Novel histone deacetylase heterocyclic inhibitor and pharmaceutical composition containing same

Abstract

The present invention relates to a novel heterocyclic histone deacetylase (HDAC) inhibitor, a novel therapeutic agent for HDAC-related diseases, and a pharmaceutical composition comprising the inhibitor. More specifically, the compound according to the present invention exhibits more selective and more effective inhibitory activity against HDAC6 even in HDAC, and thus can be usefully used as a therapeutic agent for various HDAC6-related diseases such as cancer, inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases.

Description

Technical Field

[0001] The present invention relates to a novel heterocyclic compound having the ability to inhibit histone deacetylase and its medical use, and in particular to an HDAC6 inhibitor which is more selective and more effective against HDAC6 among histone deacetylases (HDACs), and the treatment of histone deacetylase-related diseases. Background Art

[0002] Histone deacetylase (HDAC) plays an important role in gene expression and differentiation as well as maintaining cell homeostasis by promoting the process of removing acetyl groups from acetylated 3-aminolysine residues on histones and non-histone proteins. HDAC includes four classes and 18 subtypes, which are divided into class I (HDAC1, 2, 3 and 8), class II (HDAC4, 5, 7, 9, 6 and 10), class III (SIRT1-7) and class IV (HDAC11). HDAC belongs to class I, II and IV. 2+ Class I HDACs are nicotinamide adenine dinucleotide (NAD)-dependent enzymes, whereas class III HDACs are characterized as nicotinamide adenine dinucleotide (NAD)-dependent enzymes.

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

[0004] Numerous reports have shown that HDAC6 is associated with a variety of physiological processes such as cell migration, autophagy, endocytosis, protein transport, apoptosis, and degradation, and due to these important physiological functions, HDAC6 is becoming an effective therapeutic target for a variety of human diseases (e.g., cancer, inflammation, and immune dysfunction).

[0005] To date, various types of HDAC inhibitors have been studied and developed, and five types of FDA-approved HDAC inhibitory anticancer drugs are in use. However, since these drugs are non-selective HDAC inhibitors, there is a need to develop selective inhibitors that target specific isoforms and thus have reduced side effects. Since there are great similarities between HDAC isoforms, it is not easy to discover isoform-selective inhibitors, but there is an urgent need to develop more selective and more effective HDAC6 inhibitors. Summary of the invention Technical Purpose

[0006] One object of the present disclosure is to provide a novel HDAC6 inhibitor.

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

[0008] Another object of the present disclosure is to provide therapeutic agents for HDAC6-related diseases by discovering novel HDAC6 inhibitors.

[0009] Another object of the present disclosure is to provide a method for treating an HDAC6-related disease, the method comprising administering a novel HDAC6 inhibitor to a subject in need of treatment for an HDAC6-related disease. Technical Solution

[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] [Chemical formula 1]

[0012]

[0013] In Chemical Formula 1,

[0014] X is selected from hydrogen, fluorine, chlorine or bromine,

[0015] A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,

[0016] The substitution is carried out by one or more substituents selected from (C1-C10) alkyl, (C1-C10) alkoxy, halogen, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy or phenoxy,

[0017] The heterocyclic compound is a heteroaryl compound having a 5-membered or 6-membered ring, and

[0018] n is an integer of 1 to 3.

[0019] In addition, the present disclosure provides a pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-related disease, the pharmaceutical composition comprising a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0020] In addition, the present disclosure provides a health functional food for improving or preventing histone deacetylase 6 (HDAC6) related diseases, the health functional food comprising a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0021] In addition, the present disclosure provides a composition for inhibiting histone deacetylase 6 (HDAC6), the composition comprising a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0022] In addition, the present disclosure provides a method for inhibiting histone deacetylase 6 (HDAC6), the method comprising treating a compound selected from the group consisting of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0023] In addition, the present disclosure provides a method for treating a histone deacetylase 6 (HDAC6)-related disease, the method comprising administering a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from the histone deacetylase 6 (HDAC6)-related disease. Beneficial Effects

[0024] The present disclosure relates to a novel heterocyclic histone deacetylase inhibitor, and in particular, by providing an HDAC6 inhibitor that is more selective and more effective against HDAC6 among histone deacetylases (HDACs), a treatment method for a variety of diseases (e.g., cancer, inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases) related to HDAC6 can be developed. DETAILED DESCRIPTION

[0025] Hereinafter, the present disclosure will be described in detail.

[0026] In order to develop more effective HDAC6 inhibitors, the present inventors have completed the present disclosure by synthesizing novel indazole-based HDAC6 inhibitors and identifying excellent HDAC6 inhibitory activities.

[0028] Therefore, the present disclosure provides a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

[0029] [Chemical formula 1]

[0030]

[0031] In Chemical Formula 1,

[0032] X may be selected from hydrogen, fluorine, chlorine or bromine,

[0033] A may be selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,

[0034] Substitution may be carried out by one or more substituents selected from (C1-C10)alkyl, (C1-C10)alkoxy, halogen, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy or phenoxy,

[0035] The heterocyclic compound may be a heteroaryl compound having a 5-membered or 6-membered ring, and

[0036] n may be an integer from 1 to 3.

[0037] The heterocyclic compound may be selected from the group consisting of thiophene, furan, pyrazole, pyridine, pyran, oxazine, thiazine, pyrimidine and piperazine, but is not limited thereto.

[0038] Preferably, the compound may be a compound represented by the following Chemical Formula 1-1:

[0039] [Chemical formula 1-1]

[0040]

[0041] In Chemical Formula 1-1,

[0042] X can be hydrogen or fluorine,

[0043] A may be selected from phenyl, naphthyl or pyrimidinyl,

[0044] R 1 and R 2 may be the same or different and are selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, difluoromethyl, trifluoromethyl, phenyl, benzyloxy or phenoxy, and

[0045] n may be an integer from 1 to 3.

