Thiadiazole compound and pharmaceutical composition for preventing or treating inflammatory disease comprising same

Abstract

The present disclosure relates to: a novel thiadiazole derivative compound; and a pharmaceutical composition for preventing or treating inflammatory diseases, said composition comprising the novel thiadiazole derivative compound as an active ingredient. The compound according to one embodiment is an effective PPAR [delta] agonist, which can effectively inhibit the generation of inflammatory factors and nitric oxide and effectively prevent infiltration of macrophages into an inflammatory site, and thus can be effectively used as a pharmaceutical composition for preventing or treating inflammatory diseases.

Description

Technical Field

[0001] The present disclosure relates to a thiadiazole compound and a pharmaceutical composition comprising the compound for preventing or treating inflammatory diseases. Background Art

[0002] Peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptor ligand-activated transcription factors. According to their ligand specificity, physiological effects and tissue distribution, PPARs are divided into three types: PPARα, PPARγ and PPARδ. In particular, PPARδ (also referred to as PPARβ) is one of the PPAR transcription factors that are crucial to a variety of biological functions, and unlike PPARα and PPARγ, PPARδ is widely expressed. Therefore, its function and application in the field of drug development are the least understood in PPARs. However, since the discovery of high-affinity PPARδ agonists such as GW0742 and GW501516, some researchers have studied the role of PPARδ in diseases (such as obesity and diabetes and cancer, nervous system diseases, inflammation, dyslipidemia, heart disease and liver disease). Summary of the invention Technical Purpose

[0003] One embodiment aims to provide a novel thiadiazole derivative compound.

[0004] Another embodiment is directed to providing a pharmaceutical composition for preventing or treating an inflammatory disease, wherein the pharmaceutical composition comprises a thiadiazole derivative compound.

[0005] Another embodiment is to provide a health functional food composition for preventing or improving inflammatory diseases, wherein the health functional food composition comprises a thiadiazole derivative compound.

[0006] Another embodiment is directed to a method for treating an inflammatory disease, comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0007] Another embodiment is directed to providing a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in treating inflammatory diseases.

[0008] Another embodiment is to provide use of the compound, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof in preparing a medicament for treating inflammatory diseases. Technical Solution

[0009] One embodiment provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof.

[0010] [Chemical formula 1]

[0011]

[0012] In Chemical Formula 1,

[0013] R 1 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 Haloalkoxy;

[0014] R 2 Each independently is -H, C 1-5 Alkyl or -OR 21 ,

[0015] Among them, R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or

[0016] Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and

[0017] R 214 -H or C 1-5 Alkyl; and

[0018] x and y are each independently an integer of 1 to 5.

[0019] Another embodiment provides a pharmaceutical composition for preventing or treating an inflammatory disease, the pharmaceutical composition comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] Another embodiment provides a health functional food composition for preventing or improving inflammatory diseases, the health functional food composition comprising the compound represented by Chemical Formula 1, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] Another embodiment provides a method for treating an inflammatory disease, comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0022] Another embodiment provides a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in treating inflammatory diseases.

[0024] *Another embodiment provides use of the compound, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an inflammatory disease. Beneficial Effects

[0025] The present disclosure relates to a novel thiadiazole derivative compound and a pharmaceutical composition for preventing or treating inflammatory diseases comprising the same as an active ingredient. According to one embodiment, the compound is an effective PPARδ agonist, which can effectively inhibit the production of inflammatory factors and nitric oxide and effectively prevent the infiltration of macrophages into inflammatory sites, and can therefore be effectively used as a pharmaceutical composition for preventing or treating inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a graph showing the results of analyzing the cytotoxicity of the compound of Example 1.

[0027] Figure 2 This is a graph showing the results of analyzing the nitric oxide (NO) production inhibitory effect of the compound of Example 1.

[0028] Figure 3 This is a graph showing the results of analyzing the NO synthase iNOS protein expression inhibitory effect of the compound of Example 1.

[0029] Figure 4 This is a graph showing the results of analyzing the inhibitory effect of the compound of Example 1 on the production of inflammatory factors TNF-α and IL-6.

[0030] Figure 5 This is a graph showing the results of analyzing the inhibitory effect of the compound of Example 1 on the activity of inflammatory factor NF-κ.

[0031] Figure 6 This is a graph showing the results of analyzing the effect of the compound of Example 1 on reducing the expression of p-IKKαβ protein involved in inflammation.

[0032] Figure 7 FIG. 5 is a graph showing the process of a macrophage tracking experiment using the compound of Example 1. FIG.

[0033] Figure 8 and Fig. 9 This is a graph showing the results of analyzing the macrophage infiltration inhibitory effect of the compound of Example 1 using mice in which acute inflammation was induced. DETAILED DESCRIPTION

[0034] The embodiments described herein may be modified into various other forms, and the technology according to one embodiment is not limited to the embodiments described below. In addition, an example of an embodiment is provided in order to explain the present disclosure more comprehensively to a person having general knowledge in the relevant technical field. In addition, unless otherwise explicitly stated, throughout the specification, "comprising / including / including" a certain element means that other elements may be further included, rather than excluding other elements.

[0035] As used herein, numerical ranges include lower and upper limits and all values ​​within the range, increments logically derived from the shape and breadth of the defined range, all double defined values, and all possible combinations of upper and lower limits of numerical ranges defined in different forms. As an example, if the content of the composition is defined as 10% to 80% or 20% to 50%, then the numerical range of 10% to 50% or 50% to 80% should also be interpreted as described herein. Unless otherwise specified herein, values ​​outside the numerical range that may appear due to experimental errors or numerical rounding are also included in the defined numerical range.

[0036] Hereinafter, unless otherwise specified herein, "about" may be considered a value within 30%, 25%, 20%, 15%, 10% or 5% of a specified value.

[0038] One embodiment provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof.

[0039] [Chemical formula 1]

[0040]

[0041] In Chemical Formula 1,

[0042] R 1 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 Haloalkoxy;

[0043] R 2 Each independently is -H, C 1-5 Alkyl or -OR 21 ,

[0044] Among them, R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or

[0045] Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and

[0046] R 214 -H or C 1-5 Alkyl; and

[0047] x and y are each independently an integer of 1 to 5.

[0048] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 2 below.

[0049] [Chemical formula 2]

[0050]

[0051] In chemical formula 2,

[0052] R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy;

[0053] R 22 -H or C 1-5 Alkyl; and

[0054] R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or

[0055] Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and

[0056] R 214 -H or C 1-5 alkyl.

[0057] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 3 below.

[0058] [Chemical formula 3]

[0059]

[0060] In chemical formula 3,

[0061] R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy;

[0062] R 211 and R 212 Each is independently -H or C 1-5 Alkyl; and

[0063] R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 alkyl.

[0064] In one embodiment, R 1 , R 11 , R 12 and R 13 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3, C 1-4 Haloalkyl, C 1-3 Haloalkyl, C 1-2 Haloalkyl, C1 haloalkyl, -CF3, C 1-4 Halogenated alkoxy, C 1-3 Halogenated alkoxy, C 1-2 Haloalkoxy, C1 haloalkoxy or -OCF3.

[0065] In one embodiment, R 2 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0066] In one embodiment, R 21 Can be cyano C 1-4 Alkyl, cyano C 1-3 Alkyl, cyano C 1-2 Alkyl, heteroaryl C containing 5 to 6 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-4 Alkyl, heteroaryl C containing 5 to 6 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-3 Alkyl, heteroaryl C containing 5 to 6 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-2 alkyl, heteroarylC1alkyl of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0067] In one embodiment, R 211 and R 212 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0068] In one embodiment, R 214 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0069] In one embodiment, x and y may each independently be an integer of 1 to 4 or an integer of 1 to 3.

[0070] In one embodiment, the compound represented by Chemical Formula 1 may be any one selected from the following compound group.

[0071] (1) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0072] (2) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0073] (3) 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0074] (4) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile;

[0075] (5) 2-(((4-((2H-tetrazolyl-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole;

[0076] (6) N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0077] (7) N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0078] (8) N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0079] (9) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0080] (10) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0081] (11) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0082] (12) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0083] (13) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0084] (14) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0085] (15) 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0086] (16) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0087] (17) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0088] (18) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0089] (19) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0090] (20) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0091] (21) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0092] (22) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0093] (23) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0094] (24) 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0095] (25) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0096] (26) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; and

[0097] (27) 2-Methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid.

[0098] In one embodiment, the compound represented by Chemical Formula 1 can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed from a pharmaceutically acceptable free acid is useful. Acid addition salts can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These types of pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioic acid salt, hexane-1,6-dioic acid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0099] One embodiment includes not only the compound represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof, but also a solvate, an optical isomer, a hydrate, and the like that can be prepared therefrom.

[0101] One embodiment provides a pharmaceutical composition for preventing or treating an inflammatory disease, the pharmaceutical composition comprising a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0102] [Chemical formula 1]

[0103]

[0104] In Chemical Formula 1,

[0105] R 1 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 Haloalkoxy;

[0106] R 2 Each independently is -H, C 1-5 Alkyl or -OR 21 ,

[0107] Among them, R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or

[0108] Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and

[0109] R 214 -H or C 1-5 Alkyl; and

[0110] x and y are each independently an integer of 1 to 5.

[0111] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 2 below.

[0112] [Chemical formula 2]

[0113]

[0114] In chemical formula 2,

[0115] R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy;

[0116] R 22 -H or C 1-5 Alkyl; and

[0117] R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or

[0118] Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and

[0119] R 214 -H or C 1-5 alkyl.

[0120] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 3 below.

[0121] [Chemical formula 3]

[0122]

[0123] In chemical formula 3,

[0124] R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy;

[0125] R 211 and R 212 Each is independently -H or C 1-5 Alkyl; and

[0126] R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 alkyl.

[0127] In one embodiment, R 1 , R 11 , R 12 and R 13 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3, C 1-4 Haloalkyl, C1-3 Haloalkyl, C 1-2 Haloalkyl, C1 haloalkyl, -CF3, C 1-4 Halogenated alkoxy, C 1-3 Halogenated alkoxy, C 1-2 Haloalkoxy, C1 haloalkoxy or -OCF3.

