Benzoheterocyclic compound and composition containing the same as an active ingredient for preventing or treating cancer diseases

Abstract

The present invention provides a new benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The compound or the salt exhibits a high antiproliferative effect on cancer cell lines. By using the compound or the salt, the present invention provides a pharmaceutical composition for preventing or treating cancer diseases, the composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention provides a health functional food composition for preventing or improving cancer diseases, the composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient. Various cancer diseases can be effectively prevented or treated by the pharmaceutical composition or the health functional food composition.

Description

Technical Field

[0001] The present invention relates to a benzoheterocyclic compound and a composition containing the same as an active ingredient for preventing or treating cancer diseases. Background Art

[0002] Brain tumors refer to any tumor that develops in the skull and include all tumors that develop in the brain and surrounding structures. Due to the anatomical characteristics of the brain, tumors that form in the brain without cancer cells, so-called benign tumors, may cause loss of life due to increased brain pressure if they are large in size.

[0003] Brain cancer, one of these, is a malignant brain tumor, a cancer that causes great damage to the brain and has a very low survival rate. Primary brain cancer does not metastasize to other body organs, but metastatic brain cancer is caused by lung cancer, breast cancer, and digestive system cancer metastases to the brain. Primary brain cancer includes neuromas, astrocytomas, neuroblastomas, gliomas, meningiomas, oligodendrogliomas, medulloblastomas, spinal cord tumors, and schwannomas, but is not limited to these. Clinical symptoms of brain cancer include headaches, seizures, vomiting, motor paralysis, overlapping objects, decreased vision, hormonal abnormalities, hearing loss, dizziness, and speech disorders.

[0004] As a conventional treatment for brain cancer, surgical resection is the most effective depending on the type or location of brain cancer, but surgery is often impossible and the risk of postoperative complications is very high when completely resected. In addition, due to the presence of the blood-brain barrier (BBB) ​​that inhibits the entry of drugs into the brain, drug absorption is low, so in order to treat brain cancer with anticancer drugs by chemotherapy, it is necessary to administer high concentrations of anticancer drugs compared to other cancers. As a result, there is a problem of causing serious side effects to other organs of the body. Summary of the invention

[0005] Technical issues

[0006] In order to solve the above problems, the present invention provides a novel compound or a pharmaceutically acceptable salt thereof.

[0007] The present invention provides a pharmaceutical composition for preventing or treating cancer diseases, which comprises a novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] In addition, the present invention provides a health functional food composition for preventing or improving cancer diseases, which comprises the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] Technical Solution

[0010] The novel compound of the present invention may be a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0011] [Chemical formula 1]

[0012]

[0013] In Chemical Formula 1, R is selected from O, S or NR 1 , and R 1 It may be selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, halogen or nitro.

[0014] The pharmaceutical composition of the present invention may include the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] The health functional food composition of the present invention may include the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] Beneficial Effects

[0017] The novel compound or its pharmaceutically acceptable salt described in the present invention has high anti-proliferative activity against cancer cell lines and can be used as an effective anti-cancer therapeutic agent. The pharmaceutical composition and health functional food composition for preventing or treating cancer diseases containing the compound or its pharmaceutically acceptable salt as an active ingredient can prevent, treat or improve various cancer diseases, such as breast cancer, lung cancer and brain cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a schematic design diagram of new compounds derived from the structure of amyloid-β probe.

[0019] Figure 2 The inhibitory effect of compound 9b described in the experimental example of the present invention is shown. DETAILED DESCRIPTION

[0020] Hereinafter, the present invention will be described in detail.

[0021] Figure 1It is a schematic design diagram of a new compound derived from the structure of an amyloid-β probe. A large amount of research has been conducted to develop an amyloid-β probe with high brain uptake, resulting in a variety of radiolabeled molecular probes for in vivo amyloid-β imaging. In the scaffold derived from the molecular probe, thioflavin-T analogs such as benzothiazole, benzoxazole and benzimidazole not only show excellent binding affinity to amyloid-β aggregates, but also show high uptake into the brain. Due to various physiological activities in cancer treatment, this benzoheterocycle has received attention in oncology, and based on this, a benzoheterocycle derivative for the development of an anticancer agent with high central nervous system permeability has been synthesized, thereby completing the present invention.

[0022] The present invention provides a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

[0023] [Chemical formula 1]

[0024]

[0025] In Chemical Formula 1, R is selected from O, S or NR 1 , and R 1 It may be selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, halogen or nitro.

[0026] Preferably, in Chemical Formula 1, R is selected from O, S or NR 1 , and R 1 R may be hydrogen or a C1-C4 alkyl group, and more preferably, R may be O or S.

[0027] More specifically, the compound can be selected from the group consisting of 4-(1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide, N-hydroxy-4-(1-methyl-1H-benzo[d]imidazol-2-yl)benzamide, 4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide, N-hydroxy-4-(1-propyl-1H-benzo[d]imidazol-2-yl)benzamide, 4-(1-butyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide, 4-(benzo[d]oxazol-2-yl)-N-hydroxybenzamide, 4-(benzo[d]thiazole-2-yl)- benzamide, 3-(1-methyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide, 3-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide, N-hydroxy-3-(1-propyl-1H-benzo[d]imidazol-2-yl)benzamide, 3-(1-butyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide, 3-(benzo[d]oxazol-2-yl)-N-hydroxybenzamide and 3-(benzo[d]thiazol-2-yl)-N-hydroxybenzamide.

[0028] The compound described in the present invention can be used in the form of a pharmaceutically acceptable salt, and the salt can be used in the form of a pharmaceutically acceptable basic salt or acidic salt.

[0029] The basic salt may be used in the form of an organic base salt or an inorganic base salt, and may be selected from the group consisting of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethyl salt, aluminum salt and pyridinium salt, but is not limited thereto.

[0030] As the acid salt, an acid addition salt formed from a free acid is useful. Inorganic acids and organic acids can be used as free acids, and hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, diphosphoric acid, nitric acid, etc. can be used as inorganic acids; and citric acid, acetic acid, maleic acid, malic acid, fumaric acid, gluconic acid, etc. can be used as free acids. 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, aspartic acid, stearic acid, etc. can be used as the organic acid. Preferably, hydrochloric acid can be used as the inorganic acid, and methanesulfonic acid can be used as the organic acid.

[0031] In addition, the compound of the present invention may include all salts, hydrates and solvates that can be prepared by conventional methods, and pharmaceutically acceptable salts. In the compound of the present invention, addition salts can be prepared by conventional methods, and can be prepared by dissolving the compound in a water-miscible organic solvent (such as acetone, methanol, ethanol or acetonitrile) and adding an excessive amount of an inorganic base water-based solution or an organic base, then precipitating or crystallizing to prepare addition salts. Alternatively, a mixture can be prepared by evaporating solvent or excess alkali and drying to obtain addition salts or by filtering precipitated salts. Alternatively, a mixture can be prepared by evaporating solvent or excess alkali from a mixture and drying to obtain addition salts or filtering precipitated salts.

[0032] As used herein, "prevention" refers to any action to inhibit or delay the onset of a cancer disease or at least one symptom thereof by administering the pharmaceutical composition or health functional food composition of the present invention. In addition, it includes treatment of subjects in remission for preventive treatment and prevention of recurrence.

