrochloride (3 mmol), BOP (benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate; 1.7 mmol), and DIPEA (diisopropylethylamine; 3 mmol) was added to DMSO (5-10 ml) and stirred at room temperature for 6-8 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The product was purified by column chromatography using chloroform:methanol (90:10) as the eluent.

[0197] 1) SPA3602 [2-benzyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 50)]

[0198] White solid; 68% yield 1 H NMR (500MHz, DMSO-d6) δ11.22(s, 1H), 9.02(s, 1H), 8.56(s, 1H), 8.02(s, 1H), 7.77(d, J=8.7Hz, 1H), 7.41(d, J=8.7Hz, 1H), 7.39-7.29(m, 5H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 147.9, 137.2, 130.6, 129.0, 128.4, 124.8, 123.1, 121.3, 120.0, 116.8, 56.9; MS (in mouse) 79.3, (in human) 97.6.

[0199] 2) SPA3603 [2-(4-methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 51)]

[0200] White solid; yield 62% 1H NMR (500MHz, DMSO-d6) δ11.22 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.75 (d, J=8.7Hz, 1 H), 7.40 (d, J=8.7Hz, 1H), 7.33 (d, J=8.7Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 5.60 (s, 2H), 3.73 (s, 3H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 159.5, 14738, 130.5, 130.0, 129.1, 124.4, 123.1, 121.2, 119.9, 11638, 114.4, 56.5, 55.5; MS (in mouse) 98.6, (in human) 76.7.

[0201] 3) SPA3606 [2-(4-メチルベンジル)-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 52)]

[0202] White solid; yield 75%, 1 H NMR (500MHz, DMSO-d6) δ11.22 (s, 1H), 9.01 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=8.7Hz, 1 H), 7.40(d, J=8.7Hz, 1H), 7.24(d, J=8.0Hz, 2H), 7.17(d, J=8.0Hz, 2H), 5.63(s, 2H), 2.28(s, 3H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 147.8, 137.7, 137.7, 134.1, 130.4, 129.6, 128.4, 124.7, 123.0, 121.2, 119.9, 116.7, 56.7, 21.1.

[0203] 4) SPA3608 [2-(4-フルオロベンジル)-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 53)]

[0204] White solid; yield 66%, 1H NMR (500MHz, DMSO-d6) δ11.23(s, 1H), 9.02(s, 1H), 8.56(s, 1H), 8.02(s, 1H), 7.77(d, J=8.7Hz, 1H), 7.39-7.43(m, 3H), 7.20(t, J=8.8Hz, 2H), 5.68(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 163.2, 161.3, 147.9, 133.4, 130.7, 130.6, 124.8, 121.3, 120.0, 116.8, 115.8, 56.1; MS (in mouse) 71.3, (in human) 85.9.

[0205] 5) SPA3610 [2-(4-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 54)]

[0206] White solid; 77% yield; 1 H NMR (500MHz, DMSO-d6) δ11.28(s, 1H), 9.07(s, 1H), 8.61(s, 1H), 8.07(s, 1H), 7.82(d, J=8.7Hz, 1H), 7.45-7.49(m, 3H), 7.40(d, J=8.4Hz, 2H), 5.74(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 148.0, 136.1, 133.1, 130.7, 130.3, 129.0, 125.0, 123.1, 121.1, 120.1, 116.8, 56.1; MS (in mouse) 40.8, (in human) 49.3.

[0207] 6) SPA3612 [2-(4-bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 55)]

[0208] White solid; 59% yield 1H NMR (500MHz, DMSO-d6) δ11.23(s, 1H), 9.02(s, 1H), 8.56(s, 1H), 8.02(s, 1H), 7.77(d, J=8. 7Hz, 1H), 7.57(d, J=8.4Hz, 2H), 7.41(d, J=8.7Hz, 1H), 7.28(d, J=8.4Hz, 2H), 5.68(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 148.0, 136.6, 132.0, 130.7, 130.6, 125.1, 123.0, 121.6, 121.6, 120.1, 116.8, 56.1.

[0209] 7) SPA3614 [2-(3-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 56)]

[0210] White solid; 74% yield 1 H NMR (500MHz, DMSO-d6) δ11.23(s, 1H), 9.03(s, 1H), 8.61(s, 1H), 8.03(s, 1H), 7.79(d, J=8.7Hz, 1H), 7.50(t, J=7.9Hz, 1H), 7.42(d, J=8.7Hz, 1H), 7.37(s, 1H), 7.31-7.35(m, 2H), 5.77(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 148.7, 148.0, 139.9, 131.1, 130.7, 127.4, 125.2, 123.0, 122.0, 121.4, 120.8, 120.1, 119.4, 116.8, 56.1.

