Novel compound having inhibitory activity against leukemia cell lines and medical use thereof

Abstract

The present invention relates to a novel compound having inhibitory activity against leukemia cell lines and a medical use thereof. The novel compound according to the present invention has excellent inhibitory activity against leukemia cell lines and thus can treat related diseases, and in particular, has an excellent therapeutic effect on acute myeloid leukemia (AML) and thus can be effectively used for treating leukemia as described above.

Description

Novel compound having inhibitory activity against leukemia cell lines and its medical uses

[0001] The present invention relates to a novel compound and its medical use, and more specifically, to a novel compound having inhibitory activity against leukemia cell lines and its use in treating leukemia.

[0002] Leukemia is a blood cancer that occurs when normal blood cells in the bone marrow, the body's hematopoietic organ, transform into cancer cells and proliferate due to some cause. Leukemia cells proliferate indefinitely, interfering with the production of normal white blood cells, red blood cells, and platelets, thereby reducing the levels of normal blood cells and causing fatal problems in the body.

[0003] Acute leukemia is a disease in which hematopoietic stem cells transform into malignant cells, proliferate in the bone marrow, spread into the peripheral blood, and then spread throughout the body, invading organs such as the liver, spleen, and lymph nodes. Acute leukemia is classified into acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) depending on the type of leukemia cells. Acute myeloid leukemia is the most common form of leukemia; it primarily affects adults, and the incidence rate increases with age.

[0004] Myeloid leukemia refers to a condition in which myeloblasts account for more than 20% of the bone marrow or peripheral blood. When cancer cells grow in the bone marrow, they inhibit normal hematopoietic cells, thereby interfering with hematopoiesis. Consequently, anemia, leukopenia, thrombocytopenia, and leukocytosis occur, leading to symptoms. Among these, the acute form of myeloid leukemia is called acute myeloid leukemia.

[0005] Standard treatment methods for leukemia include chemotherapy, hematopoietic stem cell transplantation, and radiation therapy; in the case of chemotherapy, the combination of two or more anticancer drugs is typically employed. Ideally, anti-leukemia drugs should exhibit a selective effect only on leukemia cells without inhibiting normal hematopoiesis or causing other harmful side effects. However, while most anti-leukemia drugs can kill leukemia cells to some extent by approaching this ideal state, they also inhibit normal hematopoiesis and cause other harmful side effects, thus limiting their effectiveness in leukemia treatment. Furthermore, in drug-resistant leukemia cells, the anti-tumor effect is weak, and there are cases where sufficient chemotherapy cannot be administered due to potential side effects.

[0006] Therefore, there is a need for a new leukemia treatment with minimal side effects and excellent therapeutic efficacy.

[0007] The objective of the present invention is to provide a novel anticancer compound having inhibitory activity against leukemia cell lines.

[0008] Another objective of the present invention is to provide medical uses for the above-mentioned compound.

[0009] To achieve the above objective, the present invention provides a compound selected from a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0010] <Chemical Formula 1>

[0011]

[0012] In the above chemical formula 1, R 1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, or amino, and R 2 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)alkoxy, and

[0013] R 3 Is or Selected from, where, R 3' ≡ is hydrogen or (C1-C4)alkyl, and X can be oxygen or sulfur.

[0014] The present invention provides a pharmaceutical composition for the prevention or treatment of leukemia comprising the above-mentioned novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] In addition, the present invention provides a health functional food composition for the prevention or improvement of leukemia, comprising the novel compound described above or a food-grade acceptable salt thereof as an active ingredient.

[0016] The novel compound according to the present invention has excellent inhibitory and anticancer activity against leukemia cell lines, so it can treat related diseases, and in particular, it has an excellent therapeutic effect on acute myeloid leukemia (AML), so it can be effectively utilized in the treatment of leukemia as described above.

[0017] Figure 1 shows the results of evaluating cell viability under single administration conditions in human myeloid leukemia cell line MV4-11 of representative novel compounds according to one experimental example of the present invention.

[0018] Figure 2 evaluates the cell proliferation inhibitory activity of each novel compound in the MV4-11 cell line, and the GI of each compound 50 (Growth Inhibition 50%) value and coefficient of determination (R 2 ) confirmed.

[0019] Figure 3 evaluates the cytotoxicity of the representative compound 1 (DN302319) in various leukemia cell lines (MV4-11, MOLM-13, THP-1, K562), and confirms that it does not show toxicity in normal cells but exhibits excellent selective inhibitory activity in leukemia cell lines.

[0020] Figure 4 shows the cell proliferation inhibitory activity (GI) of four representative compounds 50 , R2 This is a graph showing the experimental results.

[0021] The present invention will be described in detail below.

[0022]

[0023] The inventors synthesized a novel compound and confirmed that the compound exhibits excellent inhibitory activity against leukemia cell lines, thereby effectively treating acute myeloid leukemia, and thus completed the present invention.

[0024]

[0025] The present invention provides a compound selected from a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0026] <Chemical Formula 1>

[0027]

[0028] In the above chemical formula 1, R 1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, or amino, and R 2 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)alkoxy, and

[0029] R 3 Is or Selected from, where, R 3' ≡ is hydrogen or (C1-C4)alkyl, and X can be selected from oxygen or sulfur.

[0030] Preferably, in the above formula 1, R 1 It is selected from (C1-C2)alkyl, trifluoromethyl, or amino, and R 2 is selected from hydrogen, halogen, (C1-C2)alkyl, trifluoromethyl, or (C1-C2)alkoxy, and R 3' It can be selected from hydrogen or (C1-C2)alkyl.

[0031] More preferably, the compound is 3-(4-thiouredobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamido (Compound 1), 3-(4-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 2), 4-methyl-3-(3-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 3), 4-methyl-3-(3-(3-methyluredo)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido (Compound 4), 4-methyl-3-(3-thiouredobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 5), 3-thiouredo-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 6), 4-methyl-3-(3-(3-methyluredobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 7), 3-(3-methyluredo)-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 8), 3-(3-methyluredo)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 9), 3-thiouredo-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 10), 4-fluoro-3-(3-thiouredobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 11), 3-(4-thiouredobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 12), 3-(4-(3-methyluredo)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 13), 4-methyl-3-(4-(3-methyluredo)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 14), 4-methyl-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 15),3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 16), 4-methyl-3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 17), 4-methyl-3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 18), 3-(4-(3-methylthioureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 19), N-(3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-ureidobenzamido)benzamide (Compound 20), 4-fluoro-3-(4-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 21), 2-fluoro-5-(3-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 23), 2-methyl-5-(4-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 24), N-(3-(methylsulfonyl)phenyl)-3-(3-thiouredobenzamido)benzamide (Compound 25), N-(3-(methylsulfonyl)phenyl)-3-(4-thiouredobenzamido)benzamide (Compound 26), 3-methyl-5-(4-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 29), 3-methyl-5-(3-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 30), 3-(4-(3-methylthiouredo)benzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 31), N-(3-sulfamoylphenyl)-3-(4-thiouredobenzamido)benzamide (Compound 32), N-(3-(ethylsulfonyl)phenyl)-3-(4-thiouredobenzamido)benzamide (Compound 33), 3-Guanidino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 34),3-(3-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 35), 3-(3-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 36), 3-carbamothioil-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 37), 3-carbamothioil-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 38), 3-(4-carbamothioilbenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 39), 3-(4-carbamothioyylbenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 40), 3-(4-carbamothioyylbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 41), 3-(4-carbamothioyylbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 42), 3-(3-carbamothioyylbenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 43), 3-(3-carbamothioyylbenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 44), 3-(3-carbamothioyylbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 45), 3-(3-carbamothioyylbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 46), 3-(4-carbamothioyylbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 47), 3-(4-carbamothioyylbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 48), 5-(3-carbamothioyylbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 49),5-(4-carbamothioyylbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 50), 3-(4-carbamothioyylbenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide (Compound 51), 5-(4-carbamothioyylbenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 52), 3-(4-carbamothioyylbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (Compound 53), It may be selected from the group consisting of 3-(3-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 54) and 3-carbamothioil-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 55).

[0032]

[0033] The above compound may be used in the form of a pharmaceutically or food-grade acceptable salt within a range having the same efficacy.

[0034] In this specification, "pharmaceutical or food-acceptable salt" means a salt having a safety and efficacy profile suitable for administration to humans, having no toxicity to cells or humans exposed to the composition.

[0035] The above salt may be used in the form of either a basic salt or an acidic salt that is pharmaceutically or food-grade acceptable. The basic salt may be used in the form of either an organic basic salt or an inorganic basic salt, and may be selected from the group consisting of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aluminum salt, ammonium salt, triethylaminium salt, and pyridinium salt. For the acidic salt, an acid addition salt formed by a free acid is useful. Inorganic and organic acids may be used as free acids. Inorganic acids may include hydrochloric acid, bromic acid, sulfuric acid, sulfite, phosphoric acid, diphosphate, nitric acid, etc., and organic acids may include citric acid, acetic acid, maleic acid, malic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, emvonic acid, glutamic acid, citric acid, aspartic acid, stearic acid, etc., but are not limited thereto and may include all salts formed using various inorganic and organic acids commonly used in the industry.

[0036] In addition, the above-mentioned compound may include not only the above-mentioned salt, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared according to conventional methods. The addition salt can be prepared by conventional methods, and can be prepared by dissolving it in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base or an aqueous solution of an inorganic base, and then precipitating or crystallizing it. Alternatively, the addition salt can be obtained by evaporating the solvent or the excess base from the mixture and then drying it, or by suction filtration of the precipitated salt.

[0037]

[0038] The above compound can have excellent inhibitory activity against leukemia cell lines.

[0039] The above leukemia cell line may be MV4-11, MOLM-13, THP-1, or K562 cell line, and the compound has excellent antiproliferative or anticancer activity against the cell line, so it can be used to treat related leukemia disease.

[0040]

[0041] The present invention provides a pharmaceutical composition for the prevention or treatment of leukemia comprising the above-mentioned novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0042] The above leukemia may be acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia, and preferably may be acute myeloid leukemia, but is not limited thereto.

[0043]

[0044] In this specification, "pharmaceutical composition" means a composition administered for the purpose of preventing or treating a specific disease, and for the purposes of the present invention, means administered for the treatment of leukemia or diseases or complications caused by it.

[0045] The pharmaceutical composition according to the present invention may be prepared according to conventional methods in the pharmaceutical field. The pharmaceutical composition may be combined with a suitable pharmaceutically acceptable carrier depending on the formulation, and may be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc., as needed. The suitable carrier, etc., may be selected differently depending on the dosage form and formulation, as it does not impair the activity and properties of the compound or salt thereof according to the present invention.

[0046] Examples of carriers, excipients, diluents, etc. that may be included in the above pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc.

[0047] The above pharmaceutical composition can be applied in any dosage form, and more specifically, can be formulated and used in oral dosage forms, topical preparations, suppositories, and parenteral dosage forms of sterile injectable solutions according to conventional methods, but is not limited thereto.

[0048] Among the above oral formulations, solid formulations may be in the form of tablets, pills, powders, granules, capsules, etc., and may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc., and may also include lubricants such as magnesium stearate and talc in addition to simple excipients. Furthermore, in the case of capsule formulations, in addition to the substances mentioned above, liquid carriers such as fatty oils may be further included. Among the above oral formulations, liquid formulations may include suspensions, liquid formulations, emulsions, syrups, etc., and may include various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.

[0049] The parenteral formulations described above may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerogelatin, etc., may be used. However, they are not limited thereto, and any suitable formulation known in the art may be used.

[0050]

[0051] The pharmaceutical composition according to the present invention can be administered in a pharmaceutically effective amount.

[0052] In this specification, "pharmaceuticalally effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause adverse effects.

[0053] The effective dose level of the above pharmaceutical composition may be determined differently depending on factors including the purpose of use, the patient's age, gender, weight and health status, type and severity of the disease, drug activity, sensitivity to the drug, method of administration, time of administration, route of administration and elimination rate, duration of treatment, drugs used in combination or concurrently, and other factors well known in the medical field. For example, although not constant, it may generally be administered at a dose of 0.001 to 1000 mg / kg, preferably 0.01 to 100 mg / kg, once or several times daily. The above dosage does not limit the scope of the present invention in any way.

[0054] The above pharmaceutical composition may be administered to any animal capable of developing leukemia, and said animals may include, for example, humans and primates, as well as livestock such as cattle, pigs, horses, and dogs.

[0055] The above pharmaceutical composition may be administered via a suitable route of administration depending on the formulation form, and may be administered via various oral or parenteral routes as long as it reaches the target tissue. The method of administration may be administered by conventional methods, such as oral, rectal or intravenous, intramuscular, topical application, respiratory inhalation, intrathecal or intracerebral (intracere-broventricular) injection, without needing to be particularly limited.

[0056] The above pharmaceutical composition may be used alone for the prevention or treatment of leukemia, or may be used in combination with surgery or other drug treatments.

[0057]

[0058] The present invention provides a food composition for preventing or improving leukemia, comprising the above-mentioned novel compound or a food-grade acceptable salt thereof as an active ingredient.

[0059] The food composition of the present invention may include all forms such as functional food, nutritional supplement, health food, and food additives.

[0060] Corresponding features can be substituted with those described above.

[0061]

[0062] In addition, the present invention provides a health functional food composition for the prevention or improvement of leukemia, comprising the novel compound described above or a food-grade acceptable salt thereof as an active ingredient.

[0063] Corresponding features can be substituted with those described above.

[0064]

[0065] The term "health functional food" above refers to a food manufactured and processed using raw materials or ingredients that have functional properties beneficial to the human body, and is a food with high medical or therapeutic effects that is processed to efficiently exhibit biological regulatory functions in addition to providing nutrition; it may be used interchangeably with terms known in the industry, such as functional food.

[0066] The food or health functional food composition according to the present invention may be manufactured into a powder, granule, tablet, capsule, syrup, or beverage, etc., for the purpose of preventing or improving leukemia, and there are no restrictions on the form in which the food may take place, and it may include all foods in the conventional sense. For example, beverages and various drinks, fruits and their processed foods (canned fruit, jam, etc.), fish, meat and its processed foods (ham, bacon, etc.), breads and noodles, cookies and snacks, dairy products (butter, cheese, etc.), etc. are possible, and it may include all functional foods in the conventional sense. In addition, it may also include foods used as animal feed.

[0067] The above food composition may be prepared by further including food-grade acceptable food additives commonly used in the industry and appropriate other auxiliary ingredients. Unless otherwise stipulated, suitability as a food additive may be determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety. Items listed in the above 'Food Additives Codex' may include, for example, chemically synthesized products such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamon acid; natural additives such as persimmon dye, licorice extract, crystalline cellulose, sorghum dye, and guar gum; and mixed preparations such as L-sodium glutamate preparations, alkaline noodle additives, preservative preparations, and tar dye preparations.