[0033] As used herein, "treatment" refers to any action to improve or beneficially alter a condition by administering the pharmaceutical composition described herein, such as alleviating, reducing or eliminating the onset of a cancer disease or at least one symptom thereof.

[0034] As used herein, "improvement" refers to any action of improving or beneficially changing a condition by taking the health functional food composition of the present invention, such as alleviating, reducing or eliminating the onset of a cancer disease or at least one symptom thereof.

[0035] As used herein, a "pharmaceutical composition" refers to a composition that is administered for a specific purpose, and for the purposes of the present invention, it refers to a composition that is administered for the purpose of preventing or treating a cancer disease or at least one symptom thereof.

[0036] As used herein, "health functional food" has a similar meaning to food for specified health uses (FoSHU), and refers to food with high medical and pharmaceutical effects that is processed to effectively exhibit bioregulatory functions in addition to nutritional supply.

[0037] The present invention provides a pharmaceutical composition for preventing or treating cancer diseases, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0038] In the pharmaceutical composition of the present invention, since the compound or salt has antiproliferative activity against cancer cells, it can be applied to various cancer diseases. The cancer disease can be selected from the group consisting of brain cancer, breast cancer, lung cancer, skin cancer, ovarian cancer, uterine cancer, prostate cancer, kidney cancer, colon cancer, pancreatic cancer, stomach cancer, liver cancer, colorectal cancer, head and neck cancer, laryngeal cancer, esophageal cancer, blood cancer and leukemia, but is not limited thereto.

[0039] According to the above formulation, the pharmaceutical composition of the present invention can be prepared by further comprising an appropriate pharmaceutically acceptable carrier, excipient or diluent. "Pharmaceutically acceptable" means showing a property of being non-toxic to cells or humans exposed to the pharmaceutical composition.

[0040] The carriers, excipients or diluents that can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate / ester, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil, but are not limited thereto, and any suitable agent known in the art can be used.

[0041] The pharmaceutical composition of the present invention can be formulated and used in the form of oral preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injectable solutions according to conventional methods.

[0042] When the pharmaceutical composition of the present invention is prepared in the above-mentioned form, it can be prepared using a diluent or excipient (e.g., commonly used fillers, weighting agents, adhesives, wetting agents, disintegrants and surfactants). Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations can be prepared by mixing at least one excipient (e.g., starch, calcium carbonate, sucrose, lactose, gelatin, etc.).

[0043] In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. In addition to liquid and liquid paraffin for oral use, it can also be prepared by adding various excipients (such as wetting agents, sweeteners, aromatics, preservatives, etc.).

[0044] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used. As the base of suppositories, witepsol, macrosol, Tween 61, cocoa butter, lauric acid, glycerin gelatin, etc. can be used.

[0045] Additionally, calcium or vitamin D3 may be added to enhance the therapeutic effect.

[0046] In the pharmaceutical composition of the present invention, the pharmaceutical composition can be administered in a pharmaceutically effective amount. "Pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment without producing side effects, and the effective dosage level can be determined based on factors including: the patient's health status, ulcer type, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, duration of treatment, combined or simultaneous medication, and other factors well known in the medical field.

[0047] The amount of the compound as the active ingredient in the pharmaceutical composition of the present invention can vary according to the patient's age, sex, body weight and disease, but can be administered once or multiple times per day at 0.001 mg / kg to 100 mg / kg, preferably 0.01 mg / kg to 10 mg / kg. In addition, the dosage of the compound of the present invention can be increased or decreased according to the administration route, disease degree, sex, body weight, age, etc. Therefore, the above dosage does not limit the scope of the present invention in any way.

[0048] The pharmaceutical composition can be administered to mammals, such as rats, mice, livestock and humans, by various routes. All modes of administration are contemplated, for example, administration can be by oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine septum or intracerebroventricular injection.

[0049] In addition, the present invention provides a health functional food composition for preventing or improving cancer diseases, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0050] In the health functional food composition of the present invention, since the compound or salt has antiproliferative activity against cancer cells, it can be applied to various cancer diseases. The cancer disease can be selected from the group consisting of: brain cancer, breast cancer, lung cancer, skin cancer, ovarian cancer, uterine cancer, prostate cancer, kidney cancer, colon cancer, pancreatic cancer, stomach cancer, liver cancer, colorectal cancer, head and neck cancer, laryngeal cancer, esophageal cancer, blood cancer and leukemia, but is not limited thereto.

[0051] The health functional food of the present invention can be provided in the form of powder, granules, tablets, capsules, syrups or beverages, and in addition to the compound of the present invention, the health functional food is used together with other foods or food additives, and the compound of the present invention is an active ingredient and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined according to the purpose of its use (e.g., prevention, health care or treatment).

[0052] The effective dose of the compounds contained in the health functional food described in the present invention can be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or for health control purposes, it can be the above range or less, and since there is no problem with safety, the active ingredient can be used in an amount of at least the above range.

[0053] There is no particular limitation on the type of health functional food described in the present invention, and examples include meat, sausages, bread, chocolate, candy, snacks, cakes, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, etc.

[0054] Example

[0055] Hereinafter, the present invention is described in more detail by examples. These examples are only intended to illustrate the present invention in more detail, and it will be apparent to those skilled in the art that, according to the gist of the present invention, the scope of the present invention is not limited by these examples. Embodiments of the present invention are provided to more fully explain the present invention to those of ordinary skill in the art.

[0056] [Synthesis preparation]

[0057] All reagents and solvents were purchased from commercial suppliers and used without further purification. All experiments dealing with moisture-sensitive compounds were performed under an argon atmosphere. Concentration or solvent removal was performed under reduced pressure using a rotary evaporator. 254 Analytical thin layer chromatography was performed on TLC plates (E, Merck) and visualized under UV light or by staining with iodine gas. Column chromatography was performed on silica (Merck Silica Gel 40-63m) at medium pressure or by using a Biotage SP1 rapid purification system with pre-filled silica gel cartridges (Biotage). NMR analysis was performed using a JNM-ECZ500R (500 MHz) manufactured by Jeol resonance.

[0058] Chemical shifts (δ) are reported in parts per million. The deuterium lock signal of the sample solvent is used as a reference, and coupling constants (J) are expressed in Hertz (Hz). The abbreviations for the splitting patterns are as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; td, triplet of doublets; m, multiplet.

[0059] The purity of all final compounds was confirmed to be higher than 95% by analytical HPLC using a dual-pump Shimadzu LC-6AD system equipped with a VP-ODS C18 column.

[0060] [Example 1] Synthesis of Compounds (5, 6a-6d)

[0061] [Reaction Scheme 1]

[0062]

[0063] The above reaction scheme 1 shows the synthesis process of compound 5 and compound 6a-compound 6d.

[0064] Referring to Scheme 1, in brief, the reaction of o-phenylenediamine 1 with aldehyde 2 in dimethylformamide (hereinafter DMF) aqueous solution provides the key intermediate compound 3 by aerobic oxidation in 88% yield. Compound 3 is treated with sodium hydride in DMF for 2 hours, and then various alkyl iodides are added to provide compounds 4a-4d in 45%-70% yield. Finally, compound 3 and compound 4a-4d are treated with NH2OH and KOH in methanol in turn to obtain compound 5 and compound 6a-6d in 32%-35% yield. In more detail, the process is carried out as follows.