[0211] 8) SPA3616 [2-(4-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 57)]

[0212] White solid; 71% yield 1H NMR (500MHz, DMSO-d6) δ11.22 (s, 1H), 9.02 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.78 (d, J=8. 7Hz, 1H), 7.46 (d, J=8.7Hz, 2H), 7.41 (d, J=8.7Hz, 1H), 7.37 (d, J=8.7Hz, 2H), 5.74 (s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 148.4, 148.0, 136.7, 130.7, 125.1, 123.1, 121.7, 121.3, 120.8, 120.1, 117.0, 116.8, 56.1.

[0213] 9) SPA3618 [2-ナフタレン-2-イルメチル-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 58)]

[0214] White solid; yield 71%, 1 H NMR (500MHz, DMSO-d6) δ11.23 (s, 1H), 9.02 (s, 1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.89-7.93 (m, 4H), 7 .78(d, J=8.7Hz, 1H), 7.57-7.50(m, 2H), 7.48(d, J=7.7Hz, 1H), 7.42(d, J=8.7Hz, 1H), 5.86(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 147.9, 134.7, 133.2, 132.9, 130.6, 128.7, 128.2, 127.3, 126.9, 126.3, 125.0, 123.1, 121.3, 120.0, 116.8, 57.1.

[0215] 10) SPA3620 [2-フェネチル-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 59)]

[0216] White solid; yield 77%, 1H NMR (500MHz, DMSO-d6) δ11.25(s, 1H), 9.04(s, 1H), 8.32(s, 1H), 8.04(s, 1H), 7.72(d, J=8.6H) z, 1H), 7.38(d, J=8.6Hz, 1H), 7.17-7.27(m, 5H), 4.72(t, J=6.9Hz, 2H), 3.28(t, J=6.9Hz, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 147.6, 138.4, 129.0, 128.8, 126.9, 124.7, 122.7, 121.2, 119.8, 116.7, 54.5, 36.4.

[0217] 11) SPA3622 [2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 60)]

[0218] White solid; yield 66% 1 H NMR (500MHz, DMSO-d6) δ11.25(s, 1H), 9.04(s, 1H), 8.31(s, 1H), 8.04(s, 1H), 7.72(d, J=8.7Hz, 1H), 7.38(d, J=8. 7Hz, 1H), 7.08(d, J=8.6Hz, 2H), 6.81(d, J=8.6Hz, 2H), 4.66(t, J=7.2Hz, 2H), 3.69(s, 3H), 3.20(t, J=7.2Hz, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 158.3, 147.6, 130.4, 130.2, 130.1, 124.7, 122.7, 121.2, 119.7, 116.7, 114.2, 55.4, 54.8, 35.6.

[0219] 12) SPA3624 [2-(3,5-difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 61)]

[0220] White solid; 79% yield 1H NMR (500MHz, DMSO-d6) δ11.24(s, 1H), 9.03(s, 1H), 8.60(s, 1H), 8.04(s, 1H), 7.79(d, J=8.7Hz) , 1H), 7.42(d, J=8.7Hz, 1H), 7.21(tt, J=8.9Hz, 2.3Hz, 1H), 7.05(d, J=6.2Hz, 2H), 5.73(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 163.7, 161.8, 148.1, 141.4, 130.8, 125.4, 123.0, 121.4, 120.2, 116.8, 111.5, 103.9, 55.8.

[0221] 13) SPA3626 [2-(4-difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 62)]

[0222] White solid; yield 62% 1 H NMR (500MHz, DMSO-d6) δ11.22(s, 1H), 9.02(s, 1H), 8.56(s, 1H), 8.02(s, 1H), 7.76(d, J=8.7, 1H ), 7.39-7.43(m, 3H), 7.21(t, J=74.0, 1H), 7.17(d, J=8.8, 2H), 7.26-6.99(m, 3H), 5.69(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 151.0, 147.9, 134.1, 130.6, 130.2, 124.9, 123.1, 121.3, 120.0, 119.4, 118.8, 116.8, 56.2.

[0223] 14) SPA3628 [2-biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 63)]

[0224] White solid; 78% yield 1H NMR (500MHz, DMSO-d6) δ11.23 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.79 (d, J =8.7Hz, 1H), 7.63-7.67(m, 4H), 7.51-7.40(m, 5H), 7.37(t, J=7.3Hz, 1H), 5.74(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.2, 147.9, 140.3, 140.1, 136.4, 130.6, 129.4, 129.0, 128.0, 127.3, 127.1, 125.0, 123.1, 121.3, 120.0, 116.8, 56.6.

