Novel triazine derivative effective in treating liver and kidney inflammation and fibrosis and preparation method thereof

Abstract

The present invention relates to a compound selected from novel triazine derivative compounds, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof, which can act as a PAR2 (Protease-activated receptor 2) antagonist. Since PAR2 antagonists block pathways associated with the proliferation of cancer cells or inflammatory responses, they can be expected to act as anticancer agents or anti-inflammatory agents. This allows for the improvement of various fibroses, including liver and kidney fibrosis, as well as inflammatory diseases, vascular aging, and metabolic diseases, and can be utilized in various ways as a medicine.

Description

Technology Field

[0001] The present invention provides a novel triazine derivative having therapeutic effects on inflammation and fibrosis of the liver and kidneys, and a method for preparing the same. Background Technology

[0002] Chronic liver or kidney disease occurs in response to persistent, long-term liver or kidney damage caused by viral hepatitis, obesity, or alcohol abuse. While liver or kidney disease can vary, a common pathological feature is inflammation or liver fibrosis. Fibrosis of the liver or kidney, in which extracellular matrix (ECM) fills areas that are not regenerated by liver and kidney cells, leads to an excessive accumulation of inflammatory mediators due to chronic and / or severe liver and kidney damage. This disrupts the normal functioning of the liver and kidneys, eventually leading to terminal stages of liver or kidney cirrhosis or liver or kidney cancer, creating a need for treatments.

[0003] Meanwhile, PAR2 (Protease-activated receptor 2) is a family of G-protein coupled receptors (GPCRs) that is irreversibly activated through the cleavage of its N-terminus. The transmembrane receptor domain triggers cellular signaling cascades in response to inflammatory signals and other stimuli. Once the original N-terminal domain is removed, the tether ligand activates intracellular G protein or β-arrestin-mediated signaling pathways to induce a wide range of intracellular physiological responses.

[0004] These PAR2s are central mediators of diseases such as cancer, inflammation, asthma, pancreatitis, and irritable bowel syndrome. In addition, PAR2 antagonists are expected to act as therapeutic agents by blocking the inflammatory and fibrotic pathways of the liver and kidneys, and research on this is currently ongoing. Prior art literature

[0005] 1. Republic of Korea Published Patent No. 10-2020-0143429. The problem to be solved

[0006] The object of the present invention is to provide a compound selected from novel triazine derivative compounds, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof.

[0007] Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of fibrosis comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0008] Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0009] Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of metabolic diseases comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0010] Another objective of the present invention is to provide a health functional food composition for the prevention or improvement of fibrosis comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0011] Another objective of the present invention is to provide a health functional food composition for anti-inflammatory purposes comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0012] Another objective of the present invention is to provide a health functional food composition for improving vascular aging comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0013] Another objective of the present invention is to provide a health functional food composition for the prevention or improvement of metabolic diseases comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof. means of solving the problem

[0014] To achieve the above objective, the present invention provides a compound selected from a triazine derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1, L 1 to L 3 Each may be the same or different, is any one of CH2, O, S, and NH, and R 1 is any one of a halogen, hydroxy (OH), trifluoromethyl (CF3), (C1–C4)alkyl, and (C1–C4)alkoxy, and R 2 is hydrogen (H), and R 3 Each may be the same or different, and (C1–C4)alkyl, (C1–C4)alkene, (C2–C4)alkyne, -NHC(O)-(C1–C4)alkyl, phenyl, benzyl, thiazole, benzothiazole, and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 2 and R3 They can combine with each other to form a benzene ring, and R 4 is hydrogen (H), and R 5 may each be the same or different, and are any one of (C1–C4)alkyl, (C1–C4)alkene, (C1–C4)alkyne, -NHC(O)-(C1–C4)alkyl, phenyl, benzyl, thiazole, benzothiazole, and 6,7-dihydro-5H-indeno[5,6-d]thiazol; R 4 and R 5 They can combine with each other to form a benzene ring.

[0018] In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of fibrosis comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0019] In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0020] In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of metabolic diseases comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0021] In addition, the present invention provides a health functional food composition for the prevention or improvement of fibrosis comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0022] In addition, the present invention provides a health functional food composition for anti-inflammatory purposes comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0023] In addition, the present invention provides a health functional food composition for improving vascular aging comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0024] In addition, the present invention provides a health functional food composition for the prevention or improvement of metabolic diseases comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof. Effects of the invention

[0025] The present invention relates to a compound selected from novel triazine derivative compounds, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof, which acts as a PAR2 (Protease-activated receptor 2) antagonist and can be utilized in various ways as a medicine by improving inflammatory diseases, vascular aging, fibrosis, and metabolic diseases. Brief explanation of the drawing

[0026] Figure 1 shows the structure of a novel triazine derivative compound. Figure 2 shows a schematic diagram of the synthesis method of a novel triazine derivative compound. Figure 3 shows the results of a cytotoxicity test of a novel triazine derivative compound. Figure 4 shows the results of confirming changes in inflammatory NF-κB phosphorylation and COX-2 by novel triazine derivative compounds. Figure 5 shows the results of confirming the degree of regulation of inflammatory cytokines and chemokines by novel triazine derivative compounds. Figure 6 shows 6-chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalene-1-yl)-1,3,5-triazine-2,4-diamine [6-Chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalen-1-yl)-1,3,5-triazine-2,4-diamine; hereinafter referred to as Cpd. 1) exhibits inhibitory effects on the expression of inflammatory proteins, cytokines, and chemokines in an LPS-induced inflammatory mouse model. Figure 7 shows the inhibitory effect of Cpd. 1 on inflammatory protein and cytokine expression in vascular endothelial cells. Figure 8 shows the regulatory effect of Cpd. 1 on the expression of vascular inflammatory factors (VCAM and ICAM) in an LPS-induced inflammatory mouse model and in vascular endothelial cells. Figure 9 shows the weight loss and serum indicator reduction effects of Cpd. 1 in metabolic diabetes disease models (mouse and db / db mouse). Figure 10 shows the metabolic disease regulatory mechanism and the anti-inflammatory and anti-vascular aging activities of Cpd. 1 in the metabolic disease model db / db mouse. Figure 11 shows the fibrosis-inhibiting effect of Cpd. 1 in metabolic disease mouse models db / db mice (A, B) and high-fat diet mice (C). Figure 12 shows the pharmacophore analysis and MD (Molecular Dynamics) analysis data of the PAR2-Cpd. 1 complex. Specific details for implementing the invention

[0027] The present invention will be described in more detail below.

[0029] The present invention provides a compound selected from a triazine derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0030] [Chemical Formula 1]

[0031]

[0032] In the above chemical formula 1, L 1 to L 3 Each may be the same or different, is any one of CH2, O, S, and NH, and R 1 is any one of a halogen, hydroxy (OH), trifluoromethyl (CF3), (C1–C4)alkyl, and (C1–C4)alkoxy, and R 2 is hydrogen (H), and R 3 Each may be the same or different, and (C1–C4)alkyl, (C1–C4)alkene, (C2–C4)alkyne, -NHC(O)-(C1–C4)alkyl, phenyl, benzyl, thiazole, benzothiazole, and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 2 and R 3 They can combine with each other to form a benzene ring, and R 4 is hydrogen (H), and R 5 may each be the same or different, and are any one of (C1–C4)alkyl, (C1–C4)alkene, (C1–C4)alkyne, -NHC(O)-(C1–C4)alkyl, phenyl, benzyl, thiazole, benzothiazole, and 6,7-dihydro-5H-indeno[5,6-d]thiazol; R 4 and R 5 They can combine with each other to form a benzene ring.

[0033] The above compound may be a compound represented by the following chemical formula 2.

[0034] [Chemical Formula 2]

[0035]

[0036] In the above chemical formula 2, L 2 and L 3 Each may be the same or different, is O or NH, and R 1 is a halogen or trifluoromethyl (CF3), and R 2 is hydrogen (H), and R 3 They may each be the same or different, and (C2–C4)alkynes, -NHC(O)-(C1–C2)alkyl, phenyl, and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 2 and R 3 They can combine with each other to form a benzene ring, and R 4 is hydrogen (H), and R 5 These may be the same or different, and include (C2–C4)alkynes, -NHC(O)-(C1–C2)alkyl, phenyl, and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 4 and R 5 They can combine with each other to form a benzene ring.