[0065] (1-1) Compound 3: 4-(1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0066] A mixture of o-phenylenediamine (5.84 g, 53.98 mmol) and methyl 4-formylbenzoate (9.75 mL, 59.37 mmol) was stirred in 180 mL of DMF and 20 mL of water at 80° C. in an open flask for 36 hours. The mixture was concentrated under reduced pressure and purified by column to provide compound 3 in 88% yield. f =0.23 (3:7 = ethyl acetate: hexane).

[0067] 1 H NMR (500MHz, CD3OD) δ8.19-8.14(m, 4H), 7.63(s, 2H), 7.30-7.27(m, 2H), 3.93(s, 3H). 13 C NMR (125MHz, CD3OD) δ166.5, 150.6, 133.9, 131.2, 129.9, 126.4, 123.1, 51.5.

[0068] (1-2) Compound 4a: 4-(1-methyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0069] 60% sodium hydride (0.09 g, 2.25 mmol) in DMF (5 mL) was added to compound 3 (0.32 g, 1.25 mmol) in DMF (5 mL) at 0 ° C. The mixture was stirred at room temperature for 2 hours. Iodomethane (0.09 mL, 1.38 mmol) was added and stirred for 8 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried with Na2SO4, concentrated under reduced pressure, and purified by MPLC to provide compound 4a in a yield of 70%. f =0.26 (3:7 = ethyl acetate: hexane).

[0070] 1 H NMR (500MHz, CDCl3) δ8.17 (d, J=8.5Hz, 2H), 7.85-7.81 (m, 3H), 7.38-7.36 (m, 1H), 7.33-7.30 (m, 2H), 3.94 (s, 3H), 3.84 (s, 3H). 13 C NMR (125MHz, CDCl3) δ166.5, 152.5, 143.0, 136.7, 134.5, 131.1, 129.9, 129.4, 123.3, 122.7, 120.1, 109.8, 52.4.31.8.

[0071] (1-3) Compound 4b: 4-(1-ethyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0072] 60% sodium hydride (0.09 g, 2.25 mmol) in DMF (5 mL) was added to compound 3 (0.32 g, 1.25 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Ethyl iodide (0.09 mL, 1.38 mmol) was added and stirred for 8 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 4b in a yield of 49%. f =0.25 (3:7 = ethyl acetate: hexane).

[0073] 1 H NMR (500MHz, CDCl3) δ8.19 (d, J=8.5Hz, 2H), 7.85-7.81 (m, 3H), 7.45-7.43 (m, 1H), 7.35-7.31(m, 2H), 4.32-4.27(m, 2H), 3.96(s, 3H), 1.47(t, J=7.0Hz, 3H). 13C NMR (125MHz, CDCl3) δ166.6, 152.3, 143.3, 135.6, 134.9, 131.2, 130.0, 129.3, 123.2, 122.7, 120.3, 110.1, 52.4, 39.8, 15.4.ESI MS(m / e)181.12[M+H] + .

[0074] (1-4) Compound 4c: 4-(1-propyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0075] 60% sodium hydride (0.08 g, 3.50 mmol) in DMF (5 mL) was added to compound 3 (0.32 g, 1.25 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Iodopropane (0.13 mL, 1.28 mmol) was added and stirred for 8 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 4c in a yield of 45%. f =0.30 (3:7=ethyl acetate:hexane).

[0076] 1 H NMR (500MHz, CDCl3) δ8.19 (d, J=8.5Hz, 2H), 7.83-7.79 (m, 3H), 7.42-7.40 (m, 1H), 7.33-7 .29 (m, 2H), 4.19 (t, J=7.5Hz, 2H), 3.95 (s, 3H), 1.85-1.80 (m, 2H), 0.84 (t, J=7.1Hz, 3H). 13 C NMR (125MHz, CDCl3) δ166.5, 152.5, 143.0, 136.7, 134.5, 131.1, 129.9, 129.4, 123.3, 122.7, 120.1, 109.8, 52.4, 31.8, 29.7, 15.4.ESI MS(m / e)195.14[M+H] + .

[0077] (1-5) Compound 4d: 4-(1-butyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0078] 60% sodium hydride (0.09 g, 2.25 mmol) in DMF (5 mL) was added to compound 3 (0.30 g, 1.20 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Iodobutane (0.15 mL, 1.32 mmol) was added and stirred for 8 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 4d in a yield of 46%. f =0.35 (3:7 = ethyl acetate: hexane).

[0079] 1 H NMR (500MHz, CDCl3) δ8.17 (d, J=8.5Hz, 2H), 7.85-7.81 (m, 3H), 7.38-7.36 (m, 1H), 7.33-7.30 (m, 2H ), 4.20 (t, J=7.5Hz, 2H), 3.94 (s, 3H), 1.81-1.74 (m, 2H), 1.24-1.22 (m, 2H), 0.83 (t, J=7.5Hz, 3H). 13 C NMR (125MHz, CDCl3) δ166.5, 152.5, 143.0, 136.7, 134.5, 131.1, 129.9, 129.4, 123.3, 122.7, 120.1, 109.8, 52.4, 44.6, 31.9, 19.9, 13.5.

[0080] (1-6) Compound 5: 4-(1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide

[0081] Hydroxylamine hydrochloride (3.72 g, 53.51 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (3.00 g, 53.51 mmol) in methanol (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 3 (0.30 g, 1.20 mmol) in tetrahydrofuran (10 mL) at 0 ° C, and stirred at the same temperature for 2 hours. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 5 in a yield of 40%. f =0.08 (9:1=ethyl acetate:hexane).

[0082] 1H NMR (500MHz, DMSO-D6) δ8.13 (d, J=8.5Hz, 2H), 7.89 (d, J=8.0Hz, 2H), 7.59-7.57 (m, 2H), 7.20-7.18 (m, 2H). 13 C NMR (125MHz, DMSO-D6) δ163.3, 151.2, 137.2, 130.4, 126.6, 125.9, 122.1.ESI MS (m / e) 254.09[M+H] + .

[0083] (1-7) Compound 6a: N-hydroxy-4-(1-methyl-1H-benzo[d]imidazol-2-yl)benzamide

[0084] Hydroxylamine hydrochloride (1.29 g, 18.6 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (1.04 g, 18.6 mmol) in methanol (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 4a (0.11 g, 0.41 mmol) in tetrahydrofuran (10 mL) at 0 ° C, and stirred at the same temperature for 2 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 6a in a yield of 36%. R f =0.17 (9:1=ethyl acetate:hexane).

[0085] 1 H NMR (500MHz, DMSO-D6) δ8.11 (d, J=8.0Hz, 2H), 8.02 (d, J=8.5Hz, 1H), 7.91 (dd, J=8.0Hz, 1.5Hz, 1H), 7 .86 (d, J=8.5Hz, 1H), 7.69 (t, J=8.5Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 7.43 (t, J=7.5Hz, 1H), 3.71 (s, 3H). 13 C NMR (125MHz, DMSO-D6) δ154.5, 152.9, 138.8, 134.5, 133.9, 132.8, 131.5, 130.3, 129.8, 129.7, 129.2, 126.7, 124.3, 115.4, 29.8.ESI MS(m / e)167.11[M+H] + .