[0046] More preferably, in the compound, i) A can be selected from phenyl, naphthyl or pyrimidinyl, R 1 can be selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, difluoromethyl, trifluoromethyl, phenyl, benzyloxy or phenoxy, R 2 It can be selected from hydrogen, (C1-C4) alkoxy or halogen, and n can be an integer from 1 to 2.

[0047] In an exemplary embodiment, the compound can be selected from the group consisting of the following compounds: 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-(3-trifluoromethoxybenzyl)-2H-indazole-6- Carboxylic acid hydroxyamide (Compound 56); 2-(4-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 57); 2-naphth-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide (Compound 58); 2-phenethyl-2H-indazole-6-carboxylic acid hydroxyamide (Compound 59); 2-(2-4-methoxyphenethyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 60); 2-(3,5-difluorobenzyl)-2H-indazole-6-carboxylic acid 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); 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).

[0048] The compounds according to the present disclosure are able to more selectively inhibit histone deacetylase 6 (HDAC6).

[0049] The term "pharmaceutically acceptable salt" as used herein can be used in the form of a pharmaceutically acceptable alkaline salt or an acidic salt. The alkaline salt can be used in any form of organic or inorganic salt, such as sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt and amine salt, ammonium salt, triethylamine salt and pyridinium salt, but is not limited thereto.

[0050] In addition, as acid salts, acid addition salts formed by free acids are useful. Inorganic acids and organic acids can be used as free acids, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid or phosphoric acid can be used as inorganic acids, and 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, pamoic acid, glutamic acid, citric acid and aspartic acid can be used as organic acids. Preferably, hydrochloric acid can be used as inorganic acid, and methanesulfonic acid can be used as organic acid.

[0051] Furthermore, the compounds according to the present disclosure may include not only pharmaceutically acceptable salts but also all salts, hydrates and solvates that can be prepared by conventional methods.

[0052] The addition salts according to the present disclosure can be prepared by conventional methods, for example, they can be prepared by dissolving the compound in a water-soluble organic solvent (e.g., acetone, methanol, ethanol or acetonitrile), and then precipitating or crystallizing by adding an excess of an aqueous solution of an organic or inorganic base. Alternatively, the solvent or excess base in the mixture is evaporated and dried to obtain an addition salt, or the precipitated salt is prepared by suction filtration.

[0054] In addition, the present disclosure provides a pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-related disease, the pharmaceutical composition comprising a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0056] In addition, the present disclosure provides a method for treating a histone deacetylase 6 (HDAC6)-related disease, the method comprising administering a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from the histone deacetylase 6 (HDAC6)-related disease.

[0058] The histone deacetylase 6 (HDAC6)-related disease may be selected from the group consisting of cancer diseases, inflammatory diseases, autoimmune diseases, fibrotic diseases and degenerative diseases.

[0059] The cancer disease can 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, colon cancer, peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, osteosarcoma, fibrous tumors, brain tumors, acute lymphocytic leukemia, acute myeloid leukemia, lymphoma and neuroblastoma, but is not limited thereto.

[0060] The above-mentioned inflammatory diseases or autoimmune diseases can be 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, Sjögren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, polymyositis, scleroderma, Addison disease, vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection, autoimmune diabetes, diabetic retinopathy, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive pulmonary disease (COPD), Graves' disease and acute and chronic inflammatory diseases, but are not limited thereto.

[0061] The fibrotic disease may be selected from the group consisting of pulmonary fibrosis, renal fibrosis, cardiac fibrosis, liver fibrosis, scleroderma, skeletal muscle fibrosis and diabetic fibrosis, but is not limited thereto.

[0062] In addition, liver fibrosis may include non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), but is not limited thereto.

[0063] The degenerative disease may be a neurodegenerative disease selected from the group consisting of cerebral infarction, stroke, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease and amyotrophic lateral sclerosis, but not limited thereto.

[0064] The pharmaceutical composition can be provided in one or more preparations according to conventional methods, and the preparations are selected from the group consisting of gel, emulsion, injection, acid, granule, aerosol, paste, transdermal absorption agent and patch, but are not limited thereto.

[0065] In another exemplary embodiment of the present disclosure, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, expanders, lubricants, glydents, flavoring agents, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and friction reducers commonly used in the manufacture of pharmaceutical compositions.

[0066] Specifically, for carrier, excipient and diluent, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talcum, magnesium stearate and mineral oil can be used, the solid preparation of oral administration comprises tablet, pill, acid agent, granule and capsule, wherein, these solid preparations can be prepared by mixing at least one or more excipients (such as starch, calcium carbonate, sucrose or lactose and gelatin) in the composition. Except simple excipient, lubricant can also be used, such as magnesium stearate and talcum. For oral liquid preparation, suspensoid, liquid, emulsion and syrup can be used, except common simple diluent (such as water and liquid paraffin), various excipients can also be included, such as humectant, sweetener, spices and preservative. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, and suppositories. For non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable esters (e.g., ethyl oleate) can be used. For the base of suppositories, witepsol, macrogol, Tween 61, cocoa butter, laurin butter, and glycerin gelatin can be used.

[0067] The pharmaceutical compositions may be administered to a subject in a conventional manner by intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhalation, topical, rectal, oral, intraocular or intradermal routes.

[0068] The preferred dosage of the compound can vary according to the condition and body weight of the subject, the type and severity of the disease, the drug form, and the route and duration of administration, and can be appropriately selected by those skilled in the art. According to exemplary embodiments of the present disclosure, the daily dose can be 0.01 mg / kg to 200 mg / kg, specifically 0.1 mg / kg to 200 mg / kg, and more specifically 0.1 mg / kg to 100 mg / kg, but not limited thereto. It can be administered once a day or in multiple separate doses, but the scope of the present disclosure is not limited thereto.