[0128] In one embodiment, R 2 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0129] In one embodiment, R 21 Can be cyano C 1-4 Alkyl, cyano C 1-3 Alkyl, cyano C 1-2 Alkyl, heteroaryl C containing 5 to 6 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-4 Alkyl, heteroaryl C containing 5 to 6 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-3 Alkyl, heteroaryl C containing 5 to 6 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-2 alkyl, heteroarylC1alkyl of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0130] In one embodiment, R 211 and R 212 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0131] In one embodiment, R 214 Can be independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0132] In one embodiment, x and y may each independently be an integer of 1 to 4 or an integer of 1 to 3.

[0133] In one embodiment, the compound represented by Chemical Formula 1 may be any one selected from the following compound group.

[0134] (1) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0135] (2) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0136] (3) 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0137] (4) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile;

[0138] (5) 2-(((4-((2H-tetrazolyl-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole;

[0139] (6) N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0140] (7) N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0141] (8) N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0142] (9) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0143] (10) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0144] (11) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0145] (12) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0146] (13) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0147] (14) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0148] (15) 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0149] (16) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0150] (17) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0152] *(18) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0153] (19) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0154] (20) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0155] (21) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0156] (22) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0158] *(23) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0159] (24) 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0160] (25) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0161] (26) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; and

[0162] (27) 2-Methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid.

[0163] In one embodiment, the inflammatory disease is not particularly limited as long as it is an inflammatory disease. Examples of inflammatory diseases include, but are not limited to, inflammatory bowel disease, osteoarthritis, bronchitis, rheumatoid arthritis, degenerative arthritis, asthma, atopy, diabetes, myocardial infarction, Crohn's disease, or psoriasis.

[0164] The compound represented by Chemical Formula 1 or its pharmaceutically acceptable salt can be administered by various oral and parenteral preparations during clinical administration. In terms of preparations, commonly used diluents or excipients (such as fillers, extenders, adhesives, wetting agents, disintegrants and surfactants) are used to prepare. Solid preparations for oral administration include tablets, pills, acid agents, granules and capsules, etc., and such solid preparations can be prepared by mixing at least one or more excipients (such as starch, calcium carbonate, sucrose, lactose and gelatin) in addition to one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents (such as water and liquid paraffin), various excipients such as wetting agents, sweeteners, aromatics and preservatives may also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions and emulsions. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils (eg, olive oil), and injectable esters (eg, ethyl oleate) can be used.

[0165] The pharmaceutical composition comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

[0166] At this time, in order to prepare a preparation for parenteral administration, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water and a stabilizer or a buffer to prepare a solution or suspension, which can be prepared in the form of a unit dose of an ampoule or a vial. The composition may be sterile and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts and / or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation or coating methods.

[0167] Preparations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, lozenges, etc., and in addition to the active ingredient, such preparations also contain diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silicon dioxide, talc, stearic acid and its magnesium salt or calcium salt and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, etc., and, depending on the circumstances, may contain disintegrants such as starch, agar, alginic acid or its sodium salt, etc., or effervescent mixtures and / or absorbents, colorants, flavorings and sweeteners.

[0169] One embodiment provides a health functional food composition for preventing or improving an inflammatory disease, the health functional food composition comprising a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.

[0170] The compound represented by Chemical Formula 1 according to one embodiment can be directly added to food, or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined according to the purpose of use (prevention or improvement). In general, the amount of the above-mentioned compound in health food can be 0.1 parts by weight to 90 parts by weight of the total weight of the food. However, in the case of long-term intake for health and hygiene purposes or health management, the amount may be lower than the above range, and since there is no problem in terms of safety, the active ingredient can be used in an amount exceeding the above range.

[0171] In addition, the health functional food composition according to one embodiment has no particular limitation on other ingredients except the above-mentioned compounds, and may contain various flavoring agents or natural carbohydrates as additional ingredients like ordinary beverages.

[0172] In addition, it may contain various nutrients, vitamins, minerals (electrolytes), flavorings (such as synthetic flavorings and natural flavorings), coloring agents and fillers (cheese, chocolate, etc.), pectin acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0174] One embodiment provides a method for treating an inflammatory disease, the method comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0175] One embodiment provides a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in treating an inflammatory disease.

[0176] One embodiment provides use of the compound, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an inflammatory disease. Example

[0177] Hereinafter, embodiments and experimental examples will be described in detail. However, the embodiments and experimental examples described below are only for illustration, and the technology described in this specification is not limited thereto.

[0179] <Example 1> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0180] Step 1: Preparation of 4-(trifluoromethyl)benzoylhydrazide (b-1)

[0181]

[0182] Ethyl 4-(trifluoromethyl)benzoate (2.033 mL, 11.46 mmol) was dissolved in MeOH (10 mL), hydrazine hydrate (1.671 mL, 27.5 mmol) was added at 0°C, and stirred at 25°C for 5 hours, and then at 70°C for 1 hour. After the reaction was completed, cold water was added to solidify it to obtain compound b-1 (2.21 g, 10.83 mmol).

[0183] Step 2: Preparation of ethyl 2-oxo-2-(2-(4-(trifluoromethyl)benzoyl)hydrazino)acetate (c-1)

[0184]

[0185] Compound b-1 (2.21 g, 10.83 mmol) was dissolved in dichloromethane (20 mL), TEA (1.521 mL, 10.83 mmol) was added dropwise at 0 ° C, and then ethyl 2-chloro-2-oxoacetate (1.210 mL, 10.83 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with water, extracted with dichloromethane, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound c-1 (2.8 g, 85% yield). It can be used in the next step without further purification.

[0186] Step 3: Preparation of ethyl 5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-1)

[0187]

[0188] Compound c-1 (1 g, 3.29 mmol) was dissolved in THF (1 mL), Lawesson's reagent (1.99 g, 4.93 mmol) was added, and the mixture was heated at 55° C. for 12 hours. After the reaction was completed, it was filtered through celite, washed with NaHCO3, and the organic layer was dried over anhydrous MgSO4. The resulting residue was concentrated under reduced pressure and purified by MPLC (silica gel, 0-25%, EtOAc / hexane) to give compound d-1 (0.88 g, 89% yield).

[0189] ESI LC / MS: m / z calculated for C 12 H 10 F3N2O2S[M+H] + :303.04; measured value 303.1. 1 H NMR (CD3OD, 400MHz) δ8.31 (d, J = 7.2Hz, 2H), 7.91 (d, J = 7.44Hz, 2H), 4.55 (q, J = 6.64Hz, 2H), 1.47 (t, J = 6.1Hz, 3H).

[0190] Step 4: Preparation of 5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-1)

[0191]

[0192] Compound d-1 (0.8 g, 2.64 mmol) was dissolved in methanol, sodium borohydride (0.31 g, 7.94 mmol) was slowly added at 0°C, and then stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with NH4Cl aqueous solution, concentrated under reduced pressure, extracted with ethyl acetate, and dried over anhydrous Na2SO4. The resulting residue was concentrated under reduced pressure, purified by MPLC (silica gel, 5-30%, EtOAc / hexane), and concentrated under reduced pressure to obtain compound e-1 (0.61 g, 89% yield) as a light yellow solid.

[0193] ESI LC / MS: m / z calculated for C 10 H8F3N2OS[M+H] + :261.03; measured value 261.11. 1 H NMR (CD3OD, 400MHz) δ8.19 (d, J = 8.12Hz, 2H), 7.86 (d, J = 8.24Hz, 2H), 5.03 (s, 2H). 13 C NMR(CD3OD,100MHz)174.77,167.79,133.38,132.17,128.06,127.63,126.03,125.91,122.49,58.61.

[0194] Step 5: Preparation of 2-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (f-1)

[0195]

[0196] Compound e-1 (1 g, 3.84 mmol) was dissolved in CH2Cl2 (10 mL), then triphenylphosphine (1.2 g, 4.61 mmol) and isothiocyanate (NCS) (0.616 g, 4.61 mmol) were added, and then stirred at room temperature for 2 hours. After the reaction was completed, it was washed with water and saline, and dried over anhydrous MgSO4. Volatiles were removed by concentrating under reduced pressure, and the resulting residue was purified by MPLC (silica gel, 0-20%, EtOAc / hexane) to obtain compound f-1 (0.203 g, 19% yield).

[0197] ESI LC / MS: m / z calculated for C 10 H7ClF3N2S[M+H] + :279.01; measured value 279.1. 1 H NMR (CD3OD, 400MHz) δ8.22 (d, J = 8.12Hz, 2H), 7.87 (d, J = 8.24Hz, 2H), 5.17 (s, 2H). 13C NMR (CD3OD, 100MHz) δ169.38,168.29,133.05,132.48,128.20,128.06,125.98,125.14,122.45,37.42.

[0198] Step 6: Preparation of 2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-1)

[0199]

[0200] 4-mercapto-2-methylphenol (0.27 g, 1.97 mmol) was dissolved in acetonitrile (8 mL), and then cesium carbonate (0.64 g, 1.97 mmol) and compound f-1 (0.5 g, 1.97 mmol) were added, and then stirred at room temperature for 2 hours. After the solvent was removed by concentration under reduced pressure, it was extracted with ethyl acetate and dried over anhydrous Na2SO4. The obtained residue was concentrated under reduced pressure, purified by MPLC (silica gel, 5-20%, EtOAc / hexane), and concentrated under reduced pressure to obtain compound g-1 (0.64 g, 85% yield).

[0201] ESI LC / MS: m / z calculated for C 17 H 14 F3N2OS2[M+H] + : 383.04; measured value 383.1. 1 H NMR(DMSO-d6,400MHz)δ9.63(s,1H),8.15(d,J=8.12Hz,2H),7.91(d,J=8.28Hz,2H),7 .20(s,1H),7.09(d,J=8.24Hz,1H),6.71(d,J=8.28Hz,2H),4.57(s,2H),2.06(s,3H). 13 C NMR (DMSO-d6, 100MHz) δ171.03,167.61,156.28,135.19,133.72,131.59,128.85,126.86,126.83,125.71,121.19,115.81,34.02,16.28.