[0086] (1-8) Compound 6b: 4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide

[0087] Hydroxylamine hydrochloride (1.12 g, 16.05 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (0.90 g, 16.05 mmol) in methanol (5 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 4b (0.10 g, 0.36 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 6b in a yield of 51%. f =0.19 (9:1=ethyl acetate:hexane).

[0088] 1 H NMR (500MHz, DMSO-D6) δ11.42 (s, 1H), 9.22 (s, 1H), 7.95 (d, J = 7.5Hz, 2H), 7.87 (d, J = 8.5Hz, 2H), 7.71 ( d, J=8.0Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 7.33-7.25 (m, 2H), 4.34 (q, J=7.5Hz, 2H), 1.33 (t, J=7.5Hz, 3H). 13 C NMR (125MHz, CD3OD) δ167.1, 153.6, 143.4, 136.4, 135.2, 134.2, 130.7, 128.7, 124.6, 124.1, 119.9, 111.9, 40.8, 15.4.ESI MS (m / e) 282.12[M+H] + .

[0089] (1-9) Compound 6c: N-hydroxy-4-(1-propyl-1H-benzo[d]imidazol-2-yl)benzamide

[0090] Hydroxylamine hydrochloride (1.06 g, 15.29 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (0.86 g, 15.29 mmol) in methanol (5 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, the precipitated potassium chloride was removed, and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 4c (0.11 g, 0.34 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred for 2 hours at the same temperature. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 6c in a yield of 49%. f =0.19 (9:1=ethyl acetate:hexane).

[0091] 1 H NMR (500MHz, DMSO-D6) δ11.41 (s, 1H), 9.19 (s, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.86 (d, J = 8.5Hz, 2H), 7.70 (d, J=8.5Hz, 2H), 7.33-7.25 (m, 2H), 4.29 (t, J=7.5Hz, 2H), 1.72-1.65 (m, 2H), 0.72 (t, J=7.5Hz, 3H). 1 3C NMR (125MHz, DMSO-D6) δ163.7, 152.1, 142.2, 135.7, 133.8, 132.9, 129.3, 127.4, 122.8, 122.3, 119.2, 111.2, 45.7, 22.7, 11.0.ESI MS(m / e)296.14[M+H] + .

[0092] (1-10) Compound 6d: 4-(1-butyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide

[0093] Hydroxylamine hydrochloride (2.03 g, 29.19 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (1.64 g, 29.19 mmol) in methanol (5 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 4d (0.20 g, 0.65 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 6d in a yield of 51%. f =0.26 (9:1=ethyl acetate:hexane).

[0094] 1 H NMR (500MHz, DMSO-D6) δ11.40 (s, 1H), 9.18 (s, 1H), 7.93 (d, J=8.5Hz, 2H), 7.86 (d, J=8.0Hz, 2H), 7.68 (t, J=8.5 Hz, 2H), 7.32-7.24 (m, 2H), 4.32 (t, J=7.0Hz, 2H), 1.67-1.61 (m, 2H), 1.16-1.08 (m, 2H), 0.74 (t, J=7.5Hz, 3H). 13C NMR (125MHz, DMSO-D6) δ164.1, 152.6, 143.1, 136.2, 134.1, 133.6.129.7, 127.8, 123.2, 122.6, 119.8, 111.6, 44.4, 31.7, 19.7, 13.8.ESI MS(m / e)310.16[M+H] + .

[0095] [Example 2] Synthesis of Compounds (9a-9b)

[0096] [Reaction Scheme 2]

[0097]

[0098] Reaction Scheme 2 shows the synthesis process of Compound 9a-Compound 9b.

[0099] Referring to Reaction Scheme 2, compounds 8a and 8b were synthesized in 32%-35% yields by iodine-mediated cyclization of 2-aminophenol 7a or 2-aminothiophenol 7b with aldehyde 2, wherein 2-aminophenol 7a or 2-aminothiophenol 7b was the corresponding starting material. Compounds 9a and 9b were successfully obtained in 42%-45% yields by treating esters 8a and 8b with NH2OH and KOH in methanol in sequence. In more detail, the process was performed as follows.

[0100] (2-1) Compound 8a: 4-(Benzo[d]oxazol-2-yl)benzoic acid methyl ester

[0101] 2-aminophenol (0.20g, 1.83mmol) and methyl 4-formylbenzoate (0.30g, 1.83mmol) are dissolved in dichloromethane (20ml), and stirred for 4 hours at room temperature under argon atmosphere.The reaction mixture is added to iodine (0.12g, 0.92mmol) and stirred for 1 hour in an open flask at room temperature.The mixture is concentrated under reduced pressure and purified by column to obtain compound 8a, yield 32%. f =0.31 (1:9=ethyl acetate:hexane).

[0102] 1 H NMR (500MHz, CDCl3) δ8.32 (d, J=8.5Hz, 2H), 8.18 (d, J=8.5Hz, 2H), 7.80-7.79 (m, 1H), 7.61-7.59 (m, 1H), 7.40-7.37 (m, 2H), 3.96 (s, 3H). 13C NMR (125MHz, CDCl3) δ166.5, 162.1, 151.0, 142.1, 132.6, 131.1, 130.2, 127.6, 125.9, 125.0, 120.5, 110.9, 52.6.

[0103] (2-2) Compound 8b: 4-(Benzo[d]thiazol-2-yl)benzoic acid methyl ester

[0104] 2-Aminothiophenol (1.71mL, 15.98mmol) and methyl 4-formylbenzoate (2.62g, 15.98mmol) were dissolved in dichloromethane (100mL) and stirred for 4 hours at room temperature under argon atmosphere. The reaction mixture was added to iodine (1.01g, 7.99mmol) and stirred in an open flask at room temperature for 45 minutes. The mixture was concentrated under reduced pressure and purified by column to obtain compound 8b in a yield of 35%. f =0.31 (1:9=ethyl acetate:hexane).

[0105] 1 H NMR (500MHz, CDCl3) δ 8.15-8.14 (m, 4H), 8.09 (d, J=7.5Hz, 1H), 7.91 (d, J=8.5Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.41 (t, J=7.5Hz, 1H), 3.95 (s, 3H). 13 C NMR (125MHz, CDCl3) δ166.5, 154.2, 137.6, 135.4, 132.2, 130.4, 129.7, 127.6, 126.7, 125.8, 123.7, 121.9, 52.5.

[0106] (2-3) Compound 9a: 4-(Benzo[d]oxazol-2-yl)-N-hydroxybenzamide

[0107] Hydroxylamine hydrochloride (2.47 g, 35.56 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (1.99 g, 35.56 mmol) in methanol (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, and the precipitated potassium chloride was removed, and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 8a (0.2 g, 0.79 mmol) in tetrahydrofuran (10 mL) at 0 ° C, and stirred at the same temperature for 2 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 9a in a yield of 45%. f =0.24 (7:3=ethyl acetate:hexane).

[0108] 1 H NMR (500MHz, DMSO-D6) δ11.41 (s, 1H), 9.17 (s, 1H), 8.12 (d, J = 8.0Hz, 2H), 8.01 (d, J = 8.5Hz, 2 H), 7.71 (d, J=8.0Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.33 (t, J=6.5Hz, 1H), 7.29 (t, J=7.5Hz, 1H). 13 C NMR (125MHz, DMSO-D6) δ163.3, 161.5, 150.3, 141.4, 135.7, 128.6, 127.9, 127.3, 125.9, 125.1, 120.1, 111.1.ESI MS (m / e) 255.08[M+H] + .