[0070] In the present disclosure, a "subject" may be a mammal including a human being, but is not limited to these examples.

[0072] In addition, the present disclosure provides a health functional food for improving or preventing histone deacetylase 6 (HDAC6) related diseases, the health functional food comprising a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0073] The term "health functional food" as used herein refers to food manufactured and processed with raw materials or ingredients that have useful functions for the human body in accordance with the Health Functional Food Act, and the term "functional" as used herein refers to nutrients that are ingested to obtain health benefits, such as physiological effects or regulation of human body structure and function.

[0074] Health functional foods may include conventional food additives, unless otherwise specified, whose suitability as “food additives” is determined by standards and guidelines related to corresponding items according to the general rules and general test methods of the Korean Food Additives Codex approved by the Ministry of Food and Drug Safety.

[0075] Items listed in the Korean Food Additives Code may include, for example, chemically synthesized compounds such as ketones, glycine, potassium citrate, niacin, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle alkali agents, preservatives, and tar coloring agents.

[0076] The effective dose of the active ingredient contained in the health functional food can be used according to the effective dose of the therapeutic agent, but in the case of long-term intake for health and hygiene purposes or for the purpose of health management, the amount may be lower than the above range, but since there is no problem in terms of safety, the active ingredient can certainly be used in an amount exceeding this range.

[0077] There are no specific restrictions on the types of health functional foods, such as meat, sausages, bread, chocolate, candy, snacks, sweets, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes.

[0079] In addition, the present disclosure provides a composition for inhibiting histone deacetylase 6 (HDAC6), the composition comprising a compound selected from the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0080] In addition, the present disclosure provides a method for inhibiting histone deacetylase 6 (HDAC6), the method comprising treating a compound selected from the group consisting of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0081] The description of the compound is the same as described above, and thus duplicate description is omitted.

[0082] The composition can be used as a pharmaceutical composition, a health functional food and a reagent composition. Example

[0084] Hereinafter, the present disclosure will be described in detail by way of examples. These examples are only intended to describe the present disclosure in more detail, and it is obvious to those skilled in the art that the scope of the present disclosure is not limited to these examples according to the spirit of the present disclosure.

[0086] <Example> Synthesis of indazole derivatives as HDAC6 inhibitors

[0087] As HDAC6 inhibitors, indazole derivatives are synthesized by a typical process according to the following Scheme 1, Scheme 2, or Scheme 3. The specific synthesis process of each compound will then be described in detail.

[0088] [Solution 1]

[0089]

[0090] (a) Alkyl bromide / chloride, Cs 2 CO 3 , DMF, 100°C, 4 to 8 hours;

[0091] (b) 2N NaOH, MeOH, room temperature (rt), 6 to 12 hours;

[0092] (c)NH 2 OH, BOP, DIPEA, DMSO, room temperature (rt), 6 to 8 hours.

[0093] [Solution 2]

[0095] (a) Alkyl bromide / chloride, Cs 2 CO 3, DMF, 100°C, 4 to 8 hours;

[0096] (b) 2N NaOH, MeOH, room temperature (rt), 6 to 12 hours;

[0097] (c)NH 2 OH, BOP, DIPEA, DMSO, room temperature (rt), 6 to 8 hours.

[0098] [Solution 3]

[0099]

[0100] (a)H 2 SO 4 , HNO 3 , 0℃, 3 hours;

[0101] (b)H 2 SO 4 , MeOH, 65 °C, 20 hours;

[0102] (c)Pd / C,H 2 , EtOAc, room temperature (rt), 2 hours;

[0103] (d) KOAc, AcOH, isoamyl nitrate, CHCl 3 , room temperature (rt), 3 hours;

[0104] (e) Alkyl bromide / chloride, Cs 2 CO 3 , DMF, room temperature (rt), 2 h;

[0105] (f) 2N NaOH, MeOH, THF, room temperature (rt), 2 h;

[0106] (g)NH 2 OH, BOP, DIPEA, DMSO, room temperature (rt), 6 to 8 hours.

[0108] 1. Synthesis of N2-substituted 2H-indazole-6-carboxylic acid methyl ester compounds (Compounds 2 to 25, Compound 74)

[0109] Indazole (1; 5.02 mmol), alkyl bromide / chloride (5.52 mmol) and Cs 2 CO 3A mixture of (5.52 mmol) was heated at 100°C for 4 to 8 hours. After the reaction was completed, the reaction mixture was added to water and the crude product was extracted with ethyl acetate. Using hexane: ethyl acetate (80:20) as the eluent, the N2-substituted indazole derivatives (2 to 25, 74) were separated by column chromatography.

[0110] 1) 2-Benzyl-2H-indazole-6-carboxylic acid methyl ester [Compound 2]

[0111] White solid; yield 45%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0112] 2) 2-(4-methoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 3]

[0113] White solid; yield 42%, 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).

[0114] 3) 2-(4-methylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 4]

[0115] White solid; yield 40%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0116] 4) 2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 5]

[0117] White solid; yield 38%, 1 H NMR (500 MHz, 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).

[0118] 5) 2-(4-chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 6]

[0119] White solid; yield 41%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0120] 6) 2-(4-bromobenzyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 7]

[0121] White solid; yield 39%, 1H NMR (500MHz, MeOD-d 4 )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).

[0122] 7) 2-(3-trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 8]

[0123] 8) 2-(4-trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 9]

[0124] White solid; yield 40%, 1 H NMR (500 MHz, DMSO-d 6 )δ8.65(s,1H),8.31(s,1H),7.86-7.27(m,6H),5.77(s,2H),3.88(s,3H).