[0037] In the above chemical formula 2, R 1 is fluorine (F) or trifluoromethyl (CF3), and R 2 is hydrogen (H), and R 3 They may be the same or different, -NHC(O)CH3, phenyl and 6,7-dehydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H-indeno[5,6-d]thiazol) either one of these; R 2 and R 3 They can combine with each other to form a benzene ring, and R 4 is hydrogen (H), and R 5 may each be the same or different, and are any one of ethinyl (-C≡CH), -NHC(O)CH3 and phenyl; R 4 and R 5 They can combine with each other to form a benzene ring.

[0038] The above triazine derivative compound is 6-chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalene-1-yl)-1,3,5-triazine-2,4-diamine [6-Chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalen-1-yl)-1,3,5-triazine-2,4-diamine], 6-([1,1'-biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine [6-([1,1'-Biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine], 4,6-bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2-amine [4,6-Bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine], 6-([1,1'-biphenyl]-3-yloxy)- N2 -(Naphthalene-1-il)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-([1,1'-Biphenyl]-3-yloxy)- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine], N , N '-(((6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide [ N , N '-(((6-((3-(Trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide], 6-(4-(6,7-dihydro-5 H -Indeno[5,6-d]thiazole-2-yl)phenoxy)- N 2 -(Naphthalene-1-il)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-(4-(6,7-Dihydro-5 H -indeno[5,6-d]thiazol-2-yl)phenoxy)- N 2 -(naphthalen-1-yl)- N 4It may be selected from either -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine] and N-(4-((4-(naphthalen-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-yl)oxy)phenyl)acetamide [N-(4-((4-(Naphthalen-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)oxy)phenyl)acetamide].

[0039] The above compound may be a PAR2 (Protease-activated receptor 2) antagonist.

[0041] In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of fibrosis comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, preferably fibrosis of the liver or kidney.

[0042] The above fibrosis may be any one of fibrosis induced by solid tumors, metabolic disease-induced fibrosis, NAFLD-induced fibrosis, NASH-induced fibrosis, alcohol-induced fibrosis, drug-induced fibrosis, parasitic infection-induced fibrosis, bacterial infection-induced fibrosis, viral infection-induced fibrosis, HBV-induced fibrosis, HCV-induced fibrosis, HIV-induced fibrosis, dual HCV and HIV-induced fibrosis, radiation- or chemotherapy-induced fibrosis, and fibrosis due to chronic cholestatic disease, but is not limited thereto.

[0043] The above solid tumor may be any one of breast cancer, lung cancer, thyroid cancer, colorectal cancer, and prostate cancer, but is not limited thereto.

[0044] The above drug may be any one of thioacetamide, dimethylnitrosamine, triclosan, and carbon tetrachloride, but is not limited thereto.

[0046] In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0047] The above inflammatory diseases may be any one of hepatitis, nephritis, vascular aging due to inflammation, asthma, bronchitis, sepsis, rheumatoid arthritis, osteoarthritis, ulcerative colitis, myocarditis, and multiple sclerosis, but are not limited thereto.

[0048] The above hepatitis may be one of, but is not limited to, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced hepatitis, alcohol-induced hepatitis, and immune system dysfunction-mediated hepatitis.

[0049] The above-mentioned nephritis may be one of drug-induced nephritis, alcohol-induced nephritis, or immune system dysfunction-mediated nephritis, but is not limited thereto.

[0050] In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of metabolic diseases comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0051] The aforementioned metabolic diseases include dyslipidemia, cardiovascular disease, recurrent stenosis, syndrome X, metabolic syndrome, diabetes mellitus, obesity, hypertension, chronic cholangiopathy such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, keloids, chronic myocardial infarction, scleroderma / systemic sclerosis, neurodegenerative diseases, cancer, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, meningioma associated with neurofibromatosis, pancreatic neuroendocrine tumors, pancreatic neuroexocrine tumors, leukemia, myeloproliferative / myelodysplastic disorders, mastocytosis, cutaneous fibrosarcoma, solid tumors such as breast cancer, lung cancer, thyroid cancer or colorectal cancer, prostate cancer, biliary fibrosis, gastrointestinal fibrosis, Crohn's disease-induced colon fibrosis, ulcerative Colitis-induced colonic fibrosis, intestinal (e.g., small intestine) fibrosis, colonic fibrosis, gastric fibrosis, cutaneous fibrosis, epidermal fibrosis, endothelial fibrosis, cutaneous fibrosis due to scleroderma / systemic fibrosis, chronic inflammatory airway diseases, e.g., COPD (Chronic obstructive lung disease), asthma, emphysema, smoker's lungs, tuberculosis, pulmonary fibrosis, pulmonary fibrosis following idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, nephrogenic systemic fibrosis, myofibrosis, soft tissue (e.g., mediastinal or retroperitoneal) fibrosis, myelofibrosis, articular fibrosis, chondrofibrosis, pancreatic fibrosis, uterine fibrosis, nervous system fibrosis, testicular fibrosis, ovarian fibrosis, adrenal fibrosis, arterial fibrosis, venous fibrosis, ocular fibrosis, endocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive megafibrosis (complication of coal miner's pneumoconiosis), proliferative It may be any one of fibrosis, neoplastic fibrosis, peri-implant fibrosis and asbestosis, joint fibrosis, and adhesive capsulitis, but is not limited thereto.

[0052] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, leavening agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders, and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0053] Specifically, the carrier, excipient, and diluent may be 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, and mineral oil. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc. These solid dosage forms may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the above composition. In addition, lubricants such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, and syrups, and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents like water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. Witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerogelatin, etc. may be used as the base for suppositories.

[0054] According to one embodiment of the present invention, the pharmaceutical composition may be administered to a subject in a conventional manner through an intravenous, intra-arterial, intra-abdominal, intramuscular, intra-arterial, intra-abdominal, intrasternal, transdermal, nasal, inhalation, local, rectal, oral, ocular, or intradermal route.

[0055] The dosage of the active ingredient according to the present invention may vary depending on the subject's condition and body weight, the type and severity of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by a person skilled in the art. The daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. The administration may be performed once a day or divided into several doses, and the scope of the present invention is not limited by this.

[0057] In addition, the present invention provides a health functional food composition for the prevention or improvement of fibrosis comprising a compound selected from the novel triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0058] In addition, the present invention provides a health functional food composition for anti-inflammatory purposes comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0059] In addition, the present invention provides a health functional food composition for improving vascular aging comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0060] In addition, the present invention provides a health functional food composition for the prevention or improvement of metabolic diseases comprising a compound selected from the triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0061] The above health functional food may contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0062] In addition, it may contain fruit pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients may be used independently or in combination. Furthermore, the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, chewing gum, ice cream, soup, beverage, tea, functional water, drinkables, alcohol, and vitamin complexes.

[0063] In addition, the above-mentioned health functional food may further include food additives, and unless otherwise stipulated, suitability as a "food additive" shall be determined in accordance with the specifications and standards for the relevant item, based on the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety.

[0064] Examples of items listed in the above "Food Additives Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid; natural additives such as persimmon dye, licorice extract, crystalline cellulose, kohlrabi dye, and guar gum; L-sodium glutamate preparations; alkaline agents added to noodles; preservative preparations; and mixed preparations such as tar dye preparations.

[0065] At this time, the content of the active ingredient added to the food during the process of manufacturing the health functional food can be appropriately increased or decreased as needed, and preferably, it can be added in an amount of 1 to 90 parts by weight per 100 parts by weight of the food.