[0225] 15) SPA3630 [2-(4-イソプロピルベンジル)-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 64)]

[0226] Light yellow solid; yield 77%, 1 H NMR (500MHz, DMSO-d6) δ11.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=8.7Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.28 (d, J=8.0Hz, 2H), 7.23 (d, J=8.0Hz, 2H), 5.63 (s, 2H), 2.91-2.84 (m, 1H), 1.14 (dd, J=33.7, 6.8Hz, 6H).

[0227] 16)SPA3632[2-(2-4-フルオロフェニルエチル)-2 H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 65)]

[0228] Red solid; yield 19%, 1 H NMR (500MHz, DMSO-d6) δ11.23 (s, 1H), 9.01 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.72 (d, J=8.7Hz, 1H), 7.38 (d, J =8.7Hz, 1H), 7.20 (dd, J=8.4, 5.7Hz, 2H), 7.07 (t, J=8.4Hz, 2H), 4.70 (t, J=7.2Hz, 2H), 3.27 (t, J=7.2Hz, 2H).

[0229] 17) SPA3634 [2-(3-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 66)]

[0230] White solid; yield 67% 1 H NMR (500MHz, DMSO-d6) δ11.24(s, 1H), 9.05(s, 1H), 8.58(s, 1H), 8.03(s, 1H) ), 7.78(d, J=8.7Hz, 1H), 7.47-7.33(m, 2H), 7.21-7.09(m, 3H), 5.71(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 161.6, 148.0, 139.9, 131.1, 130.7, 125.2, 124.5, 123.1, 121.4, 120.1, 116.8, 115.3, 115.1, 56.3.

[0231] 18) SPA3636 [2-(3-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 67)]

[0232] Light orange solid; 90% yield 1 H NMR (500MHz, DMSO-d6) δ11.22(s, 1H), 9.01(s, 1H), 8.59(s, 1H), 8.02(s, 1H), 7.78(d, J=8.7Hz, 1H), 7.52-7.32(m, 4H), 7.28(s, 1H), 5.70(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ148.0, 139.6, 133.6, 131.0, 130.8, 128.4, 128.2, 127.1, 125.2, 123.1, 121.4, 120.1, 116.8, 108.3, 56.2.

[0233] 19) SPA3638 [2-(3-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 68)]

[0234] White solid; yield 63% 1H NMR (500MHz, DMSO-d6) δ11.23(s, 1H), 9.03(s, 1H), 8.62(s, 1H), 8.03(s, 1H), 7.79(d, J=8.8Hz, 1H), 7.75(s, 1H), 7.72-7.65(m, 1H), 7.60(d, J=5.2Hz, 2H), 7.42(d, J=8.8Hz, 1H), 5.81(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 148.1, 138.6, 132.6, 130.8, 130.3, 129.7, 125.3, 125.2, 125.0, 124.5, 123.1, 121.4, 120.2, 116.8, 56.2.

[0235] 20) SPA3640 [2-(4-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 69)]

[0236] White solid; yield 62% 1 H NMR (500MHz, DMSO-d6) δ11.23(s, 1H), 9.02(s, 1H), 8.61(s, 1H), 8.02(s, 1H), 7.83-7.76(m, 1H), 7.73(d, J=8.1Hz, 2H), 7.49(d, J=8.1Hz, 2H), 7.41(dd, J=8.7, 1.4Hz, 1H), 5.81(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 148.1, 141.9, 130.8, 129.0, 128.9, 126.0, 125.4, 124.6, 123.1, 121.4, 120.2, 116.8, 56.3.

[0237] 21) SPA3642 [2-(3-methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 70)]

[0238] White solid; 77% yield 1H NMR (500MHz, DMSO-d6) δ11.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=8.7Hz, 1H), 7.43-7.35 (m, 1H), 7.26 (t, J=7.9Hz, 1H), 6.92 (s, 1H), 6.90-6.81 (m, 2H), 5.64 (s, 2H), 3.72 (s, 3H).

[0239] 22) SPA3644 [2-(3-ベンジルオキシベンジル)-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 71)]

[0240] White solid; yield 54%, 1 H NMR (500MHz, DMSO-d6) δ11.23 (s, 1H), 9.02 (s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.77 (d, J=8.7Hz, 1H), 7.46 -7.23(m, 7H), 7.00(s, 1H), 6.97(dd, J=8.3, 2.6Hz, 1H), 6.90(d, J=7.6Hz, 1H), 5.65(s, 2H), 5.07(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ165.3, 158.9, 147.9, 138.7, 137.3, 130.6, 130.2, 128.9, 1 28.3, 128.2, 125.0, 123.1, 121.3, 120.7, 120.0, 116.9, 115.1, 114.5, 69.7, 56.9.