[0109] (2-4) Compound 9b: 4-(Benzo[d]thiazol-2-yl)-N-hydroxybenzamide

[0110] Hydroxylamine hydrochloride (43.44 g, 3.02 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (43.44 g, 2.24 mmol) in methanol (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 8b (0.26 g, 0.79 mmol) in tetrahydrofuran (10 mL) at 0 ° C, and stirred at the same temperature for 2 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 9b in a yield of 42%. f =0.30 (7:3=ethyl acetate:hexane).

[0111] 1 H NMR (500MHz, DMSO-D6) δ11.41 (s, 1H), 9.19 (s, 1H), 8.19-8.17 (m, 3H), 8.10 (d, J =8.0Hz, 1H), 7.94 (d, J = 9.0Hz.2H), 7.57 (t, J = 7.3Hz, 1H), 7.49 (t, J = 7.3Hz, 1H). 13 CNMR (125MHz, DMSO-D6) δ166.4., 163.2, 153.5, 135.1, 135.0, 134.7, 127.9, 127.2, 126.9, 125.9, 123.1, 122.5.ESI MS (m / e) 271.05[M+H] + .

[0112] [Example 3] Synthesis of Compounds (13, 14a-14d)

[0113] [Reaction Scheme 3]

[0114]

[0115] Reaction Scheme 3 shows the synthetic process of compound 13 and compound 14a-compound 14e to explore the biological activity of the meta-regioisomer.

[0116] Referring to reaction scheme 3, similar to reaction scheme 1, compound 11 was obtained from o-phenylenediamine 1 and aldehyde 10 in DMF aqueous solution with a yield of 86%. Compound 11 was treated with sodium hydride in DMF for 2 h, and then alkylated with the corresponding alkyl iodide to obtain compounds 12a-12d with a yield of 11%-91%. Compound 11 and compound 12a-12d were reacted with NH2OH and KOH in methanol to finally obtain compounds 13 and compounds 14a-14d with a yield of 33%-55%.

[0117] (3-1) Compound 11: 3-(1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0118] A mixture of o-phenylenediamine (2.00 g, 18.50 mmol) and methyl 3-formylbenzoate (3.03 g, 18.50 mmol) was stirred in 180 mL of DMF and 20 mL of water at 80° C. in an open flask for 48 hours. The mixture was concentrated under reduced pressure and purified by column to give compound 11 in 86% yield. f =0.25 (3:7 = ethyl acetate: hexane).

[0119] 1 H NMR (500MHz, DMSO-d6) δ 8.80 (s, 1H), 8.45 (d, J = 8Hz, 1H), 8.05 (d, J = 7.5Hz, 1H), 7.70 (t, J = 8.0Hz, 1H), 7.63 (s, 2H), 7.23-7.22 (m, 2H), 3.92 (s, 3H). 13 C NMR (125MHz, DMSO-D6) 165.9, 150.3, 131.0, 130.8, 130.7, 130.5, 130.3, 129.6, 127.1, 127.1, 127.0, 122.6, 122.3, 52.4.ESI MS (m / e) 253.10[M+H] + .

[0120] (3-2) Compound 12a: methyl 3-(1-methyl-1H-benzo[d]imidazol-2-yl)benzoate

[0121] 60% sodium hydride (0.05 g, 1.24 mmol) in DMF (5 mL) was added to compound 11 (0.21 g, 0.82 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Iodomethane (0.06 mL, 0.91 mmol) was added and stirred for 2.5 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 12a in a yield of 91%. f =0.25 (4:6 = ethyl acetate: hexane).

[0122] 1 H NMR (500MHz, CDCl3) δ8.44 (s, 1H), 8.19 (d, J = 8.0Hz, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.85-7.83 ( m, 1H), 7.63 (t, J=8.0Hz, 1H), 7, 43-7.41 (m, 1H), 7.37-7.33 (m, 2H), 4.0 (s, 3H), 3.90 (s, 3H). 13 C NMR (125MHz, DMSO-D6) δ166.6, 152.8, 143.0, 134.0, 130.9, 130.8, 130.4, 129.2, 123.2, 122.8, 120.1, 109.9, 52.5, 31.97.ESI MS(m / e)267.11[M+H] + .

[0123] (3-3) Compound 12b: 3-(1-ethyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0124] 60% sodium hydride (0.05 g, 1.24 mmol) in DMF (5 mL) was added to compound 11 (0.20 g, 0.81 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Ethyl iodide (0.07 mL, 0.89 mmol) was added and stirred for 2.5 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 12b in a yield of 11%. f =0.28 (4:6=ethyl acetate:hexane).

[0125] 1H NMR (500MHz, CDCl3) δ8.41 (s, 1H), 8.19 (d, J = 8.0Hz, 1H), 7.97 (d, J = 8.0Hz, 1H), 7.84 (d, J = 8.5Hz, 1H), 7.63 (t, J =8.0Hz, 1H), 7.45 (d, J = 9.5Hz, 1H), 7.36-7.26 (m, 2H), 4.31 (q, J = 7.5Hz, 2H), 3.96 (s, 3H), 1.50 (t, J = 7.0Hz, 3H). 13 C NMR (125MHz, DMSO-D6) δ166.6, 152.4, 143.3, 135.5, 133.9, 131.1, 131.9, 130.8, 130.3, 129.2, 123.1, 122.7, 120.3, 110.2, 52.5, 39.9, 15.4.ESI MS(m / e)281.13[M+H] + .

[0126] (3-4) Compound 12c: 3-(1-propyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0127] 60% sodium hydride (0.07 g, 1.78 mmol) in DMF (5 mL) was added to compound 11 (0.30 g, 1.19 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Iodopropane (0.12 mL, 1.31 mmol) was added and stirred for 8 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 12c in a yield of 28%. f =0.32 (3:7=ethyl acetate:hexane).

[0128] 1 H NMR (500MHz, CDCl3) δ8.38 (t, J=1.0Hz, 1H), 8.17 (td, J=8.0Hz, 1.0Hz, 1H), 7.94 (td, J=7.5Hz, 2.0Hz, 1H), 7.83-7.81 (m, 1H), 7.59 ( t, J=8.0Hz, 1H), 7.42-7.40 (m, 1H), 7.31-7.29 (m, 2H), 4.19 (t, J=7.5Hz, 2H), 3.93 (s, 3H), 1.87-1.82 (m, 2H), 0.85 (t, J=7.0Hz, 3H). 13C NMR (125MHz, CDCl3) δ166.4, 152.6, 143.1, 135.7, 133.9, 131.1, 130.7, 130.2, 129.1, 123.0.122.5, 120.1, 110.3, 52.4, 46.4, 23.3, 11.2.ESI MS(m / e)295.14[M+H] + .

[0129] (3-5) Compound 12d: 3-(1-butyl-1H-benzo[d]imidazol-2-yl)benzoic acid methyl ester

[0130] 60% sodium hydride (0.07 g, 1.78 mmol) in DMF (5 mL) was added to compound 11 (0.30 g, 1.19 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Iodobutane (0.15 mL, 1.31 mmol) was added and stirred for 8 hours. The reactant was diluted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 12d in a yield of 79%. f =0.33 (3:7 = ethyl acetate: hexane).