[0068] Hereinafter, to aid in understanding the present invention, examples and the like will be described in detail. However, the following examples and the like are merely illustrative of the content of the present invention and the scope of the present invention is not limited to the following examples and the like. The examples and the like of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

[0070] [합성예] 트리아진 (triazine) 유도체 화합물 합성

[0071] Novel triazine derivative compounds were synthesized from cyanuric chloride (Fig. 2), Cpd. 1 and 6-([1,1'-biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine [6-([1,1'-Biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 3-Fluoroanilino-2,6-dichloro-1,3,5-triazine (hereinafter referred to as Cpd. 8), a common intermediate of -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine (hereinafter referred to as Cpd. 2), was prepared from the reaction of cyanuric chloride with 3-fluoroaniline in the presence of trimethylamine. The reaction of Cpd. 8 with 1-naphthylamine in the presence of acetic acid yielded 6-chloro-N 2 -(3-fluorophenyl)- N 4 -(naphthalene-1-yl)-1,3,5-triazine-2,4-diamine [6-Chloro- N 2 -(3-fluorophenyl)- N 4 While it produced -(naphthalen-1-yl)-1,3,5-triazine-2,4-diamine; hereinafter referred to as Cpd. 9], the reaction of 4-phenylphenol in the presence of sodium carbonate proceeded through the same reaction mechanism as 4-([1,1'-biphenyl]-4-yloxy)-6-chloro- N -(3-fluorophenyl)-1,3,5-triazine-2-amine [4-([1,1'-Biphenyl]-4-yloxy)-6-chloro- N -(3-fluorophenyl)-1,3,5-triazin-2-amine; hereinafter referred to as Cpd. 10] was produced. Cpd. 1 was synthesized by the coupling reaction of 4-phenylphenol and Cpd. 9 under basic conditions in the presence of a catalytic amount of palladium(II) acetate, and Cpd. 2 was prepared by the nucleophilic addition-elimination reaction between Cpd. 10 and 3-ethynylaniline in acetic acid.

[0072] The remaining triazine derivative compounds were synthesized in a manner similar to the synthesis of Cpd. 1 and Cpd. 2. The reaction of cyanuric chloride with 3-trifluoromethylaniline synthesized 3-trifluoromethylanilino-2,6-dichloro-1,3,5-triazine (hereinafter referred to as Cpd. 11), which was used as a common intermediate for the synthesis of the remaining triazine derivative compounds. Cpd. 11 was reacted with 4-phenylphenol and 4-acetaminophenol, respectively, under basic conditions to produce 4,6-bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2-amine [4,6-Bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine; hereinafter referred to as Cpd. 3] and N , N '-(((6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide [ N , N A compound [-(((6-((3-(Trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide; hereinafter referred to as Cpd. 5] was synthesized. By reacting Cpd. 11 with 1-naphthylamine in the presence of triethylamine, the diaminotriazine derivative 6-chloro- N 2 -(Naphthalene-1-il)- N4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-Chloro- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine; hereinafter referred to as Cpd. 12] was synthesized. Cpd. 12 and 3-phenylphenol, 4-(6,7-dihydro-5H-indeno[5,6-d]thiazole-2-yl)phenol (4-(6,7-dihydro-5 H The condensation reaction with -indeno[5,6-d]thiazol-2-yl)phenol) and 4-acetamidophenol yielded 6-([1,1'-biphenyl]-3-yloxy)- in 35-55% yields, respectively. N 2 -(Naphthalene-1-il)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-([1,1'-Biphenyl]-3-yloxy)- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine; hereinafter referred to as Cpd. 4], 6-(4-(6,7-dihydro-5 H -Indeno[5,6-d]thiazole-2-yl)phenoxy)- N 2 -(Naphthalene-1-il)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-(4-(6,7-Dihydro-5 H -indeno[5,6-d]thiazol-2-yl)phenoxy)- N 2 -(naphthalen-1-yl)- N 4-(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine; hereinafter referred to as Cpd. 6] and N -(4-((4-(naphthalene-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-yl)oxy)phenyl)acetamide [ N -(4-((4-(Naphthalen-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)oxy)phenyl)acetamide; hereinafter referred to as Cpd. 7] was produced.

[0073] Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. Low-resolution MS spectra were obtained in ESI positive / negative mode using Expression CMS (Advion Itaca, NY, USA). 1 H and 13 13C NMR (nuclear magnetic resonance) spectral data were obtained using the Varian Unity INOVA 400 spectrometer and Varian Unity AS500 spectrometer (Agilent Technologies, Santa Clara, CA, USA) for CDCl3 or DMSO- d Measurements were taken using 6 as the solvent, and the chemical change was expressed in ppm units relative to the residual solvent or deuterium peak ( d H 7.24 and d C 77.0 for CDCl3, d H 2.50 and d C 39.7 for DMSO- d6). Coupling constants were reported in Hertz, and the abbreviations used are s (singlet), brs (broad singlet), d (doublet), dd (doublet of doublets), dt (doublet of triplets), brd (broad doublet), t (triplet), td (triplet of doublets), brt (broad triplet), q (quartet), quint (quintet), m (multiplet), and brm (broad multiplet). All reactions were performed under nitrogen, using pre-coated 60F. 254 The reaction was monitored by thin-film chromatography (TLC) performed on a plate.

[0074] (1) Cpd. 8 (4,6-Dichloro- N -(3-fluorophenyl)-1,3,5-triazin-2-amine)

[0075] Trimethylamine (0.38 mL, 2.73 mmol) and 3-fluoroaniline (0.13 mL, 1.35 mmol) were added at 0 °C to a stirred solution of cyanuric chloride (500 mg, 2.71 mmol) dissolved in anhydrous acetone (10 mL). After stirring at 0 °C for 1 hour, the reaction mixture was filtered and washed with water. The filter cake was recrystallized from acetone and water to obtain solid Cpd. 8 (310 mg, 88%).

[0076] 1 ¹H NMR (500 MHz, CDCl₃) δ 7.57 (s, 1 H, NH), 7.52 (dt, 1 H, J = 11.0, 2.0 Hz, 2-H), 7.35 (td, 1 H, J = 8.5, 6.0 Hz, 5-H), 7.21 (dd, 1 H, J= 8.5, 2.0 Hz, 6-H), 6.94 - 6.91 (m, 1 H, 4-H); 13 CNMR(100MHz,CDCl3) δ 164.2, 164.2, 163.1 (d, J = 244.8 Hz), 137.5 (d, J = 10.9 Hz), 130.7 (d, J = 9.2 Hz), 116.6 (d, J = 3.1 Hz), 112.7 (d, J = 21.2 Hz), 108.8 (d, J = 26.5 Hz).

[0078] (2) Cpd. 9 (6-Chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalen-1-yl)-1,3,5-triazine-2,4-diamine)

[0079] A solution (30 mL) of a co-solvent of acetic acid and tertiary-butanol (1:1) containing Cpd. 8 (500 mg, 1.93 mmol) and 1-naphthylamine (276 mg, 1.93 mmol) was stirred at room temperature for 14 hours. The resulting precipitate was filtered, washed with water, and the filter cake was recrystallized from chloroform to obtain solid Cpd. 9 (531 mg, 75%).

[0080] 1 ¹H NMR (400 MHz, CDCl₃) δ 8.19 - 7.73 (m, 5H), 7.57 - 7.47 (m, 4H), 7.14 - 6.63 (m, 4H); LRMS (ESI-) m / z 364 (MH) - .

[0082] (3) Cpd. 1 (6-Chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalen-1-yl)-1,3,5-triazine-2,4-diamine)

[0083] A 10 mL solution of toluene containing Cpd. 9 (525 mg, 1.44 mmol) and 4-phenylphenol (244 mg, 1.43 mmol) was refluxed for 30 hours in the presence of Cs2CO3 (701 mg, 2.15 mmol) and Pd(OAc)2 (6 mg, 0.03 mmol). After cooling to room temperature, the reaction mixture was distributed between dichloromethane and water, the organic layer was dried with MgSO4, filtered, and evaporated under vacuum. The resulting solid was recrystallized in a cosolvent of chloroform and methanol to obtain the solid Cpd. 1 (281 mg, 39%).

[0084] 1 ¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, 1H, J = 9.0 Hz), 7.89 (brd, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 7.5 Hz), 7.78 - 7.68 (m, 2H), 7.65 - 7.59 (m, 4H), 7.53 - 7.50 (m, 2H), 7.46 (t, 2H, J = 8.0 Hz), 7.37 (t, 1H, J = 8.0 Hz), 7.33 (brm, 1H), 7.27 - 7.23 (m, 2H), 7.04 (brm, 1H), 6.87 (brm, 1H), 6.64 (brm, 1H); 13 CNMR(100MHz,CDCl3) δ 167.0, 165.4, 163.1 (d, J = 243.5 Hz), 151.8, 140.7, 139.8 (d, J = 11.9 Hz), 139.0, 134.5, 132.7, 129.8 (d, J = 9.3 Hz), 129.0, 128.8, 128.3, 127.5, 127.3, 126.6, 126.3, 125.6, 122.4, 121.7, 115.1, 110.1 (d,J = 21.1 Hz), 107.5 (d, J = 26.4 Hz); LRMS (ESI-) m / z 498 (MH) - .