[0241] 23) SPA3646 [2-(3,5-ジメトキシベンジル)-2H-インダゾール-6-カルボン acid ヒドロキシアミド (Compound 72)]

[0242] White solid; yield 40%, 1 H NMR (500MHz, DMSO-d6) δ11.21 (s, 1H), 9.01 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.76 ( d, J=8.8Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 6.65-6.31 (m, 3H), 5.59 (s, 2H), 3.70 (s, 6H).

[0243] 24) SPA3648 [2-(3-phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 73)]

[0244] White solid; yield 67% 1 H NMR (500MHz, DMSO-d6) δ8.55(s, 1H), 8.01(s, 1H), 7.76(d, J=8.7Hz, 1H), 7.46-7.28(m, 4H), 7.14(t , J=7.4Hz, 1H), 7.06(d, J=7.7Hz, 1H), 7.04-6.95(m, 3H), 6.91(dd, J=8.2, 2.5Hz, 1H), 5.68(s, 2H); 13 C NMR (125MHz, DMSO-d6) δ157.3, 156.7, 147.9, 139.4, 130.7, 130.7, 130.6, 1 25.1, 124.1, 123.3, 123.1, 121.4, 120.1, 119.2, 118.4, 118.2, 116.8, 56.5.

[0245] 25) SPA3650 [2-pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 76)]

[0246] 4. Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid compound (compound 78)

[0247] 2-Fluoro-4-methyl-5-nitrobenzoic acid (1.95 mmol) was completely dissolved in HSO (3 mL) at 0°C, and then a mixture of HSO (2.34 mmol) and HNO (2.92 mmol) was slowly added dropwise and reacted for 3 hours. After the reaction was complete, the reaction mixture was poured into ice water, and the precipitate was filtered and dried to obtain nitrobenzoic acid (compound 78). 1) 2-Fluoro-4-methyl-5-nitrobenzoic acid [2-Fluoro-4-methyl-5-nitrobenzoic acid; Compound 78]

[0248] White solid; 93% yield 1H NMR (500MHz, DMSO-d6) δ13.76(s, 1H), 8.45(d, J=6.8Hz, 1H), 7.55(d, J=11.3Hz, 1H), 2.59(s, 3H). 13 C NMR (125MHz, DMSO-d6) δ163.6, 162.9, 145.1, 141.8, 129.4, 121.7, 118.4, 20.4.

[0249] 5. Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid methyl ester compound (Compound 79)

[0250] 2-Fluoro-4-methyl-5-nitrobenzoic acid (compound 78, 1.51 mmol) was dissolved in methanol (3 ml), and H2SO4 (7.53 mmol) was slowly added dropwise. The reaction mixture was stirred at 65 °C for 20 hours. When the reaction was complete, the reaction mixture was poured into ice water, and the precipitate was filtered and dried to obtain 2-fluoro-4-methyl-5-nitrobenzoic acid methyl ester (compound 79). 1) 2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester [2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester; Compound 79]

[0251] White solid; 89% yield 1 H NMR (500MHz, DMSO-d6) δ8.48(d, J=6.8Hz, 1H), 7.61(d, J=11.4Hz, 1H), 3.89(s, 3H), 2.60(s, 3H). 13 C NMR (125MHz, DMSO-d6) δ162.7, 162.7, 145.2, 142.4, 129.2, 121.9, 117.2, 53.3, 20.5.

[0252] 6. Synthesis of 5-amino-2-fluoro-4-methylbenzoic acid methyl ester compound (Compound 80)

[0253] 2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester (compound 79) was completely dissolved in ethyl acetate (5 ml) under N2 gas, and then Pd / C was added. After replacing the N2 gas with Ar gas, the mixture was stirred at room temperature (rt) for 2 hours. Once the reaction was complete, the Pd / C was removed by celite filtration to terminate the reaction. 5-Amino-2-fluoro-4-methylbenzoic acid methyl ester (compound 80) was isolated by column chromatography using hexane:ethyl acetate (2:1) as the eluent.

[0254] 1) 5-Amino-2-fluoro-4-methylbenzoic acid methyl ester [5-Amino-2-fluoro-4-methylbenzoic acid methyl ester; Compound 80] Brown solid; yield 91% 1 H NMR (500MHz, DMSO-d6) δ7.10(d, J=6.6Hz, 1H), 6.91(d, J=11.7Hz, 1H), 4.99(s, 2H), 3.79(s, 3H), 2.09(s, 3H). 13 C NMR (125MHz, DMSO-d6) δ165.0, 153.3, 143.6, 129.6, 118.2, 115.5, 115.3, 52.4, 18.0.