[0125] 9) 2-Naphth-2-ylmethyl-2H-indazole-6-carboxylic acid methyl ester [Compound 10]

[0126] White solid; yield 45%,1 H NMR (500 MHz, DMSO-d 6 )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).

[0127] 10) 2-Phenethyl-2H-indazole-5-carboxylic acid methyl ester [Compound 11]

[0128] White solid; yield 41%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0129] 11) 2-(2-4-methoxyphenethyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 12]

[0130] White solid; yield 42%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0131] 12) 2-(3,5-difluorobenzyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 13]

[0132] White solid; yield 38%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0133] 13) 2-(4-difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester [Compound 14]

[0134] White solid; yield 39%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0135] 14) 2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid methyl ester [Compound 15]

[0136] White solid; yield 42%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0137] 15) 2-(4-isopropylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 16]

[0138] White solid; yield 36%, 1 H NMR (500 MHz, CDCl 3 )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),7.2 5-7.20(m,4H),5.59(s,2H),3.95(s,3H),2.90(hept,J=6.9Hz,1H),1.23(d,J=6.9Hz,6H).

[0139] 16) 2-(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 17]

[0140] White solid; yield 20%, 1 H NMR (500 MHz, CDCl 3)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).

[0141] 17) 2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 18]

[0142] White solid; yield 39%, 1 H NMR (500 MHz, CDCl 3 )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); 13 C NMR (125 MHz, CDCl 3 )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.

[0143] 18) 2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 19]

[0144] White solid; yield 39%, 1 H NMR (500 MHz, CDCl 3 )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).

[0145] 19) 2-(3-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 20]

[0146] White solid; yield 36%, 1 H NMR (500 MHz, CDCl 3)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); 13 C NMR (125 MHz, CDCl 3 )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.

[0147] 20) 2-(4-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 21]

[0148] White solid; yield 37%, 1 H NMR (500 MHz, CDCl 3 )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).

[0149] 21) 2-(3-methoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 22]

[0150] White solid; yield 39%, 1 H NMR (500 MHz, CDCl 3 )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); 13 CNMR (125MHz, CDCl 3)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.

[0151] 22) 2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 23]

[0152] White solid; yield 42%, 1 H NMR (500 MHz, CDCl 3 )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 (125 MHz, CDCl 3 )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.

[0153] 23) 2-(3,5-dimethoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 24]

[0154] White solid; yield 40%, 1 H NMR (500 MHz, CDCl 3 )δ8.51(d,J=1.1Hz,1H),7.92(d,J=1.1Hz,1H),7.69(dt,J=8.8,1.4Hz,1H),7.65-7.63(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 (125 MHz, CDCl 3)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.

[0155] 24) 2-(3-phenoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester [Compound 25]

[0156] White solid; yield 32%, 1 H NMR (500 MHz, CDCl 3 )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 (125 MHz, CDCl 3 )δ167.5,158.0,156.6,148.2,137.3,130.4,129.9,128.0,124.2,123. 7,123.2,122.5,121.5,121.4,120.2,119.2,118.5,118.2,57.6,52.2.

[0157] 25) 2-pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid methyl ester [Compound 74]

[0158] White solid; yield 51%, 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).

[0160] 2. Synthesis of N2-substituted 2H-indazole-6-carboxylic acids (Compounds 26 to 49, Compound 75)

[0161] The 2H-indazole-6-carboxylic acid methyl ester (compound 2 to compound 25 and compound 74, 1mmol) substituted by N2 was dissolved in methanol (5-10ml), and 2N NaOH solution (1-2ml) was slowly added. After stirring the reaction mixture at room temperature for 6 to 12 hours, it was placed in water and neutralized with 2N HCl, and then filtered and dried to obtain carboxylic acid derivatives (compound 26 to compound 49, compound 75).

[0162] 1) 2-Benzyl-2H-indazole-5-carboxylic acid [Compound 26]

[0163] White solid; yield 75%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0164] 2) 2-(4-methoxybenzyl)-2H-indazole-5-carboxylic acid [Compound 27]

[0165] White solid; yield 64%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.87(s,1H),8.54(s,1H),8.26(s,1H),7.79(d,J=8.7Hz,1H),7.56(d,J=8.7 Hz,1H),7.35(d,J=8.2Hz,2H),6.93(d,J=8.2Hz,2H),5.62(s,2H),3.73(s,3H).

[0166] 3) 2-(4-Methylbenzyl)-2H-indazole-5-carboxylic acid [Compound 28]

[0167] White solid; yield 69%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.88(s,1H),8.55(s,1H),8.26(s,1H),7.79(d,J=8.7Hz,1H),7.56(d,J=8.7 Hz,1H),7.26(d,J=7.9Hz,2H),7.17(d,J=7.9Hz,2H),5.65(s,2H),2.27(s,3H).

[0168] 4) 2-(4-Fluorobenzyl)-2H-indazole-5-carboxylic acid [Compound 29]

[0169] White solid; yield 77%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0170] 5) 2-(4-Chlorobenzyl)-2H-indazole-5-carboxylic acid [Compound 30]

[0171] White solid; yield 71%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.90(s,1H),8.61(s,1H),8.26(s,1H),7.81(d,J=9.4Hz,1H),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).

[0172] 6) 2-(4-bromobenzyl)-2H-indazole-5-carboxylic acid [Compound 31]

[0173] White solid; yield 73%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0174] 7) 2-(3-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid [Compound 32]

[0175] White solid; yield 79%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0176] 8) 2-(4-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid [Compound 33]

[0177] White solid; yield 69%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.90(s,1H),8.64(s,1H),8.27(s,1H),7.81(d,J=9.4Hz,1H),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).