[0086] (4) Cpd. 10 (4-([1,1'-Biphenyl]-4-yloxy)-6-chloro- N -(3-fluorophenyl)-1,3,5-triazin-2-amine)

[0087] To a stirred solution of acetone (2 mL) containing Cpd. 8 (100 mg, 0.39 mmol), an acetone (1 mL) solution of 4-phenylphenol (66 mg, 0.39 mmol), Na2CO3 (82 mg, 0.77 mmol), and water (1 mL) were added at 0 °C. The reaction mixture was stirred at room temperature for 7 hours and then distributed between dichloromethane and an aqueous solution of Na2CO3 to remove the remaining 4-phenylphenol. After drying with MgSO4, the organic layer was filtered and evaporated under vacuum, and the resulting residue was purified by silica gel column chromatography using dichloromethane as the eluent to obtain the solid Cpd. 10 (123 mg, 81%).

[0088] 1 ¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, 2H, J = 8.0 Hz, 7.61 (d, 2H, J = 7.5 Hz), 7.49 - 7.46 (m, 4H), 7.38 (t, 1H, J = 7.5 Hz), 7.32 - 7.26 (m, 2H), 7.14 (brm, 1H), 6.91 (brd, 1H, J = 7.5 Hz), 6.74 (brt, 1H, J = 8.0 Hz); 13 CNMR(100MHz,CDCl3) δ 189.2, 171.8, 165.0, 163.1 (d, J= 244.9 Hz), 151.3, 140.5, 140.0, 138.3 (d, J = 11.0 Hz), 130.2 (d, J = 8.7 Hz), 129.1, 128.7, 127.7, 127.4, 122.0, 115.4, 111.6 (d, J = 21.7 Hz), 107.9 (d, J = 26.9 Hz).

[0090] (5) Cpd. 2 (6-([1,1'-Biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine)

[0091] A solution of acetic acid (1 mL) containing Cpd. 10 (50 mg, 0.13 mmol) and 3-ethynylaniline (0.02 mL, 0.18 mmol) was refluxed for 24 hours. After cooling to room temperature, water was added to the reaction mixture. The resulting precipitate was filtered and washed with water, and the filter cake was purified by silica gel column chromatography using hexane and ethyl acetate (5:1) as the eluent to obtain the solid Cpd. 2 (29 mg, 48%).

[0092] 1 1H NMR (500 MHz, DMSO- d 6) δ 9.99 (s, 1H, NH), 9.50 (brs, 1H, NH), 7.72 (d, 1H, J = 8.5 Hz), 7.68 (d, 1H, J = 7.0 Hz), 7.54 (d, 2H, J = 8.0 Hz), 7.49 - 7.44 (m, 3H), 7.38 (t, 2H, J = 7.5 Hz), 7.38 - 7.34 (m, 2H), 7.25 (t, 1H, J= 7.5 Hz), 7.24 (brm, 1H), 7.10 (brm, 1H), 6.84 - 6.81 (m, 2H), 6.77 (brm, 1H), 4.08 (brs, 1H, acetylenic H); 13 CNMR(100MHz,DMSO- d 6) δ 171.2, 165.8, 162.8 (d, J = 239.5 Hz), 157.7, 152.3, 140.9, 140.2, 140.0 (d, J = 11.5 Hz), 138.2, 131.6, 130.5 (d, J = 8.5 Hz), 129.7, 129.4, 128.5, 128.4, 128.1, 127.3, 127.0, 126.6, 123.1, 116.3, 109.6 (d, J = 21.7 Hz), 107.7 (d, J = 26.9 Hz), 84.1, 81.2; LRMS (ESI-) m / z 472 (MH) - .

[0094] (6) Cpd. 11 (4,6-Dichloro- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine)

[0095] Trimethylamine (3.78 mL, 27.12 mmol) and 3-(trifluoromethyl)aniline (1.69 mL, 13.58 mmol) were added dropwise at 0 °C to a stirred solution of acetone (100 mL) containing cyanuric chloride (5.00 g, 27.11 mmol), and the reaction mixture was stirred at the same temperature for 1 hour. Cold water was added to the reaction mixture, and the precipitate was filtered and dried to obtain solid Cpd. 11 (3.76 g, 89%).

[0096] 1 ¹H NMR (500 MHz, CDCl₃) δ 7.84 (s, 1H, 2-H), 7.78 (d, 1H, J = 8.0 Hz, 6-H), 7.65 (brs, 1H, NH), 7.55 (t, 1H, J = 7.5 Hz, 5-H), 7.49 (d, 1H, J = 7.5 Hz, 4-H); 13 CNMR(100MHz,CDCl3) δ 170.7, 164.4, 136.6, 132.0 (q, J = 32.5 Hz), 130.2, 124.5 (q, J = 0.8 Hz), 123.7 (q, J = 271.0 Hz), 122.5 (q, J = 3.8 Hz), 118.2 (q, J = 3.9 Hz); LRMS (ESI-) m / z 307 (MH) - ,309(M-H+2) - .

[0098] (7) Cpd. 3 (4,6-Bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine)

[0099] To a stirred solution of acetone (4 mL) containing Cpd. 11 (200 mg, 0.65 mmol), an acetone solution (2 mL) containing 4-phenylphenol (121 mg, 0.71 mmol), Na2CO3 (137 mg, 1.29 mmol), and water (2 mL) were added at 0 °C. The reaction mixture was stirred at room temperature for 30 hours, cold water was added to the reaction mixture, and the precipitate was filtered and purified by silica gel column chromatography using dichloromethane and methanol (70:1) as eluents to produce solid Cpd. 3 (81 mg, 22%), and a monoaryloxy compound (163 mg, 61%) was also obtained as an intermediate.

[0100] 1 ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.69 (s, 1H), 7.63 (d, 4H, J = 8.5 Hz), 7.58 (d, 4H, J = 7.0 Hz), 7.54 - 7.52 (m, 1H), 7.45 (t, 4H, J = 7.5 Hz), 7.37 (t, 2H, J = 7.5 Hz), 7.28 - 7.25 (m, 6H); LRMS (ESI-) m / z 575 (MH) - .

[0102] (8) Cpd. 12 (6-Chloro- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine)

[0103] 1-naphthylamine acetone solution (2 mL), trimethylamine (0.02 mL, 0.16 mmol), and water (2 mL) were added to a stirred solution of acetone (3 mL) containing Cpd. 11 (50 mg, 0.16 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 22 hours and then partitioned with dichloromethane and water. The organic layer was dried with MgSO4, filtered, and then evaporated under vacuum. The resulting residue was purified by silica gel column chromatography using an eluent of hexane and ethyl acetate (5:1) to produce solid Cpd. 12 (48 mg, 71%).

[0104] 1 1H NMR (500 MHz, DMSO- d 6) δ 10.40 (brs, 2H, 2NH), 7.98 - 7.95 (m, 2H), 7.87 (d, 1H, J = 8.5 Hz), 7.59 (d, 1H, J= 7.0 Hz), 7.55 - 7.51 (m, 4H), 7.45 (brm, 1H), 7.16 (brm, 1H), 7.10 (brm, 1H); 13 CNMR(100MHz,DMSO- d 6) δ 169.1, 166.5, 164.4, 140.0, 140.0, 134.5, 133.8, 132.0 (q, J = 32.5 Hz), 130.0, 129.8, 128.8, 127.2, 126.9, 126.8, 126.2, 124.5, 123.9, 123.7 (q, J = 271.0 Hz), 119.7, 116.2; LRMS (ESI+) m / z 416 (M+H) + .