[0255] 7. Synthesis of 5-fluoro-1H-indazole-6-carboxylic acid methyl ester compound (Compound 81)

[0256] A mixture of 5-amino-2-fluoro-4-methylbenzoic acid methyl ester (compound 80, 0.55 mmol), KOAc (0.28 mmol), and acetic anhydride (1.38 mmol) in chloroform (5 mL) was stirred at room temperature (rt) for 1 hour. Isoamyl nitrite (5.51 mmol) was then added, and the mixture was heated at 65°C for 3 hours. After completion of the reaction, the reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, and the crude product was extracted with chloroform. 5-Fluoro-1H-indazole-6-carboxylic acid methyl ester (compound 81) was isolated by column chromatography using hexane:ethyl acetate (1:1) as the eluent.

[0257] 1) 5-Fluoro-1H-indazole-6-carboxylic acid methyl ester [5-Fluoro-1H-indazole-6-carboxylic acid methyl ester; Compound 81]

[0258] Yellow solid; 16% yield 1 H NMR (500MHz, CDCl3) δ10.30(s, 1H), 8.17(d, J=5.5Hz, 1H), 8.12(s, 1H), 7.47(d, J=10.6Hz, 1H), 3.98(s, 3H). 13 C NMR (125MHz, CDCl3) δ165.2, 156.4, 136.0, 134.9, 125.6, 119.0, 113.9, 106.7, 52.7.

[0259] 8. Synthesis of N2-substituted 5-fluoro-2H-indazole-6-carboxylic acid methyl ester compounds (Compounds 82-84)

[0260] A mixture of 5-fluoro-1H-indazole-6-carboxylic acid methyl ester (compound 81; 0.53 mmol), alkyl bromide / chloride (0.58 mmol), and CsCO (0.58 mmol) in DMF (2 mL) was reacted at room temperature (rt) for 2 hours. After completion of the reaction, the reaction mixture was poured into water, and the crude product was extracted with ethyl acetate. The N-substituted 5-fluoro-indazole derivatives (compounds 82-84) were separated by column chromatography using hexane:ethyl acetate (3:1) as the eluent.

[0261] 1) 2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid methyl ester [2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid methyl ester; Compound 82]

[0262] Yellow solid; 55% yield 1H NMR (500MHz, CDCl3) δ8.31(d, J=6.3Hz, 1H), 7.77(s, 1H), 7.30-7.24(m, 3H), 7.21-7.15(m, 3H), 5.51(s, 2H), 3.85(s, 3H). 13 C NMR (125MHz, CDCl3) δ165.3, 156.3, 145.1, 135.1, 129.1, 128.7, 128.1, 123.9, 123.2, 123.1, 120.0, 104.9, 58.1, 52.4.

[0263] 2) 2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester [2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester; Compound 83]

[0264] Yellow solid; 35% yield 1 H NMR (500MHz, CDCl3) δ8.41(d, J=6.3Hz, 1H), 7.91(s, 1H), 7.35-7.26(m, 4H), 7.16(dt, J=6.9, 1.5Hz, 1H), 5.58(s, 2H), 3.96(s, 3H). 13 C NMR (125MHz, CDCl3) δ165.2, 145.2, 144.2, 136.0, 130.4, 128.9, 128.1, 126.1, 124.0, 123.9, 123.1, 122.0, 120.3, 120.3, 104.6, 57.4, 52.5.

[0265] 3) 2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester [2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester; Compound 84]

[0266] Yellow solid; 32% yield 1H NMR (500MHz, CDCl3) δ8.41(d, J=6.2Hz, 1H), 7.88(s, 1H), 7.35-7.24(m, 2H) , 6.88(d, J=8.2Hz, 2H), 6.82(s, 1H), 5.58(s, 2H), 3.96(s, 3H), 3.77(s, 3H). 13 C NMR (125MHz, CDCl3) δ165.3, 160.1, 156.3, 145.0, 136.5, 130.2, 123.89, 123.87, 123.2, 123.0, 120.3, 120.0, 113.9, 104.6, 58.0, 55.3, 52.4.

[0267] 9. Synthesis of N2-substituted 5-fluoro-2H-indazole-6-carboxylic acids (compounds 85-87)

[0268] N-substituted 5-fluoro-2H-indazole-6-carboxylic acid methyl esters (Compounds 82-84, 0.34 mmol) were dissolved in methanol (1 mL) and THF (1 mL), and 2N NaOH solution (0.5 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours, then poured into water and neutralized with 2N HCl. The precipitate was filtered and dried to give the carboxylic acid derivatives (Compounds 85-87).