[0068] The above other auxiliary ingredients may additionally contain, for example, flavoring agents, natural carbohydrates, sweeteners, vitamins, electrolytes, coloring agents, pectic acid, alginic acid, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents, etc. In particular, the above natural carbohydrates may include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol, and as sweeteners, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used.

[0069] The effective dose of the compound contained in the above food composition or its food-grade acceptable salt can be appropriately adjusted according to the purpose of use, such as the prevention or improvement of leukemia. The above composition has the advantage of being made from food and thus free from side effects that may occur with the long-term use of general medicines, and due to its excellent portability, it can be consumed as an adjuvant for the prevention or improvement of leukemia.

[0070]

[0071] In addition, the present invention provides a reagent composition for inhibiting the proliferation of leukemia cell lines, comprising a compound selected from the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0072] Hereinafter, the present invention will be described in detail with reference to examples to aid in understanding. However, the following examples are merely illustrative of the content of the present invention and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

[0073]

[0074] <Example 1> Synthesis of a Compound

[0075] A compound was synthesized according to the following reaction scheme 1.

[0076] [Reaction Equation 1]

[0077]

[0078]

[0079] 1-1. Synthesis of Compound 1: 3-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamido[3-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamide, DN302319]

[0080] [Reaction Equation 1-1]

[0081]

[0082] Step 1) Synthesis of intermediate compound 1-1: 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0083] 3-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.220 mmol) was dissolved in dimethylformamide (DMF) (1 ml), and then 3-nitro-5-(trifluoromethyl)benzoic acid (1200 mg, 2.4 mmol), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) (1689 mg, 4.44 mmol), and N,N-diisopropylethylamine (DIPEA) (75 mg, 0.606 mmol) were added dropwise to the reaction mixture, which was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was extracted with EtOA and water, the resulting organic layer was washed with brine, dried with MgSO4, and filtered. The residue obtained by vacuum distillation of the filtered solution was separated and purified by MPLC to obtain the intermediate compound (1-1) 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (852 mg, 187% yield).

[0084] Step 2) Synthesis of intermediate compound 2-1: 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0085] Intermediate compound (1-1) (1128 mg, 2.89 mmol) and 10% carbon-supported palladium (923 mg, 0.87 mmol) were added dropwise to 50 ml of CH3OH. Hydrogen gas was injected and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was filtered through a Celite filter. The residue obtained by vacuum distillation of the filtered solution was separated and purified by MPLC to obtain intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (556 mg, 74% yield).

[0086] Step 3) Synthesis of Compound 1 (DN302319): 3-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamido[3-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamide]

[0087] 4-thioureidobenzoic acid (35 mg, 0.182 mmol), hexafluorophosphate benzotriazole tetramethyl uronium (HBTU) (69 mg, 0.182 mmol), and DIPEA (75 mg, 0.606 mmol) were dissolved in DMF (1 ml), and then intermediate compound (2-1) (50 mg, 0.121 mmol) was added dropwise. The reaction mixture was stirred at 50°C for 18 hours, and after the reaction was finished, the organic layer obtained by extraction with EtOH and water was washed with brine, dried with MgSO4, and filtered. The residue obtained by vacuum distillation of the filtered solution was separated and purified by MPLC to obtain compound 13-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)-phenyl)benzamido (5.4 mg, 7% yield).

[0088] 1H NMR (400 MHz, DMSO) δ11.02 (s, 1H), 10.69 (s, 1H), 10.01 (s, 1H), 8.68 (t,J= 1.8 Hz, 1H), 8.64 (d,J= 2.3 Hz, 1H), 8.51 (d,J= 1.9 Hz, 1H), 8.44 (ddd,J= 5.5, 3.5, 2.1 Hz, 1H), 8.10 (d,J= 2.0 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.89 (dd,J= 5.2, 1.4 Hz, 2H), 7.75 - 7.67 (m, 2H).; LCMS (ESI),m / z=591.31 [M+1]+.

[0089]

[0090] 1-2. Synthesis of Compound 2: 3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209152]

[0091] [Reaction Equation 1-2]

[0092]

[0093] Step 1) Synthesis of intermediate compounds 1-2: 3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0094] 3-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.22 mmol) was dissolved in dichloromethane (DCM) (23 ml), and then triethylamine (TEA) (0.43 ml, 3.11 mmol) and 3-nitrobenzoyl chloride (577 mg, 3.11 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 3 hours, and after the reaction was complete, it was extracted with EtOA and water. The resulting organic layer was washed with brine, dried with MgSO4, and filtered. The residue obtained by vacuum distillation of the filtered solution was separated and purified by MPLC to obtain the intermediate compound (1-2) 3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (1047 mg, > 99%).

[0095] 1 H NMR (400 MHz, MeOD) δ11.16 (s, 1H), 8.86 (t, J= 2.0 Hz, 1H), 8.69 (s, 1H), 8.50 - 8.41 (m, 3H), 7.91 - 7.87 (m, 3H).

[0096] Step 2) Synthesis of intermediate compound 2-2: 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide]

[0097] Intermediate (1-2) (833 mg, 2.22 mmol) and 10% Palladium on carbon (240 mg, 0.22 mmol) were added dropwise to 50 ml of CH3OH. Hydrogen gas was injected and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was filtered through a Celite filter. The residue obtained by vacuum distillation of the filtered solution was separated and purified by MPLC to obtain the intermediate compound (2-2) 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (556 mg, 74% yield).

[0098] 1H NMR (400 MHz, MeOD)δ10.67 (s, 1H), 8.69 (s, 1H), 8.37 (td,J= 4.8 Hz, 2.4 Hz, 1H), 7.84 - 7.83 (m, 2H), 7.19 (t,J= 8.0 Hz, 1H), 7.12 - 7.10 (m, 2H), 6.79 (dd,J= 7.2 Hz, 1.6 Hz, 1H), 5.39 (s, 2H).

[0099] Step 3) Synthesis of Compound 2 (DN209152): 3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0100] 4-Thiouredobenzoic acid (80 mg, 0.41 mmol), HBTU (154 mg, 0.41 mmol), and DIPEA (188 mg, 1.452 mmol) were dissolved in DMF (1 ml), and then intermediate compound (2-2) (100 mg, 0.29 mmol) was added dropwise. The reaction mixture was stirred at 60°C for 12 hours. After the reaction was complete, the organic layer obtained by extraction with EtOH and water was washed with brine, dried with MgSO4, and filtered. The residue obtained by vacuum distillation of the filtered solution was separated and purified by MPLC to obtain compound 23-(4-Thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 33% yield).

[0101] 1H NMR (400 MHz, DMSO) δ10. 86 (s, 1H), 10.39 (s, 1H), 9.97 (s, 1H), 8.68 (s, 1H), 8.42 - 8.39 (m, 2H), 8.03 (d,J= 9.2 Hz, 1H), 7.96 (d,J= 8.8 Hz, 2H), 7.86 (d,J= 4.8 Hz, 2H), 7.73 (d,J= 8.0 Hz, 1H), 7.68 (d,J= 8.8 Hz, 2H), 7.55 (t,J= 7.6 Hz, 1H).; LCMS (ESI), m / z = 523.13 [M+1]+.

[0102]

[0103] 1-3. Synthesis of Compound 3: 4-methyl-3-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN208692, JKJ-018-070]

[0104]

[0105] In the synthesis method of compound 1, compound 34-methyl-3-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, and 3-thioureidobenzoic acid (18.07 mg, 0.092 mmol) instead of the reagent 4-thioureidobenzoic acid, in the same manner as the synthesis method of compound 1 in Example 1-1 (7.1 mg, 15% yield).

[0106] 1H NMR (400 MHz, MeOD)δ8.67 (s, 1H), 8.26 (d,J= 8.1 Hz, 1H), 8.06 - 8.00 (m, 2H), 7.88 - 7.83 (m,J= 7.1, 5.4 Hz, 3H), 7.78 (t,J= 8.0 Hz, 1H), 7.65 (d,J= 8.2 Hz, 1H), 7.57 (t,J= 7.8 Hz, 1H), 7.49 (d,J= 8.0 Hz, 1H), 2.42 (s, 3H).; LCMS (ESI), m / z = 536.95 [M+1]+

[0107]

[0108] 1-4. Synthesis of Compound 4: 4-methyl-3-(3-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido[4-methyl-3-(3-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN208693, JKJ-018-071]

[0109]

[0110] In the synthesis method of Compound 1, Compound 44-methyl-3-(3-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido was obtained by the same method as the synthesis method of Compound 1 in Example 1-1, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido, and 3-(3-methylureido)benzoic acid (17.88 mg, 0.092 mmol) instead of the reagent 4-thioureidobenzoic acid (7.1 mg, 15% yield).

[0111] 1H NMR (400 MHz, MeOD)δ8.67 (s, 1H), 8.26 (d,J= 8.1 Hz, 1H), 8.04 (s, 1H), 8.01 (d,J= 1.7 Hz, 1H), 7.84 (d,J= 7.8 Hz, 2H), 7.78 (t,J= 8.0 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.49 (d,J= 8.0 Hz, 1H), 7.44 (t,J= 7.9 Hz, 1H), 2.81 (s, 3H), 2.42 (s, 3H).; LCMS (ESI), m / z = 535.00 [M+1]+.

[0112]

[0113] 1-5. Synthesis of Compound 5: 4-methyl-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN208844, KSG-012-89]

[0114]

[0115] In the synthesis method of Compound 1, Compound 54-methyl-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, and 3-thioureidobenzoic acid (30.1 mg, 0.153 mmol) instead of the reagent 4-thioureidobenzoic acid, in the same manner as the synthesis method of Compound 1 of Example 1-1 (5 mg, 6% yield).

[0116] 1H NMR (400 MHz, DMSO) δ10.92 (s, 1H), 10.08 (s, 1H), 9.87 (s, 1H), 8.32 - 8.21 (m, 2H), 8.18 - 8.07 (m, 2H), 8.02 (d, J= 1.6 Hz, 1H), 8.00 - 7.97 (m, 1H), 7.86 (dd,J= 7.9, 1.8 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.71 - 7.64 (m, 1H), 7.54 - 7.45 (m, 2H), 2.34 (s, 3H).; LCMS (ESI), m / z = 537.23 [M+1]+

[0117]

[0118] 1-6. Synthesis of Compound 6: 3-thioureido-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-thioureido-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208849, KSK-001-059]

[0119]

[0120] In the synthesis method of compound 1, compound 63-thiouredo-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.09 mmol) and 3-thiouredobenzoic acid (23.69 mg, 0.12 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 in Example 1-1 (8.22 mg, 17% yield).

[0121] 1H NMR (400 MHz, MeOD)δ8.67 (s, 1H), 8.32 - 8.27 (m, 2H), 7.98 (br s, 1H), 7.93 (dd,J= 8.0 Hz, 1.2 Hz), 7.87 - 7.76 (m, 4H), 7.63 (d,J= 8.0 Hz, 1H), 7.58 - 7.54 (m, 2H).; LCMS (ESI), m / z = 523.29 [M+1]+

[0122]

[0123] 1-7. Synthesis of Compound 7: 4-methyl-3-(3-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(3-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN208891, KSG-012-092]

[0124]

[0125] In the synthesis method of Compound 1, 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.140 mmol) was used instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, and 3-(3-methylureido)benzoic acid (29.8 mg, 0.153 mmol) was used instead of 4-thioureidobenzoic acid, and Compound 74-methyl-3-(3-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the same method as the synthesis method of Compound 1 of Example 1-1 (59 mg, 77% yield).

[0126] 1H NMR (400 MHz, DMSO) δ10.92 (s, 1H), 10.03 (s, 1H), 8.75 (s, 1H), 8.26 (d,J= 9.0 Hz, 2H), 8.13 (d,J= 8.8 Hz, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.87 - 7.82 (m, 1H), 7.69 - 7.62 (m, 1H), 7.51 (dd,J= 18.0, 7.9 Hz, 2H), 7.38 (t,J= 7.9 Hz, 1H), 6.08 (d,J= 4.6 Hz, 1H), 2.66 (d,J= 4.6 Hz, 3H), 2.33 (s, 3H).; LCMS (ESI), m / z = 535.13 [M+1]+.

[0127]

[0128] 1-8. Synthesis of Compound 8: 3-(3-methylureido)-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-(3-methylureido)-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208958, KSK-001-065]

[0129]

[0130] In the synthesis method of Compound 1, Compound 83-(3-methylureido)-N-(3-(((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (39 mg, 0.11 mmol) and 3-(3-methylureido)benzoic acid (30.8 mg, 0.16 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (14.5 mg, 25% yield) in the same manner as the synthesis method of Compound 1 in Example 1-1, using 3-amino-N-(3-(((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide and the reagent 4-thioureidobenzoic acid.

[0131] 1H NMR (400 MHz, MeOD)δ8.68 (br s, 1), 8.33 - 8.29 (m, 2H), 7.99 (t,J= 2.0 Hz, 1H), 7.93 (dd,J= 8.0 Hz, 1.2 Hz, 1H), 7.86 (d,J= 8.0 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.59 - 7.55 (m, 3H), 7.44 (t,J= 8.0 Hz), 2.82 (s, 3H).; LCMS (ESI), m / z = 521.25 [M+1]+.

[0132]

[0133] 1-9. Synthesis of Compound 9: 3-(3-methylureido)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-(3-methylureido)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208959, KSK-001-066]

[0134]

[0135] In the synthesis method of Compound 1, Compound 93-(3-methylureido)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.09 mmol) and 3-(3-methylureido)benzoic acid (23.69 mg, 0.12 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (2.9 mg, 6% yield) in the same manner as the synthesis method of Compound 1 in Example 1-1, using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (2.9 mg, 6% yield).

[0136] 1H NMR (400 MHz, MeOD4) δ8.33 (t,J= 1.6 Hz, 1H), 8.21 (d,J= 8.8 Hz, 2H), 8.08 (d,J= 8.8 Hz, 2H), 7.99 (t,J= 1.6 Hz, 1H), 7.93 (dd,J= 8.0 Hz, 1.2 Hz, 1H), 7.77 (d,J= 7.6 Hz, 1H), 7.59 - 7.55 (m, 3H), 2.82 (s, 3H). ; LCMS (ESI), m / z = 521.15 [M+1]+

[0137]

[0138] 1-10. Synthesis of Compound 10: 3-thioureido-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-thioureido-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208960, KSK-001-067]

[0139]

[0140] In the synthesis method of Compound 1, Compound 103-Thiouredo-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.09 mmol) and 3-thiouredobenzoic acid (23.69 mg, 0.12 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (7.1 mg, 15% yield) in the same manner as the synthesis method of Compound 1 of Example 1-1.