[0106] (9) Cpd. 4 (6-([1,1'-Biphenyl]-3-yloxy)- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine)

[0107] A solution of 3-phenylphenol (23 mg, 0.14 mL) was added to a stirred solution of toluene (2 mL) containing Cpd. 12 (50 mg, 0.12 mmol), Pd(OAc)2 (0.5 mg, 0.002 mmol), and Cs2CO3 (59 mg, 0.18 mmol). The reaction mixture was heated at 90 °C for 5 hours and distributed between dichloromethane and water. The organic layer was dried over MgSO4, filtered, and then evaporated under vacuum. The resulting residue was purified by silica gel column chromatography using dichloromethane as the eluent to produce solid Cpd. 4 (36 mg, 55%).

[0108] 1 1H NMR (500 MHz, DMSO- d 6) δ 9.90 (brs, 2H, 2×NH), 7.99 - 7.93 (m, 2H), 7.82 (d, 1H, J = 7.0 Hz), 7.71 - 7.66 (m, 3H), 7.58 - 7.44 (m, 11H), 7.37 (t, 1H, J = 7.0 Hz), 7.26 (brm, 1H), 7.15 (brm, 1H); 13 CNMR(100MHz,DMSO- d 6) δ 171.4, 168.0, 166.0, 153.4, 142.4, 140.8, 139.9, 134.5, 130.7, 129.9 (q, J = 32.5 Hz), 129.8, 128.7, 128.4, 127.4, 127.3, 126.8, 126.7, 126.2, 124.7, 124.2, 124.0, 123.7 (q, J = 271.0 Hz), 121.6, 120.8, 119.0, 117.5, 116.3; LRMS (ESI+) m / z 550 (M+H) + .

[0110] (10) Cpd. 5 ( N , N '-(((6-((3-(Trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide)

[0111] To acetone (2 mL) containing Cpd. 11 (50 mg, 0.16 mmol), a solution of acetone (1 mL) containing 4-acetamidophenol (54 mg, 0.36 mmol), Na2CO3 (68 mg, 0.64 mmol), and water (1 mL) were added. The reaction mixture was refluxed for 52 hours, cooled to room temperature, and then the reaction mixture was distributed between dichloromethane and water. The organic layer was dried over MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography using dichloromethane methanol (20:1) as the eluent to produce the solid Cpd. 5 (38 mg, 44%).

[0112] 1 1H NMR (500 MHz, DMSO- d 6) δ 10.45 (s, 1H, NH), 10.00 (s, 1H, 2×NHCO), 7.82 (s, 1H, 2′-H), 7.71 (d, 1H, J = 8.0 Hz, 6′-H), 7.61 (brd, 4H, J = 8.5 Hz, 2×2-H, 2×6-H), 7.33 (t, 1H, J = 8.0 Hz, 5′-H), 7.29 (d, 1H, J = 8.0 Hz, 4′-H), 7.17 (d, 4H, J = 8.5 Hz, 2×3-H, 2×5-H), 2.04 (s, 6H, 2×CH3); 13 CNMR(150MHz,DMSO- d 6) δ 172.9, 168.7, 166.5, 147.4, 139.7, 137.6, 129.9, 129.7 (q, J = 31.1 Hz), 124.3 (q, J = 271.2 Hz), 124.3, 122.2, 120.6, 119.9, 116.8, 24.6; LRMS (ESI+) m / z539 (M+H) + ,561(M+Na) + .

[0114] (11) Cpd. 6 (6-(4-(6,7-Dihydro-5 H -indeno[5,6-d]thiazol-2-yl)phenoxy)- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine)

[0115] 4-(6,7-dihydro-5) in acetone (2 mL) containing Cpd. 12 (40 mg, 0.10 mmol) H A 1 mL solution of acetone containing -indeno[5,6-d]thiazol-2-yl)phenol (4-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)phenol; 28 mg, 0.10 mmol), Na2CO3 (40 mg, 0.38 mmol), and water (1 mL) were added. The reaction mixture was refluxed for 52 hours, cooled to room temperature, and then the reaction mixture was distributed between dichloromethane and water. The organic layer was dried, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography using dichloromethane methanol (70:1) as the eluent to produce Cpd. 6 (22 mg, 35%), a white solid.

[0116] 1 1H NMR (500 MHz, DMSO- d 6) δ 9.93 (brs, 2H, 2×NH), 8.13 - 8.06 (m, 2H), 7.99 - 7.94 (m, 3H), 7.91 (s, 1H), 7.87 (s, 1H), 7.83 (d, 1H, J = 8.0 Hz), 7.58 (d, 1H, J = 6.5 Hz), 7.54 - 7.40 (m, 7H), 7.15 (brm, 1H), 2.98 (t, 2H, J = 7.0 Hz), 2.97 (t, 2H, J = 7.0 Hz), 2.09 (quint, 2H,J = 7.5 Hz); 13 CNMR(150MHz,DMSO- d 6) δ 171.0, 167.8, 165.7, 155.6, 154.6, 153.3, 144.0, 142.9, 140.5, 134.3, 134.3, 133.1, 130.8, 129.9, 129.6 (q, J = 30.4 Hz), 129.5, 128.7, 128.5, 128.5, 126.7, 126.6, 126.4, 126.0 (q, J = 21.9 Hz), 124.5, 123.7 (q, J = 6.1 Hz), 123.4 (q, J = 270.2 Hz), 123.3 (q, J = 19.5 Hz), 118.9, 118.6 (q, J = 13.8 Hz), 117.6 (q, J = 12.6 Hz), 116.2, 32.6, 26.3; LRMS (ESI-) m / z 645 (MH) - .

[0118] (12) Cpd. 7 (N-(4-((4-(Naphthalen-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)oxy)phenyl)acetamide)

[0119] To acetone (2 mL) containing Cpd. 12 (50 mg, 0.12 mmol), acetone (2 mL) containing 4-acetamidophenol (28 mg, 0.10 mmol), Na2CO3 (51 mg, 0.48 mmol), and water (1 mL) were added. The reaction mixture was refluxed for 42 hours, cooled to room temperature, extracted with dichloromethane, and the organic layer was dried over MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography using dichloromethane methanol (30:1) as the eluent to produce solid Cpd. 7 (29 mg, 45%).

[0120] 11H NMR (500 MHz, DMSO- d 6) δ 9.97 (s, 1H, NH), 9.86 (brs, 2H, 2×NH), 7.98 - 7.94 (m, 2H), 7.83 (d, 1H, J = 8.5 Hz), 7.61 - 7.56 (m, 4H), 7.53 - 7.49 (m, 4H), 7.35 - 7.12 (m, 4H), 2.05 (s, 3H, COCH3); 13 CNMR(100MHz,DMSO- d 6) δ 171.5, 168.8, 168.0, 165.9, 148.0, 140.8, 137.2, 134.6, 135.5, 130.1, 129.8 (q, J = 31.3 Hz), 129.8, 128.7, 126.8, 126.7, 126.2, 124.7, 124.6 (q, J = 270.2 Hz), 124.0, 122.7, 120.8, 118.9, 116.3, 24.6; LRMS (ESI+) m / z 531 (M+H) + ,553(M+Na) + .

[0122] [Experimental Example 1] Computer Modeling and Docking Simulation

[0123] Computer modeling for the search for novel active substances against discovered key target molecules (Computational modeling) and docking simulation were utilized. Using the SWISS-MODEL website (https: / / swissmodel.expasy.org / ), the protein sequence of PAR2 was converted into a 3D structure based on the 3D structure of PAR1. The compounds to be used for the docking simulation were converted into mol files using Chemsketch software (https: / / www.acdlabs.com / resources / free-chemistry-software-apps / chemsketch-freeware / ), and then converted into file formats (pdb, mol2) suitable for docking simulation using UCSF Chimera software (https: / / www.cgl.ucsf.edu / chimera / ). Finally, to perform the docking simulation, Autodock Vina (https: / / vina.scripps.edu / ) and Autodock 4 ( https: / / autodock.scripps.edu / Three programs were used: ) and Dock6 (https: / / dock.compbio.ucsf.edu / DOCK_6 / index.htm).

[0125] [Experimental Example 2] ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) Analysis

[0126] ADMET analysis was performed to predict the drug suitability of novel active substances. For this analysis, the results were synthesized and summarized using two websites: PreADMET (https: / / preadmet.webservice.bmdrc.org / ) and ADMETlab 2.0 (https: / / admetmesh.scbdd.com / ).