[0131] 1 H NMR (500MHz, CDCl3) δ8.39 (t, J=1.5Hz, 1H), 8.17 (td, J=7.5Hz, 1.5Hz, 1H), 7.95 (td, J=8.0Hz, 1.5Hz, 1H), 7.83-7.81 (m, 1H), 7.60 (t, J=8.0H z, 1H), 7.43-7.41 (m, 1H), 7.32-7.28 (m, 2H), 4.23 (t, J=7.5Hz, 2H), 3. 93(s, 3H), 1.84-1.78(m, 2H), 1.31-1.24(m, 2H), 0.85(t, J=7.5Hz, 3H). 13 C NMR (125MHz, CDCl3) δ166.4, 152.5, 143.1, 135.7, 133.9, 131.1, 130.8, 130.7 ,130.2,129.1,123.0,122.7,120.1,110.3,52.4,44.7,31.9,20.0,13.6.ESI MS(m / e)309.16[M+H] + .

[0132] (3-6) Compound 13: 3-(1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide

[0133] Hydroxylamine hydrochloride (3.72 g, 53.51 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (3.00 g, 53.51 mmol) in methanol (5 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 11 (0.3 g, 11.89 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give compound 13 in a yield of 33%.

[0134] 1 H NMR (500MHz, DMSO-D6) δ10.12 (brs, 2H), 8.91 (s, 1H), 8.72 (d, J = 8.5Hz, 1H), 8.22 (d, J = 8.0Hz, 1H), 7.86-7.83 (m, 3H), 7.56-7.54 (m, 2H). 13 C NMR (125MHz, CD3OD) δ167.5, 149.5, 135.4, 133.9, 133.0, 131.5, 132.8, 129.9, 127.9, 124.2, 115.1.ESI MS (m / e) 254.09[M+H] + .

[0135] (3-7) Compound 14a: N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)benzamide

[0136] Hydroxylamine hydrochloride (3.72 g, 53.51 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (3.00 g, 53.51 mmol) in methanol (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 12a (0.30 g, 11.89 mmol) in tetrahydrofuran (10 mL) at 0 ° C, and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 14a in a yield of 49%.

[0137] 1H NMR (500MHz, DMSO-D6) δ11.4 (s, 1H), 9.24 (s, 1H), 8.23 ​​(s, 1H), 8.01 (d, J=8 Hz, 1H), 7.94 (d, J=8.5Hz, 1H), 7.71-7.62 (m, 4H), 7.33 (m, 2H), 3.90 (s, 3H) 13 C NMR (125MHz, DMSO-D6) δ163.6, 152.4, 142.5, 136.5, 133.3, 131.9, 130.4, 129.0, 128.1, 127.7, 122.6, 122.2, 119.1, 110.8, 31.8.ESI MS(m / e)268.11[M+H] + .

[0138] (3-8) Compound 14b: 3-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide

[0139] Hydroxylamine hydrochloride (3.72 g, 53.51 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (3.00 g, 53.51 mmol) in methanol (5 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 12b (0.30 g, 11.89 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give compound 14b in a yield of 43%.

[0140] 1 H NMR (500MHz, DMSO-D6) δ8.33 (s, 1H), 8.12 (d, J = 8Hz, 1H), 8.03 (d, J = 8Hz, 1H), 7.74-7.67(m, 3H), 7.33-7.25(m, 2H), 4.33(q, J=7Hz, 2H), 1.36(t, J=7Hz, 3H) 13 C NMR (125MHz, CD3OD) δ168.4, 152, 5, 141.9, 135.0, 132.9, 131.0, 130.0, 129.9, 128.9, 123.2, 122.7, 118.5, 39.4, 14.1.ESI MS (m / e) 282.12[M+H] + .

[0141] (3-9) Compound 14c: N-hydroxy-3-(1-propyl-1H-benzo[d]imidazol-2-yl)benzamide

[0142] Hydroxylamine hydrochloride (2.83 g, 40.71 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (2.28 g, 40.71 mmol) in methanol (5 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, and the precipitated potassium chloride was removed and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 12c (0.28 g, 0.90 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred for 3 hours at the same temperature. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give compound 14c in a yield of 55%. f =0.22 (8:2=ethyl acetate:hexane).

[0143] 1 H NMR (500MHz, DMSO-D6) δ11.39 (s, 1H), 9.14 (s, 1H), 8.09 (s, 1H), 7.89 (d, J=6.5Hz, 2H), 7.67-7.6 2 (m, 3H), 7.28-7.21 (m, 2H), 4.25 (t, J = 7.5Hz, 2H), 1.66 (q, J = 6.5Hz, 2H), 0.69 (t, J = 7.0Hz, 3H). 13 C NMR (125MHz, DMSO-D6) δ163.5.152.3, 142.6, 135.8.133.2, 131.7, 131.2, 129.1, 128.2, 127.6, 122.6, 122.1, 119.3, 111.1, 45.6, 22.7, 11.0.ESI MS(m / e)296.13[M+H] + .

[0144] (3-10) Compound 14d: 3-(1-butyl-1H-benzo[d]imidazol-2-yl)-N-hydroxybenzamide

[0145] Hydroxylamine hydrochloride (2.83 g, 40.71 mmol) in methanol (5 mL) was added to a solution of potassium hydroxide (2.28 g, 40.71 mmol) in methanol (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, and the precipitated potassium chloride was removed, and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 12d (0.28 g, 0.90 mmol) in tetrahydrofuran (10 mL) at 0 ° C, and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with acetic acid and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to obtain compound 14d in a yield of 50%. f =0.28 (8:2=ethyl acetate:hexane).

[0146] 1 H NMR (500MHz, DMSO-D6) δ11.45 (s, 1H), 9.21 (s, 1H), 8.15 (t, J=1.5Hz, 1H), 7.95-7.92 (m, 2H), 7.71-7.66 (m, 3H), 7.33-7.25 (m, 2H), 4.32 (t, J=7.5Hz, 2H), 1.69-1.63 (m, 2H), 1.18-1.10 (m, 2H), 0.74 (t, J=7.5Hz, 3H). 13 C NMR (125MHz, DMSO-D6) δ163.4, 152.3, 142.6, 135.7, 133.3, 131.7, 130.8, 1 29.0, 128.0, 127.6, 122.7, 122.1, 119.3, 111.1, 43.8, 31.3, 19.2, 13.3.ESI MS(m / e)310.15[M+H] + .

[0147] [Example 4] Synthesis of Compounds (17a-17b)

[0148] [Reaction Scheme 4]

[0149]

[0150] Reaction Scheme 4 shows the synthesis process of Compound 17a-Compound 17b.

[0151] In Reaction Scheme 4, unlike Reaction Scheme 2, the first attempt to construct Compounds 16a-16b via iodine-mediated cyclization of Compounds 15a-15b with aldehyde 10 was not good. Therefore, sodium cyanide-catalyzed cyclization of Compounds 15a-15b with aldehyde 10 in DMF successfully provided Compounds 16a-16b in 44%-67% yields. Finally, Compounds 16a-16b were converted to Compounds 17a-17b using NH2OH and KOH in methanol. In more detail, the process was performed as follows.