[0141] 1H NMR (400 MHz, MeOD) δ8.21 (t,J= 2.0 Hz, 1H), 8.09 (d,J= 9.2 Hz, 2H), 7.96 (d,J= 8.8 Hz, 2H), 7.86 (br s, 1H), 7.81 (dd,J= 8.4 Hz, 0.8 Hz, 1H), 7.71 (d,J= 7.6 Hz, 1H), 7.65 (d,J= 8.0 Hz, 1H), 7.51 (d,J= 8.0 Hz, 1H), 7.47 - 7.42 (m, 2H). ; LCMS (ESI), m / z = 523.22 [M+1]+.

[0142]

[0143] 1-11. Synthesis of Compound 11: 4-fluoro-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-fluoro-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209164, KSH-004-025]

[0144]

[0145] In the synthesis method of compound 1, compound 114-fluoro-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.14 mmol) and 3-thioureidobenzoic acid (23.69 mg, 0.12 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thioureidobenzoic acid, in the same manner as the synthesis method of compound 1 of Example 1-1 (8 mg, 11% yield).

[0146] 1H NMR (400 MHz, MeOD) δ8.44 (dd,J= 7.2, 2.2 Hz, 1H), 8.17 (d,J= 8.9 Hz, 2H), 8.06 (d,J= 8.9 Hz, 2H), 7.99 (s, 1H), 7.90 (ddd,J= 8.6, 4.6, 2.3 Hz, 1H), 7.82 (d,J= 7.7 Hz, 1H), 7.64 (d,J= 8.6 Hz, 1H), 7.55 (t,J= 7.8 Hz, 1H), 7.40 (dd, J = 9.9, 8.8 Hz, 1H).; LCMS (ESI), m / z = 541.16 [M+1]+.

[0147]

[0148] 1-12. Synthesis of Compound 12: 3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209147, KSK-001-098]

[0149]

[0150] In the synthesis method of compound 1, compound 123-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.12 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 of Example 1-1 (7.2 mg, 12% yield).

[0151] 1H NMR (400 MHz, DMSO) δ10.99 (s, 1H), 10.40 (s, 1H), 9.97 (s, 1H), 8.37 (s, 1H), 8.25 (d,J= 9.2 Hz, 2H), 8.14 (d,J= 9.2 Hz, 2H), 8.06 (d,J= 8.8 Hz, 7.96 (d,J= 8.8 Hz, 2H), 7.72 (d,J= 7.6 Hz. 1H), 7.68 (d,J= 8.8 Hz, 2H), 7.55 (t,J= 8.0 Hz, 1H).; LCMS (ESI), m / z = 523.15 [M+1]+.

[0152]

[0153] 1-13. Synthesis of Compound 13: 3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209154, KSK-002-001]

[0154]

[0155] In the synthesis method of compound 1, compound 133-(4-(3-methylurido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.12 mmol) and 4-(3-methylurido)benzoic acid (31.6 mg, 0.16 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thiouredobenzoic acid, in the same manner as the synthesis method of compound 1 of Example 1-1 (4.7 mg, 7% yield).

[0156] 1H NMR (400 MHz, MeOD)δ8.68 (s, 1H), 8.31 - 8.28 (m, 2H), 7.95 - 7.90 (m, 3H), 7.86 (d,J= 8.0 Hz, 7.82 (d,J= 8.0 Hz, 1H), 7.75 (d,J= 7.6 Hz, 1H), 7.58 - 7.54 (m, 3H), 2.82 (s, 3H), m / z = 521.14 [M+1]+.

[0157]

[0158] 1-14. Synthesis of Compound 14: 4-methyl-3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209156, KSK-002-003]

[0159]

[0160] In the synthesis method of Compound 1, Compound 144-methyl-3-(4-(3-methyluredo)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.11 mmol) and 4-(3-methyluredo)benzoic acid (30.3 mg, 0.16 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thiouredobenzoic acid, in the same manner as the synthesis method of Compound 1 of Example 1-1 (12.1 mg, 19% yield).

[0161] 1H NMR (400 MHz, MeOD) δ8.19 (d,J= 8.8 Hz, 2H), 8.07 (d,J= 8.8 Hz, 2H), 7.99 (d,J= 1.6 Hz, 1H), 7.96 (d,J= 8.8 Hz, 2H), 7.84 (dd,J= 8.0 Hz, 2.0 Hz, 1H), 7.57 (d,J= 8.8 Hz, 2H), 7.50 (d,J= 4.0 Hz, 1H), 2.82 (s, 3H), 2.42 (s, 3H).; LCMS (ESI), m / z = 535.25 [M+1]+.

[0162]

[0163] 1-15. Synthesis of Compound 15: 4-methyl-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209157, KSK-002-004]

[0164]

[0165] In the synthesis method of compound 1, compound 154-methyl-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.11 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 of Example 1-1 (4.7 mg, 7% yield).

[0166] 1H NMR (400 MHz, MeOD)δ8.66 (s, 1H), 8.27 (d,J= 8.0 Hz, 1H), 8.05 - 8.01 (m, 3H), 7.85 (d,J= 8.0 Hz, 2H), 7.79 (t,J= 8.0 Hz, 1H), 7.66 (d,J= 8.4 Hz, 2H), 7.50 (d,J= 8.0 Hz, 1H), 2.43 (s, 3H).; LCMS (ESI), m / z = 537.14 [M+1]+.

[0167]

[0168] 1-16. Synthesis of Compound 16: 3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209151, KSK-001-099]

[0169]

[0170] In the synthesis method of compound 1, compound 163-(4-(3-methyluredo)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as the synthesis method of compound 1 in Example 1-1 by using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.12 mmol) and 4-(3-methyluredo)benzoic acid (31.6 mg, 0.16 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (2 mg, 3% yield) with the reagent 4-thiouredobenzoic acid.

[0171] 1H NMR (400 MHz, MeOD)δ8.32 (s, 1H), 8.21 (d,J= 9.2 Hz, 2H), 8.08 (d,J= 8.8 Hz, 2H), 7.94 - 7.91 (m, 3H), 7.75 (d,J= 8.0 Hz, 1H), 7.57 - 7.54 (m, 3H), 2.82 (s, 3H).; LCMS (ESI), m / z = 521.17 [M+1]+.

[0172]

[0173] 1-17. Synthesis of Compound 17: 4-methyl-3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209155, KSK-002-002]

[0174]

[0175] In the synthesis method of compound 1, compound 174-methyl-3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.11 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 of Example 1-1 (2.1 mg, 3% yield).

[0176] 1 H NMR (400 MHz, MeOD) δ8.19 (d,J= 8.8 Hz, 2H), 8.07 - 8.00 (m, 5H), 7.85 (dd,J= 7.6 Hz, 1.6 Hz, 1H), 7.66 (d,J= 8.4 Hz, 2H), 7.50 (d,J= 8.0 Hz, 1H), 2.42 (s, 3H).; LCMS (ESI), m / z = 537.17 [M+1]+.

[0177]

[0178] 1-18. Synthesis of Compound 18: 4-methyl-3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209160, KSK-002-005]

[0179]

[0180] In the synthesis method of compound 1, compound 184-methyl-3-(4-(3-methyluredo)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the same method as the synthesis method of compound 1 in Example 1-1, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.11 mmol) and 4-(3-methyluredo)benzoic acid (30.3 mg, 0.16 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thiouredobenzoic acid (12.1 mg, 19% yield).

[0181] 1 H NMR (400 MHz, MeOD)δ8.66 (s, 1H), 8.27 (d,J= 7.2 Hz, 1H), 7.99 - 7.95 (m, 3H), 7.84 (d,J= 7.6 Hz, 7.79 (t,J= 8.0 Hz, 1H), 7.57 (d,J= 8.4 Hz, 2H), 7.49 (d,J= 8.0 Hz, 1H), 2.82 (s, 3H), 2.42 (s, 3H).; LCMS (ESI), m / z = 535.20 [M+1]+

[0182]

[0183] 1-19. Synthesis of Compound 19: 3-(4-(3-methylthioureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-(3-methylthioureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301372, KNY-020-23]

[0184]

[0185] In the synthesis method of compound 1, compound 193-(4-(3-methylthiouraido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained (15 mg, 10% yield) by using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.11 mmol) and 4-(3-methylthiouraido)benzoic acid (74 mg, 0.35 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thioureidobenzoic acid, in the same manner as the synthesis method of compound 1 of Example 1-1.

[0186] 1 H NMR (400 MHz, DMSO) δ10.85 (s, 1H), 10.38 (s, 1H), 9.86 (br s, 1H), 8.68 (s, 1H), 8.45 - 8.35 (m, 2H), 8.06 - 8.00 (m, 1H), 7.96 (d,J= 8.7 Hz, 3H), 7.86 (d,J= 5.1 Hz, 2H), 7.73 (d,J= 7.8 Hz, 1H), 7.64 (d,J= 8.6 Hz, 2H), 7.55 (t,J= 7.9 Hz, 1H), 2.96 (d,J= 4.2 Hz, 3H).; LCMS (ESI), m / z = 537.05 [M+1]+.

[0187]

[0188] 1-20. Synthesis of Compound 20: N-(3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-ureidobenzamido)benzamide [N-(3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-ureidobenzamido)benzamide, DN301632, KNY-020-27]

[0189]

[0190] In the synthesis method of compound 1, compound 20N-(3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-ureidobenzamido)benzamide was obtained by using 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (103 mg, 0.3 mmol) and 4-ureidobenzoic acid (60 mg, 0.33 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thioureidobenzoic acid in the same manner as the synthesis method of compound 1 of Example 1-1 (22 mg, 13% yield).

[0191] 1 H NMR (400 MHz, DMSO) δ10.86 (s, 1H), 10.29 (s, 1H), 8.93 (s, 1H), 8.68 (s, 1H), 8.44 - 8.39 (m, 1H), 8.39 - 8.35 (m, 1H), 8.03 (dd,J= 8.0, 1.6 1H), 7.91 (d,J= 8.8 Hz, 2H), 7.85 (d,J= 5.2 Hz, 3H), 7.71 (d,J= 8.0 Hz, 1H), 7.55 (d,J= 8.9 Hz, 3H), 6.04 (s, 1H).; LCMS (ESI), m / z = 507.13 [M+1]+.

[0192]

[0193] 1-21. Synthesis of Compound 21: 4-fluoro-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-fluoro-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301634, KSG-015-50]

[0194]

[0195] In the synthesis method of compound 1, compound 214-fluoro-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.083 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 of Example 1-1 (7.1 mg, 16% yield).

[0196] 1 H NMR (400 MHz, MeOD)δ8.65 (s, 1H), 8.42 (dd,J= 7.2, 2.0 Hz, 1H), 8.28 (d,J= 8.2 Hz, 1H), 8.02 (d,J= 8.5 Hz, 2H), 7.94 - 7.88 (m, 1H), 7.86 (d,J= 7.9 Hz, 1H), 7.79 (t,J= 8.0 Hz, 1H), 7.66 (d,J= 8.5 Hz, 2H), 7.46 - 7.33 (m, 1H).; LCMS (ESI), m / z = 541.13 [M+1]+.

[0197]

[0198] 1-23. Synthesis of Compound 23: 2-fluoro-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [2-fluoro-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301772, KSH-006-52]

[0199]

[0200] 5-amino-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.083 mmol) was dissolved in DMF (0.4 ml), then 3-thiouredobenzoyl chloride (53.3 mg, 0.248 mmol) and pyridine (33.5 μl, 0.414 mmol) were added dropwise, and the reaction mixture was stirred at room temperature for 18 hours. After concentrating the DMF by vacuum distillation, the residue was separated and purified by MPLC to obtain the compound 232-fluoro-5-(3-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (2.8 mg, 6% yield).

[0201] 1 H NMR (400 MHz, MeOD)δ8.64 (s, 1H), 8.20 (d,J= 8.2 Hz, 1H), 8.11 (dd,J= 6.2, 2.7 Hz, 1H), 7.95 - 7.91 (m, 2H), 7.86 (d,J= 7.9 Hz, 2H), 7.80 - 7.76 (m, 2 H), 7.61 (d,J= 8.7, 1H), 7.54 (t,J= 7.8 Hz, 1H), 7.30 (t,J= 9.5 Hz, 1H).; LCMS (ESI), m / z=541.18 [M+1]+.

[0202]

[0203] 1-24. Synthesis of Compound 24: 2-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [2-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301944, KSG-015-90]

[0204]

[0205] In the synthesis method of compound 1, compound 242-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 5-amino-2-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.140 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 of Example 1-1 (3.5 mg, 5% yield).

[0206] 1 H NMR (400 MHz, MeOD)δ8.66 (s, 1H), 8.22 - 8.16 (m, 1H), 8.01 - 7.96 (m, 2H), 7.94 (d,J= 2.2 Hz, 1H), 7.86 (d,J= 8.0 Hz, 1H), 7.79 (t,J= 8.0 Hz, 1H), 7.69 (dd,J= 8.3, 2.3 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.35 (d,J= 8.4 Hz, 1H), 2.48 (s, 3H).; LCMS (ESI), m / z=537.25 [M+1]+

[0207]

[0208] 1-25. Synthesis of Compound 25: N-(3-(methylsulfonyl)phenyl)-3-(3-thioureidobenzamido)benzamide [N-(3-(methylsulfonyl)phenyl)-3-(3-thioureidobenzamido)benzamide, DN301092, KNY-020-05]

[0209]

[0210] In the synthesis method of compound 1, compound 25N-(3-(methylsulfonyl)phenyl)-3-(3-thioureidobenzamido)benzamide was obtained (12 mg, 7% yield) by using 3-amino-N-(3-(methylsulfonyl)phenyl)benzamide (100 mg, 0.344 mmol) and 3-thioureidobenzoic acid instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-(trifluoromethyl)sulfonyl)phenyl)benzamide and the reagent 4-thioureidobenzoic acid in the same manner as the synthesis method of compound 1 of Example 1-1.

[0211] 1 H NMR (400 MHz, DMSO) δ10.69 (s, 1H), 10.50 (s, 1H), 9.91 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.15 - 8.11 (m, 1H), 8.03 (d,J= 8.1 Hz, 1H), 7.97 (s, 1H), 7.74 (d,J= 7.7 Hz, 2H), 7.66 (dd,J= 8.5, 5.4 Hz, 3H), 7.55 (t,J= 8.0 Hz, 1H), 7.49 (tJ= 7.9 Hz, 1H), 3.23 (s, 3H).;LCMS (ESI),m / z=469.06 [M+1]+

[0212]

[0213] 1-26. Synthesis of Compound 26: N-(3-(methylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide [N-(3-(methylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide, DN301097, KNY-020-11]

[0214]

[0215] In the synthesis method of compound 1, compound 26N-(3-(methylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide was obtained (25 mg, 15% yield) by using 3-amino-N-(3-(methylsulfonyl)phenyl)benzamide (100 mg, 0.290 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-(trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of compound 1 of Example 1-1.

