Thiadiazole compound and pharmaceutical composition containing same for preventing or treating inflammatory diseases

Abstract

The present invention relates to a novel thiadiazole derivative compound and a pharmaceutical composition for preventing or treating inflammatory diseases comprising the same as an active ingredient. The compound according to one embodiment is an effective PPARδ agonist, and can effectively inhibit the production of inflammatory factors and nitric oxide, and is effective in preventing the infiltration of macrophages into inflammatory sites, and therefore can be usefully used as a pharmaceutical composition for preventing or treating inflammatory diseases.

Description

[Technical field]

[0001] The present invention relates to a thiadiazole compound and a pharmaceutical composition containing the same for preventing or treating an inflammatory disease. [Background technology]

[0002] Peroxisome proliferator-activated receptors (PPARs) are the nuclear receptors that constitute the ligand-activated transcription factors. According to their ligand specificity, physiological role and tissue distribution, PPARs are classified into three subtypes: PPARα, PPARγ and PPARδ. In particular, PPARδ (also called PPARβ) is one of the PPAR transcription factors essential for various biological functions, and unlike PPARα and PPARγ, PPARδ is expressed ubiquitously. Therefore, the content regarding its function and application in the field of drug development is least known among the PPARs. However, since the discovery of high-affinity PPARδ agonists such as GW0742 and GW501516, many researchers have studied the role of PPARδ in diseases such as cancer, nervous system disorders, inflammation, dyslipidemia, heart disease and liver disease, as well as obesity and diabetes. Summary of the Invention [Problem to be solved by the invention]

[0003] One embodiment is to provide novel thiadiazole derivative compounds.

[0004] Another embodiment provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising a thiadiazole derivative compound.

[0005] Another embodiment is to provide a health functional food composition for preventing or improving an inflammatory disease, comprising a thiadiazole derivative compound.

[0006] Another embodiment of the present invention 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 pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0007] Another embodiment of the present invention provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of an inflammatory disease.

[0008] Another embodiment provides the use of the compound, its stereoisomer, its hydrate or its pharma- ceutically acceptable salt for the manufacture of a medicament for the treatment of an inflammatory disease. [Means for solving the problem]

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

[0010] [ka]

[0011] In the above Chemical Formula 1,

[0012] R 1 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 haloalkoxy;

[0013] R 2 are independently -H, C 1-5 Alkyl or -OR 21 and

[0014] R 21 Cyano C 1-5 Heteroaryl C having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S1-5 Alkyl or [ka] and

[0015] R 211 and R 212 are each independently -H or C 1-5 alkyl, and R 213 -OH, -NH2, -NHOR 214 or -NHCN,

[0016] R 214 is -H or C 1-5 is alkyl; and

[0017] x and y each independently represents an integer of 1 to 5.

[0018] Another embodiment provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0019] Another embodiment provides a health functional food composition for preventing or improving an inflammatory disease, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0020] Another embodiment provides a method for treating an inflammatory disease, comprising administering the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0021] Another embodiment provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of an inflammatory disease.

[0022] Another embodiment provides a use of the compound, its stereoisomer, its hydrate or its pharma- ceutically acceptable salt for the manufacture of a medicament for the treatment of an inflammatory disease. Effect of the Invention

[0023] The present invention 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, and can effectively inhibit the production of inflammatory factors and nitric oxide, and is effective in preventing the infiltration of macrophages into inflammatory sites, and therefore can be usefully used as a pharmaceutical composition for preventing or treating inflammatory diseases. [Brief description of the drawings]

[0024] [Figure 1] 1 shows the results of analyzing the cytotoxicity of the compound of Example 1. [Diagram 2] 1 is a diagram showing the results of analyzing the nitric oxide (NO) production inhibitory effect of the compound of Example 1. [Diagram 3] 1 is a diagram showing the results of analyzing the inhibitory effect of the compound of Example 1 on the expression of nitric oxide synthase iNOS protein. [Figure 4] 1 is a diagram 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. [Diagram 5] 1 is a diagram showing the results of analyzing the inhibitory effect of the compound of Example 1 on the activity of an inflammatory factor, NF-κ. [Figure 6] 1 is a diagram showing the results of analyzing the effect of the compound of Example 1 in reducing the expression of inflammation-related p-IKKαβ protein. [Figure 7] 1 is a diagram showing the process of a macrophage tracking experiment carried out using the compound of Experimental Example 1. [Figure 8] 1 shows the results of analyzing the macrophage infiltration inhibitory effect of the compound of Experimental Example 1 using mice with induced acute inflammation. [Figure 9]1 shows the results of analyzing the macrophage infiltration inhibitory effect of the compound of Experimental Example 1 using mice with induced acute inflammation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The embodiments described herein may be modified into various other forms, and the technology according to one embodiment is not limited to the embodiment described below. Moreover, the embodiment of one embodiment is provided to more completely explain the present invention to those skilled in the art. Furthermore, the term "including" a certain element in the entire specification means that it does not exclude other elements, but may further include other elements, unless otherwise specified to the contrary.