[0269] 1) 2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid [2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid; Compound 85]

[0270] Yellow solid; 76% yield 1 H NMR (500MHz, DMSO-d6) δ13.08(s, 1H), 8.47(s, 1H), 8.09(d, J=6.4Hz, 1H), 7.48(d, J=11.5Hz, 1H), 7.36-7.17(m, 5H), 5.61(s, 2H). 13 C NMR (125MHz, DMSO-d6) δ166.0, 156.7, 144.9, 136.9, 129.1, 128.53, 128.51, 125.3, 122.9, 122.8, 120.8, 105.7, 57.2.

[0271] 2) 2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid [2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid; Compound 86]

[0272] White solid; 65% yield 1 H NMR (500MHz, MeOD) δ8.43-8.22(m, 2H), 7.49-7.19(m, 5H), 5.67(s, 2H).

[0273] 3) 2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid [2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid; Compound 87]

[0274] White solid; 99% yield 1 H NMR (500MHz, MeOD) δ8.32(s, 1H), 8.29(d, J=6.3Hz, 1H), 7.43(dd, J=11.2, 1. 7Hz, 1H), 7.27(t, J=7.8Hz, 1H), 6.93-6.85(m, 3H), 5.63(s, 2H), 3.76(s, 3H). 13 C NMR (125MHz, MeOD) δ166.4, 160.1, 156.2, 144.8, 137.2, 129.6, 124.6, 123.1, 122.4, 122.4, 119.8, 113.4, 104.6, 57.1, 54.3.

[0275] 10. Synthesis of N2-substituted 2-benzyl-5-fluoro-2H-indazole-6-carboxylic acids (compounds 88-90)

[0276] A mixture of carboxylic acid derivatives (compounds 85-87; 0.27 mmol), hydroxylamine hydrochloride (0.82 mmol), BOP (0.41 mmol), and DIPEA (0.82 mmol) was added to DMSO (1-2 ml) and stirred at room temperature for 6-8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The product was purified by column chromatography using chloroform:methanol (90:10) as the eluent.

[0277] 1) SPA3659 [2-benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 88)]

[0278] Brown solid; yield 18% 1 H NMR (500MHz, DMSO-d6) δ11.05(s, 1H), 9.27(s, 1H), 8.15(s, 1H), 7.94(d, J=5.3Hz, 1H), 7.65(d, J=10.0Hz, 1H), 7.37-7.17(m, 5H), 5.71(s, 2H).

[0279] 2) SPA3662 [2-(3-chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 89)]

[0280] Light yellow solid; 24% yield 1 H NMR (500MHz, MeOD) δ8.37(s, 1H), 7.92(d, J=5.9Hz, 1H), 7.46(d, J=10.6Hz, 1H), 7.35-7.30(m, 3H), 7.28-7.22(m, 1H), 5.65(s, 2H). 13 C NMR (125MHz, MeOD) δ163.8, 155.9, 145.1, 138.2, 134.3, 130.1, 128.1, 127.6, 126.0, 124.9, 123.1, 122.2, 119.4, 104.4, 56.3.

[0281] 3) SPA3663 [2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 90)]

[0282] Brown solid; yield 22% 1 H NMR (500MHz, MeOD) δ8.36(s, 1H), 7.94(d, J=5.6Hz, 1H), 7.48(d, J=10.5Hz, 1H), 7.35-7.24(m, 1H), 6.97-6.87(m, 3H), 5.64(s, 2H), 3.78(s, 3H).

[0283] <Experimental Example 1> Evaluation of HDAC6 and HDAC8 inhibitory activity of synthetic compounds

[0284] 1) Deacetylation and development processes of the substrate

[0285] 2X HDAC enzyme was dispensed into each well of the reaction plate, except for the control wells without HDAC enzyme, which were dispensed with buffer. Compounds dissolved in 100% DMSO were added to the enzyme mixture using acoustic technology (Echo550, nanoliter range), spun down, and pre-incubated at room temperature for 10 minutes. 2X substrate mixture (Fluorogenic HDAC substrate) was added to all reaction wells, initiated, and spun down. HDAC6 was incubated for 1 hour, and HDAC8 for 2 hours at 30°C.

[0286] The reaction was stopped by adding a developer solution containing trichostatin A to induce fluorescence. Kinetic measurements were performed at 5-minute intervals for 20 minutes using Envision (Ex / Em = 360 / 460 nm), and after the development reached a plateau, an end-point reading was taken for analysis.