[0152] (4-1) Compound 16a: 3-(Benzo[d]oxazol-2-yl)benzoic acid methyl ester

[0153] 2-aminophenol (0.50g, 4.58mmol) and methyl 3-formylbenzoate (0.75g, 4.58mmol) in 40mL DMF were added to molecular sieves (molecular filter). Then, the reaction mixture was stirred in an open flask at 60°C for 4 hours. After 4 hours, the reaction mixture was cooled at room temperature and added to sodium cyanide (NaCN, 0.02g, 0.46mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure and purified by column to obtain compound 16a in a yield of 67%. f =0.25 (1:9 = ethyl acetate: hexane).

[0154] 1 H NMR (500MHz, DMSO-D6) δ8.70 (s, 1H), 8.43 (d, J = 8.5Hz, 1H), 8.17 (d, J = 8.0Hz, 1H), 7.84-7.82 (m, 2H), 7.77 (t, J = 7.5Hz 1H), 7.48-7.41(m, 2H), 3.92(s, 1H). 13 C NMR (125MHz, CDCl3) δ166.3, 162.2, 150.9, 142.1, 132.5, 131.8, 131.2, 129.3, 128.8, 127.7, 125.6, 124.9, 120.3, 52.5.ESI MS (m / e) 254.08[M+H] + .

[0155] (4-2) Compound 16b: 3-(Benzo[d]thiazol-2-yl)benzoic acid methyl ester

[0156] 2-aminothiophenol (0.50g, 4.58mmol) and methyl 3-formylbenzoate (0.66g, 4.0mmol) in 40mL DMF were added to molecular sieves (molecular filter). Then, the reaction mixture was stirred for 4 hours at 60°C in an open flask. After 4 hours, the reaction mixture was cooled at room temperature and added to sodium cyanide (0.02g, 0.46mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure and purified by column to obtain compound 16b in a yield of 44%. R f =0.26 (1:9 = ethyl acetate: hexane).

[0157] 1H NMR (500MHz, DMSO-D6) δ8.57 (s, 1H), 8.26 (d, J = 7.5Hz, 1H), 8.13 (d, J = 7.5HZ, 1H), 8.08 (d, J = 8.5Hz, 2H), 7.68 (t, J=7.5Hz, 1H), 7.55 (t, J=8.0Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 3.90 (s, 3H). 13 C NMR (125MHz, CDCl3) δ166.8, 166.4, 154.1, 135.1, 134.0, 131.8, 131.6, 131.1, 129.2, 128.6, 126.5, 126.5, 125.5, 123.4, 52.4.ESI MS(m / e)270.06[M+H] + .

[0158] (4-3) Compound 17a: 3-(Benzo[d]oxazol-2-yl)-N-hydroxybenzamide

[0159] Hydroxylamine hydrochloride (3.70 g, 53.31 mmol) in methanol (6 mL) was added to a solution of potassium hydroxide (2.99 g, 53.31 mmol) in methanol (6 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, the precipitated potassium chloride was removed, and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 16a (0.30 g, 1.18 mmol) in tetrahydrofuran (12 mL) at 0°C and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give compound 17a in a yield of 50%.

[0160] 1 H NMR (500MHz, DMSO-D6) δ11.52 (s, 1H), 9.24 (s, 1H), 8.61 (s, 1H), 8.33 (d, J=7.5Hz, 1H) , 8.0 (d, J=8.0Hz, 1H), 7.83 (t, J=8.0Hz, 2H), 7.71 (t, J=8.0Hz, 1H), 7.46-7.43 (m, 2H). 13 C NMR (125MHz, DMSO-D6) δ163.2, 161.7, 150.3, 141.4, 133.8, 130.1, 129.4, 129.7, 126.7, 125.9, 125.1, 120.0, 111.1.ESI MS (m / e) 255.08[M+H] + .

[0161] (4-4) Compound 17b: 3-(benzo[d]thiazol-2-yl)-N-hydroxybenzamide

[0162] Hydroxylamine hydrochloride (2.32 g, 33.42 mmol) in methanol (6 mL) was added to a solution of potassium hydroxide (1.87 g, 33.42 mmol) in methanol (6 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes, the precipitated potassium chloride was removed, and the filtrate was used as such; freshly prepared hydroxylamine was added to a solution of compound 16b (0.20 g, 0.74 mmol) in tetrahydrofuran (12 mL) at 0°C and stirred at the same temperature for 3 hours. The mixture was neutralized to pH 7 with 3N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by MPLC to give compound 17b in a yield of 4%.

[0163] 1 H NMR (500MHz, DMSO-D6) δ11.51 (s, 1H), 8.47 (s, 1H), 8.24 (d, J = 8.0Hz, 1H), 8.20 (d, J = 7.5Hz, 1H), 8.11 (d, J=8.0Hz, 1H), 7.94 (d, J=7.5Hz, 1H), 7.67 (t, J=7.5Hz, 1H), 7.58 (t, J=7.0Hz, 1H), 7.50 (t, J=7.0Hz, 1H). 13 C NMR (125MHz, DMSO-D6) δ166.6, 163.3, 153.5, 134.6, 133.9, 133.1, 129.8, 129.7, 129.6, 126.9, 125.8, 125.6, 123.1.122.6.ESIMS (m / e) 271.05[M+H] + .

[0164] [Experimental Example 1] Antiproliferative effect in SH-SY5Y cell line

[0165] The compounds synthesized by the above Examples 1 to 4 were used to study the antiproliferative activity against the human neuroblastoma cell line SH-SY5Y (an in vitro model of human malignant metastatic neuroblastoma).

[0166] 1. Cell Culture

[0167] SH-SY5Y cells were cultured in DMEM (Dulbecco's modified Eagle's medium) with L-glutamine and supplemented with 500 mg / mL streptomycin, 100 units / mL penicillin and 10% fetal bovine serum (FBS). Cells were grown to confluence in a humidified atmosphere (37° C., 5% CO 2 ).

[0168] 2. Experimental results

[0169] Table 1 below shows the results of the antiproliferative activity experiment according to Experimental Example 1, and shows the cytotoxicity value for the cell line SH-SY5Y after 72 hours, i.e., the maximum concentration value (GI) at which the compound reduces cell proliferation by half. 50 ; half maximal growth inhibitory concentration).

[0170] [Table 1]

[0171]

[0172] Referring to Table 1, compound 9b exerted the most effective antiproliferative activity against SH-SY5Y cell line, GI 50 The value was 2.01 μM. The reference drug SAHA also provided good antiproliferative activity against the SH-SY5Y cell line, GI 50 The value is 2.90 μM. SAHA is a drug used to treat cutaneous T-cell lymphoma (a type of cancer).

[0173] Compared with the benzothiazole analog compound 9b, the para-substituted benzimidazole analogs 5 and 6a-6d showed relatively lower antiproliferative activity, GI 50 The values ​​were 38.1 μM-60 μM, but the longer butyl substituent on the nitrogen atom of the benzimidazole group (6d) showed increased antiproliferative activity, GI 50 The GI value was 26.8 μM. Benzoxazole 9a (which has an oxygen atom replacing the sulfur atom of the most effective compound 9b) has a GI of 25.7 μM 50 The value of 0.05 was 0.01, providing a potent antiproliferative activity 12-fold lower than that of compound 9b. This may be because the hydrophobicity of the sulfur atom plays a key role in binding to HDAC enzymes and in cell permeability.