[0026] Numerical ranges used herein include lower and upper limits and all values ​​within the range, increments logically derived from the form and width of the range defined, all values ​​that are doubly limited, and all possible combinations of upper and lower limits of numerical ranges that are limited in different forms. For example, if the content of a composition is limited to 10-80% or 20-50%, the numerical ranges of 10-50% or 50-80% should also be interpreted as being described in the present specification. In the present specification, unless otherwise specified, values ​​outside the numerical range that may occur due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0027] Hereinafter, unless otherwise defined, "about" is considered to mean a value within 30%, 25%, 20%, 15%, 10% or 5% of the specified value.

[0028] One embodiment provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof:

[0029] [ka]

[0030] In the above Chemical Formula 1,

[0031] R 1 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 haloalkoxy;

[0032] R 2 are independently -H, C 1-5 Alkyl or -OR 21 and

[0033] R 21 Cyano C 1-5 Heteroaryl C having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-5 Alkyl or [ka] and

[0034] R 211 and R 212 are each independently -H or C 1-5 alkyl, and R 213 -OH, -NH2, -NHOR 214 or -NHCN,

[0035] R 214 is -H or C 1-5 is alkyl; and

[0036] x and y each independently represents an integer of 1 to 5.

[0037] In one embodiment, the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 2 below.

[0038] [ka]

[0039] In the above Chemical Formula 2,

[0040] R 11 , R 12 and R 13 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 haloalkoxy;

[0041] R 22 is -H or C 1-5 is alkyl; and

[0042] R 21 Cyano C 1-5 Heteroaryl C having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-5 Alkyl or [ka] and

[0043] R 211 and R 212 are each independently -H or C 1-5 alkyl, and R 213 -OH, -NH2, -NHOR 214 or -NHCN,

[0044] R 214 is -H or C 1-5 It is an alkyl.

[0045] In one embodiment, the compound represented by Formula 1 is a compound represented by Formula 3 below.

[0046] [ka]

[0047] In the above Chemical Formula 3,

[0048] R11 , R 12 and R 13 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 haloalkoxy;

[0049] R 211 and R 212 are each independently -H or C 1-5 is alkyl; and

[0050] R 213 -OH, -NH2, -NHOR 214 or -NHCN, wherein R 214 is -H or C 1-5 It is an alkyl.

[0051] In one embodiment, the R 1 , R 11 , R 12 , and R 13 are each 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 Haloalkoxy, C 1-3 Haloalkoxy, C 1-2 It is haloalkoxy, C1 haloalkoxy or -OCF3.

[0052] In one embodiment, the R 2 are each independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0053] In one embodiment, the R 21 Cyano C 1-4 Alkyl, Cyano C 1-3 Alkyl, Cyano C 1-2Heteroaryl C having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-4 Heteroaryl C having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-3 Heteroaryl C having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-2 heteroaryl C1 alkyl having 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S; [ka] It is.

[0054] In one embodiment, the R 211 and R 212 are each independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0055] In one embodiment, the R 214 are each independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0056] In one embodiment, the x and y are each independently an integer of 1 to 4 and an integer of 1 to 3.

[0057] In one embodiment, the compound represented by Chemical Formula 1 is any one selected from the following compound group:

[0058] (1) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0059] (2) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0060] (3) 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0061] (4) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile;

[0062] (5) 2-(((4-((2H-tetrazol-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole;

[0063] (6) N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0064] (7) N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0065] (8) N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0066] (9) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0067] (10) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0068] (11) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0069] (12) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0070] (13) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0071] (14) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0072] (15) 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0073] (16) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0074] (17) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0075] (18) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0076] (19) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0077] (20) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0078] (21) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0079] (22) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0080] (23) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0081] (24) 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0082] (25) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0083] (26) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; and

[0084] (27) 2-Methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid.

[0085] In one embodiment, the compound represented by Chemical Formula 1 may be used in the form of a pharma- ceutically acceptable salt, and the salt may be an acid addition salt formed with a pharma- ceutically acceptable free acid. The acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, non-toxic organic acids such as aliphatic mono- and di-carboxylates, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. Such pharma- ceutically non-toxic salt types include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexane-1,6-dioate, benzoate, benzoic acid ... These include phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0086] An embodiment includes not only the compound represented by Chemical Formula 1 and its pharma- ceutically acceptable salts, but also solvates, optical isomers, hydrates, and the like that can be produced thereby.

[0087] In one embodiment, there is provided a pharmaceutical composition for preventing or treating an inflammatory disease, comprising a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient:

[0088] [ka]

[0089] In the above Chemical Formula 1,

[0090] R 1 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy or C 1-5 haloalkoxy;

[0091] R 2 are independently -H, C 1-5 Alkyl or -OR 21 and

[0092] R 21 Cyano C 1-5 Heteroaryl C having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-5 Alkyl or [ka] and

[0093] R 211 and R 212 are each independently -H or C 1-5 alkyl, and R 213 -OH, -NH2, -NHOR 214 or -NHCN,

[0094] R 214 is -H or C 1-5 is alkyl; and

[0095] x and y each independently represents an integer of 1 to 5.