[0287] 2) HDAC6 and HDAC8 inhibitory activity of synthetic compounds

[0288] As a result of examining the inhibitory activity of the synthesized compounds against HDAC6 and HDAC8, SPA3602, 3603, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3621, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3638, 3640, 3642, 3644, 3646, and 3648 had IC values ​​in the range of 1.3 to 29.3 nM, as shown in the following table. 50 It showed effective inhibitory activity against HDAC6 and an IC50 range of 500.3–8392.0 nM against HDAC8. 50 These results confirm that the N2-substituted derivatives are selective yet effective inhibitors of HDAC6, and may be used as therapeutic agents for a variety of diseases, including cancer, inflammatory diseases, autoimmune diseases, and fibrotic diseases.

[0289] [Table 1-1] [Table 1-2]

[0290] [Table 2-1] [Table 2-2]

[0291] Formulation examples of compositions containing compound 50 (SPA3602) according to the present invention will be described below, but the present invention is not limited thereto and is merely provided for illustrative purposes.

[0292] <Formulation Example 1> Formulation example of pharmaceutical composition

[0293] <Prescription Example 1-1> Manufacturing of powder

[0294] 20 mg of compound 50 (SPA3602), 100 mg of lactose, and 10 mg of talc were mixed and filled into an airtight cloth to prepare a powder.

[0295] <Prescription Example 1-2> Tablet manufacturing

[0296] 10 mg of Compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed and compressed into tablets by a conventional tablet manufacturing method.

[0297] <Prescription Example 1-3> Manufacturing of capsules

[0298] 10 mg of compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed, and then the ingredients were mixed and filled into a gelatin capsule according to a conventional capsule manufacturing method to prepare capsules.

[0299] <Prescription Example 1-4> Manufacturing of injections

[0300] 10 mg of Compound 50 (SPA3602), an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and then prepared according to a conventional injection manufacturing method with the above-mentioned ingredient content per ampoule (2 ml).

[0301] <Prescription Example 2> Dietary supplement

[0302] <Prescription Example 2-1> Manufacturing of health foods

[0303] 1 mg of compound 50 (SPA3602), an appropriate amount of a vitamin mixture (vitamin A acetate 70 μg, vitamin E 1.0 mg, vitamin B1 0.13 mg, vitamin B2 0.15 mg, vitamin B6 0.5 mg, vitamin B12 0.2 μg, vitamin C 10 mg, biotin 10 μg, nicotinamide 1.7 mg, folic acid 50 μg, calcium pantothenate 0.5 mg), and an appropriate amount of a mineral mixture (ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium monophosphate 15 mg, calcium phosphate 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, magnesium chloride 24.8 mg) were mixed together, and then granules were prepared, followed by producing a health food product by a conventional method.

[0304] <Prescription Example 2-2> Manufacturing a health drink

[0305] Compound 50 (SPA3602) 1 mg, citric acid 1000 mg, oligosaccharide 100 g, plum concentrate 2 g, taurine 1 g, and purified water were added to a total volume of 900 ml, and the ingredients were mixed according to a typical health drink manufacturing method, followed by stirring and heating at 85°C for about 1 hour. The resulting solution was then filtered and placed in a sterilized 2 L container, which was then sealed and sterilized and stored in a refrigerator.

[0306] While certain aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the true scope of the present invention is defined by the claims and their equivalents.

Claims

1. A compound selected from the group consisting of compounds represented by the following Chemical Formula 1 or pharmaceutically acceptable salts thereof: 【Chemistry 1】 In the above Chemical Formula 1, X is selected from hydrogen, fluorine, chlorine or bromine; A is selected from substituted or unsubstituted phenyl, naphthyl, or heterocycles; the substitution is with one or more substituents selected from (C1-C10) alkyl, (C1-C10) alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy; the heterocyclic compound is a 5- or 6-ring heteroaryl compound, n is an integer of 1 to 3.

2. 2. The compound of claim 1, wherein the heterocyclic compound is selected from the group consisting of thiophene, furan, pyrrozole, pyridine, pyran, oxazine, thiazine, pyrimidine, and piperazine.

3. The compound according to claim 1, wherein the compound is a compound represented by the following chemical formula 1-1: 【Chemistry 2】 In the above Chemical Formula 1-1, X is hydrogen or fluorine; A is selected from phenyl, naphthyl or pyrimidyl; R １ and R ２ are the same or different and are selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy; n is an integer of 1 to 3.

4. The compound is selected from the group consisting of i) A is selected from phenyl, naphthyl, and pyrimidyl; １ is selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy; R ２ 4. The compound of claim 3, wherein is selected from hydrogen, (C1-C4)alkoxy, or halo, and n is an integer from 1 to 2.