[0216] 1 H NMR (400 MHz, DMSO) δ10.68 (s, 1H), 10.41 (s, 1H), 10.01 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 8.17 - 8.10 (m, 1H), 8.02 (dd,J= 8.2, 1.2 Hz, 1H), 7.97 (d,J= 8.7 Hz, 2H), 7.72 (d,J= 7.9 Hz, 1H), 7.70 - 7.64 (m, 4H), 7.54 (t,J= 7.9 Hz, 1H), 3.23 (s, 3H).; LCMS (ESI),m / z=469.10 [M+1]+

[0217]

[0218] 1-29. Synthesis of Compound 29: 3-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN302971, KNY-020-85]

[0219]

[0220] Compound 293-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-amino-5-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (80 mg, 0.0.223 mmol) instead of intermediate compound (2-1) 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of Compound 1 of Example 1-1 (12 mg, 10% yield).

[0221] 1 H NMR (400 MHz, MeOD)δ8.65 (s, 1H), 8.27 (d,J= 9.2 Hz, 1H), 8.09 (s, 1H), 7.98 (d,J= 8.6 Hz, 2H), 7.84 (d,J= 8.0 Hz, 1H), 7.77 (t,J= 8.0 Hz, 1 H), 7.73 (s, 1H), 7.63 (d,J= 8.6 Hz, 2H), 7.59 (s, 1H).; LCMS (ESI)M,m / z=537.16 [M+1]+.

[0222]

[0223] 1-30. Synthesis of Compound 30: 3-methyl-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-methyl-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN302972, KNY-020-88]

[0224]

[0225] Compound 303-methyl-5-(3-thiouredobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-thiouredobenzoic acid (88 mg, 0.447 mmol) instead of the reagent 4-thiouredobenzoic acid in the synthesis method of Compound 1, and 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (80 mg, 0.223 mmol) instead of the intermediate compound (2-1) 3-amino-5-(trifluoromethyl)sulfonyl)phenyl)benzamide in the same manner as the synthesis method of Compound 1 in Example 1-1 (10 mg, 8% yield).

[0226] 1 H NMR (400 MHz, DMSO) δ10.83 (s, 1H), 10.41 (s, 1H), 9.87 (s, 1H), 8.67 (s, 1H), 8.44 - 8.41 (m, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.86 (d,J= 5.3 Hz, 2H), 7.73 (d,J= 7.9 Hz, 1H), 7.67 (d,J= 7.7 Hz, 1H), 7.59 (s,1H), 7.49 (t,J= 7.9 Hz, 1H), 2.70 (s, 3H).; LCMS (ESI),m / z=537.15 [M+1]+.

[0227]

[0228] 1-31. Synthesis of Compound 31: 3-(4-(3-methylthioureido)benzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-(3-methylthioureido)benzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN302982, KNY-020-89]

[0229]

[0230] Compound 313-(4-(3-methylthiouredo)benzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 4-(3-methylthiouredo)benzoic acid (82 mg, 0.388 mmol) instead of the reagent 4-thiouredobenzoic acid in the synthesis method of Compound 1, in the same manner as the synthesis method of Compound 1 of Example 1-1 (10 mg, 8% yield).

[0231] 1 H NMR (400 MHz, MeOD) δ8.66 (s, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 8.29 (d,J= 8.3 Hz, 1H), 8.05 (s, 1H), 7.99 (d,J= 8.7 Hz, 2H), 7.86 (d,J= 7.8 Hz, 1H), 7.79 (t,J= 8.0 Hz, 1H), 7.63 (d,J= 8.6 Hz, 2H); LCMS (ESI), m / z=605.14 [M+1]+.

[0232]

[0233] 1-32. Synthesis of Compound 32: N-(3-sulfamoylphenyl)-3-(4-thioureidobenzamido)benzamide [N-(3-sulfamoylphenyl)-3-(4-thioureidobenzamido)benzamide, DN301940, KNY-020-44]

[0234]

[0235] 4-Thiouredobenzoic acid (303 mg, 1.545 mmol), HBTU (586 mg, 1.545 mmol), and DIPEA (333 mg, 2.57 mmol) were dissolved in DMF (1 ml), then 3-amino-N-(3-sulfamoylphenyl)benzamide (150 mg, 0.515 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 18 hours. After concentrating the DMF by vacuum distillation, the residue was separated and purified by MPLC to obtain the compound 32N-(3-sulfamoylphenyl)-3-(4-thiouredobenzamido)benzamide (1.8 mg, 1% yield).

[0236] 1 H NMR (400 MHz, DMSO) δ10.58 (s, 1H), 10.38 (s, 1H), 9.98 (s, 1H), 8.36 (d, J= 7.1 Hz, 2H), 8.04 - 7.99 (m, 2H), 7.99 - 7.94 (m, 3H), 7.71 (d,J= 8.1 Hz, 1H), 7.67 (d,J= 8.7 Hz, 2H), 7.58 - 7.55 (m, 2H), 7.52 (t,J= 8.0 Hz, 2H), 7.39 (s, 2H).; LCMS (ESI), m / z=470.26 [M+1]+.

[0237]

[0238] 1-33. Synthesis of Compound 33: N-(3-(ethylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide [N-(3-(ethylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide, DN301945, KSG-015-91]

[0239]

[0240] 4-Thiouredobenzoic acid (303 mg, 1.545 mmol), HBTU (586 mg, 1.545 mmol), and DIPEA (333 mg, 2.57 mmol) were dissolved in DMF (1 ml), then 3-amino-N-(3-(ethylsulfonyl)phenyl)benzamide (150 mg, 0.515 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 18 hours. The DMF was concentrated by vacuum distillation, and the residue was separated and purified by MPLC to obtain the compound 33N-(3-(ethylsulfonyl)phenyl)-3-(4-thiouredobenzamido)benzamide (1.8 mg, 1% yield).

[0241] 1 H NMR (400 MHz, DMSO) δ10.58 (s, 1H), 10.38 (s, 1H), 9.98 (s, 1H), 8.36 (d, J= 7.1 Hz, 2H), 8.04 - 7.99 (m, 2H), 7.99 - 7.94 (m, 3H), 7.71 (d,J= 8.1 Hz, 1H), 7.67 (d,J= 8.7 Hz, 2H), 7.58 - 7.55 (m, 2H), 7.52 (t,J= 8.0 Hz, 2H), 7.39 (s, 2H).; LCMS (ESI), m / z=470.26 [M+1]+.

[0242]

[0243] 1-34. Synthesis of Compound 34: 3-guanidino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-guanidino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208996, KJA-020-014, 016]

[0244]

[0245] (E)-3-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoic acid (a-2)] (13 mg, 0.035 mmol) was dissolved in DMF (1 ml), and then 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronum, hexafluorophosphate (V) salt, HATU (22 mg, 0.058 mmol), and DIPEA (10 μL, 0.058 mmol) were added at 0°C. After 5 minutes, 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (10 mg, 0.029 mmol) was added, and the reaction mixture was heated at 40°C for 12 hours. After concentrating the DMF by vacuum distillation, the residue was dissolved in CH2Cl2 (1 mL), trifluoroacetic acid (TFA) (44 μL, 0.567 mmol) was added, and the mixture was heated at 40°C for 12 hours. After concentrating the reaction mixture, it was separated and purified by prep HPLC (ACN (0.1% TFA) water (0.1% TFA) with a gradient of 5-100% ACN) to obtain the compound 343-guanidino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (4.7 mg, 33% yield).

[0246] 1 H NMR (400 MHz, DMSO) δ10.87 (s, 1H), 9.91 (s, 1H), 8.69 (s, 1H), 8.44 - 8.36 (m, 2H), 8.10 - 8.03 (m, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.78 (d,J= 8.2 Hz, 1H), 7.66 - 7.53 (m, 3H), 7.49 - 7.45 (m, 1H).; LCMS (ESI), m / z = 506.19 [M+1]+.

[0247]

[0248] Table 1 below shows the compounds synthesized according to Example 1.

[0249] No.DN.StructureMW1DN302319 590.512DN209152 522.523DN208692 536.544DN208693 534.515DN208844 536.546DN208849 522.527DN208891 534.488DN208958 520.489DN208959 520.4810DN208960 522.5211DN209164 520.4812DN209147 522.5213DN209154 520.4814DN209156 534.5115DN209157 536.5416DN209151 520.4817DN209155 536.5418DN209160 534.5119DN301372 536.5420DN301632 506.4621DN301634 540.5123DN301772 540.5124DN301944 536.5425DN301092 468.5526DN301097 468.5529DN302971 536.5430DN302972 536.5431DN302982 550.5732DN301940 469.5333DN301945 482.5734DN208996 505.47

[0250]

[0251] <Example 2> Synthesis of a Compound

[0252] A compound was synthesized according to the following reaction scheme 2.

[0253] [Reaction Equation 2]

[0254]

[0255]

[0256] 2-1. Synthesis of Compound 35: 3-(3-carbamothioylbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN208888, KSG-012-095]

[0257] Intermediate 2 obtained using the preparation method of steps 1) and 2) of Example 1 above was used.

[0258] Step 3) Synthesis of Intermediate Compound 3: 3-(3-cyanobenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0259]

[0260] 4-methyl-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (397 mg, 1.022 mmol) was dissolved in MeOH (5 ml), and then Pd / C (39 mg, 0.366 mmol) was added and stirred under hydrogen gas for 1 hour. After concentrating the MeOH by vacuum distillation, the compound 3-(3-cyanobenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained (364 mg, 99% yield).

[0261] 1H NMR (400 MHz, DMSO) δ10.92 (s, 1H), 10.31 (s, 1H), 8.50 - 8.41 (m, 1H), 8.33 - 8.28 (m, 1H), 8.28 - 8.21 (m, 2H), 8.16 - 8.07 (m, 3H), 8.01 (d,J= 1.7 Hz, 1H), 7.88 (dd,J= 7.9, 1.8 Hz, 1H), 7.79 (t,J= 7.8 Hz, 1H), 7.51 (d,J= 8.1 Hz, 1H), 2.35 (s, 3H).; LCMS (ESI), m / z = 488.24 [M+1]+

[0262] Step 4) Synthesis of Compound 35 (DN208888): 3-(3-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0263]

[0264] Intermediate compound 3 (60 mg, 0.123 mmol) was dissolved in DMF (2 ml), followed by the addition of MgSO4 (58 mg, 0.618 mmol) and sodium hydrosulfide (35 mg, 0.618 mmol), and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, ethyl acetate (EA) was added and the mixture was filtered. The resulting solid was separated and purified by prep-HPLC to obtain compound 353-(3-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (21 mg, 30% yield).

[0265] 1H NMR (400 MHz, DMSO) δ10.92 (s, 1H), 10.21 (s, 1H), 10.04 (s, 1H), 9.66 (s, 1H), 8.50 - 8.42 (m, 1H), 8.31 - 8.21 (m, 2H), 8.16 - 8.04 (m, 4H), 8.01 (d,J= 1.6 Hz, 1H), 7.87 (dd,J= 7.9, 1.8 Hz, 1H), 7.60 (t,J= 7.8 Hz, 1H), 7.50 (d,J= 8.1 Hz, 1H), 2.35 (s, 3H).; LCMS (ESI), m / z = 522.17 [M+1]+.

[0266]

[0267] 2-2. Synthesis of Compound 36: 3-(3-carbamothioylbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN208890, KSG-012-098]

[0268]

[0269] Compound 363-(3-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (64 mg, 0.131 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(3-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of intermediate compound 3 of Example 2-1 (5 mg, 7% yield).

[0270] 1H NMR (400 MHz, DMSO) δ10.92 (s, 1H), 10.21 (s, 1H), 10.04 (s, 1H), 9.66 (s, 1H), 8.50 - 8.43 (m, 1H), 8.32 - 8.20 (m, 2H), 8.18 - 8.03 (m, 4H), 8.01 (d,J= 1.6 Hz, 1H), 7.87 (dd,J= 7.9, 1.8 Hz, 1H), 7.60 (t,J= 7.8 Hz, 1H), 7.50 (d,J= 8.1 Hz, 1H), 2.35 (s, 3H).; LCMS (ESI), m / z = 522.17 [M+1]+.

[0271]

[0272] 2-3. Synthesis of Compound 37: 3-carbamothioyl-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-carbamothioyl-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208962, KSK-001-069]

[0273]

[0274] Compound 373-carbamothioil-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide was obtained by the same method as the synthesis method of Example 2-1 using 3-cyano-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (9.3 mg, 41% yield) instead of intermediate compound 3 of Example 2-1.

[0275] 1H NMR (400 MHz, DMSO) δ11.04 (br s, 1H), 10.63 (s, 1H), 10.05 (s, 1H), 9.67 (br s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.26 (d, J= 8.8 Hz, 2H), 8.15 - 8.07 (m, 5H), 7.76 (d,J= 8.0 Hz, 1H), 7.62 - 7.56 (m, 2H).; LCMS (ESI), m / z = 508.15 [M+1]+.

[0276]

[0277] 2-4. Synthesis of Compound 38: 3-carbamothioyl-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-carbamothioyl-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN208957, KSK-001-064]

[0278]

[0279] Compound 383-carbamothioil-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide was obtained by the same method as the synthesis method of Example 2-1 using 3-cyano-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (28.3 mg, 50% yield) instead of intermediate compound 3 of Example 2-1.

[0280] 1 H NMR (400 MHz, MeOD) δ8.68 (s, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.29 (d,J= 8.0 Hz), 8.11 (t, 2H,J= 6.4 Hz), 7.96 (d,J= 7.6 Hz, 1H), 7.87 - 7.77 (m, 3H), 7.61 - 7.56 (m, 2H).; LCMS (ESI), m / z = 508.22 [M+1]+.

[0281]

[0282] 2-5. Synthesis of Compound 39: 3-(4-carbamothioylbenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209021, KSK-001-089]

[0283]

[0284] Compound 393-(4-carbamothioilbenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the same method as in the synthesis of Example 2-1 using 3-(4-cyanobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (7.5 mg, 17% yield) instead of intermediate compound 3 of Example 2-1.

[0285] 1 H NMR (400 MHz, DMSO) δ11.02 (br s, 1H), 10.60 (s, 1H), 10.05 (s, 1H), 9.67 (br s, 1H), 8.38 (t,J= 2.0 Hz, 1H), 8.24 (d,J= 8.8 Hz, 2H), 8.13 (d,J= 8.8 Hz, 2H), 8.08 (dd,J= 8.0 Hz, 1.6 Hz, 1H), 8.03 - 7.98 (m, 4H), 7.76 (d,J= 7.6 Hz, 1H), 7.57 (t,J= 8.0 Hz, 1H).; LCMS (ESI), m / z = 508.14 [M+1]+.