[0178] 9) 2-Naphthalen-2-ylmethyl-2H-indazole-5-carboxylic acid [Compound 34]

[0179] White solid; yield 71%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0180] 10) 2-Phenethyl-2H-indazole-5-carboxylic acid [Compound 35]

[0181] White solid; yield 79%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0182] 11) 2-[2-(4-methoxyphenethyl)]-2H-indazole-5-carboxylic acid [Compound 36]

[0183] White solid; yield 82%, 1 H NMR (500 MHz, DMSO-d 6)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,1H),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).

[0184] 12) 2-(3,5-difluorobenzyl)-2H-indazole-5-carboxylic acid [Compound 37]

[0185] White solid; yield 68%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0186] 13) 2-(4-difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid [Compound 38]

[0187] White solid; yield 60%, 1 H NMR (500MH DMSO-d 6 )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).

[0188] 14) 2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid [Compound 39]

[0189] White solid; yield 71%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.90(s,1H),8.64(s,1H),8.29(s,1H),7.82(d,J=8.7Hz,1H),7.67-7.62(m,4 H),7.58(d,J=9.9Hz,1H),7.48-7.44(m,4H),7.36(t,J=7.4Hz,1H),5.76(s,2H).

[0190] 15) 2-(4-isopropylbenzyl)-2H-indazole-6-carboxylic acid [Compound 40]

[0191] White solid; yield 96%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0192] 16) 2-[2-(4-Fluorophenylethyl)]-2H-indazole-6-carboxylic acid [Compound 41]

[0193] White solid; yield 61%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.88(s,1H),8.35(s,1H),8.27(s,1H),7.75(d,J=8.7Hz,1H),7.55(d,J=8.7Hz,1H),7.2 1(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).

[0194] 17) 2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid [Compound 42]

[0195] White solid; yield 83%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0196] 18) 2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid [Compound 43]

[0197] White solid; yield 92%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0198] 19) 2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid [Compound 44]

[0199] White solid; yield 97%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0200] 20) 2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid [Compound 45]

[0201] White solid; yield 93%, 1 H NMR (500 MHz, DMSO-d 6)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 (125 MHz, DMSO-d 6 )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.

[0202] 21) 2-(3-methoxybenzyl)-2H-indazole-6-carboxylic acid [Compound 46]

[0203] White solid; yield 67%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0204] 22) 2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid [Compound 47]

[0205] White solid; yield 98%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, 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.

[0206] 23) 2-(3,5-dimethoxybenzyl)-2H-indazole-6-carboxylic acid [Compound 48]

[0207] White solid; yield 87%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0208] 24) 2-(3-phenoxybenzyl)-2H-indazole-6-carboxylic acid [Compound 49]

[0209] White solid; yield 99%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6)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.

[0210] 25) 2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid [Compound 75]

[0211] White solid; yield 80%, 1 H NMR (500 MHz, DMSO-d 6 )δ12.90(s,1H),9.02(s,1H),8.88(d,J=5.4Hz,1H),8.77(s,1H),8.46(d,J=8.1Hz,1H),8.2 5(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 (125 MHz, DMSO-d 6 )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.

[0213] 3. Synthesis of N2-substituted 2H-indazole-6-carboxylic acid hydroxyamide derivatives (Compounds 50 to 73, Compound 76)

[0214] A mixture of carboxylic acid derivatives (compounds 26 to 49 and 75; 1 mmol), hydroxylamine hydrochloride (3 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)phosphine hexafluorophosphate (BOP; 1.7 mmol) and diisopropylethylamine (DIPEA, 3 mmol) was added to DMSO (5-10 ml) and stirred at room temperature for 6 to 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 eluent.

[0215] 1) SPA3602 (2-benzyl-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 50]

[0216] White solid; yield 68%, 1 H NMR (500 MHz, DMSO-d 6)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 CNMR (125MHz, DMSO-d 6 )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 mice) 79.3, (in humans) 97.6.

[0217] 2) SPA3603 (2-(4-methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 51]

[0218] White solid; yield 62%, 1 H NMR (500 MHz, DMSO-d 6 )δ11.22(s,1H),9.01(s,1H),8.49(s,1H),8.02(s,1H),7.75(d,J=8.7Hz,1H),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 (125 MHz, DMSO-d 6 )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 mice) 98.6, (in humans) 76.7.

[0219] 3) SPA3606 (2-(4-methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 52]

[0220] White solid; yield 75%, 1 H NMR (500 MHz, DMSO-d 6 )δ11.22(s,1H),9.01(s,1H),8.51(s,1H),8.02(s,1H),7.76(d,J=8.7Hz,1H),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); 13C NMR (125 MHz, DMSO-d 6 )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.

[0221] 4) SPA3608 (2-(4-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 53]

[0222] White solid; yield 66%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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 mice) 71.3, (in humans) 85.9.

[0223] 5) SPA3610 (2-(4-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 54]

[0224] White solid; yield 77%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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 mice) 40.8, (in humans) 49.3.

[0225] 6) SPA3612 (2-(4-bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 55]

[0226] White solid; yield 59%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0227] 7) SPA3614 (2-(3-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 56]

[0228] White solid; yield 74%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0229] 8) SPA3616 (2-(4-trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 57]

[0230] White solid; yield 71%, 1 H NMR (500 MHz, DMSO-d 6)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 (125 MHz, DMSO-d 6 )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.

[0231] 9) SPA3618 (2-naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 58]

[0232] White solid; yield 71%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0233] 10) SPA3620 (2-phenylethyl-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 59]

[0234] White solid; yield 77%, 1 H NMR (500 MHz, DMSO-d 6 )δ11.25(s,1H),9.04(s,1H),8.32(s,1H),8.04(s,1H),7.72(d,J=8.6Hz,1H),7.3 8(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 (125 MHz, DMSO-d 6 )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.