[0128] [Experimental Example 3] Cell Culture

[0129] YPEN-1 endothelial cells, a rat endothelial cell line, were purchased as ATCC (CRL-2222) for the experiment. DMEM nutrient medium containing antibiotics (100 units / mL penicillin, 100 μg / mL streptomycin) and 5% FBS (fetal bovine serum) was purchased from Welgene (Daegu) and used for the experiment in a 37 ℃, 5% CO2 incubator.

[0131] [Experimental Example 4] Confirmation of Cell Survival of PAR2 Antagonists in Mouse Endothelial Cells

[0132] To confirm the toxicity of the triazine derivatives prepared according to the above synthesis example in YPEN-1 mouse endothelial cells, 1×10⁶ were placed in a 96-well culture vessel. 4 After dispensing 100 μL of cells at a cells / well concentration, the cells were treated for 24 hours with each concentration of the derivatives or the positive control (GB83) at concentrations of 0, 2, 5, 10, and 20 μM. Subsequently, 10 μL of EZ-cytox solution (Daeillab, Seoul) was added and incubated for 2 to 3 hours. The inhibitory concentration of cell viability was determined by measuring the absorbance at a wavelength of 450 nm using a microplate reader.

[0134] [Experimental Example 5] Experimental Animals

[0135] (1) LPS-induced inflammation mouse model

[0136] In vivo To confirm the anti-inflammatory activity of Cpd. 1, Cpd. 1 was orally administered to C57BL / 6J mice at a dose of 1 or 5 mg / kg once daily for 3 days. On the 3rd day, 3 hours after oral administration of the drug, the endotoxin LPS (lipopolysaccharide) was administered intraperitoneally, and the mice were euthanized 5 hours later. Organs and blood were collected and analyzed.

[0138] (2) Metabolic diabetes disease model (Diet Induced Obese, DIO) mouse model

[0139] In vivoTo confirm the improvement of metabolic diseases by Cpd. 1, C57BL / 6J mice were fed a free-range high-fat diet (60% fat diet) while Cpd. 1 was orally administered once daily at a dose of 2 or 6 mg / kg for 16 days. After the diet was finished, the mice were euthanized, and their organs and blood were collected and analyzed.

[0141] (3) Obesity / diabetes db / db mouse model

[0142] In vivo To confirm the improvement of diabetic metabolic diseases by Cpd. 1, Cpd. 1 was orally administered at a dose of 2 or 6 mg / kg once daily for 18 days to db / db mice, a genetic obesity animal model in which obesity occurs due to leptin receptor deficiency, while on a free diet. After the diet was finished, the mice were euthanized, and organs and blood were collected and analyzed.

[0144] [Experimental Example 6] RNA isolation, cDNA synthesis, and qRT-PCR (quantitative real-time polymerase chain reaction) analysis

[0145] Total RNA was isolated from mouse tissues and cells treated with Cpd. 1 using Ribo-Ex (GeneAll Biotechnology, Seoul, Korea), and cDNA was synthesized using the Suprime Script RT Premix with random hexamer cDNA Synthesis Kit (GeNet Bio, Daejeon, Korea). To relatively quantify the expression of inflammatory cytokine and chemokine genes induced by Cpd. 1, SensiFAST TM Real-time PCR (CFX-96, Bio-rad, Hercules, CA, USA) analysis was performed using SYBR No-ROX dye (Bioline, London, UK) and gene-specific primers. The expression levels of each gene were corrected for the relative expression levels of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and 2 - ΔΔIt was calculated using the CT method.

[0147] [Experimental Example 7] Western Blot

[0148] Mouse tissues or cells treated with Cpd. 1 were lysed with 30 μL of NP40 buffer (50 mM Tris-HCl pH 8.0, 1% NP40, Triton X-100, 150 mM NaCl, Protease inhibitor cocktail) for 20 minutes, and protein concentrations were measured using a protein assay (BCA protein assay, Pierce, Rockford, IL, USA). Each tissue or cell protein was subjected to 8 to 10% SDS-PAGE (polyacrylamide gel electrophoresis), and the proteins present on the gel were semi-dry transferred to a PVDF membrane (Bio-Rad Laboratories, Hercules, CA, USA) at 25 V for 10 minutes. The membrane was blocked with a 5% skim milk solution at room temperature for 1 hour to prevent non-specific reactions. After that, the primary antibody was reacted overnight at 4°C, and the secondary antibody conjugated with HRP was reacted for 1 hour. Next, color development was performed using the ECL reagent SuperSignal West Pico Chemiluminescent Substrate kit (Advansta, San Jose, CA, USA), and each labeled protein was identified using the Davinch-Chemi imager (Davinch-K, Seoul, Korea).

[0150] [Example 1] Confirmation of anti-inflammatory effects of triazine derivative compounds in vascular endothelial cells

[0151] vascular endothelial cells in vitroFor the study, the toxicity of the triazine derivative compounds synthesized by the above synthesis example was measured. As a result, according to Figure 3, it was confirmed that the triazine derivative compounds did not exhibit cytotoxicity even at the maximum concentration tested, which is 20 μM.

[0152] To confirm the anti-inflammatory activity of triazine derivative compounds, the samples were pretreated with 5 μM of the triazine derivative compound and a previously known PAR2 antagonist (GB83) for 1 hour, followed by treatment with 1 μg / mL of LPS for 3 hours to induce inflammation. Subsequently, the expression of the inflammation-related transcription factor NF-κB and the target pro-inflammatory genes COX-2 and p-p65 was confirmed via Western blot. As a result, according to Figure 4, it was confirmed that the LPS-induced NF-κB phosphorylation and the expression of COX-2 and p-p65 were reduced more by the triazine derivative compound than by GB8.

[0153] To confirm the inhibitory effect of triazine derivative compounds on inflammatory cytokine expression induced by PAR2 activation in vascular endothelial cells (YPEN-1 cells), inflammation was induced with a PAR2 activator after pretreatment with each compound. As a result, according to Figure 5, the expression of inflammatory cytokines was reduced in the group pretreated with triazine derivative compounds.

[0154] Using bioinformatics software to evaluate the pharmacological efficacy of triazine derivative compounds in silicoAnalysis was performed. Table 1 shows the results of predicting the binding strength of PAR2 proteins and derivative compounds using three docking simulation programs (Autodock Vina, Autodock 4, and Dock 6). It was found that most of the derivative compounds bind stably to PAR2, as most of these novel synthetic substances had binding energies similar to the control group when compared to GB83, GB88, and AZ3451, which are known as PAR2 antagonists.

[0155] Docking score (kcal / mol) compound Autodock Vina Autodock 4 Dock6 GB83 (Control) -5.6 -8.65 -32.70 AZ3451(Control) -6.7 -7.56 -36.17 GB88 (Control) -5.5 -8.63 -36.87 Cpd. 1 -6.5 -8.51 -28.50 Cpd. 2 -6.6 -7.72 -30.15 Cpd. 3 -7 -8.15 -26.91 Cpd. 4 -7.9 -8.65 -27.60 Cpd. 5 -6.9 -6.63 -32.88 Cpd. 6 -7 -7.7 -35.29 Cpd. 7 -6.9 -7.67 -29.13

[0157] [Example 2] Anti-inflammatory effect of a triazine derivative compound

[0158] LPS was administered to confirm the anti-inflammatory effect of Cpd. 1 in vivo The anti-inflammatory activity of Cpd. 1 was confirmed in an inflammation model. As a result, according to Figure 6, in the kidneys of the group administered Cpd. 1, a concentration-dependent decrease in protein expression of NF-kB phosphorylation (Figure 5A) and mRNA levels of inflammatory cytokines and chemokines (IL-1β, TNF-α, IL-6, and MCP-1) (Figure 5B) were observed.