[0286]

[0287] 2-6. Synthesis of Compound 40: 3-(4-carbamothioylbenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209023, KSK-001-090]

[0288]

[0289] Compound 403-(4-carbamothioilbenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the same method as the synthesis method of Example 2-1 using 3-(4-cyanobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (29 mg, 66% yield) instead of intermediate compound 3 of Example 2-1.

[0290] 1 H NMR (400 MHz, DMSO) δ10.86 - 10.61 (m, 2H), 10.54 - 9.68 (m, 2H), 8.69 (s, 1H), 8.43 - 8.41 (m, 2H), 8.07 - 7.99 (m, 5H), 7.86 (d,J= 5.2 Hz, 2H), 7.76 (d,J= 8.0 Hz, 1H), 7.57 (t,J= 8.0 Hz). ; LCMS (ESI), m / z = 508.14 [M+1]+.

[0291]

[0292] 2-7. Synthesis of Compound 41: 3-(4-carbamothioylbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209025, KSK-001-093]

[0293]

[0294] Compound 413-(4-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the same method as the synthesis method of Example 2-1 using 3-(4-cyanobenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (22 mg, 92% yield) instead of intermediate compound 3 of Example 2-1.

[0295] 1 H NMR (400 MHz, DMSO) δ10.91 (br s, 1H), 10.21 (s, 1H), 10.05 (s, 1H), 9.67 (br s), 8.25 (d,J= 8.4 Hz, 2H), 8.11 (d,J= 8.4 Hz, 2H), 8.02 - 7.99 (m, 5H), 7.87 (d,J= 8.0 Hz, 1H), 7.49 (d,J= 8.4 Hz, 1H), 2.34 (s, 3H).; LCMS (ESI), m / z = 522.08 [M+1]+.

[0296]

[0297] 2-8. Synthesis of Compound 42: 3-(4-carbamothioylbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209146, KSK-001-097]

[0298]

[0299] Compound 423-(4-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.08 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(4-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of intermediate compound 3 of Example 2-1 (26.1 mg, 61% yield).

[0300] 1 H NMR (400 MHz, DMSO) δ10.78 (br s, 1H), 10.19 (s, 1H), 10.05 (s, 1H), 9.67 (br s, 1H), 8.68 (s, 1H), 8.42 (td,J= 4.8 Hz, 2.4 Hz, 1H), 8.04 - 7.99 (m, 5H), 7.88 - 7.84 (m, 3H), 7.50 (d,J= 8.0 Hz, 1H), 2.34 (s, 3H).; LCMS (ESI), m / z = 522.09 [M+1]+.

[0301]

[0302] 2-9. Synthesis of Compound 43: 3-(3-carbamothioylbenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209163, KSH-004-022]

[0303]

[0304] Compound 433-(3-carbamothioilbenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (20 mg, 0.04 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(3-cyanobenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of intermediate compound 3 of Example 2-1 (12 mg, 58% yield).

[0305] 1H NMR (400 MHz, MeOD) δ8.50 (t,J= 1.7 Hz, 1H), 8.44 (dd,J= 7.2, 2.3 Hz, 1H), 8.18 (d,J= 9.0 Hz, 2H), 8.12 - 8.08 (m, 2H), 8.06 (d,J= 8.9 Hz, 2H), 7.91 (ddd,J= 8.6, 4.6, 2.4 Hz, 1H), 7.58 (t,J= 7.8 Hz, 1H), 7.41 (dd,J= 10.0, 8.7 Hz, 1H).; LCMS (ESI), m / z = 526.1 [M+1]+.

[0306]

[0307] 2-10. Synthesis of Compound 44: 3-(3-carbamothioylbenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN209609, KSK-002-013]

[0308]

[0309] Compound 443-(3-carbamothioilbenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the same method as the synthesis method of Example 2-1 using 3-(3-cyanobenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (26.1 mg, 61% yield) instead of intermediate compound 3 of Example 2-1.

[0310] 1H NMR (400 MHz, MeOD)δ8.61 (s, 1H), 8.50 (s, 1H), 8.19 (d,J= 8.8 Hz, 2H), 8.13 - 8.06 (m, 4H), 7.91 (dd,J= 8.8 Hz, 2.0 Hz, 1H), 7.60 (t,J= 7.6 Hz, 1H), 7.27 (d,J= 8.8 Hz, 1H), 4.05 (s, 3H). LCMS (ESI), m / z = 538.02 [M+1]+.

[0311]

[0312] 2-11. Synthesis of Compound 45: 3-(3-carbamothioylbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301234, KSG-015-28]

[0313]

[0314] Compound 453-(3-carbamothioilbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (40 mg, 0.08 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(3-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of intermediate compound 3 of Example 2-1 (27 mg, 62% yield).

[0315] 1H NMR (400 MHz, MeOD)δ8.65 (s, 1H), 8.54 - 8.49 (m, 1H), 8.45 (dd,J= 7.2, 2.3 Hz, 1H), 8.31 - 8.25 (m, 1H), 8.16 - 8.08 (m, 2H), 7.96 - 7.89 (m, 1H), 7.86 (d,J= 7.9 Hz, 1H), 7.80 (t,J= 8.0 Hz, 1H), 7.60 (t,J= 7.8 Hz, 1H), 7.42 (dd,J= 10.0, 8.7 Hz, 1H).; LCMS (ESI), m / z = 526 [M+1]+.

[0316]

[0317] 2-12. Synthesis of Compound 46: 3-(3-carbamothioylbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301359, KSH-006-20]

[0318]

[0319] Compound 463-(3-carbamothioilbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (15 mg, 0.03 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(3-cyanobenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (5 mg, 34% yield).

[0320] 1H NMR (400 MHz, DMSO) δ11.05 (s, 1H), 10.45 (s, 1H), 10.03 (s, 1H), 9.66 (s, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.43 - 8.42 (m, 1H), 8.18 - 8.15 (m, 2H), 8.09 - 8.03 (m, 3H), 7.90 - 7.86 (m, 2H), 7.61 (t,J= 7.7 Hz, 1 H).; LCMS (ESI), m / z = 576.18 [M+1]+

[0321]

[0322] 2-13. Synthesis of Compound 47: 3-(4-carbamothioylbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301360, KSH-006-21]

[0323]

[0324] Compound 473-(4-carbamothioilbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.06 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(4-cyanobenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (16 mg, 51% yield).

[0325] 1H NMR (400 MHz, DMSO) δ11.05 (s, 1H), 10.45 (s, 1H), 10.03 (s, 1H), 9.66 (s, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.43 - 8.42 (m, 1H), 8.18 - 8.15 (m, 2H), 8.09 - 8.03 (m, 3H), 7.90 - 7.86 (m, 2H), 7.61 (t,J= 7.7 Hz, 1 H).; LCMS (ESI), m / z = 576.18 [M+1]+.

[0326]

[0327] 2-14. Synthesis of Compound 48: 3-(4-carbamothioylbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301371, KSG-015-44]

[0328]

[0329] Compound 483-(4-carbamothioilbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido (30 mg, 0.06 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(4-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (12 mg, 37% yield) instead of intermediate compound 3 of Example 2-1.

[0330] 1H NMR (400 MHz, MeOD)δ8.65 (s, 1H), 8.43 (dd,J= 7.2, 2.3 Hz, 1H), 8.30 - 8.25 (m, 1H), 8.07 - 7.98 (m, 4H), 7.96 - 7.90 (m, 1H), 7.86 (d,J= 7.9 Hz, 1H), 7.79 (t,J= 8.0 Hz, 1H), 7.42 (dd,J= 10.0, 8.7 Hz, 1H), 3.01 (s, 1H), 2.88 (s, 1H).; LCMS (ESI), m / z = 525.70 [M+1]+.

[0331]

[0332] 2-15. Synthesis of Compound 49: 5-(3-carbamothioylbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-(3-carbamothioylbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301686, HJY-010-50]

[0333]

[0334] Compound 495-(3-carbamothioilbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (20 mg, 0.04 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 5-(3-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of intermediate compound 3 of Example 2-1 (13 mg, 61% yield).

[0335] 1H NMR (400 MHz, DMSO) δ11.30 (s, 1H), 10.88 (s, 1H), 10.07 (s, 1H), 9.68 (s, 1H), 8.60 (s, 1H), 8.45 (t,J= 1.8 Hz, 1H), 8.24 - 8.14 (m, 3H), 8.13 - 8.04 (m, 2H), 7.98 - 7.84 (m, 3H), 7.62 (t,J= 7.8 Hz, 1H).; LCMS (ESI), m / z = 576.16 [M+1]+.

[0336]

[0337] 2-16. Synthesis of Compound 50: 5-(4-carbamothioylbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-(4-carbamothioylbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301687, HJY-010-48]

[0338]

[0339] Compound 505-(4-carbamothioilbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (20 mg, 0.04 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 5-(4-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (16 mg, 75% yield).

[0340] 1H NMR (400 MHz, DMSO) δ11.30 (s, 1H), 10.88 (s, 1H), 10.07 (s, 1H), 9.68 (s, 1H), 8.60 (s, 1H), 8.45 (t,J= 1.8 Hz, 1H), 8.24 - 8.14 (m, 3H), 8.13 - 8.04 (m, 2H), 7.98 - 7.84 (m, 3H), 7.62 (t,J= 7.8 Hz, 1H).; LCMS (ESI), m / z = 576.16 [M+1]+.

[0341]

[0342] 2-17. Synthesis of Compound 51: 3-(4-carbamothioylbenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide, DN301780, KSG-015-74]

[0343]

[0344] Compound 513-(4-carbamothioilbenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide was obtained by using 3-(4-cyanobenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide (40 mg, 0.09 mmol) instead of intermediate compound 3 of Example 2-1, in the same manner as the synthesis method of Example 2-1 (9.5 mg, 21% yield).

[0345] 1H NMR (400 MHz, DMSO) δ10.70 (s, 1H), 10.60 (s, 1H), 10.06 (s, 1H), 9.68 (s, 1H), 8.44 - 8.32 (m, 2H), 8.20 - 8.11 (m, 1H), 8.11 - 7.91 (m, 5H), 7.80 - 7.71 (m, 1H), 7.67 (t,J= 7.9 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.56 (t,J= 7.9 Hz, 1H), 3.33 - 3.23 (m, 2H), 1.13 (t,J= 7.3 Hz, 3H).; LCMS (ESI), m / z = 468.17 [M+1]+.

[0346]

[0347] 2-18. Synthesis of Compound 52: 5-(4-carbamothioylbenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-(4-carbamothioylbenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301925, KSH-006-69]

[0348]

[0349] Compound 525-(4-carbamothioilbenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (10 mg, 0.02 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 5-(4-cyanobenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide instead of intermediate compound 3 of Example 2-1 (3 mg, 36% yield).

[0350] 1H NMR (400 MHz, DMSO) δ11.08 (s, 1H), 10.59 (s, 1H), 10.07 (s, 1H), 9.68 (s, 1H), 8.64 (s, 1H), 8.27 (dt,J= 7.4, 2.0 Hz, 1H), 8.16 (dd,J= 6.2, 2.7 Hz, 1H), 8.03 - 8.00 (m, 5H), 7.91 - 7.85 (m, 2H), 7.43 (t,J= 9.3 Hz, 1H).; LCMS (ESI), m / z = 526.20 [M+1]+.

[0351]

[0352] 2-19. Synthesis of Compound 53: 3-(4-carbamothioylbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-carbamothioylbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301932, HJY-010-55]

[0353]

[0354] Compound 533-(4-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (47 mg, 0.09 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(4-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 61% yield).

[0355] 1H NMR (400 MHz, DMSO) δ11.04 (s, 1H), 10.88 (s, 1H), 10.09 (s, 1H), 9.69 (s, 1H), 8.70 - 8.61 (m, 2H), 8.51 (s, 1H), 8.43 (dd,J= 5.9, 3.1 Hz, 1H), 8.13 (s, 1H), 8.03 (q,J= 8.6 Hz, 4H), 7.94 - 7.88 (m, 2H).; LCMS (ESI), m / z = 576.22 [M+1]+.

[0356]

[0357] 2-20. Synthesis of Compound 54: 3-(3-carbamothioylbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-carbamothioylbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, DN301933 HJY-010-56]

[0358]

[0359] Compound 543-(3-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (48 mg, 0.09 mmol) was obtained by the same method as the synthesis method of Example 2-1 using 3-(3-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (38 mg, 75% yield).

[0360] 1H NMR (400 MHz, DMSO) δ11.04 (s, 1H), 10.90 (s, 1H), 10.07 (s, 1H), 9.69 - 9.65 (m, 1H), 8.69 - 8.61 (m, 2H), 8.49 (dt,J= 12.0, 1.9 Hz, 2H), 8.43 (ddd,J= 7.0, 5.7, 3.1 Hz, 1H), 8.16 - 8.04 (m, 3H), 7.90 (dd,J= 5.0, 1.8 Hz, 2H), 7.62 (t,J= 7.8 Hz, 1H).; LCMS (ESI), m / z = 576.19 [M+1]+.

[0361]

[0362] 2-21. Synthesis of Compound 55: 3-carbamothioyl-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-carbamothioyl-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide, DN301939, KNY-020-41]

[0363]

[0364] Compound 553-carbamothioil-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide was obtained by using 3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide (40 mg, 0.09 mmol) instead of intermediate compound 3 of Example 2-1, in the same manner as the synthesis method of Example 2-1 (14 mg, 32% yield).

[0365] 1H NMR (400 MHz, DMSO) δ10.66 (s, 1H), 10.47 (s, 1H), 9.86 (s, 1H), 8.39 (t,J= 1.8 Hz, 1H), 8.35 (t,J= 1.9 Hz, 1H), 8.15 (d,J= 8.0 Hz, 1H), 8.03 (dd,J= 8.0, 1.3 Hz, 1H), 7.74 (d,J= 7.8 Hz, 1H), 7.66 (t,J= 7.9 Hz, 2H), 7.63-7.59 (m, 1H), 7.54 (t,J= 7.9 Hz, 1H), 7.49 (t,J= 7.9 Hz, 1H), 3.29 (q,J= 7.4 Hz. 2H), 1.13 (t,J= 7.3 Hz, 3H).; LCMS (ESI), m / z = 468 [M+1]+.

[0366]

[0367] Table 2 below shows the compounds synthesized according to Example 2.