[0235] 11) SPA3622 (2-(2-4-methoxyphenethyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 60]

[0236] White solid; yield 66%, 1 H NMR (500 MHz, DMSO-d 6 )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 CNMR (125MHz, DMSO-d 6 )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.

[0237] 12) SPA3624 (2-(3,5-difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 61]

[0238] White solid; yield 79%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6)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.

[0239] 13) SPA3626 (2-(4-difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 62]

[0240] White solid; yield 62%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0241] 14) SPA3628 (2-Biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 63]

[0242] White solid; yield 78%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0243] 15) SPA3630 (2-(4-isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 64]

[0244] Light yellow solid; yield 77%, 1 H NMR (500 MHz, DMSO-d 6 )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=8.7Hz,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).

[0245] 16) SPA3632 (2-(2-4-Fluorophenethyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 65]

[0246] Red solid; yield 19%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0247] 17) SPA3634 (2-(3-fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 66]

[0248] White solid; yield 67%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6)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.

[0249] 18) SPA3636 (2-(3-chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 67]

[0250] Light orange solid; yield 90%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0251] 19) SPA3638 (2-(3-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 68]

[0252] White solid; yield 63%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0253] 20) SPA3640 (2-(4-trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 69]

[0254] White solid; yield 62%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0255] 21) SPA3642 (2-(3-methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 70]

[0256] White solid; yield 77%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0257] 22) SPA3644 (2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 71]

[0258] White solid; yield 54%, 1 H NMR (500 MHz, DMSO-d 6 )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,7 H),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 (125 MHz, DMSO-d6 )δ165.3,158.9,147.9,138.7,137.3,130.6,130.2,128.9,128.3,128. 2,125.0,123.1,121.3,120.7,120.0,116.9,115.1,114.5,69.7,56.9.

[0259] 23) SPA3646 (2-(3,5-dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 72]

[0260] White solid; yield 40%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0261] 24) SPA3648 (2-(3-phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 73]

[0262] White solid; yield 67%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )δ157.3,156.7,147.9,139.4,130.7,130.7,130.6,125.1,124.1,123.3,123.1,121.4,120.1,119.2,118.4,118.2,116.8,56.5.

[0263] 25) SPA3650 (2-pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 76]

[0266] 4. Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid compound (Compound 78)

[0267] 2-Fluoro-4-methyl-5-nitrobenzoic acid (1.95 mmol) was completely dissolved in H 2 SO 4 (3 ml), then slowly add H 2 SO 4 (2.34mmol) and HNO 3 (2.92mmol) of the mixture was reacted for 3 hours. After the reaction was completed, the reaction mixture was placed in ice water, and then the precipitate was filtered and dried to obtain nitrobenzoic acid (Compound 78). 1) 2-Fluoro-4-methyl-5-nitrobenzoic acid [Compound 78]

[0268] White solid; yield 93%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )δ163.6,162.9,145.1,141.8,129.4,121.7,118.4,20.4.

[0270] 5. Synthesis of methyl 2-fluoro-4-methyl-5-nitrobenzoate (Compound 79)

[0271] 2-Fluoro-4-methyl-5-nitrobenzoic acid (Compound 78, 1.51 mmol) was dissolved in methanol (3 ml) and H 2 SO 4 (7.53 mmol). After stirring the reaction mixture at 65°C for 20 hours, the reaction was checked for termination and then placed in ice water. The precipitate was filtered and dried to obtain methyl 2-fluoro-4-methyl-5-nitrobenzoate (Compound 79). 1) Methyl 2-fluoro-4-methyl-5-nitrobenzoate [Compound 79]

[0272] White solid; yield 89%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6)δ162.7,162.7,145.2,142.4,129.2,121.9,117.2,53.3,20.5.

[0274] 6. Synthesis of methyl 5-amino-2-fluoro-4-methylbenzoate (Compound 80)

[0275] In N 2 In the presence of N gas, methyl 2-fluoro-4-methyl-5-nitrobenzoate (Compound 79) was completely dissolved in ethyl acetate (5 ml), and then Pd / C was added. 2 After the gas was replaced with Ar gas, the mixture was stirred at room temperature (rt) for 2 hours. After checking the termination of the reaction, Pd / C was removed by diatomaceous earth filtration to terminate the reaction. Methyl 5-amino-2-fluoro-4-methylbenzoate (Compound 80) was separated by column chromatography using hexane:ethyl acetate (2:1) as the eluent.

[0276] 1) 5-amino-2-fluoro-4-methylbenzoic acid methyl ester (Compound 80) brown solid; yield 91%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )δ165.0,153.3,143.6,129.6,118.2,115.5,115.3,52.4,18.0.

[0278] 7. Synthesis of 5-fluoro-1H-indazole-6-carboxylic acid methyl ester [Compound 81]

[0279] At room temperature (rt), a mixture of 5-amino-2-fluoro-4-methylbenzoic acid methyl ester (compound 80, 0.55mmol), KOAc (0.28mmol) and anhydrous acetic acid (1.38mmol) was stirred in chloroform (5ml) for 1 hour. Then, isoamyl nitrite (5.51mmol) was added and heated for 3 hours at 65°C. After the reaction was completed, 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 separated by column chromatography using hexane: ethyl acetate (1:1) as eluent.

[0280] 1) 5-Fluoro-1H-indazole-6-carboxylic acid methyl ester [Compound 81]

[0281] Yellow solid; yield 16%, 1 H NMR (500 MHz, CDCl 3 )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 (125 MHz, CDCl 3 )δ165.2,156.4,136.0,134.9,125.6,119.0,113.9,106.7,52.7.