[0174] Compared with methyl substituted compound 13 and unsubstituted compound 14a, ethyl, propyl and butyl substituents on the nitrogen atom of the meta-substituted benzimidazole moiety (including compounds 14b-compound 14d) also have increased cell antiproliferative activity against the SH-SY5Y cell line. However, compared with para-substituted benzothiazole 9b, all meta-substituted compounds 13, compounds 14a-compound 14d and compounds 17a-compound 17b show relatively poor or moderate antiproliferative activity.

[0175] [Experimental Example 2] Antiproliferative effect in breast cancer cell line MDA-MB-231

[0176] The compounds synthesized by the above Examples 1 to 4 were used to study the antiproliferative activity on the breast cancer cell line MDA-MB-231.

[0177] Table 2 below shows the results of the antiproliferative activity test on the breast cancer cell line MDA-MB-231. Referring to Table 2, compound 9b showed the strongest antiproliferative activity on the MDA-MB-231 cell line, GI 50 The value was 3.86 μM, while the reference drug SAHA also showed excellent antiproliferative activity against MDA-MB-231 cell line. 50 The GI of benzoxazole 9a (which has an oxygen atom replacing the sulfur atom of the most potent compound 9b) is 8.31 μM. 50 value, which was not as potent as compound 9b, but provided high antiproliferative activity.

[0178] [Table 2]

[0179]

[0180] [Experimental Example 3] Antiproliferative effect of compound 9b in H1975, A549 and HeLa cell lines

[0181] Compound 9b was used to study the antiproliferative activity against non-small cell lung cancer cell line H1975, lung cancer cell line A549 and cervical cancer cell line HeLa, and it showed high antiproliferative activity in Experimental Examples 1 and 2 above.

[0182] [Table 3]

[0183] Compound <![CDATA[H1975(GI 50 ;μM)]]> <![CDATA[A549(GI 50 ;μM)]]> <![CDATA[HeLa(GI 50 ;μM)]]> 9b 3.71 15.6 13.5

[0184] Table 3 shows the results of the antiproliferative activity test on non-small cell lung cancer cell line H1975, lung cancer cell line A549 and cervical cancer cell line HeLa. Referring to Table 3, compound 9b generally provides high antiproliferative activity on cell lines, and it can be confirmed that it exhibits antiproliferative effects in various cancer cell lines.

[0185] [Experimental Example 4] Colony formation analysis

[0186] Non-anchorage-dependent cell growth is a characteristic of cell carcinogenesis and indicates the ability of transformed cells to grow independently of solid surfaces. The soft agar colony formation assay is a widely used method for measuring the in vitro growth ability of non-anchorage-dependent cells. Therefore, the inhibitory effect of compound 9b on non-anchorage-dependent cell growth was explored by the soft agar colony formation assay.

[0187] 1. Experimental Methods

[0188] SH-SY5Y cells were seeded on a plate with 1.2% agar (4 × 10 5Cells / well) were placed in a 6-well plate, and compound 9b was added at concentrations of 1 μM, 3 μM, and 5 μM, and cultured for 1 to 2 weeks. DMSO (0.5%) was used as a negative control. After incubation, the colonies were stained with 0.05% crystal violet for 10 minutes. The colonies were washed with triple distilled water and captured.

[0189] 2. Experimental results

[0190] Figure 2 The inhibitory effect of compound 9b described in the experimental example of the present invention is shown. Figure 2 , treatment of SH-SY5Y cells with compound 9b showed an inhibitory effect on the colony formation of SH-SY5Y neuroblastoma. In addition, as the concentration of compound 9b increased, the ability of SH-SY5Y cells to form colonies decreased in a dose-dependent manner, and when the concentration of compound 9b was 3 μM, the non-anchorage-dependent cell growth of SH-SY5Y neuroblastoma was almost completely inhibited. In summary, the experimental data show that compound 9b effectively inhibits the non-anchorage-dependent growth ability of SH-SY5Y cells in a concentration-dependent manner.

[0191] Hereinafter, the preparation example of the composition containing compound 9b according to the present invention is described, but the present invention is not limited thereto, and is intended to be described in detail.

[0192] [Formulation Example 1] Formulation Example of Pharmaceutical Composition

[0193] [Formulation Example 1-1] Preparation of powder

[0194] Powders were prepared by mixing 20 mg of Compound 9b, 100 mg of lactose and 10 mg of talc and filling in sealed bags.

[0195] [Formulation Example 1-2] Preparation of Tablets

[0196] Tablets were prepared by mixing and tableting 20 mg of Compound 9b, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate according to a conventional tablet preparation method.

[0197] [Formulation Examples 1-3] Preparation of Capsules

[0198] According to a conventional capsule preparation method, capsules were prepared by mixing 10 mg of Compound 9b, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate and filling the above components into gelatin capsules.

[0199] [Formulation Examples 1-4] Preparation of Injections

[0200] According to a conventional method for preparing injections, 10 mg of compound 9b, an appropriate amount of sterile distilled water for injection and an appropriate amount of a pH adjuster were mixed and the above components were processed into individual ampoules (2 mL) to prepare injections.

[0201] [Formulation Examples 1-5] Preparation of Ointment

[0202] According to a conventional ointment preparation method, 10 mg of compound 9b, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg of white vaseline, 1.44 mg of methylparaben, 0.18 mg of propylparaben and the remaining amount of purified water were mixed and processed to prepare an ointment.

[0203] [Formulation Example 2] Health Functional Food

[0204] [Formulation Example 2-1] Production of health food

[0205] According to the conventional method, 1 mg of compound 9b, 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 an inorganic 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 dicalcium phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, 24.8 mg of magnesium chloride) are mixed, and then granules are prepared to prepare a health food.

[0206] [Formulation Example 2-2] Preparation of healthy drinks

[0207] 1 mg of compound 9b, 1000 mg of citric acid, 100 g of oligosaccharides, 2 g of plum concentrate, 1 g of taurine and purified water were mixed to make a total amount of 900 ml, and the above ingredients were mixed according to a conventional health drink preparation method, heated and stirred at 85°C for about 1 hour, and the resulting solution was filtered and added to a sterilized 2L container, sealed and sterilized, and then stored in a refrigerator.

[0208] So far, the present invention has been studied through specific embodiments of the present invention. It will be appreciated by those skilled in the art that the present invention may be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered from an explanatory point of view rather than a restrictive point of view. The scope of the present invention is shown in the claims rather than in the above description, and all differences within the scope equivalent thereto should be interpreted as included in the present invention.

Claims

1. A compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, [Chemical formula 1] in, R is O or S, wherein the compound is any one compound selected from the group consisting of 4-(benzo[d]oxazol-2-yl)-N-hydroxybenzamide, 4-(benzo[d]thiazol-2-yl)-N-hydroxybenzamide, 3-(benzo[d]oxazol-2-yl)-N-hydroxybenzamide and 3-(benzo[d]thiazol-2-yl)-N-hydroxybenzamide.

2. A pharmaceutical composition for preventing or treating cancer diseases, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

3. Use of the pharmaceutical composition according to claim 2 in the preparation of a drug for preventing or treating cancer, wherein: The cancer disease is selected from the group consisting of human malignant metastatic neuroblastoma, breast cancer, lung cancer and cervical cancer.

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