[0368] No.DN.StructureMW35DN208888 521.5336DN208890 521.8337DN208962 508.1538DN208957 507.5039DN209021 507.5040DN209023 507.5041DN209025 521.5242DN209146 521.5343DN209163 525.4944DN209609 538.0245DN301235 525.4946DN301359 541.4247DN301360 505.5048DN301371 525.4949DN301686 520.5050DN301687 575.5051DN301780 467.5652DN301925 525.4953DN301932 575.5054DN301933 575.5055DN301939 467.56

[0369]

[0370] <Preparation Example 1> Preparation of Compound 1, an intermediate of Compound 1 of Example 1

[0371] Intermediate compound 1-3:4-methyl-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-012-084]

[0372]

[0373] 4-((trifluoromethyl)sulfonyl)aniline (300 mg, 1.332 mmol) was dissolved in DCM (3 ml), and TEA (186 μl, 1.332 mmol) was added dropwise. After 10 minutes, 4-methyl-3-nitrobenzoyl chloride (272 μl, 1.865 mmol) was slowly added dropwise to the reaction mixture and stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed by vacuum distillation and washed with DCM to obtain the white solid compound 4-methyl-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (397 mg, 77% yield).

[0374] 1 H NMR (400 MHz, MeOD) δ8.62 (d,J= 1.8 Hz, 1H), 8.25 - 8.17 (m, 3H), 8.12 - 8.05 (m, 2H), 7.66 (d,J= 8.1 Hz, 1H), 2.68 (s, 3H).

[0375]

[0376] Intermediate compound 1-4:3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-052]

[0377]

[0378] Compound 3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by performing the same method as intermediate compounds 1-2 of Example 1 using 4-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.22 mmol) and 3-nitrobenzoyl chloride (577 mg, 3.11 mmol) instead of the reagents 5-aminonaphthalene-2-sulfonic acid and 4-methyl-3-nitrobenzoyl chloride (889 mg, > 99% yield).

[0379] 1 H NMR (400 MHz, DMSO) δ11.21 (s, 1H), 8.63 (d,J= 1.6 Hz, 1H), 8.29 - 8.26 (m, 3H), 8.16 (d,J= 8.8 Hz, 2H), 7.73 (d,J= 8.0 Hz, 1H), 2.62 (s, 3H).

[0380]

[0381] Intermediate compound 1-5: 3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-053]

[0382]

[0383] Compound 3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by performing the same method as intermediate compounds 1-2 of Example 1 using 3-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.22 mmol) and 3-nitrobenzoyl chloride (577 mg, 3.11 mmol) instead of the reagents 5-aminonaphthalene-2-sulfonic acid and 4-methyl-3-nitrobenzoyl chloride (1047 mg, > 99% yield).

[0384] 1 H NMR (400 MHz, MeOD) δ11.16 (s, 1H), 8.86 (t, J= 2.0 Hz, 1H), 8.69 (s, 1H), 8.50 - 8.41 (m, 3H), 7.91 - 7.87 (m, 3H).

[0385]

[0386] Intermediate compound 1-6: 4-methyl-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-methyl-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-039, 094]

[0387]

[0388] Compound 4-methyl-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by performing the same method as intermediate compounds 1-2 of Example 1 using 3-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.22 mmol) instead of the reagent 5-aminonaphthalene-2-sulfonic acid (805 mg, 93% yield).

[0389] 1 H NMR (400 MHz, DMSO) δ10.99 (s, 1H), 8.66 - 8.63 (m, 2H), 8.39 (m, 1H), 8.25 (d,J= 8.0 Hz, 1H), 7.89 - 7.87 (m, 2H), 7.73 (d,J= 8.0 Hz, 1H), 2.62 (s, 3H).

[0390]

[0391] Intermediate compound 1-7: 4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSH-004-016]

[0392]

[0393] 4-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.2 mmol) was dissolved in DCM (4 ml), after which 4-fluoro-3-nitrobenzoyl chloride (633 mg, 3.1 mmol) and TEA (270 mg, 2.7 mmol) were added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. Once the reaction was complete, the organic layer obtained after extraction with DCM was washed with water, dried with anhydrous MgSO4, and filtered. The solvent of the filtered solution was concentrated by vacuum distillation, and the compound 4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained without separation or purification (498 mg, 57% yield).

[0394] 1 H NMR (400 MHz, MeOD) δ8.77 (dd,J= 7.1, 2.3 Hz, 1H), 8.37 (ddd,J= 8.7, 4.2, 2.4 Hz, 1H), 8.19 (d,J= 9.0 Hz, 2H), 8.07 (d,J= 8.9 Hz, 2H), 7.62 (dd,J= 10.7, 8.8 Hz, 1H).

[0395]

[0396] Intermediate compound 1-8: 4-fluoro-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-fluoro-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSH-004-016]

[0397]

[0398] 3-((trifluoromethyl)sulfonyl)aniline (500 mg, 2.2 mmol) was dissolved in DCM (4 ml), after which 4-fluoro-3-nitrobenzamide (572 mg, 3.1 mmol) and TEA (315 mg, 3.1 mmol) were added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. Once the reaction was complete, the organic layer obtained after extraction with DCM was washed with water, dried with anhydrous MgSO4, and filtered. The solvent of the filtered solution was concentrated by vacuum distillation, and the compound 4-fluoro-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained without separation or purification (781 mg, 90% yield).

[0399]

[0400] Intermediate compound 1-9: 4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-015-68]

[0401]

[0402] 2-methyl-5-nitrobenzoic acid (241 mg, 1.33 mmol), HATU (675 mg, 1.8 mmol), and DIPEA (344 mg, 2.66 mmol) were dissolved in DMF and stirred for 30 minutes. 3-((trifluoromethyl)sulfonyl)aniline (200 mg, 0.89 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted using EA, the resulting organic layer was washed with water, dried with anhydrous MgSO4, and filtered. The reaction mixture, from which the solvent had been removed from the filtered solution, was separated by MPLC under conditions of Silica, EA : Hex = 1 : 2, and concentrated by vacuum distillation to obtain the compound 4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (335 mg, 97% yield).

[0403]

[0404] Intermediate compound 1-10: 5-nitro-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-nitro-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, HJY-010-41]

[0405]

[0406] Compound 5-nitro-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by the synthesis method of the intermediate compound 1-9 using 5-nitro-2-(trifluoromethyl)benzoic acid (313 mg, 1.33 mmol) instead of 2-methyl-5-nitrobenzoic acid (241 mg, 1.33 mmol) (393 mg, 139% yield).

[0407]

[0408] Intermediate compound 1-11 :N-(3-(methylsulfonyl)phenyl)-3-nitrobenzamide[N-(3-(methylsulfonyl)phenyl)-3-nitrobenzamide, KNY-020-01]

[0409]

[0410] Compound N-(3-(methylsulfonyl)phenyl)-3-nitrobenzamide was obtained in the same manner as intermediate compounds 1-2 of Example 1 using 3-(((trifluoromethyl)sulfonyl)aniline (2 g, 11.7 mmol) instead of 3-((trifluoromethyl)sulfonyl)aniline (393 mg, 139% yield).

[0411] 1H NMR (400 MHz, DMSO) δ10.97 (s, 1H), 8.84 (t,J= 2.1 Hz, 1H), 8.79 - 8.40 (m, 3H), 8.15 (dt,J= 7.14, 2.17 Hz, 1H), 7.87 (t,J= 8.06 Hz, 1H) 7.73 - 7.65 (m, 2H), 3.23 (s, 3H)

[0412]

[0413] Intermediate compound 1-12: 3-methyl-5-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-methyl-5-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KNY-020-81]

[0414]

[0415] Compound 3-methyl-5-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained by using 3-methyl-5-nitrobenzoic acid (200 mg, 0.89 mmol) instead of 3-nitro-5-(trifluoromethyl)benzoic acid in the same manner as intermediate compound 1-1 of Example 1 (64 mg, 40% yield).

[0416] 1 H NMR (400 MHz, CDCl3)δ8.53 (s, 1H), 8.34 (d,J= 8.2 Hz, 1H), 8.30 - 8.24 (m, 3H), 8.10 (s, 1H), 7.86 (d,J= 7.92 Hz, 1H), 7.73 (t,J= 8.0 Hz, 1H), 2.59 (s, 3H)

[0417]

[0418] Intermediate compound 1-13: 3-nitro-N-(3-sulfamoylphenyl)benzamide [3-nitro-N-(3-sulfamoylphenyl)benzamide, KNY-020-31]

[0419]

[0420] Compound 3-nitro-N-(3-sulfamoylphenyl)benzamide was obtained in the same manner as intermediate compounds 1-2 of Example 1 using 3-aminobenzenesulfonamide (500 mg, 2.9 mmol) instead of 3-((trifluoromethyl)sulfonyl)aniline (560 mg, 60% yield).

[0421]

[0422] Intermediate compound 1-14: N-(3-(ethylsulfonyl)phenyl)-3-nitrobenzamide, KNY-020-30]

[0423]

[0424] N-(3-(ethylsulfonyl)phenyl)-3-nitrobenzamide was obtained (1.5 g, 83% yield) by using 3-(ethylsulfonyl)aniline (1.0 g, 5.4 mmol) instead of 3-((trifluoromethyl)sulfonyl)aniline in the same manner as intermediate compounds 1-2 of Example 1.

[0425] 1 H NMR (400 MHz, DMSO) δ10.99 (s, 1H), 8.85 (t,J= 1.9 Hz, 1H), 8.46 (t,J= 8.8 Hz, 2H), 8.39 (t,J= 1.8, 1H), 8.19 (dt,J= 7.8, 1.7 Hz, 1H), 7.87 (t,J= 8.0 Hz, 1H), 7.70 (t,J= 7.8 Hz, 1H), 7.66 (dt,J= 7.7, 1.5 Hz, 1H), 3.31 (q,J= 7.36 Hz, 2H), 1.19 (t,J= 7.28 Hz, 3H)

[0426]

[0427] <Preparation Example 2> Preparation of Compound 2, an intermediate of Compound 1

[0428] Intermediate compound 2-3:3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-012-085]

[0429]

[0430] Compound 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 4-methyl-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (397 mg, 1.022 mmol) instead of 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (364 mg, 99% yield).

[0431] 1 H NMR (400 MHz, MeOD) δ8.21 - 8.13 (m, 2H), 8.10 - 7.99 (m, 2H), 7.29 (d,J= 1.7 Hz, 1H), 7.23 (dd,J= 7.8, 1.8 Hz, 1H), 7.16 (d,J= 7.8 Hz, 1H), 2.25 (s, 3H).

[0432]

[0433] Intermediate compound 2-4:3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-012-096]

[0434]

[0435] Compound 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 4-methyl-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (300 mg, 0.773 mmol) instead of 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (258 mg, 93% yield).

[0436] 1H NMR (400 MHz, DMSO) δ10.75 (s, 1H), 9.91 (br, 2H), 8.27 - 8.19 (m, 2H), 8.13 - 8.07 (m, 2H), 7.19 (d, J= 1.6 Hz, 1H), 7.15 - 7.07 (m, 2H), 2.13 (s, 3H).

[0437]

[0438] Intermediate compound 2-5:3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide[3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-054, KSK-001-080, KSK-001-084]

[0439]

[0440] Compound 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (831 mg, 2.22 mmol) instead of 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (368 mg, 48% yield).

[0441] 1 H NMR (400 MHz, DMSO) δ10.80 (s, 1H), 8.23 ​​(d,J= 8.8 Hz, 2H), 8.10 (d,J= 8.8 Hz, 2H), 7.19 (t,J= 8.0 Hz, 1H), 7.11 - 7.08 (m, 2H), 6.81 (dd,J= 8.0 Hz, 1.2 Hz, 1H), 5.39 (s, 2H).

[0442]

[0443] Intermediate compound 2-6:3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-055]

[0444]

[0445] Compound 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (831 mg, 2.22 mmol) instead of 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (556 mg, 74% yield).

[0446] 1 H NMR (400 MHz, MeOD)δ10.67 (s, 1H), 8.69 (s, 1H), 8.37 (td,J= 4.8 Hz, 2.4 Hz, 1H), 7.84 - 7.83 (m, 2H), 7.19 (t,J= 8.0 Hz, 1H), 7.12 - 7.10 (m, 2H), 6.79 (dd,J= 7.2 Hz, 1.6 Hz, 1H), 5.39 (s, 2H).

[0447]

[0448] Intermediate compound 2-7: 3-amino-4-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide [3-amino-4-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide, TK-005-073]

[0449]

[0450] Compound 3-amino-4-methyl-N-(4-(methylsulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 4-methyl-N-(4-(methylsulfonyl)phenyl)-3-nitrobenzamide (546 mg, 1.633 mmol) instead of 3-amino-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (292 mg, 59% yield).

[0451] 1H NMR (400 MHz, DMSO) δ10.45 (s, 1H), 8.03 (d, J= 8.76 Hz, 2H), 7.88 (d, J= 8.84 Hz, 2H), 8.18 (s, 1H), 7.12-7.08 (m, 2H), 3.18 (s, 3H), 2.12 (s, 3H).; LCMS (ESI), m / z = 305.03 [M+1]+.

[0452]

[0453] Intermediate compound 2-8: 3-amino-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-amino-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSH-004-017]

[0454]

[0455] 4-fluoro-3-nitro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (498 mg, 1.3 mmol) was dissolved in methanol (20 ml), then Pd / C (17 mg, 0.155 mmol) was added dropwise, and the reaction mixture was stirred at room temperature under hydrogen gas for at least 12 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was subjected to vacuum distillation to obtain the compound 3-amino-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (443 mg, 96% yield).

[0456] 1 H NMR (400 MHz, MeOD) δ8.14 (d,J= 9.0 Hz, 2H), 8.03 (d,J= 8.9 Hz, 2H), 7.41 (dd, J = 8.5, 2.3 Hz, 1H), 7.24 (ddd,J= 8.4, 4.4, 2.3 Hz, 1H), 7.08 (dd,J= 11.0, 8.4 Hz, 1H).

[0457]

[0458] Intermediate compound 2-9: 3-amino-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-amino-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-015-09]

[0459]

[0460] Compound 3-amino-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 4-fluoro-3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (781 mg, 1.99 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (525 mg, 73% yield).

[0461]

[0462] Intermediate compound 2-10:5-amino-2-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-amino-2-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-015-71]

[0463]

[0464] Compound 5-amino-2-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 2-methyl-5-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (332 mg, 0.86 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (160 mg, 52% yield).

[0465]

[0466] Intermediate compound 2-11: 5-amino-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-amino-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, HJY-010-42]

[0467]

[0468] Compound 5-amino-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 5-nitro-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (545 mg, 1.23 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (533 mg, 105% yield).