[0202] Step 7: Preparation of methyl 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetate (h-1)

[0203]

[0204] Compound g-1 (0.3 g, 0.78 mmol) was dissolved in acetonitrile (5 mL), cesium carbonate (0.38 g, 1.17 mmol) and methyl 2-bromoacetate (0.9 mL, 0.94 mmol) were added dropwise, and then stirred at room temperature for 1 hour and 30 minutes. After the reaction was completed, it was concentrated under reduced pressure to remove acetonitrile, washed with water and saline, extracted with EtOAc, and dried over anhydrous Na2SO4. The obtained residue was concentrated under reduced pressure, purified by MPLC (silica gel, 5-20%, EtOAc / hexane), and concentrated under reduced pressure to obtain compound h-1 (0.32 g, 96% yield).

[0205] Step 8: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (1)

[0206]

[0207] Compound h-1 (0.32 g, 0.7 mmol) was dissolved in tetrahydrofuran, 2M lithium hydroxide aqueous solution (1.5 mL) was added at 0°C, and then stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with water and acidified with 1N HCl. Subsequently, it was concentrated under reduced pressure to remove the solvent, extracted with EtOAc, and dried over anhydrous Na2SO4 to obtain compound 1 (0.25 g, yield 93%).

[0208] ESI LC / MS: m / z calculated for C 19 H 16 F3N2O3S2[M+H] + :441.06; measured value 441.1. 1 H NMR(DMSO-d6,400MHz)δ8.14(d,J=8.08Hz,2H),7.88(d,J=8.2Hz,2H),7.28(s,1H),7.21 (dd,J=8.44,1.92Hz,1H),6.77(d,J=8.56Hz,1H),4.67(s,2H),4.64(s,2H),2.13(s,3H). 13 CNMR(DMSO-d6,400MHz)δ170.69,170.29,167.41,156.01,133.83,133.44,13 0.34,128.61,127.44,126.59,126.55,123.78,112.28,64.88,33.03,16.12.

[0210] <Example 2> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propionic acid

[0211] Step 1: Preparation of ethyl 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thiophenoxy)propanoate (i-1)

[0212]

[0213] In the same manner as in Step 7 of Example 1, except that ethyl 2-bromopropionate was used instead of methyl 2-bromoacetate, compound i-1 (59 mg, 94% yield) was obtained.

[0214] Step 2: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thiophenoxy)propanoic acid (2)

[0215]

[0216] In the same manner as in Step 8 of Example 1, except that Compound i-1 was used instead of Compound h-1, Compound 2 (46 mg, 83% yield) was obtained.

[0217] ESI LC / MS: m / z calculated for C 20 H 18 F3N2O3S2[M+H] + :455.07; measured value 455.1. 1 H NMR(CD3OD,400MHz)δ8.08(d,J=8.16Hz,2H),7.80(d,J=8.24Hz,2H),7.25(s,1H),7.19(dd,J=8.44,2.02 Hz,1H),6.89(d,J=8.48Hz,1H),4.78(q,J=6.76Hz,1H),4.46(s,2H),2.19(s,3H),1.59(d,J=6.8Hz,3H), 13 C NMR(CD3OD,100MHz)δ175.57,172.53,169.61,157.85,136.35,132.69,132.56 ,129.89,129.50,127.46,127.42,125.23,113.57,73.65,35.09,19.01,16.47.

[0219] <Example 3> Preparation of 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propionic acid

[0220] Step 1: Preparation of ethyl 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoate (j-1)

[0221]

[0222] In the same manner as in Step 7 of Example 1, except using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, compound j-1 (18 mg, 28% yield) was obtained.

[0223] Step 2: Preparation of 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (3)

[0224]

[0225] In the same manner as in Step 8 of Example 1, except that Compound j-1 was used instead of Compound h-1, Compound 3 (9 mg, 64% yield) was obtained.

[0226] ESI LC / MS: m / z calculated for C 21 H 20 F3N2O3S2[M+H] + :469.09; measured value 469.12. 1 H NMR(CD3OD,400MHz)δ8.11(d,J=8.12Hz,2H),7.82(d,J=8.24Hz,2H),7.26(s,1H),7.16( dd,J=8.48,1.99Hz,1H),6.69(d,J=8.52Hz,1H),4.51(s,2H),2.16(s,3H),1.56(s,6H), 13 CNMR(CD3OD,100MHz)δ177.71,172.53,169.65,155.73,136.30,131.93,13 1.88,129.51,127.49,127.45,125.90,118.15,80.33,34.91,25.83,16.87.

[0227] <Example 4> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile

[0228]

[0229] In the same manner as in Step 7 of Example 1, except using 2-bromoacetonitrile instead of methyl 2-bromoacetate, Compound 4 (0.163 g, 67% yield) was obtained.

[0230] 1 H NMR (CDCl3, 400MHz) δ8.04(d,J=8.1Hz,2H),7.72(d,J=8.2Hz,2H),7.27-7.24(m,2H),6.82(d,J=8.0Hz,1H),4.76(s,2H),4.45(s,2H),2.20(s,3H).

[0232] <Example 5> Preparation of 2-(((4-((2H-tetrazolyl-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole

[0233]

[0234] Compound 4 (21 mg, 0.050 mmol), NaN3 (3.9 mg, 0.060 mmol), and ZnCl2 (6.8 mg, 0.050 mmol) were dissolved in 0.4 mL of n-butanol and reacted at 120° C. for 12 hours. The reaction mixture was distilled under reduced pressure and separated using Prep-HPLC to obtain compound 5 (9.5 mg, 41% yield).

[0235] 1 H NMR (CDCl3, 400MHz) δ7.99(d,J=8.1Hz,2H),7.72(d,J=8.2Hz,2H),7.13-7.12(m,2H),6.82(d,J=8.0Hz,1H),5.38(s,2H),4.37(s,2H),1.99(s,3H).

[0237] <Example 6> Preparation of N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide

[0238]

[0239] Compound 1 (3.7 mg, 0.008 mmol) was dissolved in 1 mL of THF, and then 1,1'-carbonyl diimidazole (3.4 mg, 0.021 mmol) was added, and then reacted at room temperature for 1 hour. Hydroxylamine hydrochloride (1.5 mg, 0.021 mmol) was added to the reaction mixture, and then reacted for another 16 hours at room temperature. Potassium hydrogen sulfate (5.7 mg, 0.042 mmol) was added to the mixture, and then 0.5 mL of distilled water was added, and then reacted for another 1 hour at room temperature. The solvent was removed by distillation under reduced pressure, and Prep-HPLC was used to separate to obtain compound 6 (2.7 mg, 69% yield).

[0240] 1 H NMR(CD3OD,400MHz)δ8.14(d,J=7.8Hz,2H),7.85(d,J=8.1Hz,2H),7.30(s,1H),7. 26(d,J=8.0Hz,1H),6.83(d,J=7.9Hz,1H),4.56(s,2H),4.53(s,2H),2.24(s,3H).

[0242] <Example 7> Preparation of N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide

[0243]

[0244] Compound 7 (9.2 mg, 85% yield) was obtained in the same manner as in Example 6, except that O-methylhydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride.

[0245] 1 H NMR(CD3OD,400MHz)δ8.12(d,J=7.8Hz,2H),7.84(d,J=8.0Hz,2H),7.30(s,1H),7.26(d, J=8.3Hz,1H),6.82(d,J=8.2Hz,1H),4.56(s,2H),4.52(s,2H),3.71(s,3H),2.24(s,3H).

[0247] <Example 8> Preparation of N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide

[0248]

[0249] Compound 8 (14 mg, 42% yield) was obtained in the same manner as in Example 6, except that cyanamide was used instead of hydroxylamine hydrochloride.

[0250] 1 H NMR (CDCl3, 400MHz) δ8.11(d,J=8.0Hz,2H),7.83(d,J=8.3Hz,2H),7.30-7.22(m,2H),6.81-6.75(m,1H),4.69(s,2H),4.51(s,2H),2.23(s,3H).

[0252] <Example 9> Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0253] Step 1: Preparation of 4-fluorobenzoylhydrazide (b-2)

[0255] In the same manner as in Step 1 of Example 1, except that Compound a-2 was used instead of Compound a-1, Compound b-2 (1.03 g, 67% yield) was obtained.

[0256] Step 2: Preparation of ethyl 2-(2-(4-fluorobenzoyl)hydrazine)-2-oxoacetate (c-2)

[0257]

[0258] In the same manner as in Step 2 of Example 1, except that Compound b-2 was used instead of Compound b-1, Compound c-2 (0.236 g, 93% yield) was obtained.

[0259] Step 3: Preparation of ethyl 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-2)

[0260]

[0261] In the same manner as in Step 3 of Example 1, except that Compound c-2 was used instead of Compound c-1, Compound d-2 (0.256 g, 78% yield) was obtained.

[0262] Step 4: Preparation of (5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-2)

[0263]

[0264] In the same manner as in Step 4 of Example 1, except that Compound d-2 was used instead of Compound d-1, Compound e-2 (0.185 g, 88% yield) was obtained.

[0265] Step 5: Preparation of (5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (f-2)

[0266]

[0267] In the same manner as in Step 5 of Example 1, except that Compound e-2 was used instead of Compound e-1, Compound f-2 (0.178 g, 78% yield) was obtained.

[0268] Step 6: Preparation of 4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio-2-methylphenol (g-2)

[0269]

[0270] In the same manner as in Step 6 of Example 1, except that Compound f-2 was used instead of Compound f-1, Compound g-2 (0.332 g, 97% yield) was obtained.

[0271] Step 7: Preparation of methyl 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetate (h-2)

[0272]

[0273] In the same manner as in Step 7 of Example 1, except that Compound g-2 was used instead of Compound g-1, Compound h-2 (0.340 g, 84% yield) was obtained.

[0274] Step 8: Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (9)

[0275]

[0276] In the same manner as in Step 8 of Example 1, except using Compound h-2 instead of Compound h-1, Compound 9 (0.363 g, 93% yield) was obtained.