[0283] 8. Synthesis of N2-substituted 5-fluoro-2H-indazole-6-carboxylic acid methyl ester compounds (Compounds 82 to 84)

[0284] At room temperature (rt), 5-fluoro-1H-indazole-6-carboxylic acid methyl ester (compound 81; 0.53 mmol), alkyl bromide / chloride (0.58 mmol) and Cs 2 CO 3 (0.58mmol) was reacted in DMF (2ml) for 2 hours. After the reaction was completed, the reaction mixture was placed in water and the crude product was extracted with ethyl acetate. Hexane: ethyl acetate (3:1) was used as eluent, and the 5-fluoro-indazole derivatives (compounds 82 to 84) substituted with N2 were separated by column chromatography.

[0285] 1) 2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid methyl ester [Compound 82]

[0286] Yellow solid; yield 55%, 1 H NMR (500 MHz, CDCl 3 )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 (125 MHz, CDCl 3 )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.

[0287] 2) 2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester [Compound 83]

[0288] Yellow solid; yield 35%, 1 H NMR (500 MHz, CDCl 3 )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 (125 MHz, CDCl 3 )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.

[0289] 3) 2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester [Compound 84]

[0290] Yellow solid; yield 32%, 1 H NMR (500 MHz, CDCl 3 )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 (125 MHz, CDCl 3 )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.

[0292] 9. Synthesis of N2-substituted 5-fluoro-2H-indazole-6-carboxylic acid compounds (Compounds 85 to 87)

[0293] The 5-fluoro-2H-indazole-6-carboxylic acid methyl ester (compound 82 to compound 84, 0.34mmol) substituted by N2 was dissolved in methanol (1ml) and THF (1ml), and 2N NaOH solution (0.5ml) was slowly added. After stirring the reaction mixture at room temperature for 2 hours, it was placed in water and neutralized with 2N HCl, then filtered and dried precipitate to obtain carboxylic acid derivatives (compound 85 to compound 87).

[0294] 1) 2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid [Compound 85]

[0295] Yellow solid; yield 76%, 1 H NMR (500 MHz, DMSO-d 6 )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 (125 MHz, DMSO-d 6 )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.

[0296] 2) 2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid [Compound 86]

[0297] White solid; yield 65%, 1 H NMR (500MHz, MeOD) δ8.43-8.22(m,2H),7.49–;7.19(m,5H),5.67(s,2H).

[0298] 3) 2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid [Compound 87]

[0299] White solid; yield 99%, 1 H NMR (500MHz, MeOD) δ8.32 (s, 1H), 8.29 (d, J = 6.3 Hz, 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.

[0301] 10. Synthesis of N2-substituted 2-benzyl-5-fluoro-2H-indazole-6-carboxylic acid compounds (Compounds 88 to 90)

[0302] A mixture of carboxylic acid derivatives (Compound 85 to Compound 87; 0.27 mmol), hydroxylamine hydrochloride (0.82 mmol), benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphine hexafluorophosphate (BOP; 0.41 mmol) and diisopropylethylamine (DIPEA; 0.82 mmol) was added to DMSO (1-2 ml) and stirred at room temperature for 6 to 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 eluent.

[0303] 1) SPA3659 (2-benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 88]

[0304] Brown solid; yield 18%, 1 H NMR (500 MHz, DMSO-d 6 )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).

[0305] 2) SPA3662 (2-(3-chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 89]

[0306] Light yellow solid; yield 24%, 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.

[0307] 3) SPA3663 (2-(3-methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide) [Compound 90]

[0308] Brown solid; yield 22%, 1H 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).

[0310] <Experimental Example 1> Evaluation of HDAC6 and HDAC8 inhibitory activity of synthetic compounds

[0311] 1) Deacetylation process and color development process of substrate

[0312] In addition to the control wells without HDAC enzyme, 2X HDAC enzyme is distributed in each well of the reaction plate, and buffer is distributed in the control wells without enzyme. Using acoustic technology (Echo550, nanoliter range), the compound dissolved in 100% DMSO is added to the enzyme mixture, centrifuged, and pre-cultured at room temperature for 10 minutes. 2X substrate mixture (fluorescent HDAC substrate) is placed in all reaction wells to start the reaction, and then centrifuged. HDAC6 is cultured at 30°C for 1 hour, and HDAC8 is cultured at 30°C for 2 hours.

[0313] Subsequently, a colorimetric agent and trichostatin A were added to terminate the reaction and generate fluorescence. Dynamic measurements were performed using Envision (Ex / Em=360 / 460 nm) for 20 minutes, with measurements taken every 5 minutes. After the phenomenon reached a stable state, the values ​​were obtained from the endpoint readings for analysis.

[0314] 2) HDAC6 and HDAC8 inhibitory activities of synthesized compounds

[0315] As a result of examining the inhibitory activities of the synthesized compounds against HDAC6 and HDAC8, as shown in the following table, 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 showed potent inhibitory activities against HDAC6, IC 50 The range was from 1.3 nM to 29.3 nM and showed relatively low activity against HDAC8, IC 50 The range is 500.3nM to 8392.0nM, indicating selectivity for HDAC6. From these results, it was found that the N2-substituted derivatives are selective and potent inhibitors of HDAC6 and can be used for the treatment of various diseases (e.g., cancer diseases, inflammatory diseases, autoimmune diseases, and fibrotic diseases).

[0316] Table 1

[0317] Table 2

[0318] Described below are formulation examples of the composition comprising compound 50 (SPA3602) according to the present disclosure, but the present disclosure is intended only to describe it in detail rather than to limit it.