[0159] Furthermore, changes in Cpd. 1 inflammatory proteins in vascular endothelial cells were confirmed via Western blot. As shown in Figure 7A, while LPS-induced protein expression of phosphorylated p65 in the cell nucleus and the target pro-inflammatory genes COX-2 and iNOS in the cytoplasm increased, treatment with Cpd. 1 resulted in a concentration-dependent decrease in the expression of phosphorylated p65, COX-2, and iNOS. Additionally, to determine whether Cpd. 1 treatment regulates the expression of LPS-induced NF-κB inflammatory cytokines and chemokines, Western blot and quantitative PCR techniques were used. As a result, according to Figures 7B and 7C, the expression of inflammatory proteins and cytokine and chemokine mRNAs (IL-6, TNF-α, and MCP-1) was reduced in the group treated with Cpd. 1; therefore, Cpd. It was found that 1 is effective in suppressing inflammation.

[0161] [Example 3] Inhibitory effect of triazine derivative compounds on vascular aging

[0162] To confirm the inhibition of vascular aging by Cpd. 1, adhesion molecules, which are markers of vascular aging, were examined at protein and mRNA levels in an LPS-induced inflammatory mouse model and LPS-treated vascular endothelial cells. As a result, according to Figure 8, it was confirmed that the expression of VCAM and ICAM, which was increased by LPS treatment, decreased in a concentration-dependent manner upon administration of Cpd. 1. From these results, it was found that Cpd. 1 is effective in inhibiting vascular aging.

[0164] [Example 4] Regulatory effect of triazine derivative compounds on metabolic diseases

[0165] To confirm the metabolic disease-improving effects of PAR2 inhibitors, the study was conducted in a diet-induced obesity mouse model and an obesity / diabetes db / db mouse model. Figures 9A and 9B show the changes in body weight and the results of the oral glucose tolerance test (GTT) measured during the experiment in the diet-induced obesity mouse model; Cpd. 1 was confirmed to inhibit diet-induced weight gain (Figure 9A) and to increase glucose tolerance (Figure 9B). Figure 9C shows the results of measuring blood insulin, glucose, triglycerides, and total cholesterol; it was confirmed that the levels of insulin, triglycerides, and total cholesterol decreased (Figure 9C). Furthermore, according to Figures 9D and 9E, a weight reduction effect induced by Cpd. 1 was confirmed in the obesity / diabetes db / db mouse model as well, and Cpd. It was confirmed that glucose tolerance increased (Fig. 9E), and Cpd. 1 reduced blood total cholesterol, insulin, and triglyceride levels (Fig. 9F). From the above results, it was determined that Cpd. 1 contributes to the improvement of metabolic syndrome.

[0166] In the metabolic disease diet-induced obesity mouse model and the db / db mouse model, Cpd.1 was administered at a daily dose of 2 or 6 mg / kg during the experimental period of the example, while the control drug empagliflozin was administered at a dose of 10 mg / kg and metformin at a dose of 200 mg / kg; therefore, it was determined that Cpd.1 contributed to the improvement of metabolic syndrome more effectively than the control drugs used in the experiment.

[0167] To investigate the molecular mechanism of the body weight-loss effect of Cpd. 1 in a metabolic disease (obesity / diabetes) db / db mouse model, protein and mRNA expression were examined in liver tissue. As a result, according to Figure 10, Cpd. 1 increased the expression of IRS tyrosine 632 phosphate groups and AKT phosphorylation in a concentration-dependent manner, while decreasing the expression of IRS serine 307 phosphate groups. Additionally, the expression of ACC and FAS, genes related to lipid synthesis, was reduced by the administration of Cpd. 1. Furthermore, in kidney tissue, it was confirmed that the expression of p65 phosphate groups, an inflammatory protein, in the cell nucleus was reduced by the administration of Cpd. 1. Moreover, by confirming that the mRNA expression of MCP-1, E-selectin, and VCAM, markers of vascular aging, was reduced by Cpd. 1, it was found that Cpd. 1 is effective in inhibiting inflammation and vascular aging, as well as improving metabolic syndrome.

[0169] [Example 5] Fibrosis-regulating effect of triazine derivative compounds

[0170] To confirm the fibrosis-inhibiting effect of Cpd. 1, mRNA levels of fibrosis markers (CCL5, VIM, α-SMA, TGF1β, Col3a1, and Col4a1) were examined in the liver (Fig. 11A) and kidney tissues (Fig. 11B) of a metabolic disease db / db mouse model. As a result, according to Figs. 11A and 11B, Cpd. 1 reduced the expression of these fibrosis markers in liver and kidney tissues; thus, it was found that Cpd. 1 is effective in improving liver and kidney fibrosis caused by obesity and diabetes.

[0171] In addition, mRNA levels of fibrosis markers (α-SMA, TGF1β, Col1a2, Col3a1) were examined in liver tissue (Fig. 11C) of a diet-induced obesity mouse model of metabolic disease with Cpd. 1. As a result, according to Fig. 11C, Cpd. 1 reduced the expression of these fibrosis markers in the liver tissue of the diet-induced obesity mouse model, indicating that Cpd. 1 is effective in improving liver fibrosis caused by metabolic diabetes.

[0173] [Example 6] Triazine derivative compound in silico Analysis results

[0174] Based on the docking simulation results, the pharmacophore predicting the binding between PAR2 and Cpd. 1 was analyzed. According to Figures 12A and 12B, it was confirmed that Cpd. 1 forms a total of three hydrogen bonds with the Val154 (one hydrogen bond) and Asp153 (two hydrogen bonds) residues of the PAR2 protein, and that GB83 binds to one hydrogen bond residue (Ser245) of PAR2.

[0175] Molecular Dynamics (MD) were analyzed using the complex structure of PAR2 and Cpd. 1. Through MD analysis, the Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and the number of hydrogen bonds were determined. As a result, according to Figures 12C, 12D, and 12E, although Cpd. 1 had a higher RMSD value than GB83, it maintained that value stably (Figure 12D), indicating that Cpd. 1 maintains a relatively stable state when complexed with PAR2. In the case of RMSF as well, the variability of GB83 and Cpd. 1 at each amino acid residue of PAR2 was generally similar (Figure 12C). This indicated that Cpd. 1 can perform a function similar to GB83 when bound to PAR2. Furthermore, Cpd. compared to GB83 As it was shown that the number of hydrogen bonds of 1 was greater over most of the running time (Fig. 12E), this was consistent with the pharmacophore analysis. From the above results, it was found that Cpd. 1 binds more strongly to PAR2 than GB83.

[0176] To determine the drug suitability of Cpd. 1, ADMET was analyzed using the ADMETlab 2.0 website (https: / / admetmesh.scbdd.com / ). As a result, according to Table 2, Cpd. 1 possesses physicochemical properties similar to GB83, passed the drug-likeness criteria of the Lipinski Rule and Pfizer Rule, and showed values ​​equal to or slightly better than GB83 in terms of toxicity. In conclusion, in silicoWhen synthesizing the analysis, it was found that Cpd. 1 is an inhibitor that binds to and acts on PAR2, and compared to existing drugs, it has the potential to have better efficacy and safety.