[0277] ESI LC / MS: m / z calculated for C 18 H 16 FN2O3S2[M+H] + :391.06; measured value 391. 1H NMR (400MHz, CDCl3) δ7.84(dd,J=8.5,5.3Hz,2H),7.13-7.07(m,4H),6.54(d,J=8.4Hz,1H),4.47(s,2H),4.33(s,2H),2.12(s,3H); 13 CNMR (100MHz, CDCl3) δ171.38, 169.49, 168.57, 164.44 (d, JCF = 251.2Hz), 156.14, 134.7 6,130.75,129.85,128.60,126.11,124.51,116.28,112.21,60.50,34.28,16.13,14.20.

[0279] <Example 10> Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0280] Step 1: Preparation of ethyl 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoate (i-2)

[0281]

[0282] In the same manner as in Step 7 of Example 1, except that Compound g-2 was used instead of Compound g-1 and ethyl 2-bromopropionate was used instead of methyl 2-bromoacetate, Compound i-2 (0.320 g, 74% yield) was obtained.

[0283] Step 2: Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (10)

[0284]

[0285] In the same manner as in Step 8 of Example 1, except using Compound i-2 instead of Compound h-1, Compound 10 (0.259 g, 64% yield) was obtained.

[0286] ESI LC / MS: m / z calculated for C 19 H 18 FN2O3S2[M+H] + :405.08; measured value 405. 1H NMR(DMSO-d6,400MHz)δ8.01-7.97(m,2H),7.38(t,J=8.8Hz,2H),7.28(s,1H),7.20(dd,J=8.5,1.8H z,1H),6.72(d,J=8.6Hz,1H),4.77(q,J=6.7Hz,1H),4.61(s,2H),2.13(s,3H),1.49(d,J=6.7Hz,3H). 13 C NMR (DMSO-d6, 100MHz) δ173.56, 169.86, 167.97, 164.19 (d, JCF = 248.0Hz), 156.09, 134. 09,130.45,127.87,126.64,123.96,116.91,112.98,72.42,49.07,33.30,18.83,16.41.

[0288] <Example 11> Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0289] Step 1: Preparation of ethyl 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoate (j-2)

[0290]

[0291] In the same manner as in Step 7 of Example 1, except using Compound g-2 instead of Compound g-1 and using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, Compound j-2 (0.174 g, 39% yield) was obtained.

[0292] Step 2: Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (11)

[0293]

[0294] In the same manner as in Step 8 of Example 1, except using Compound j-2 instead of Compound h-1, Compound 11 (0.167 g, 40% yield) was obtained.

[0295] ESI LC / MS: m / z calculated for C 20 H 20 FN2O3S2[M+H] +:419.09; measured value 419. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=8.4, 5.2Hz, 2H), 7.21 (s, 1H), 7.15 (t, J=8.5Hz, 2H) ,7.10(d,J=8.0Hz,1H),6.70(d,J=8.5Hz,1H),4.40(s,2H),2.17(s,3H),1.25(s,3H). 13 C NMR (CDCl3, 100MHz) δ171.34, 169.42, 168.50, 164.45 (d, JCF = 250.9Hz), 153.60, 134.5 5,131.01,129.87,126.25,125.33,117.79,116.28,79.52,60.49,34.15,25.27,16.75.

[0297] <Example 12> Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0298] Step 1: Preparation of 3,4-difluorobenzoylhydrazide (b-3)

[0299]

[0300] In the same manner as in Step 1 of Example 1, except that Compound a-3 was used instead of Compound a-1, Compound b-3 (0.34 g, 73.5% yield) was obtained.

[0301] Step 2: Preparation of ethyl 2-(2-(3,4-difluorobenzoyl)hydrazine)-2-oxoacetate (c-3)

[0302]

[0303] In the same manner as in Step 2 of Example 1, except that Compound b-3 was used instead of Compound b-1, Compound c-3 (0.36 g, 67% yield) was obtained.

[0304] Step 3: Preparation of ethyl 5-(3,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-3)

[0305]

[0306] In the same manner as in Step 3 of Example 1, except that Compound c-3 was used instead of Compound c-1, Compound d-3 (54 mg, 34% yield) was obtained.

[0307] Step 4: Preparation of (5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (e-3)

[0308]

[0309] In the same manner as in Step 4 of Example 1, except that Compound d-3 was used instead of Compound d-1, Compound e-3 (45 mg, 99% yield) was obtained.

[0310] Step 5: Preparation of 2-(chloromethyl)-5-(3,4-difluorophenyl)-1,3,4-thiadiazole (f-3)

[0311]

[0312] In the same manner as in Step 5 of Example 1, except that Compound e-3 was used instead of Compound e-1, Compound f-3 (36 mg, 74% yield) was obtained.

[0313] Step 6: Preparation of 4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenol (g-3)

[0314]

[0315] In the same manner as in Step 6 of Example 1, except that Compound f-3 was used instead of Compound f-1, Compound g-3 (50 mg, 98% yield) was obtained.

[0316] Step 7: Preparation of methyl 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methyl)phenoxy)acetate (h-3)

[0317]

[0318] In the same manner as in Step 7 of Example 1, except using Compound g-3 instead of Compound g-1, Compound h-3 (64 mg, 99% yield) was obtained.

[0319] Step 8: Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (12)

[0320]

[0321] In the same manner as in Step 8 of Example 1, except using Compound h-3 instead of Compound h-1, Compound 12 (25 mg, 39.8% yield) was obtained.

[0322] ESI LC / MS: m / z calculated for C 18 H 15 F2N2O3S2[M+H] + :409.05; measured value 409. 1 H NMR (DMSO, 400MHz) δ8.07 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 7.28Hz, 1H), 7.25 (s, 1H),7.19(s,1H),6.71(s,1H),4.62(s,2H),4.43(s,2H),2.13(d,J=7.3Hz,3H).

[0324] <Example 13> Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0325] Step 1: Preparation of ethyl 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoate (i-3)

[0326]

[0327] In the same manner as in Step 7 of Example 1, except using Compound g-3 instead of Compound g-1 and using 2-bromopropionate instead of methyl 2-bromoacetate, Compound i-3 (67 mg, 97% yield) was obtained.

[0328] Step 2: Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (13)

[0329]

[0330] In the same manner as in Step 8 of Example 1, except using Compound i-3 instead of Compound h-1, Compound 13 (3 mg, 5% yield) was obtained.

[0331] ESI LC / MS: m / z calculated for C 19 H 18 FN2O3S2[M+H] + :423.07; measured value 423. 1H NMR(CD3OD,400MHz)δ7.93(m,1H),7.74(s,1H),7.47(m,1H),7.27(s,1H),7.22(d,J=8 .44Hz,1H),6.73(d,J=8.40Hz,1H),4.47(s,2H),2.21(s,3H),1.61(d,J=6.72Hz,3H).

[0333] <Example 14> Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0334] Step 1: Preparation of ethyl 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoate (j-3)

[0335]

[0336] In the same manner as in Step 7 of Example 1, except using Compound g-3 instead of Compound g-1 and using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, Compound j-3 (33 mg, 50% yield) was obtained.

[0337] Step 2: Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (14)

[0338]

[0339] In the same manner as in Step 8 of Example 1, except using Compound j-3 instead of Compound h-1, Compound 14 (12 mg, 38% yield) was obtained.

[0340] ESI LC / MS: m / z calculated for C 19 H 18 FN2O3S2[M+H] + :437.08; measured value 437.1. 1 H NMR(CD3OD,400MHz)δ7.93(m,1H),7.74(m,1H),7.47(m,1H),7.27(s,1H),7.18(dd,J =2.12Hz, 6.40Hz, 1H), 6.72 (d, J = 8.52Hz, 1H), 4.49 (s, 2H), 2.17 (s, 3H), 1.58 (s, 6H). 13C NMR(CD3OD,100MHz)δ15.37,24.33,33.37,78.81,116.08,116.28,116.61, 118.07,118.25,124.39,124.71,130.38,134.76,154.20,170.68,176.20.

[0342] <Example 15> Preparation of 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0343] Step 1: Preparation of 3,4,5-trifluorobenzoylhydrazide (b-4)

[0344]

[0345] In the same manner as in Step 1 of Example 1, except that Compound a-4 was used instead of Compound a-1, Compound b-4 (0.74 g, 39% yield) was obtained.

[0346] Step 2: Preparation of ethyl 2-oxo-2-(2-(3,4,5-trifluorobenzoyl)hydrazine)acetate (c-4)

[0347]

[0348] In the same manner as in Step 2 of Example 1, except that Compound b-4 was used instead of Compound b-1, Compound c-4 (0.209 g, 72% yield) was obtained.

[0349] Step 3: Preparation of ethyl 5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-4)

[0350]

[0351] In the same manner as in Step 3 of Example 1, except using Compound c-4 instead of Compound c-1, Compound d-4 (0.21 g, 56% yield) was obtained.

[0352] Step 4: Preparation of (5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (e-4)

[0353]

[0354] In the same manner as in Step 4 of Example 1, except that Compound d-4 was used instead of Compound d-1, Compound e-4 (0.24 g, 99% yield) was obtained.

[0355] Step 5: Preparation of 2-(chloromethyl)-5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazole (f-4)

[0356]

[0357] In the same manner as in Step 5 of Example 1, except that Compound e-4 was used instead of Compound e-1, Compound f-4 (0.18 g, 68% yield) was obtained.

[0358] Step 6: Preparation of 2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-4)

[0359]

[0360] In the same manner as in Step 6 of Example 1, except that Compound f-4 was used instead of Compound f-1, Compound g-4 (0.368 g, 99% yield) was obtained.

[0361] Step 7: Preparation of methyl 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetate (h-4)

[0362]

[0363] In the same manner as in Step 7 of Example 1, except using Compound g-4 instead of Compound g-1, Compound h-4 (0.247 g, 56% yield) was obtained.

[0364] Step 8: Preparation of 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (15)

[0365]

[0366] In the same manner as in Step 8 of Example 1, except using Compound h-4 instead of Compound h-1, Compound 15 (64 mg, 15% yield) was obtained.