[0469]

[0470] Intermediate compound 2-12:3-amino-N-(3-(methylsulfonyl)phenyl)benzamide[3-amino-N-(3-(methylsulfonyl)phenyl)benzamide, KNY-020-02]

[0471]

[0472] Compound 3-amino-N-(3-(methylsulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using N-(3-(methylsulfonyl)phenyl)-3-nitrobenzamide (1 g, 3.12 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (670 mg, 74% yield).

[0473] 1H NMR (400 MHz, DMSO) δ10.47 (s, 1H), 8.44 (s, 1H), 8.12 - 8.06 (m, 1H), 7.66 - 7.62 (m, 2H), 7.17 (t,J= 7.7 Hz, 1H), 7.14 - 7.07 (m, 2 H), 6.77 (d,J= 7.7 Hz, 1H), 5.37 (s, 2H), 3.21 (s, 3H)

[0474]

[0475] Intermediate compound 2-13: 3-amino-N-(3-sulfamoylphenyl)benzamide [3-amino-N-(3-sulfamoylphenyl)benzamide, KNY-020-84]

[0476]

[0477] Compound 3-amino-N-(3-sulfamoylphenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 3-methyl-5-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (662 mg, 1.7 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (485 mg, 72% yield).

[0478] 1 H NMR (400 MHz, CDCl3)δ8.37(dd,J= 8.2, 1.3 Hz, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.81 (d,J= 7.92, 1H), 7.69 (t,J= 8.0 Hz, 1H), 7.03 (m, 2H), 6.72 (s, 1H), 3.80 (br s, 2H), 2.36 (s, 3H)

[0479]

[0480] Intermediate compound 2-14: 3-amino-N-(3-sulfamoylphenyl)benzamide [3-amino-N-(3-sulfamoylphenyl)benzamide, KNY-020-42]

[0481]

[0482] Compound 3-amino-N-(3-sulfamoylphenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using 3-nitro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (500 mg, 2.9 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (340 mg, 63% yield).

[0483] 1 H NMR (400 MHz, DMSO) δ10.38 (s, 1H), 8.38 (s, 1H), 7.95 - 7.89 (m, 1H), 7.55 - 7.52 (m, 2H), 7.39 (m, 2H), 7.16 (t, J= 7.7 Hz, 1H), 7.12 - 7.08 (m, 2H), 6.77 (d,J= 6.80 Hz, 1H)

[0484]

[0485] Intermediate compound 2-15: 3-amino-N-(3-(ethylsulfonyl)phenyl)benzamide [3-amino-N-(3-(ethylsulfonyl)phenyl)benzamide, KNY-020-32]

[0486]

[0487] Compound 3-amino-N-(3-(ethylsulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 2-1 of Example 1 using N-(3-(ethylsulfonyl)phenyl)-3-nitrobenzamide (1.0 g, 2.99 mmol) instead of 3-nitro-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (262 mg, 30% yield).

[0488] 1H NMR (400 MHz, DMSO) δ10.46 (s, 1H), 8.39 (t,J= 1.8 Hz, 1H), 8.10 (d,J= 8.6 Hz, 1H), 7.62 (t,J= 7.9, 1H), 7.57 (d,J= 7.9 Hz, 1H), 7.16 (t,J= 7.7 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.77 (dq,J= 8.0, 1.1 Hz, 1H), 3.27 (q,J= 7.3 Hz, 2H), 1.12 (t,J= 7..4 Hz, 3H)

[0489]

[0490] <Preparation Example 3> Preparation of Compound 3, an intermediate of Compound 2

[0491] Intermediate compound 3-2: 3-(3-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-012-097]

[0492]

[0493] 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.279 mmol) was dissolved in tetrahydrofuran (THF) (3 ml), and then pyridine (67.7 μl, 0.837 mmol) and 3-cyanobenzoyl chloride (55.4 mg, 0.335 mmol) were added dropwise and reacted at room temperature for 2 hours. After the reaction was complete, a saturated aqueous solution of NaHCO3 was added, washed with water, and extracted with ethyl acetate. The resulting organic layer was dried with Na2SO4, the solvent was removed by vacuum distillation, and purified by MPLC to obtain the compound 3-(3-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (77 mg, 56% yield).

[0494] 1H NMR (400 MHz, DMSO) δ10.92 (s, 1H), 10.31 (s, 1H), 8.48 - 8.41 (m, 1H), 8.33 - 8.28 (m, 1H), 8.28 - 8.20 (m, 2H), 8.17 - 8.08 (m, 3H), 8.01 (d,J= 1.6 Hz, 1H), 7.88 (dd,J= 7.9, 1.8 Hz, 1H), 7.79 (t,J= 7.8 Hz, 1H), 7.51 (d,J= 8.1 Hz, 1H), 2.35 (s, 3H).; LCMS (ESI), m / z = 488.21 [M+1]+.

[0495]

[0496] Intermediate compound 3-3:3-cyano-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-cyano-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, KSK-001-068]

[0497]

[0498] Compound 3-cyano-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.29 mmol) and 3-cyanobenzoyl chloride (57.7 mg, 0.35 mmol) instead of 3-amino-4-methyl-N-(((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (53.04 mg, 37% yield) using 3-amino-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.29 mmol) and 3-cyanobenzoyl chloride (57.7 mg, 0.35 mmol) instead of 3-amino-4-methyl-N-(((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (53.04 mg, 37% yield).

[0499] 1H NMR (400 MHz, MeOD)δ8.36 (br s, 2H), 8.29 (d,J= 8.0 Hz, 1H), 8.21 (d,J= 8.8 Hz, 2H), 8.09 (d,J= 8.8 Hz, 2H), 8.00 - 7.95 (m, 2H), 7.80 - 7.74 (m, 2H), 7.59 (t,J= 7.6 Hz, 1H).; LCMS (ESI), m / z = 515 [M+42]+.

[0500]

[0501] Intermediate compound 3-4:3-cyano-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-cyano-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide, KSK-001-062]

[0502]

[0503] Compound 3-cyano-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.290 mmol) and 3-cyanobenzoyl chloride (57.7 mg, 0.35 mmol) instead of 3-amino-4-methyl-N-(((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (148 mg, > 99% yield) using 3-amino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (148 mg, > 99% yield) instead of 4-methyl-3-nitrobenzoyl chloride and 4-methyl-3-nitrobenzoyl chloride.

[0504] 1 H NMR (400 MHz, MeOD)δ8.68 (s, 1H), 8.35 (d,J= 8.0 Hz, 2H), 8.29 (d,J= 8.0 Hz, 2H), 7.99 - 7.94 (m, 2H), 7.86 (d,J= 7.6 Hz, 1H), 7.82 - 7.73 (m, 3H), 7.57 (t,J= 8.0 Hz, 1H). ; LCMS (ESI), m / z = 515.20 [M+42]+

[0505]

[0506] Intermediate compound 3-5: 3-(4-cyanobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-086]

[0507]

[0508] Compound 3-(4-cyanobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.29 mmol) and 4-cyanobenzoyl chloride (120 mg, 0.73 mmol) instead of 3-amino-4-methyl-N-(((trifluoromethyl)sulfonyl)phenyl)benzamide and 4-methyl-3-nitrobenzoyl chloride (75 mg, 54% yield).

[0509] 1 H NMR (400 MHz, DMSO)δ11.01 (s, 1H), 10.73 (s, 1H), 8.36 (s, 1H), 8.24 (d,J= 9.2 Hz), 8.16 - 8.12 (m, 4H), 8.06 - 8.04 (m, 3H), 7.78 (d,J= 7.6 Hz, 1H), 7.58 (t,J= 8.0 Hz, 1H).; LCMS (ESI), m / z = 515.21 [M+42]+.

[0510]

[0511] Intermediate compound 3-6: 3-(4-cyanobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-088]

[0512]

[0513] Compound 3-(4-cyanobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.29 mmol) and 4-cyanobenzoyl chloride (120 mg, 0.73 mmol) instead of 3-amino-4-methyl-N-(((trifluoromethyl)sulfonyl)phenyl)benzamide and 4-methyl-3-nitrobenzoyl chloride (73 mg, 52% yield).

[0514] 1 H NMR (400 MHz, DMSO) δ10.85 - 10.76 (m, 2H), 8.68 (s, 1H), 8.42 - 8.38 (m, 2H), 8.15 (2,J= 8.4 Hz, 2H), 8.07 - 8.03 (m, 3H), 7.87 - 7.86 (m, 2H), 7.58 (t,J= 8.0 Hz, 1H).; LCMS (ESI), m / z = 515.19 [M+42]+.

[0515]

[0516] Intermediate compound 3-7: 3-(4-cyanobenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-091]

[0517]

[0518] Compound 3-(4-cyanobenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.29 mmol) and 4-cyanobenzoyl chloride (116 mg, 0.7 mmol) instead of 3-amino-4-methyl-N-(((trifluoromethyl)sulfonyl)phenyl)benzamide and 4-methyl-3-nitrobenzoyl chloride (58.7 mg, 39% yield).

[0519] 1 H NMR (400 MHz, DMSO) δ10.92 (br s, 1H), 10.36 (br s, 1H), 8.23 ​​(d,J= 8.0 Hz, 2H), 8.16 (d,J= 8.0 Hz, 2H), 8.11 - 8.09 (m, 2H), 8.07 - 8.02 (m, 3H), 7.88 (d,J= 7.6 Hz, 1H), 7.49 (d,J= 8.0 Hz, 1H), 2.33 (s, 3H).; LCMS (ESI), m / z = 529.19 [M+42]+.

[0520]

[0521] Intermediate compound 3-8: 3-(4-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSK-001-096]

[0522]

[0523] Compound 3-(4-cyanobenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (100 mg, 0.29 mmol) and 4-cyanobenzoyl chloride (116 mg, 0.7 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (141 mg, > 99% yield).

[0524] 1 H NMR (400 MHz, DMSO) δ10.78 (s, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 8.41 (td,J= 4.0 Hz, 2.0 Hz, 1H), 8.16 (d,J= 8.4 Hz, 2H), 8.07 - 8.03 (m, 3H), 7.89 - 7.84 (m, 3H), 7.50 (d,J= 8.0 Hz, 1H), 2.34 (s, 3H).; LCMS (ESI), m / z = 529.16 [M+42]+.

[0525]

[0526] Intermediate compound 3-9: 3-(3-cyanobenzamido)-4-methyl-N-(4-(methylsulfonyl)phenyl)benzamide [3-(3-cyanobenzamido)-4-methyl-N-(4-(methylsulfonyl)phenyl)benzamide, TK-005-076]

[0527]

[0528] Compound 3-(3-cyanobenzamido)-4-methyl-N-(4-(methylsulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 using 3-amino-4-methyl-N-(4-(methylsulfonyl)phenyl)benzamide (60 mg, 0.237 mmol) instead of 5-aminonaphthalene-2-sulfonic acid (47 mg, 55% yield).

[0529] 1 H NMR (400 MHz, MeOD)δ8.39 (s, 1H), 8.32 (d,J= 8.0 Hz, 1H), 8.07 - 7.99 (m, 4H), 7.96 (d,J= 8.9 Hz, 2H), 7.86 (dd,J= 8.0, 1.8 Hz, 1H), 7.78 (t,J= 7.9 Hz, 1H), 7.52 (d,J= 8.0 Hz, 1H), 3.15 (s, 3H), 2.43 (s, 3H).; LCMS (ESI) m / z = 433.48 [M+1]+.

[0530]

[0531] Intermediate compound 3-10: 3-(3-cyanobenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-cyanobenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSH-004-021]

[0532]

[0533] Compound 3-(3-cyanobenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained in the same manner as intermediate compound 1-1 of Example 1 by using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.14 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (47 mg, 70% yield).

[0534] 1H NMR (400 MHz, MeOD) δ8.44 (dd,J= 7.2, 2.3 Hz, 1H), 8.35 (t,J= 1.4 Hz, 1H), 8.28 (dt,J= 8.0, 1.4 Hz, 1H), 8.18 (d,J= 9.0 Hz, 2H), 8.06 (d,J= 8.9 Hz, 2H), 7.99 (dt,J= 7.8, 1.3 Hz, 1H), 7.92 (ddd,J= 8.6, 4.6, 2.4 Hz, 1H), 7.75 (t,J= 7.9 Hz, 1H), 7.42 (dd,J= 10.0, 8.7 Hz, 1H).; LCMS (ESI), m / z = 533.13 [M+41]+.

[0535]

[0536] Intermediate compound 3-11: 3-(3-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide

[0537]

[0538] Compound 3-(3-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as in Example 1-32, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.14 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (58 mg, 82% yield).

[0539] 1H NMR (400 MHz, MeOD)δ8.66 (s, 1H), 8.45 (dd,J= 7.2, 2.3 Hz, 1H), 8.39 - 8.35 (m, 1H), 8.33 - 8.25 (m, 2H), 8.04 - 7.98 (m, 1H), 7.97 - 7.90 (m, 1H), 7.86 (d,J= 8.0 Hz, 1H), 7.83 - 7.72 (m, 2H), 7.43 (dd,J= 10.0, 8.7 Hz, 1H).; LCMS (ESI), m / z = 492 [M+1]+.

[0540]

[0541] Intermediate compound 3-12: 3-(4-cyanobenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSH-006-18]

[0542]

[0543] Compound 3-(4-cyanobenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 3-amino-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.21 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (53 mg, 81% yield).

[0544] 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 10.65 (s, 1H), 8.66 (s, 1H), 8.42 (dt,J= 6.9, 2.2 Hz, 1H), 8.17 (s, 2H), 8.12 (d,J= 8.3 Hz, 2H), 8.08 - 8.03 (m, 3H), 7.89 - 7.86 (m, 2H).; LCMS (ESI), m / z = 542.20 [M+1]+.

[0545]

[0546] Intermediate compound 3-13: 3-(4-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSG-015-40]

[0547]

[0548] Compound 3-(4-cyanobenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.14 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (34 mg, 50% yield).

[0549] 1 H NMR (400 MHz, CDCl3)δ8.93 (dd,J= 7.1, 2.2 Hz, 1H), 8.61 (s, 1H), 8.35 - 8.25 (m, 2H), 8.21 - 8.13 (m, 1H), 8.02 (d,J= 8.5 Hz, 2H), 7.90 - 7.77 (m, 4H), 7.69 (t,J= 8.3 Hz, 1H), 7.32 (dd,J= 10.2, 8.7 Hz, 1H).; LCMS (ESI), m / z = 492.00 [M+1]+

[0550]

[0551] Intermediate compound 3-14: 5-(4-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-(4-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, HJY-010-43]

[0552]

[0553] Compound 5-(4-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 5-amino-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.14 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (35 mg, 53% yield).