[0320] <Prescription Example 1> Prescription Example of Pharmaceutical Composition

[0321] <Formulation Example 1-1> Preparation of Acid

[0322] The acid was prepared by mixing 20 mg of compound 50 (SPA3602), 100 mg of lactose and 10 mg of talc and filling the mixture into an airtight cloth.

[0323] <Prescription Example 1-2> Preparation of Tablets

[0324] 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 formulated into a tablet form according to a conventional tablet manufacturing method to prepare a tablet.

[0325] <Prescription Examples 1-3> Preparation of Capsules

[0326] After mixing 10 mg of Compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate, the above ingredients were mixed and filled into gelatin capsules according to a conventional capsule preparation method to prepare capsules.

[0327] <Prescription Examples 1-4> Preparation of Injections

[0328] After mixing 10 mg of compound 50 (SPA3602), an appropriate amount of sterile distilled water for injection and an appropriate amount of a pH adjuster, the mixture was prepared according to a conventional method for injections so that the above ingredients were contained in one ampoule (2 ml).

[0330] <Prescription Example 2> Health Food

[0331] <Prescription Example 2-1> Preparation of health food

[0332] 1 mg of compound 50 (SPA3602) was mixed with an appropriate amount of a vitamin mixture (70 μg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B1, 0.15 mg of vitamin B2, 0.5 mg of vitamin B6, 0.2 μg of vitamin B12, 10 mg of vitamin C, 10 μg of biotin, 1.7 mg of niacinamide, 50 μg of folic acid, 0.5 mg of calcium pantothenate) and an appropriate amount of a mineral mixture (1.75 mg of ferrous sulfate, 0.82 mg of zinc oxide, 25.3 mg of magnesium carbonate, 15 mg of potassium dihydrogen phosphate, 55 mg of potassium dihydrogen phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride), and the mixture was prepared into granules according to a conventional method to prepare a health food.

[0333] <Prescription Example 2-2> Preparation of health drink

[0334] 1 mg of compound 50 (SPA3602), 1000 mg of citric acid, 100 g of oligosaccharides, 2 g of plum concentrate, 1 g of taurine and purified water were added to adjust the volume to a total of 900 ml. The above ingredients were mixed according to a conventional health drink manufacturing method, and then stirred and heated at 85°C for about 1 hour. The resulting solution was filtered in a 2L sterile container, and then sealed, sterilized and stored under refrigerated conditions.

[0336] Although the specific part of the present invention has been described in detail above, it is clear to those skilled in the art that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. Therefore, the essential scope of the present disclosure is defined by the appended claims and their equivalents.

Claims

1. A compound selected from the group consisting of a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] in, In chemical formula 1: X is selected from hydrogen, fluorine, chlorine or bromine, A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds, The substitution is carried out by one or more substituents selected from (C1-C10) alkyl, (C1-C10) alkoxy, halogen, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy or phenoxy, The heterocyclic compound is a heteroaryl compound having a 5-membered or 6-membered ring, and n is an integer of 1 to 3.

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

3. The compound according to claim 1 or 2, wherein The compound is a compound represented by the following chemical formula 1-1: [Chemical formula 1-1] Among them, in chemical formula 1-1, X is hydrogen or fluorine, A is selected from phenyl, naphthyl or pyrimidinyl, R 1 and R 2 are the same or different and are selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, difluoromethyl, trifluoromethyl, phenyl, benzyloxy or phenoxy, and n is an integer of 1 to 3.

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

5. The compound according to claim 1, wherein The compound is selected from the group consisting of: 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-(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-Methoxyphenethyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 60); 2-(3,5-Difluorobenzyl)-2H-indazole-6-carboxylic acid 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); 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 according to claim 1 or 2, wherein The compounds selectively inhibit histone deacetylase 6 (HDAC6).

7. A pharmaceutical composition for treating or preventing a histone deacetylase 6 (HDAC6)-related disease, the pharmaceutical composition comprising a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, wherein The compound is a compound represented by the following chemical formula 1-1: [Chemical formula 1-1] Among them, in chemical formula 1-1, X is hydrogen or fluorine, A is selected from phenyl, naphthyl or pyrimidinyl, R 1 and R 2 are the same or different and are selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, difluoromethyl, trifluoromethyl, phenyl, benzyloxy or phenoxy, and n is an integer of 1 to 3.

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

10. The pharmaceutical composition according to claim 7, wherein The compound is selected from the group consisting of: 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-(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-Methoxyphenethyl)-2H-indazole-6-carboxylic acid hydroxyamide (Compound 60); 2-(3,5-Difluorobenzyl)-2H-indazole-6-carboxylic acid 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); 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).

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

12. The pharmaceutical composition according to 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, colon cancer, peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, osteosarcoma, fibrous tumors, brain tumors, acute lymphocytic leukemia, acute myeloid leukemia, lymphoma and neuroblastoma.

13. The pharmaceutical composition according to claim 11, wherein The inflammatory disease 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, Sjögren's syndrome, multiple sclerosis, Hashimoto's thyroiditis, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection, autoimmune diabetes, diabetic retinopathy, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive pulmonary disease (COPD), Graves' disease, and acute and chronic inflammatory diseases.

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

15. The pharmaceutical composition according to claim 11, wherein The degenerative disease is a neurodegenerative disease selected from the group consisting of cerebral infarction, stroke, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease and amyotrophic lateral sclerosis.

16. A health functional food for improving or preventing histone deacetylase 6 (HDAC6) related diseases, the health functional food comprising a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

17. A method for treating a histone deacetylase 6 (HDAC6)-related disease, the method comprising administering a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject suffering from the histone deacetylase 6 (HDAC6)-related disease.

18. A composition for inhibiting histone deacetylase 6 (HDAC6), the composition comprising a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

19. A method for inhibiting histone deacetylase 6 (HDAC6), the method comprising treating a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

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