[0367] ESI LC / MS: m / z calculated for C 18 H 14 F3N2O3S2[M+H] + :427.04; measured value 427. 1H NMR (CD3OD, 400MHz) δ7.67(t,J=7.4Hz,2H),7.15-7.09(m,2H),6.63(d,J=8.3Hz,1H),4.37(s,2H),3.55(s,2H),2.10(s,3H).

[0369] <Example 16> Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0370] Step 1: Preparation of 3-chloro-4-fluorobenzoylhydrazide (b-5)

[0371]

[0372] In the same manner as in Step 1 of Example 1, except that Compound a-5 was used instead of Compound a-1, Compound b-5 (0.60 g, 88% yield) was obtained.

[0373] Step 2: Preparation of ethyl 2-(2-(3-chloro-4-fluorobenzoyl)hydrazine)-2-oxoacetate (c-5)

[0374]

[0375] In the same manner as in Step 2 of Example 1, except using Compound b-5 instead of Compound b-1, Compound c-5 (0.60 g, 88% yield) was obtained.

[0376] Step 3: Preparation of ethyl 5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-5)

[0377]

[0378] In the same manner as in Step 3 of Example 1, except using Compound c-5 instead of Compound c-1, Compound d-5 (0.556 g, 60% yield) was obtained.

[0379] Step 4: Preparation of (5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (e-5)

[0380]

[0381] In the same manner as in Step 4 of Example 1, except using Compound d-5 instead of Compound d-1, Compound e-5 (0.451 g, 87% yield) was obtained.

[0382] 1H NMR (400MHz, CDCl3) δ8.06(dd,J=6.9,2.2Hz,1H),7.84(ddd,J=8.6,4.4,2.2Hz,1H),7.27(t,J=8.6Hz,1H),5.14(s,2H),2.72(brs,1H).

[0383] Step 5: Preparation of 2-(3-chloro-4-fluorophenyl)-5-(chloromethyl)-1,3,4-thiadiazole (f-5)

[0384]

[0385] In the same manner as in Step 5 of Example 1, except that Compound e-5 was used instead of Compound e-1, Compound f-5 (0.259 g, 53% yield) was obtained.

[0386] 1 H NMR (400MHz, CDCl3) δ8.07 (dd, J=6.8, 2.2Hz, 1H), 7.84 (ddd, J=8.6, 4.4, 2.3Hz, 1H), 7.28 (t, J=8.5Hz, 1H), 4.99 (s, 2H).

[0387] Step 6: Preparation of 4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenol (g-5)

[0388]

[0389] In the same manner as in Step 6 of Example 1, except that Compound f-5 was used instead of Compound f-1, Compound g-5 (69 mg, 97% yield) was obtained.

[0390] Step 7: Preparation of methyl 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetate (h-5)

[0391]

[0392] In the same manner as in Step 7 of Example 1, except using Compound g-5 instead of Compound g-1, Compound h-5 (74 mg, 89% yield) was obtained.

[0393] 1H NMR (400MHz, CDCl3) δ8.01 (dd, J=6.9, 2.2Hz, 1H), 7.79 (ddd, J=8.6, 4.5, 2.2Hz, 1H), 7.26-7.21 (m, J=5.3Hz, 2H),7.18(dd,J=8.4,2.2Hz,1H),6.61(d,J=8.5Hz,1H),4.63(s,2H),4.41(s,2H),3.79(s,3H),2.25(s,3H).

[0394] Step 8: Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (16)

[0395]

[0396] In the same manner as in Step 8 of Example 1, except using Compound h-5 instead of Compound h-1, Compound 16 (44 mg, 88% yield) was obtained.

[0397] ESI LC / MS: m / z calculated for C 18 H 15 ClFN2O3S2[M+H] + :425.02; measured value 425. 1 H NMR(CD3OD,400MHz)δ8.12-8.04(m,1H),7.91-7.82(m,1H),7.41(t,J=8.8Hz,1H),7.27(s ,1H),7.23(d,J=8.5Hz,1H),6.76(d,J=8.4Hz,1H),4.60(s,2H),4.48(s,2H),2.23(s,3H). 13 C NMR(CD3OD,100MHz)δ172.21,170.76,167.23,159.62,156.92,134.75,131.26,129 .36,128.22,128.16,127.32,123.52,121.68,117.35,111.57,65.45,33.65,14.94.

[0399] <Example 17> Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0400] Step 1: Preparation of ethyl 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoate (i-5)

[0401]

[0402] In the same manner as in Step 7 of Example 1, except using Compound g-5 instead of Compound g-1 and using ethyl 2-bromopropionate instead of methyl 2-bromoacetate, Compound i-5 (74.8 mg, 70.2% yield) was obtained.

[0403] 1 H NMR(CDCl3,400MHz)δ8.01(dd,J=6.9,2.2Hz,1H),7.79(ddd,J=8.6,4.5,2.2Hz,1H),7.25-7.21(m,2H),7.15(dd,J=8.5,2.2Hz,1H),6.58( d,J=8.5Hz,1H),4.69(q,J=6.8Hz,1H),4.40(s,2H),4.19(qd,J=7.1,1.3Hz,2H),2.23(s,3H),1.62(d,J=6.8Hz,3H),1.22(t,J=7.1Hz,3H).

[0404] Step 2: Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (17)

[0405]

[0406] In the same manner as in Step 8 of Example 1, except using Compound i-5 instead of Compound h-1, Compound 17 (33 mg, 85% yield) was obtained.

[0407] 1 H NMR(CDCl3,400MHz)δ7.99(dd,J=6.8,1.9Hz,1H),7.81-7.71(m,1H),7.34(brs,1H),7.23(m,2H),7.15(d,J =8.4Hz,1H),6.63(d,J=8.5Hz,1H),4.73(q,J=6.7Hz,1H),4.41(s,2H),2.21(s,3H),1.65(d,J=6.8Hz,3H). 13C NMR(CDCl3,100MHz)δ176.05,170.12,167.17,159.73,155.89,134.86,130.73,130.06 ,128.93,127.84,127.22,124.40,122.28,117.44,112.53,72.43,34.34,18.49,16.25.

[0409] <Example 18> Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0410] Step 1: Preparation of ethyl 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoate (j-5)

[0411]

[0412] In the same manner as in Step 7 of Example 1, except using Compound g-5 instead of Compound g-1 and using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, Compound j-5 (12 mg, 13% yield) was obtained.

[0413] Step 2: Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (18)

[0414]

[0415] In the same manner as in Step 8 of Example 1, except using Compound j-5 instead of Compound h-1, Compound 18 (3 mg, 26% yield) was obtained.

[0416] ESI LC / MS: m / z calculated for C 20 H 19 ClFN2O3S2[M+H] + :453.05; measured value 453. 1 H NMR (CD3OD, 400MHz) δ8.15-8.03(m,1H),7.93-7.83(m,1H),7.42(t,J=8.8Hz,1H),7.28(s ,1H),7.18(d,J=8.3Hz,1H),6.73(d,J=8.4Hz,1H),4.49(s,2H),2.18(s,3H),1.58(s,6H).13 C NMR (CD3OD, 400MHz) δ170.69, 170.62, 167.27, 159.65 (d, J = 253.4Hz), 154.39, 134.78, 130.45, 130.29,129.40,128.13,127.32,124.14,121.69,117.37,116.67,79.08,33.44,24.43,15.37.

[0418] <Example 19> Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0419] Step 1: Preparation of 3-fluoro-4-(trifluoromethyl)benzoylhydrazide (b-6)

[0420]

[0421] In the same manner as in Step 1 of Example 1, except that Compound a-6 was used instead of Compound a-1, Compound b-6 (2.044 g, 92% yield) was obtained.

[0422] Step 2: Preparation of ethyl 2-(2-(3-fluoro-4-(trifluoromethyl)benzoyl)hydrazino)-2-oxoacetate (c-6)

[0423]

[0424] In the same manner as in Step 2 of Example 1, except using Compound b-6 instead of Compound b-1, Compound c-6 (0.139 g, 43% yield) was obtained.

[0425] Step 3: Preparation of ethyl 5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole-2-carboxylate (d-6)

[0426]

[0427] Compound d-6 (0.371 g, 89% yield) was obtained in the same manner as in step 3 of example 1, except that compound c-6 was used instead of compound c-1.

[0428] Step 4: Preparation of (5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-6)

[0429]

[0430] In the same manner as in Step 4 of Example 1, except using Compound d-6 instead of Compound d-1, Compound e-6 (0.253 g, 91% yield) was obtained.

[0431] Step 5: Preparation of 2-(chloromethyl)-5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (f-6)

[0432]

[0433] In the same manner as in Step 5 of Example 1, except that Compound e-6 was used instead of Compound e-1, Compound f-6 (0.234 g, 79% yield) was obtained.

[0434] Step 6: Preparation of 4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenol (g-6)

[0435]

[0436] In the same manner as in Step 6 of Example 1, except that Compound f-6 was used instead of Compound f-1, Compound g-6 (0.401 g, 97% yield) was obtained.

[0437] Step 7: Preparation of methyl 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetate (h-6)

[0438]

[0439] In the same manner as in Step 7 of Example 1, except using Compound g-6 instead of Compound g-1, Compound h-6 (0.421 g, 89% yield) was obtained.

[0440] Step 8: Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (19)

[0441]

[0442] In the same manner as in Step 8 of Example 1, except using Compound h-6 instead of Compound h-1, Compound 19 (0.264 g, 60% yield) was obtained.

[0443] 1H NMR(CD3OD,400MHz)δ7.97(d,J=11.2Hz,1H),7.92-7.85(m,2H),7.29(s,1H),7.2 4(d,J=8.5Hz,1H),6.77(d,J=8.4Hz,1H),4.67(s,2H),4.52(s,2H),2.23(s,3H). 13 CNMR(DMSO-d6,100MHz)δ171.74,170.62,166.53,159.52(d,JCF=253.5Hz),156.42,136.22,134.06,13 0.59,129.04,127.69,124.63,123.84,122.76(q,JCF=271.4Hz),116.32,112.57,65.46,33.32,16.38.