[0554] 1 H NMR (400 MHz, MeOD) 8.60 - 8.56 (m, 1H), 8.21 - 8.11 (m, 4H), 8.10 - 8.05 (m, 1H), 7.97 - 7.92 (m, 2H), 7.91 - 7.78 (m, 3H).; LCMS (ESI), m / z = 542.12 [M+1]+

[0555]

[0556] Intermediate compound 3-15: 5-(3-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-(3-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, HJY-010-44]

[0557]

[0558] Compound 5-(3-cyanobenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 5-amino-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.14 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (35 mg, 53% yield).

[0559] 1 H NMR (400 MHz, MeOD) 8.60 - 8.56 (m, 1H), 8.21 - 8.11 (m, 4H), 8.10 - 8.05 (m, 1H), 7.97 - 7.92 (m, 2H), 7.91 - 7.78 (m, 3H).; LCMS (ESI), m / z = 542.13 [M+1]+

[0560]

[0561] Intermediate compound 3-16: 5-(4-cyanobenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [5-(4-cyanobenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, KSH-006-57]

[0562]

[0563] 5-(4-cyanobenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 5-amino-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.83 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (10 mg, 24% yield).

[0564] 1H NMR (400 MHz, DMSO) δ11.09 (s, 1H), 10.74 (s, 1H), 8.64 (s, 1H), 8.26 (dt,J= 7.5, 1.8 Hz, 1H), 8.16 - 8.12 (m, 3H), 8.06 (d,J= 8.5 Hz, 2H), 8.01 - 7.97 (m, 1H), 7.91 - 7.85 (m, 2H), 7.45 (t,J= 9.4 Hz, 1H).; CMS (ESI), m / z = 492.22[M+1]+

[0565]

[0566] Intermediate compound 3-17: 3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide, KNY-020-37]

[0567]

[0568] Compound 3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (30 mg, 0.83 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (10 mg, 24% yield).

[0569] 1H NMR (400 MHz, DMSO) δ10.70 (s, 1H), 10.67 (s, 1H), 8.46 (t,J= 1.4 Hz, 1H), 8.39 (t,J= 1.8 Hz, 1H), 8.36 (t,J= 1.7 Hz. 1H), 8.30 (dt,J= 7.9, 1.4 Hz, 1H), 8.18 - 8.14 (m, 1H), 8.10 (dt,J= 7.7, 1.2 Hz, 1 H), 8.04 (dd,J= 8.1, 1.3 Hz, 1H), 7.81-7.76 (m, 2H), 7.67 (t,J= 7.9 Hz, 1H), 7.62 (dt,J= 7.8, 1.4 Hz, 1 H), 7.92 (t,J= 7.9 Hz, 1H), 3.30 (q,J= 7.4 Hz, 2H), 1.34 (t,J= 7.3 Hz, 3H).; LCMS (ESI), m / z = 434.25 [M+1]+

[0570]

[0571] Intermediate compound 3-18: 3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide [3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide, KSG-015-73]

[0572]

[0573] Compound 3-cyano-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.164 mmol) instead of 3-amino-4-methyl-N-(3-(((ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide (60 mg, 84% yield).

[0574] 1H NMR (400 MHz, MeOD) δ8.45 - 8.38 (m, 1H), 8.36 - 8.27 (m, 1H), 8.17 - 8.10 (m, 2H), 8.10 - 8.02 (m, 1H), 7.97 - 7.88 (m, 3H), 7.81 - 7.75 (m, 1H), 7.70 (dt,J= 7.8, 1.5 Hz, 1H), 7.66 (t,J= 7.8 Hz, 1H), 7.57 (t,J= 7.9 Hz, 1H), 3.26 (q,J= 7.4 Hz, 2H), 1.28 (t,J= 7.4 Hz, 3H).; LCMS (ESI), m / z = 434.19 [M+1]+.

[0575]

[0576] Intermediate compound 3-19: 3-(4-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(4-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, HJY-010-53]

[0577]

[0578] Compound 3-(4-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.164 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (46 mg, 70% yield).

[0579] 1H NMR (400 MHz, MeOD) δ8.68 (t,J= 2.0 Hz, 1H), 8.59 (t,J= 1.9 Hz, 1H), 8.41 (d,J= 2.0 Hz, 1H), 8.31 (ddd,J= 8.1, 2.2, 1.2 Hz, 1H), 8.19 - 8.13 (m, 2H), 8.11 (dt,J= 2.1, 1.1 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.91 - 7.85 (m, 1H), 7.81 (t,J= 8.0 Hz, 1H)..; LCMS (ESI), m / z = 542.22 [M+1]+

[0580]

[0581] Intermediate compound 3-20: 3-(3-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide [3-(3-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide, HJY-010-54]

[0582]

[0583] Compound 3-(3-cyanobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide was obtained using the same method as intermediate compound 3 of Example 2, using 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (50 mg, 0.121 mmol) instead of 3-amino-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (44 mg, 67% yield).

[0584] 1H NMR (400 MHz, MeOD) δ8.69 (d,J= 2.1 Hz, 1H), 8.59 (t,J= 1.9 Hz, 1H), 8.40 (dt,J= 6.7, 1.8 Hz, 2H), 8.31 (ddd,J= 8.0, 2.0, 1.1 Hz, 2H), 8.11 (dt,J= 2.1, 1.0 Hz, 1H), 8.00 (dt,J= 7.8, 1.4 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.82 (t,J= 8.0 Hz, 1H), 7.77 (t,J= 7.8 Hz, 1H).; LCMS (ESI), m / z = 542.21 [M+1]+.

[0585]

[0586] <Experimental Example 1> Cytotoxicity Evaluation

[0587] To evaluate the anticancer activity of the novel compound synthesized according to the above example, a cell viability test was performed on the human myeloid leukemia cell line MV4-11 under single-dose administration conditions. MV4-11 cells were placed in a 96-well plate at a density of 1.5 × 10⁶ per well. 4 Inoculated at a density of dogs, and culture conditions were used with RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (P / S).

[0588] The drug was administered as a single dose of 10 μM in 0.1% DMSO on the day of cell inoculation (Day 0), and the test compounds used in this experimental example consisted of compound 3 (DN208692), compound 8 (DN208958), compound 12 (DN209147), compound 2 (DN209152), compound 15 (DN209157), compound 48 (DN301371), compound 19 (DN301372), compound 21 (DN301634), compound 24 (DN301944), and compound 1 (DN302319).

[0589] Cell viability analysis was performed 48 hours after drug treatment (Day 2). The analysis was performed using GLPBio’s CCK-8 kit (GK10001), which is a method for quantifying cell viability by measuring the absorbance (450 nm) of formazan produced by WST-8, which is reduced by dehydrogenase in living cells.

[0590] As shown in Figure 1, experimental results indicated that some compounds exhibited activity that reduced MV4-11 cell viability to 50% or less. Based on this criterion, six compounds—DN209152, DN301371, DN301372, DN301634, DN301944, and DN302319—were selected as candidate substances exhibiting excellent anticancer activity. Accordingly, follow-up experiments were conducted to confirm dose-dependent responses for these compounds. In these tests, each compound was treated at various concentrations (e.g., 1, 2.5, 5, 7.5, 10 μM), and changes in cell viability were measured by performing CCK-8 analysis under the same conditions. In addition, cell-selective drug activity experiments were performed on four cell lines (MV4-11, MOLM-13, THP-1, K562) for the representative compound DN302319 (Fig. 3).

[0591]

[0592] Table 3 below shows the cell viability at a single low concentration (10 μM) of the representative compound according to the above experimental method.

[0593] No.DN.Cellviability(% / 10 μM)No.DN.Cellviability(% / 10 μM)No.DN.Cellviability(% / 10 μM)1DN3023191419DN30137233.940DN20902311.22DN20915211.720DN301632118.341DN20902530.43DN208 69267.921DN3016344342DN20914632.84DN208693113.323DN30177288.643DN20916336.75DN20884499.624 DN3019445044DN20960939.46DN20884985.725DN30109296.545DN30123537.67DN208891110.626DN3010979 6.946DN30135952.58DN20895866.429DN30297146.747DN30136029.09DN20895985.530DN30297289.348DN30 13715.610DN20896083.831DN30298210.449DN30168641.011DN20916490.932DN301940101.050DN30168732 .712DN20914773.433DN30194594.651DN30178076.313DN209154109.234DN208996107.152DN30192520.214 DN209156115.735DN20888890.053DN3019323.715DN20915777.636DN20889089.354DN30193322.516DN2091 51108.237DN20896216.155DN30193993.817DN209155106.538DN2089579.318DN20916086.939DN20902111.9

[0594]

[0595] <Experimental Example 2> Evaluation of Cell Proliferation Inhibitory Activity in AML Cell Line (MV4-11)

[0596] Dose reaction curve and GI 50Value calculations were performed using GraphPad Prism 10 software. For each compound, MV4-11 cells were treated with the drug at concentrations of 1, 2.5, 5, 7.5, and 10 μM, and the control group was set based on cells treated with only 0.1% DMSO under the same conditions.

[0597] The X-axis data represents the final treatment concentration of the drug, and the log is calculated by applying the “X is log (concentration)” setting in GraphPad Prism. 10 Analysis was performed using converted concentration values. The dose response curve fitting was “Absolute IC 50 It was performed using the “X is log (concentration)” model, which calculates the top and bottom values ​​of the curve directly from the data, resulting in a more precise IC 50 / GI 50 It is possible to calculate.

[0598] The Y-axis data were used after normalizing the cell viability measured at each concentration as a percentage relative to the control (0.1% DMSO treatment group). The analysis was based on experimental data obtained under n=1, triplicate conditions, and each data point was expressed as the mean of three replicate values ​​measured at the same concentration. In the graph, the standard deviation was displayed as an error bar alongside the mean value.

[0599] As a result of the analysis, as shown in Figure 2, the GI of each compound 50 (Growth Inhibition 50%) value and coefficient of determination (R 2 ) was calculated together, and in all cases R 2 It demonstrated a high goodness of fit of > 0.96. The finally generated dose-response curves were visualized using the graphing tools in GraphPad Prism, and the GI for each compound was calculated. 50The value was specified on the graph.

[0600]

[0601] Table 4 below shows the inhibitory activity of representative compounds in MV4-11 cells at each concentration (Fig. 4).

[0602] No.DN.MV4-11(GI 50 , μM)No.DN.MV4-11(GI 50 , μM)1DN3023192.660(R 2 = 9945)24DN3019448.039(R 2 = 9878)2DN2091527.136(R 2 = 9583)29DN3029719.356(R 2 = 9648)19DN3013728.096(R 2 = 9635)31DN3029828.009(R 2 = 9808)21DN3016348.896(R 2 = 9834)48DN3013713.063(R 2 = 9928)

[0603]

[0604] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. That is, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

A compound represented by the following chemical formula 1 or a compound selected from pharmaceutically acceptable salts thereof: <Chemical Formula 1> In the above chemical formula 1, R 1 It is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, or amino, and R 2 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)alkoxy, and R 3 Is or Selected from, Here, R 3' It is hydrogen or (C1-C4)alkyl, and X is oxygen or sulfur. In Article 1, In the above chemical formula 1, R 1 It is selected from (C1-C2)alkyl, trifluoromethyl, or amino, and R 2 is selected from hydrogen, halogen, (C1-C2)alkyl, trifluoromethyl, or (C1-C2)alkoxy, and R 3' It is hydrogen or (C1-C2)alkyl. In Article 1, The above compound is, Compound characterized by comprising the following compounds: 3-(4-thioureidobenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromail)sulfonyl)-phenyl)benzamido (compound 1), 3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 2), 4-methyl-3-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 3), 4-methyl-3-(3-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamido (compound 4), 4-methyl-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 5), 3-Thioureido-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 6), 4-methyl-3-(3-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 7), 3-(3-methylureido)-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 8), 3-(3-methylureido)-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (compound 9), 3-Thioureido-N-(3-((4-((trifluoromethyl)celponyl)phenyl)carbamoyl)phenyl)benzamide (compound 10), 4-fluoro-3-(3-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 11), 3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 12), 3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 13), 4-methyl-3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 14), 4-methyl-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 15), 3-(4-(3-methylureido)benzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 16), 4-methyl-3-(4-thioureidobenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 17), 4-methyl-3-(4-(3-methylureido)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 18), 3-(4-(3-methylthiouredo)benzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 19), N-(3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-ureidobenzamido)benzamide (compound 20), 4-fluoro-3-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 21), 2-fluoro-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 23), 2-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 24), N-(3-(methylsulfonyl)phenyl)-3-(3-thioureidobenzamido)benzamide (compound 25), N-(3-(methylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide (compound 26), 3-methyl-5-(4-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 29), 3-methyl-5-(3-thioureidobenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 30), 3-(4-(3-methylthiouredo)benzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 31), N-(3-sulfamoylphenyl)-3-(4-thioureidobenzamido)benzamide (compound 32), N-(3-(ethylsulfonyl)phenyl)-3-(4-thioureidobenzamido)benzamide (compound 33), 3-Guanidino-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 34), 3-(3-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 35), 3-(3-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 36), 3-Carbamothioil-N-(3-((4-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 37), 3-Carbamothioil-N-(3-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 38), 3-(4-carbamothioilbenzamido)-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 39), 3-(4-carbamothioilbenzamido)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 40), 3-(4-carbamothioilbenzamido)-4-methyl-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 41), 3-(4-carbamothioilbenzamido)-4-methyl-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 42), 3-(3-carbamothioilbenzamido)-4-fluoro-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 43), 3-(3-carbamothioilbenzamido)-4-methoxy-N-(4-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 44), 3-(3-carbamothioilbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 45), 3-(3-carbamothioilbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 46), 3-(4-carbamothioilbenzamido)-4-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 47) 3-(4-carbamothioilbenzamido)-4-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 48), 5-(3-carbamothioilbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 49), 5-(4-carbamothioilbenzamido)-2-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 50), 3-(4-carbamothioilbenzamido)-N-(3-(ethylsulfonyl)phenyl)benzamide (compound 51), 5-(4-carbamothioilbenzamido)-2-fluoro-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 52), 3-(4-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 53), 3-(3-carbamothioilbenzamido)-5-(trifluoromethyl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide (compound 54) and 3-Carbamothioil-N-(3-((3-(ethylsulfonyl)phenyl)carbamoyl)phenyl)benzamide (Compound 55). A pharmaceutical composition for the prevention or treatment of leukemia, comprising as an active ingredient a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. In Article 4, The above compound is, A pharmaceutical composition characterized by inhibiting cell proliferation of leukemia cell lines. In Article 4, The above leukemia is, A pharmaceutical composition characterized by being acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia. A food composition for preventing or improving leukemia, comprising a compound according to any one of claims 1 to 3 or a food-grade acceptable salt thereof as an active ingredient. A health functional food composition for the prevention or improvement of leukemia, comprising a compound according to any one of claims 1 to 3 or a food-grade acceptable salt thereof as an active ingredient.

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