5. The compound is 2-benzyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 50); 2-(4-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 51); 2-(4-methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 52); 2-(4-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 53); 2-(4-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 54); 2-(4-bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 55); 2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 58); 2-phenethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 59); 2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 60); 2-(3,5-difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 61); 2-biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 63); 2-(4-isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 64); 2-(2-(4-fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 65); 2-(3-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 66); 2-(3-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 67); 2-(3-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 68); 2-(4-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 69); 2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 70); 2-(3-benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 71); 2-(3,5-dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 72); 2-(3-phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 73); 2-pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 76); 2-benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 88); 2-(3-chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 89); and 2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 90);

6. The compound of claim 1, wherein the compound selectively inhibits histone deacetylase 6 (HDAC6).

7. A pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-associated disease, comprising a compound selected from the compounds of claim 1 or pharmaceutically acceptable salts thereof.

8. The pharmaceutical composition according to claim 7, wherein the compound is a compound represented by the following formula 1-1: 【Transformation 3】 In the above Chemical Formula 1-1, X is hydrogen or fluorine; A is selected from phenyl, naphthyl or pyrimidyl; R １ and R ２ are the same or different and are selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy; n is an integer of 1 to 3.

9. The compound is selected from the group consisting of i) A is selected from phenyl, naphthyl, and pyrimidyl; １ is selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy; R ２ 8. The pharmaceutical composition of claim 7, wherein n is selected from hydrogen, (C1-C4) alkoxy or halo, and n is an integer from 1 to 2.

10. The compound is 2-benzyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 50); 2-(4-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 51); 2-(4-methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 52); 2-(4-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 53); 2-(4-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 54); 2-(4-bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 55); 2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 58); 2-phenethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 59); 2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 60); 2-(3,5-difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 61); 2-biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 63); 2-(4-isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 64); 2-(2-(4-fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 65); 2-(3-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 66); 2-(3-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 67); 2-(3-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 68); 2-(4-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 69); 2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 70); 2-(3-benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 71); 2-(3,5-dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 72); 2-(3-phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 73); 2-pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (compound 76); 2-benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 88); 2-(3-chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 89); and 8. The pharmaceutical composition of claim 7, wherein the compound is selected from the group consisting of: 2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide (compound 90).

11. The pharmaceutical composition of claim 7, wherein the histone deacetylase 6 (HDAC6)-associated disease is selected from the group consisting of cancer diseases, inflammatory diseases, autoimmune diseases, fibrotic diseases and degenerative diseases.

12. 12. The pharmaceutical composition of claim 11, wherein the cancer disease is selected from the group consisting of colon cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, peritoneal metastasis cancer, skin cancer, prostate cancer, osteosarcoma, fibrous tumor, brain tumor, acute lymphocytic leukemia, acute myeloid leukemia, lymphoma, and neuroblastoma.

13. 12. The pharmaceutical composition of claim 11, wherein the inflammatory or autoimmune disease is selected from the group consisting of osteoarthritis, rheumatoid arthritis, dermatitis, allergy, atopy, asthma, psoriasis, conjunctivitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, inflammatory bowel disease, lupus, hepatitis, cystitis, interstitial cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, Hashimoto's thyroid disease, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection disease, autoimmune diabetes, diabetic retinopathy, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive heart disease (COPD), Graves' disease, and acute and chronic inflammatory diseases.

14. The pharmaceutical composition of claim 11, wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, renal fibrosis, cardiac fibrosis, hepatic fibrosis, scleroderma, skeletal muscle fibrosis, and diabetic fibrosis.

15. 12. The pharmaceutical composition of claim 11, wherein the degenerative disease is a degenerative neurological disease selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, and Lou Gehrig's disease.

16. A health functional food for improving or preventing a histone deacetylase 6 (HDAC6)-associated disease, comprising a compound selected from the compounds according to claim 1 or pharmaceutically acceptable salts thereof.

17. A method for treating a histone deacetylase 6 (HDAC6)-associated disease, comprising administering a compound selected from the compounds of claim 1 or a pharmaceutically acceptable salt thereof to a subject (excluding humans) suffering from a histone deacetylase 6 (HDAC6)-associated disease.

18. A composition for inhibiting histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds of claim 1 or pharmaceutically acceptable salts thereof.

19. 2-(3-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 56); 2-(4-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (compound 57); and 2-(4-difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 62); 20. A pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-associated disease, comprising the compound of claim 19.

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