[0445] <Example 20> Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0446] Step 1: Preparation of ethyl 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoate (i-6)

[0447]

[0448] In the same manner as in Step 7 of Example 1, except using Compound g-6 instead of Compound g-1 and using Compound 2-bromopropionic acid ethyl ester instead of Compound 2-bromoacetate methyl ester, Compound i-6 (0.360 g, 72%) was obtained.

[0449] Step 2: Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (20)

[0450]

[0451] In the same manner as in Step 8 of Example 1, except using Compound i-6 instead of Compound h-1, Compound 20 (0.300 g, 66% yield) was obtained.

[0452] 1H NMR (CDCl3, 400MHz) δ7.81-7.68 (m, 3H), 7.22 (s, 1H), 7.15 (dd, J = 8.5, 1.9Hz, 1H), 6.62 ( d,J=8.5Hz,1H),4.73(q,J=6.8Hz,1H),4.42(s,2H),2.21(s,3H),1.65(d,J=6.8Hz,3H). 13 C NMR (CDCl3, 100MHz) δ176.22, 171.02, 166.72, 159.89 (d, JCF = 254.5Hz), 155.96, 135.47, 134.94, 130.83 ,128.99,128.16,124.24,123.43,119.53(q,JCF=246.2Hz),115.87,112.50,72.39,34.40,18.48,16.23.

[0454] <Example 21> Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0455] Step 1: Preparation of ethyl 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoate (j-6)

[0456]

[0457] In the same manner as in Step 7 of Example 1, except using Compound g-6 instead of Compound g-1 and using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, Compound j-6 (52 mg, 10% yield) was obtained.

[0458] Step 2: Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (21)

[0459]

[0460] In the same manner as in Step 8 of Example 1, except using Compound j-6 instead of Compound h-1, Compound 21 (80 mg, 17% yield) was obtained.

[0461] 1H NMR (CDCl3, 400MHz) δ7.81-7.69 (m, 3H), 7.21 (s, 1H), 7.09 (d, J = 8.2Hz, 1H), 6.69 (d, J = 8.6Hz, 1H), 2.17 (s, 3H), 0.88 (s, 6H).

[0463] <Example 22> Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0464] Step 1: Preparation of 4-methylbenzoylhydrazide (b-7)

[0465]

[0466] In the same manner as in Step 1 of Example 1, except using Compound a-7 instead of Compound a-1, Compound b-7 (0.78 g, 85% yield) was obtained.

[0467] Step 2: Preparation of ethyl 2-(2-(4-methylbenzoyl)hydrazino)-2-oxoacetate (c-7)

[0468]

[0469] In the same manner as in Step 2 of Example 1, except using Compound b-7 instead of Compound b-1, Compound c-7 (1.25 g, 96% yield) was obtained.

[0470] Step 3: Preparation of ethyl 5-(p-tolyl)-1,3,4-thiadiazole-2-carboxylate (d-7)

[0471]

[0472] In the same manner as in step 3 of example 1, except using compound c-7 instead of compound c-1, compound d-7 (0.840 g, 67.7% yield) was obtained.

[0473] Step 4: Preparation of (5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methanol (e-7)

[0474]

[0475] In the same manner as in Step 4 of Example 1, except using Compound d-7 instead of Compound d-1, Compound e-7 (0.690 g, 99% yield) was obtained.

[0476] Step 5: Preparation of 2-(chloromethyl)-5-(p-tolyl)-1,3,4-thiadiazole (f-7)

[0477]

[0478] In the same manner as in Step 5 of Example 1, except that Compound e-7 was used instead of Compound e-1, Compound f-7 (0.359 g, 47.8% yield) was obtained.

[0479] Step 6: Preparation of 2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-7)

[0480]

[0481] In the same manner as in Step 6 of Example 1, except that Compound f-7 was used instead of Compound f-1, Compound g-7 (0.560 g, 97% yield) was obtained.

[0482] Step 7: Preparation of methyl 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetate (h-7)

[0483]

[0484] In the same manner as in Step 7 of Example 1, except using Compound g-7 instead of Compound g-1, Compound h-7 (70 mg, 97% yield) was obtained.

[0485] Step 8: Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (22)

[0486]

[0487] In the same manner as in Step 8 of Example 1, except using Compound h-7 instead of Compound h-1, Compound 22 (34 mg, 96% yield) was obtained.

[0488] ESI LC / MS: m / z calculated for C 19 H 19 N2O3S2[M+H] + : 387.09; measured value 386.8. 1H NMR(DMSO,400MHz)δ7.80(d,J=7.96Hz,2H),7.34(d,J=7.84Hz,2H),7.24(s,1H),7.19(d,J =8.28Hz,1H),6.73(d,J=8.56Hz,1H),4.57(s,2H),4.47(s,2H),2.36(s,3H),2.12(s,3H).

[0490] <Example 23> Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propionic acid

[0491] Step 1: Preparation of ethyl 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoate (i-7)

[0492]

[0493] In the same manner as in Step 7 of Example 1, except using Compound g-7 instead of Compound g-1 and using ethyl 2-bromopropionate instead of methyl 2-bromoacetate, Compound i-7 (0.100 g, 97% yield) was obtained.

[0494] Step 2: Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (23)

[0495]

[0496] In the same manner as in Step 8 of Example 1, except using Compound i-7 instead of Compound h-1, Compound 23 (34 mg, 35% yield) was obtained.

[0497] ESI LC / MS: m / z calculated for C 20 H 21 N2O3S2[M+H] + :401.10; measured value 401.1. 1 H NMR(CD3OD,400MHz)δ7.78(d,J=7.84Hz,2H),7.33(d,J=7.76Hz,2H),7.25(s,1H),7.21(d,J=8.44Hz,1 H),6.72(d,J=8.40Hz,1H),4.81(m,1H),4.44(s,1H),2.40(s,3H),2.21(s,3H),1.63(d,J=6.76Hz,3H). 13C NMR(CD3OD,100MHz)δ15.00,17.56,20.07,33.64,60.71,72.35,112.03,123.76,126.8 4,127.65(2C),128.29,129.64(2C),131.19,134.87,141.99,156.37,169.57,170.04.

[0499] <Example 24> Preparation of 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propionic acid

[0500] Step 1: Preparation of ethyl 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoate (j-7)

[0501]

[0502] In the same manner as in Step 7 of Example 1, except using Compound g-7 instead of Compound g-1 and using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, Compound j-7 (94 mg, 97% yield) was obtained.

[0503] Step 2: Preparation of 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (24)

[0504]

[0505] In the same manner as in Step 8 of Example 1, except using Compound j-7 instead of Compound h-1, Compound 24 (2 mg, 3% yield) was obtained.

[0506] 1 H NMR (CD3OD, 400MHz) δ7.76 (d, J = 8.20Hz, 2H), 7.32 (d, J = 8.04Hz, 2H), 7.26 (s, 1H), 7.17 (dd, J = 2.32Hz, 6.20Hz 1H), 6.72 (d, J = 8.48Hz, 1H), 4.45 (s, 2H), 2.39 (s, 3H), 2.16 (s, 3H), 1.57 (s, 6H). 13C NMR(CD3OD,100MHz)δ15.42,20.08,24.35(2C),78.82,116.68,124.53,126.82,12 7.31(2C),129.64(2C),130.34,134.79,142.01,154.16,169.46,170.05,176.24.

[0508] <Example 25> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0509] Step 1: Preparation of 4-(trifluoromethyl)benzoylhydrazide (b-8)

[0510]

[0511] In the same manner as in Step 1 of Example 1, except that Compound a-8 was used instead of Compound a-1, Compound b-8 (1.16 g, 53%) was obtained.

[0512] Step 2: Preparation of ethyl 2-(2-(4-(fluorooxy)benzoyl)hydrazino)-2-oxoacetate (c-8)

[0513]

[0514] Compound c-8 (0.275 g, 86% yield) was obtained in the same manner as in Step 2 of Example 1, except that compound b-8 was used instead of compound b-1.

[0515] Step 3: Preparation of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate (d-8)

[0516]

[0517] In the same manner as in step 3 of example 1, except using compound c-8 instead of compound c-1, compound d-8 (0.352 g, 85% yield) was obtained.

[0518] Step 4: Preparation of (5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-8)

[0519]

[0520] In the same manner as in Step 4 of Example 1, except using Compound d-8 instead of Compound d-1, Compound e-8 (0.249 g, 90% yield) was obtained.

[0521] Step 5: Preparation of 2-(chloromethyl)-5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole (f-8)

[0522]

[0523] In the same manner as in Step 5 of Example 1, except that Compound e-8 was used instead of Compound e-1, Compound f-8 (0.206 g, 70% yield) was obtained.

[0524] Step 6: Preparation of 2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-8)

[0525]

[0526] In the same manner as in Step 6 of Example 1, except that Compound f-8 was used instead of Compound f-1, Compound g-8 (0.398 g, 97% yield) was obtained.

[0527] Step 7: Preparation of methyl 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetate (h-8)

[0528]

[0529] In the same manner as in step 7 of example 1, except using compound g-8 instead of compound g-1, compound h-8 (0.409 g, 87% yield) was obtained.

[0530] Step 8: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (25)

[0531]

[0532] In the same manner as in Step 8 of Example 1, except using Compound h-8 instead of Compound h-1, Compound 25 (0.393 g, 86% yield) was obtained.

[0533] 1H NMR(DMSO-d6,400MHz)δ8.09-8.05(m,2H),7.54(d,J=8.1Hz,2H),7.29(d,J=1.8Hz,1H),7 .21(dd,J=8.5,2.3Hz,1H),6.78(d,J=8.6Hz,1H),4.69(s,2H),4.64(s,2H),2.14(s,3H); 13 C NMR(DMSO-d6,100MHz)δ170.55,170.39,167.64,156.26,150.55,134.09,130.60,130.21 ,129.17,127.68,124.06,122.90(q,JCF=239.8Hz),122.30,112.53,65.17,33.30,16.38.