[0177] characteristic GB83 Cpd. 1 1. Physical and chemical properties molecular weight 548.34 499.18 van der Waals volume 577.302 518.415 density 0.95 0.963 Number of hydrogen bond receptors 8 6 Number of hydrogen bond donors 2 2 Rotatable number of couplings 12 5 Number of ring structures 5 6 Number of atoms in the largest ring structure 9 10 Number of heteroatoms 8 7 Formal charge 0 0 2. Medicinal Chemistry Lipinski Rules refusal reception Pfizer Rules reception reception 3. Absorption Caco-2 cell permeability (Log unit) -4.945 -3.864 MDCK cell penetration (cm / s) 1.68E-05 4.99E-05 Pgp-inhibition probability 0.98 0.161 Pgp-Substrate Probability 0.044 0.021 Human intestinal absorption rate (%) 0.4 5.5 30% biological activity rate 0.838 0.115 4. Distribution Plasma protein binding (%) 98.19 100.50 Distribution volume (L / kg) 0.848 1.278 BBB passing probability 0.082 0.034 Fu (Plasma free drug fraction %) 0.55 0.64 5. Dialogue CYP1A2 inhibition probability 0.051 0.761 CYP1A2-Substrate Probability 0.499 0.559 CYP2C19 inhibition probability 0.747 0.913 CYP2C19-Substrate Probability 0.087 0.05 CYP2C9 inhibition probability 0.933 0.505 CYP2C9-Substrate Probability 0.443 0.012 CYP2D6 inhibition probability 0.64 0.029 CYP2D6-Substrate Probability 0.342 0.002 CYP3A4 inhibition probability 0.955 0.976 CYP3A4-Substrate Probability 0.268 0.933 6. Emissions Excretion value (mL / min / kg) 2.479 3.827 T1 / 2 (half-life) 0.094 0.078 7. Toxicity hERG blocker probability 0.642 0.868 Human hepatotoxicity probability 0.7 0.999 Probability of drug-induced liver damage 0.672 0.98 Ames toxicity probability 0.024 0.866 Probability of acute oral toxicity in rats 0.994 0.173 FDAMDD (Maximum Recommended Daily Dose) Probability 0.908 0.897 Probability of skin sensitization 0.047 0.529 Carcinogenicity probability 0.137 0.528 Eye corrosiveness probability 0.003 0.003 Eye irritation probability 0.007 0.031 Probability of respiratory toxicity 0.262 0.088 8. Environmental toxicity Bioaccumulation factor (-log10[(mg / L) / (1000*MW)]) 1.087 2.665 IGC50 (-log10[(mg / L) / (1000*MW)]) 3.784 5.378 LC50 (-log10[(mg / L) / (1000*MW)]) 4.794 5.818 LC50DM (-log10[(mg / L) / (1000*MW)]) 5.221 6.126 9. Tox21 (Next Generation Stability Assessment) Path NR (nuclear receptor)-AR probability 0.019 0.205 NR-AR-LBD probability 0.004 0.011 NR-ER-LBD probability 0.065 0.309 NR-PPAR-gamma probability 0.929 0.011 SR-ATAD5 probability 0.018 0.061 SR-HSE (Thermal Shock Coefficient Response Factor) Probability 0.647 0.002 10. Toxicogen Rules Acute Toxicology Rules 0 alerts 0 alerts skin sensitivity 1 alerts 0 alerts SureChEMBL 0 alerts 0 alerts

Claims

Claim 1 delete Claim 2 A compound selected from triazine derivative compounds represented by the following chemical formula 2, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof: [Chemical Formula 2] In the above chemical formula 2, L 2 and L 3 Each may be the same or different, and is O or NH, and R 1 is fluorine (F) or trifluoromethyl (CF3), and R 2 is hydrogen (H), and R 3 It is ethinyl (-C≡CH), -NHC(O)CH3, phenyl, and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 2 and R 3 They can combine with each other to form a benzene ring, and R 4 is hydrogen (H), and R 5 is ethinyl(-C≡CH), -NHC(O)CH3, phenyl, and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 4 and R 5 A compound selected from triazine derivative compounds characterized by being able to bond with each other to form a benzene ring, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof. Claim 3 In claim 2, in the formula 2, R 1 is fluorine (F) or trifluoromethyl (CF3), and R 2 is hydrogen (H), and R 3 -NHC(O)CH3, phenyl and 6,7-dihydro-5 H -Indeno[5,6-d]thiazole (6,7-dihydro-5 H -indeno[5,6-d]thiazol) either one of these; R 2 and R 3 They can combine with each other to form a benzene ring, and R 4 is hydrogen (H), and R 5 is any one of ethinyl (-C≡CH), -NHC(O)CH3 and phenyl; R 4 and R 5 A compound selected from triazine derivative compounds characterized by being able to bond with each other to form a benzene ring, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof. Claim 4 In claim 2, the triazine derivative compound is 6-chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalene-1-yl)-1,3,5-triazine-2,4-diamine [6-Chloro- N 2 -(3-fluorophenyl)- N 4 -(naphthalen-1-yl)-1,3,5-triazine-2,4-diamine], 6-([1,1'-biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine [6-([1,1'-Biphenyl]-4-yloxy)- N 2 -(3-ethynylphenyl)- N 4 -(3-fluorophenyl)-1,3,5-triazine-2,4-diamine], 4,6-bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2-amine [4,6-Bis([1,1'-biphenyl]-4-yloxy)- N -(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine], 6-([1,1'-biphenyl]-3-yloxy)- N 2 -(Naphthalene-1-il)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-([1,1'-Biphenyl]-3-yloxy)- N 2 -(naphthalen-1-yl)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine], N , N '-(((6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide [ N , N '-(((6-((3-(Trifluoromethyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))diacetamide], 6-(4-(6,7-dihydro-5 H -Indeno[5,6-d]thiazole-2-yl)phenoxy)- N 2 -(Naphthalene-1-il)- N 4 -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine [6-(4-(6,7-Dihydro-5 H -indeno[5,6-d]thiazol-2-yl)phenoxy)- N 2 -(naphthalen-1-yl)- N 4 A compound selected from a triazine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, characterized by being selected from either -(3-(trifluoromethyl)phenyl)-1,3,5-triazine-2,4-diamine] and N-(4-((4-(naphthalen-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-yl)oxy)phenyl)acetamide [N-(4-((4-(Naphthalen-1-ylamino)-6-((3-(trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)oxy)phenyl)acetamide]. Claim 5 Claim 2, wherein the compound is a triazine derivative compound characterized as being a PAR2 (Protease-activated receptor 2) antagonist, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, selected from the group. Claim 6 A pharmaceutical composition for the treatment or prevention of fibrosis comprising a compound selected from a triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, wherein the fibrosis is fibrosis of the liver or kidney. Claim 7 A pharmaceutical composition for treating or preventing fibrosis according to claim 6, wherein the fibrosis is any one of fibrosis induced by a solid tumor, metabolic disease-induced fibrosis, NAFLD-induced fibrosis, NASH-induced fibrosis, alcohol-induced fibrosis, drug-induced fibrosis, parasitic infection-induced fibrosis, bacterial infection-induced fibrosis, viral infection-induced fibrosis, HBV-induced fibrosis, HCV-induced fibrosis, HIV-induced fibrosis, dual HCV and HIV-induced fibrosis, radiation or chemotherapy-induced fibrosis, and fibrosis caused by chronic cholestasis. Claim 8 A pharmaceutical composition for treating or preventing fibrosis according to claim 7, wherein the solid tumor is any one of breast cancer, lung cancer, thyroid cancer, colorectal cancer, and prostate cancer. Claim 9 A pharmaceutical composition for the treatment or prevention of fibrosis according to claim 7, wherein the drug is any one of thioacetamide, dimethylnitrosamine, triclosan, and carbon tetrachloride. Claim 10 A pharmaceutical composition for the treatment or prevention of inflammatory diseases as a PAR2 antagonist comprising a compound selected from the triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof. Claim 11 A pharmaceutical composition for treating or preventing inflammatory diseases according to claim 10, wherein the inflammatory disease is any one of hepatitis, nephritis, vascular aging caused by inflammation, asthma, bronchitis, sepsis, rheumatoid arthritis, osteoarthritis, ulcerative colitis, myocarditis, and multiple sclerosis. Claim 12 A pharmaceutical composition for treating or preventing inflammatory diseases according to claim 11, wherein the hepatitis is one of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced hepatitis, alcohol-induced hepatitis, or immune system dysfunction-mediated hepatitis. Claim 13 A pharmaceutical composition for treating or preventing inflammatory diseases according to claim 11, wherein the nephritis is one of drug-induced nephritis, alcohol-induced nephritis, or immune system dysfunction-mediated nephritis. Claim 14 A pharmaceutical composition for the treatment or prevention of metabolic diseases comprising a compound selected from the triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof. Claim 15 A pharmaceutical composition for treating or preventing a metabolic disease according to claim 14, wherein the metabolic disease is any one of dyslipidemia, recurrent stenosis, syndrome X, metabolic syndrome, diabetes mellitus, obesity, hypertension, and familial intrahepatic cholestasis type 3 (PFIC3). Claim 16 A health functional food composition for the prevention or improvement of fibrosis comprising a compound selected from the triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof. Claim 17 An anti-inflammatory health functional food composition comprising a compound selected from the triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, as a PAR2 antagonist for regulating an inflammatory response. Claim 18 A health functional food composition for improving vascular aging comprising a compound selected from the triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof. Claim 19 A health functional food composition for the prevention or improvement of metabolic diseases comprising a compound selected from the triazine derivative compound of claim 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

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