[0535] <Example 26> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid

[0536] Step 1: Preparation of ethyl 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoate (i-8)

[0537]

[0538] In the same manner as in Step 7 of Example 1, except using Compound g-8 instead of Compound g-1 and using ethyl 2-bromopropionate instead of methyl 2-bromoacetate, Compound i-8 (0.379 g, 76% yield) was obtained.

[0539] Step 2: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (26)

[0540]

[0541] In the same manner as in Step 8 of Example 1, except using Compound i-8 instead of Compound h-1, Compound 26 (0.409 g, 87% yield) was obtained.

[0542] 1H NMR(DMSO-d6,400MHz)δ8.09-8.05(m,2H),7.54(d,J=8.1Hz,2H),7.29(d,J=1.8Hz,1H),7.21(dd,J=8.5, 2.3Hz,1H),6.72(d,J=8.6Hz,1H),4.80(q,J=6.7Hz,1H),4.63(s,2H),2.14(s,3H),1.50(d,J=6.8Hz,3H). 13 C NMR(DMSO-d6,100MHz)δ173.44,170.38,167.64,156.03,150.57,134.13,130.56,130.21,12 9.17,127.92,124.03,122.30,120.42(q,JCF=255.7Hz),112.98,72.26,33.29,18.79,16.39.

[0544] <Example 27> Preparation of 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid

[0545] Step 1: Preparation of ethyl 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoate (j-8)

[0546]

[0547] In the same manner as in step 7 of example 1, except using compound g-8 instead of compound g-1 and using ethyl 2-bromo-2-methylpropanoate instead of methyl 2-bromoacetate, compound j-8 (0.179 g, 35% yield) was obtained.

[0548] Step 2: Preparation of 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)methyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (27)

[0549]

[0550] In the same manner as in Step 8 of Example 1, except using Compound j-8 instead of Compound h-1, Compound 27 (0.170 g, 35% yield) was obtained.

[0551] ESI LC / MS: m / z calculated for C 21 H 20F3N2O4S2[M+H] + :485.08; measured value 485. 1 H NMR (CDCl3, 400MHz) δ7.92(d,J=8.2Hz,2H),7.29(d,J=8.2Hz,2H),7.18(s,1H),7.09(s,1H),6.68(s,1H),4.41(s,2H),2.14(s,3H),1.25(s,6H). 13 C NMR(CDCl3,100MHz)δ169.86,168.17,160.90,151.16,142.81,134.57,134.52 ,129.89,129.47,128.46,121.60,121.38,119.03,34.13,29.72,25.19,16.74.

[0553] The following Tables 1 and 2 summarize the compounds of Examples 1 to 27.

[0554] Table 1

[0555] Table 2

[0557] <Experimental methods>

[0558] 1. Animals Six-week-old germ-free, immunocompetent C57BL / 6 mice were purchased from SLC, Inc (Shizuoka, Japan). All animal experimental procedures were performed in strict accordance with the appropriate institutional guidelines for animal research. The protocol was approved by the Animal Experiment Ethics Committee of Kyungpook National University (approval number: KNU2012-43).

[0561] 2. Cell Culture

[0562] RAW264.7 cells (macrophages) were purchased from Korea Cell Line Bank and used, and cultured in DMEM medium supplemented with 100 mg / mL inactivated fetal bovine serum and 10 mg / mL penicillin-streptomycin at 37°C, 5% CO2. During the experiment, all cells were passaged when grown to about 80% to 90% density, and only cells of no more than 20 generations were used.

[0564] 3. Cytotoxicity Measurement

[0565] To evaluate the cytotoxicity of the samples, cell proliferation was tested using a cell counting kit [CCK-8; Dojindo Laboratories (Tokyo, Japan)]. RAW 264.7 cells (1×10 4 Cells / mL were distributed into microplates, and after 20 hours of pre-culture, 1 μg / mL of LPS and different concentrations of the example compounds were added, and cultured in an incubator at 37°C and 5% CO2 for 24 hours. After culture, 10 μL of CCK-8 reagent was added, and cultured for another 1 to 2 hours, and the absorbance was measured. The absorbance was measured at 450 nm using a microplate reader [BMG Labtech (located in Offenburg, Germany)].

[0567] 4. Measurement of Nitric Oxide (NO) Production

[0568] The concentration of NO was determined by measuring the nitrite concentration in the culture medium using the Griess reagent system (Promega). Raw264.7 cells were adjusted to 2.5 × 10 5 Cells / mL were inoculated into 24 microwell plates and pre-cultured in a 5% CO2 incubator for 20 hours. The cells were treated with 1 μg / mL of LPS and different concentrations of the example compounds and cultured for another 24 hours. After obtaining the culture supernatant, the NO concentration was measured using the Griess reagent system according to the protocol provided by the manufacturer. The absorbance was measured at 540 nm using a microplate reader [BMG Labtech (located in Offenburg, Germany)]. The NO concentration in the cell culture medium was calculated by comparing the NO concentration in the cell culture medium with a standard curve of sodium nitrite (NaNO2) at various concentrations.

[0570] 5. Measurement of Inflammation-related Cytokine Secretion

[0571] The supernatant was partitioned using the same method as used to measure NO. TM The amount of TNF-α and IL-6 in the supernatant was quantified using a Cytometric Bead Array system and flow cytometer (BD Biosciences).

[0573] 6. Luciferase Assay

[0574] Raw264.7 / NF-kb-luc cells were treated with 1 mg / mL LPS and different concentrations of compounds using the same method used to measure NO. After 16 hours, D-luciferin solution was added to the cells and luminescence images were acquired using IVISLumina III. Luminescence images were quantified using Living Imaging software.

[0576] 7. Western Blot

[0577] The cells were washed twice with cold PBS and lysed with RIPA buffer (Roche) containing a complete protease inhibitor cocktail. Protein concentration was quantified using a BCA protein assay kit (Pierce, IL, USA), and 30 μL of lysate was separated by 10% SDS-PAGE. The separated proteins were transferred to a polyvinylidene fluoride (PVDF) membrane (Biorad, CA, USA) at 70 mA for 1 hour and 30 minutes, and then blocked for 2 hours at room temperature with Tris buffered saline (TBST; pH 7.5) containing 50 mg / mL skim milk. As antibodies to test the expression levels of iNOS and pIKKαβ, anti-iNOS and pIKKαβ were used, diluted 1:1000 and reacted at room temperature for 2 hours, then washed three times with TBST. As secondary antibodies, horseradish peroxidase (HRP)-conjugated anti-mouse IgG and anti-rabbit IgG were diluted 1:2000 and reacted at room temperature for 1 hour, then washed three times with TBST. Peroxidase activity was detected using ECL-Plus according to the manufacturer's protocol.

[0579] 8. Macrophage Image Analysis

[0580] 2 mL of thioglycolate medium (BD, USA) was injected into the peritoneal cavity of C57Bl / 6 mice. Three days later, the mice were cervically dislocated and 8 mL of Dulbecco's modified Eagle medium (DMEM) was injected into the peritoneal cavity to collect cells. After centrifugation, the cells were suspended in DMEM containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin and cultured at 37°C in a 5% CO2 incubator for 2 hours. The non-adherent cells were removed and the remaining cells were used for the experiment.

[0581] The acute anti-inflammatory activity of the example compounds was evaluated using macrophage tracking technology with fluorescence imaging. Macrophages extracted from the peritoneal cavity of mice were stained with Vybrant TM DiD Cell Labeling Solution (Vybrant TMDiD Cell-Labeling Solution) was labeled and then administered to mice by intravenous injection. The next day, 50 mg / kg of the example compound was orally administered, and 1 hour later, 0.1% carrageenan (CG) solution or PBS was subcutaneously injected into the left or right sole of the mouse. Fluorescent images were acquired using IVIS Lumina III at the specified time.

[0583] 9. Statistical Analysis

[0584] All data are expressed as mean ± standard deviation (SD) of at least three independent tests, and the statistical significance of the differences was determined by unpaired Student's test using GrahPad Prism 5. P values ​​less than 0.05 were considered statistically significant.

[0586] <Experimental Example 1> Enzyme activity (EC 50 )analyze

[0587] In order to confirm the PPARδ activation effect of the example compounds, the following experiment was performed. First, the example compounds were diluted to 100 times the final concentration in DMSO, then diluted 1 / 50 in the assay buffer, and 10 μL of each was added to a 384 microwell plate. Then, the GST-conjugated PPARδ ligand binding domain (LBD) was added to a final concentration of 5 nM, and the fluorescein-conjugated C33 coactivator peptide and Tb-α-GST antibody were added to final concentrations of 100 nM and 10 nM, respectively. The final volume of each test system was set to 20 μL, the test was repeated twice for each concentration, and the binding activity after the reaction was measured by the TR-FRET method. In other words, after excitation at 340 nm and measuring the emission values ​​at 495 nm and 520 nm, the results were analyzed using the measured value at 490 nm / the measured value at 520 nm, and the EC was calculated using the analysis program Prism6. 50 The results are summarized in Table 2 below.

[0588] The principle of this test method is as follows: GST antibody binds to GST fused to PPARδ LBD, thereby maintaining its inactive state, and the binding of agonists induces structural changes in the LBD protein. At this time, the fluorescent energy donor bound to the GST antibody transfers energy to the fluorescent energy acceptor (fluorescein) bound to the PPARδ substrate (C33 peptide), thereby emitting fluorescent energy. By measuring this value, the degree of activation of PPARδ can be measured.

[0589] Meanwhile, a previously known PPARδ agonist compound GW501516 was used as a test material, and as an experimental result, the EC50 The value is 15.5nM.

[0591] Table 3

[0592] <Experimental Example 2> Cytotoxicity Analysis

[0593] In order to evaluate the cytotoxicity of the compound of Example 1, Raw264.7 cells (macrophage cell line) were treated with the compound of Example 1 at concentrations of 0, 12 μM, 25 μM and 50 μM, and then CCK8 assay was performed according to the above <Experimental Method> 3. The results of CCK8 assay showed that there was no cytotoxicity at all concentrations ( Figure 1 Specifically, even at concentrations as high as 50 μM, cell proliferation was similar to that of the vehicle group, and no significant difference was detected.

[0595] <Experimental Example 3> Analysis of Nitric Oxide (NO) Generation

[0596] NO is generated from L-arginine by nitric oxide synthase (NOS) present in various tissues. There are three types of NOS, namely neuronal NOS, endothelial NOS and inducible NOS (iNOS). Among them, during bacterial infection, iNOS (also known as NOS-2) is expressed in various cells including macrophages through inflammatory stimuli (such as bacterial endotoxins and various inflammatory cytokines). Once iNOS is expressed, a large amount of nitric oxide (NO) will be generated for a long time and participate in cytotoxicity during inflammation. In order to analyze the NO generation of the compound of Example 1, the following experiment was performed.

[0597] 1 mg / mL of lipopolysaccharide (LPS) and the compound of Example 1 at concentrations of 0, 12 μM, 25 μM, and 50 μM were added to Raw264.7 cells, cultured for 24 hours, and the change in NO concentration in the upper layer of the culture was analyzed. As a result of the analysis, the NO concentration secreted by LPS-stimulated Raw264.7 decreased in a concentration-dependent manner of the compound of Example 1. Specifically, in LPS-stimulated Raw26.7+0 μM, LPS-stimulated Raw26.7+12.5 μM, LPS-stimulated Raw26.7+25 μM, and LPS-stimulated Raw26.7+50 μM, the NO concentrations generated were 22.8±1.3 μM, 18.9±0.3 μM, 14.8±0.54 μM, and 2.41±0.24 μM, respectively. Figure 2 ).

[0599] <Experimental Example 4> Analysis of the inhibitory effect on iNOS protein expression (Western blotting)

[0600] In order to confirm whether the NO production inhibitory effect of the compound of Example 1 is attributed to the inhibition of iNOS protein expression, 1 mg / mL of LPS and the compound of Example 1 at concentrations of 0, 12 μM, 25 μM and 50 μM were added to Raw264.7 cells, and the effect on iNOS protein expression was evaluated by the above <Experimental Method> 7. As a result, Raw264.7 cells without LPS did not express iNOS protein, and Raw264.7 cells with 1 mg / mL LPS showed higher iNOS protein expression. In addition, when treated with the compound of Example 1, it was confirmed that iNOS protein expression in LPS-stimulated Raw264.7 was significantly inhibited ( Figure 3 ).

[0602] <Experimental Example 5> Analysis of the inhibitory effect on the production of inflammation-related factors

[0603] LPS, which is a well-known endotoxin present in the outer cell membrane of Gram-negative bacteria, stimulates macrophages or monocytes to promote the secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Therefore, in order to analyze the inhibitory effect of the compound of Example 1 on cytokine secretion, RAW264.7 cells were cultured for 24 hours by adding 1 mg / mL of LPS and the compound of Example 1 at concentrations of 0, 12 μM, 25 μM, and 50 μM, and the IL-6 and TNF-α concentrations in the culture supernatant were measured. As a result, the compound of Example 1 effectively inhibited the production of TNFα and IL-6 in LPS-stimulated Raw264.7 cells in a concentration-dependent manner, and it was confirmed that it was statistically significant compared with the solvent group ( Figure 4 ).

[0605] Nuclear factor-κB (NF-κB), which plays an important role in inflammatory responses, is a transcription factor that regulates the synthesis of various cytokines, chemokines, and growth factors. NFκB consists of p50 and p65, enters the cell nucleus, acts as a transcription factor, synthesizes iNOS, COX-2, and inflammation-related cytokines, and usually binds to the inhibitory factor NF-κBα (IκBα) in the cytoplasm, thereby inhibiting the action of NF-κB. In order to confirm whether the compound of Example 1 affects NF-κB-related cell signaling induced in Raw264.7 cells, NF-κB promoter-luciferase analysis and pIKKαβ expression change analysis were performed in Raw264.7 cells using 1 mg / mL of LPS and the compound of Example 1 at concentrations of 0, 12 μM, 25 μM, and 50 μM. As a result, when the Raw264.7 / NF-κb-luciferase cells were treated with 1 mg / mL LPS, a strong luminescent signal appeared, but when treated with the compound of Example 1, the luminescent signal decreased in a concentration-dependent manner, and statistical significance was confirmed when compared with the vehicle group ( Figure 5 In addition, it was confirmed that the compound of Example 1 effectively reduced the expression of pIKKαβ protein ( Figure 6 ).

[0606] It can be seen that the compound of Example 1, as a PPARδ agonist, regulates NF-κb cell signaling in macrophages and effectively controls inflammatory cytokines.

[0608] <Experimental Example 6> Macrophage Image Analysis

[0609] The inflammation model induced by λ-carrageenan in the foot area of ​​mice is an acute arthritis model and is useful for examining the effect of inhibiting edema caused by osteoarthritis. In order to confirm the ability of the compound of Example 1 to inhibit acute inflammation, the macrophage tracking technique ( Figure 7 ) and the above <Experimental method> 8 were used for the experiment.

[0610] As a result, it was confirmed that there was no fluorescent signal in the sole of the foot of all experimental groups injected with 0.1% CG before induction of inflammation. On the other hand, 6 hours after induction of inflammation, a strong fluorescent signal was confirmed in the sole of the foot injected with 0.1% CG in the vehicle group. At the same time, in the group treated with 50 mg / kg of the compound of Example 1, a fluorescent signal lower than that of the vehicle group was confirmed in the sole of the foot injected with 0.1% CG, and a statistically significant ( Figure 8 and Fig. 9 ).

[0611] This confirmed that the compound of Example 1 is non-cytotoxic as a PPARδ agonist and effectively inhibits the production of inflammatory cytokines and NO by regulating NF-κb cell signaling in macrophages. It was also confirmed that it effectively prevents the infiltration of macrophages into acute inflammatory areas.

[0613] Although the present disclosure is described in detail through the above preferred embodiments and experimental examples, the scope of the present disclosure is not limited to the specific embodiments and should be interpreted according to the attached claims. In addition, those skilled in the art should understand that various modifications and variations can be made without departing from the scope of the present disclosure.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof or a salt thereof: [Chemical formula 1] in, In Chemical Formula 1, R 1 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 Haloalkoxy; R 2 Each independently is -H, C 1-5 Alkyl or -OR 21 , Among them, R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 Alkyl; and x and y are each independently an integer of 1 to 5.

2. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 2: [Chemical formula 2] Wherein, in Chemical Formula 2, R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy; R 22 -H or C 1-5 Alkyl; and R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 alkyl.

3. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 3: [Chemical formula 3] Among them, in chemical formula 3, R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy; R 211 and R 212 Each is independently -H or C 1-5 Alkyl; and R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 alkyl.

4. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 21 for 5. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 1 Each is independently -H, halogen, -CH3, -CF3 or -OCF3.

6. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein The compound represented by Chemical Formula 1 is any one selected from the following compound groups: (1) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (2) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (3) 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (4) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile; (5) 2-(((4-((2H-tetrazolyl-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole; (6) N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide; (7) N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide; (8) N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide; (9) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (10) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (11) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (12) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (13) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (14) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (15) 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (16) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (17) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (18) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (19) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (20) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (21) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (22) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (23) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (24) 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (25) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (26) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; and (27) 2-Methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid.

7. A pharmaceutical composition for preventing or treating an inflammatory disease, the pharmaceutical composition comprising a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, [Chemical formula 1] in, In Chemical Formula 1, R 1 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 Haloalkoxy; R 2 Each independently is -H, C 1-5 Alkyl or -OR 21 , Among them, R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 Alkyl; and x and y are each independently an integer of 1 to 5.

8. The pharmaceutical composition according to claim 7, wherein The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 2: [Chemical formula 2] Wherein, in Chemical Formula 2, R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy; R 22 -H or C 1-5 Alkyl; and R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 alkyl.

9. The pharmaceutical composition according to claim 7, wherein The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 3: [Chemical formula 3] Among them, in chemical formula 3, R 11 , R 12 and R 13 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Haloalkoxy; R 211 and R 212 Each is independently -H or C 1-5 Alkyl; and R 213 -OH, -NH2, -NHOR 214 or -NHCN, R 214 -H or C 1-5 alkyl.

10. The pharmaceutical composition according to claim 7, wherein R 21 for 11. The pharmaceutical composition according to claim 7, wherein R 1 Each is independently -H, halogen, -CH3, -CF3 or -OCF3.

12. The pharmaceutical composition according to claim 7, wherein The compound represented by Chemical Formula 1 is any one selected from the following compound groups: (1) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (2) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (3) 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (4) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile; (5) 2-(((4-((2H-tetrazolyl-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole; (6) N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide; (7) N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide; (8) N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide; (9) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (10) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (11) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (12) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (13) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (14) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (15) 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (16) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (17) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (18) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (19) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid; (20) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid; (21) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid; (22) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (23) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (24) 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; (25) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid; (26) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; and (27) 2-Methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid.

13. The pharmaceutical composition according to claim 7, wherein The inflammatory disease is inflammatory bowel disease, osteoarthritis, bronchitis, rheumatoid arthritis, degenerative arthritis, asthma, atopy, diabetes, myocardial infarction, Crohn's disease or psoriasis.

14. A health functional food composition for preventing or improving inflammatory diseases, the health functional food composition comprising a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof or a salt thereof as an active ingredient, [Chemical formula 1] in, In Chemical Formula 1, R 1 are independently -H, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 Haloalkoxy; R 2 Each independently is -H, C 1-5 Alkyl or -OR 21 , Among them, R 21 C 1-5 Alkyl, heteroaryl C containing 5 to 8 atoms selected from the group consisting of one or more heteroatoms selected from N, O and S 1-5 Alkyl, or Among them, R 211 and R 212 Each is independently -H or C 1-5 Alkyl, R 213 -OH, -NH2, -NHOR 214 or -NHCN, and R 214 -H or C 1-5 Alkyl; and x and y are each independently an integer of 1 to 5.

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