[0096] In one embodiment, the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 2 below. [ka]

[0097] In the above Chemical Formula 2,

[0098] R 11 , R 12 and R 13 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 haloalkoxy;

[0099] R 22 is -H or C 1-5 is alkyl; and

[0100] R 21 Cyano C 1-5 Heteroaryl C having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-5 Alkyl or [ka] and

[0101] R 211 and R 212 are each independently -H or C 1-5 alkyl, and R 213 -OH, -NH2, -NHOR 214 or -NHCN,

[0102] R 214 is -H or C 1-5 It is an alkyl.

[0103] In one embodiment, the compound represented by Formula 1 is a compound represented by Formula 3 below.

[0104] [ka]

[0105] In the above Chemical Formula 3,

[0106] R 11 , R 12 and R 13 are each independently -H, halogen, or C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 haloalkoxy;

[0107] R 211 and R 212 are each independently -H or C 1-5 is alkyl; and

[0108] R 213 -OH, -NH2, -NHOR 214 or -NHCN, wherein R 214 is -H or C 1-5 It is an alkyl.

[0109] In one embodiment, the R 1 , R 11 , R 12 , and R 13 are each 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 Haloalkoxy, C 1-3Haloalkoxy, C 1-2 It is haloalkoxy, C1 haloalkoxy or -OCF3.

[0110] In one embodiment, the R 2 are each independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0111] In one embodiment, the R 21 Cyano C 1-4 Alkyl, Cyano C 1-3 Alkyl, Cyano C 1-2 Heteroaryl C having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-4 Heteroaryl C having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-3 Heteroaryl C having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S 1-2 heteroaryl C1 alkyl having 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S; [ka] It is.

[0112] In one embodiment, the R 211 and R 212 are each independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0113] In one embodiment, the R 214 are each independently C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3.

[0114] In one embodiment, the x and y are each independently an integer of 1 to 4 and an integer of 1 to 3.

[0115] In one embodiment, the compound represented by Chemical Formula 1 is any one selected from the following compound group:

[0116] (1) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0117] (2) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0118] (3) 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0119] (4) 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile;

[0120] (5) 2-(((4-((2H-tetrazol-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole;

[0121] (6) N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0122] (7) N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0123] (8) N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide;

[0124] (9) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0125] (10) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0126] (11) 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0127] (12) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0128] (13) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0129] (14) 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0130] (15) 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0131] (16) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0132] (17) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0133] (18) 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0134] (19) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid;

[0135] (20) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid;

[0136] (21) 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid;

[0137] (22) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0138] (23) 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0139] (24) 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid;

[0140] (25) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid;

[0141] (26) 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid; and

[0142] (27) 2-Methyl-2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid.

[0143] In one embodiment, the inflammatory disease is not particularly limited as long as it is an inflammatory disease, examples of which include, but are not limited to, inflammatory bowel disease, osteoarthritis, bronchitis, rheumatoid arthritis, degenerative arthritis, asthma, atopy, diabetes, myocardial infarction, Crohn's disease, and psoriasis.

[0144] The compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof is administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using a diluent or excipient such as a typical filler, extender, binder, wetting agent, disintegrant, or surfactant. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing one or more compounds with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and in addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, are included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0145] The pharmaceutical composition containing the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0146] In this case, in order to prepare a formulation for parenteral administration, the compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof may be mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which may then be prepared in an ampule or vial for unit administration. The composition may be sterilized or contain auxiliary agents such as preservatives, stabilizers, hydrating agents or emulsifying agents, salts for adjusting osmotic pressure and / or buffers, and other therapeutically useful substances, and may be formulated by a conventional mixing, granulation, or coating method.

[0147] Dosage forms for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, and lozenges, which contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and may optionally contain disintegrants or boiling mixtures such as starch, agar, alginic acid or its sodium salt, and / or absorbents, colorants, flavors, and sweeteners.

[0148] In one embodiment, there is provided a health functional food composition for preventing or improving an inflammatory disease, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.

[0149] The compound represented by Chemical Formula 1 according to one embodiment may be added directly to food or may be used together with other food or food ingredients, and may be used appropriately in a conventional manner. The amount of the active ingredient to be mixed may be determined appropriately depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in a health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for the purpose of health and hygiene or health regulation, the amount is within the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.

[0150] In addition, the health functional food composition according to one embodiment is not particularly limited in terms of other ingredients other than containing the above-mentioned compound, and may contain various flavorings or natural carbohydrates, etc. as additional ingredients, like ordinary beverages.

[0151] Additionally, it may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc.

[0152] In one embodiment, there is provided a method for treating an inflammatory disease, comprising administering the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0153] An embodiment provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of an inflammatory disease.

[0154] An embodiment provides the use of the compound, its stereoisomer, its hydrate or its pharma- ceutically acceptable salt for use in the manufacture of a medicament for the treatment of an inflammatory disease.

[0155] Examples and experimental examples are specifically illustrated below. However, the examples and experimental examples described below are only a partial list, and the technology described in this specification is not limited thereto.

[0156] <Example 1> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0157] Step 1: Preparation of 4-(trifluoromethyl)benzohydrazide (b-1) [ka]

[0158] Ethyl-4-(trifluoromethyl)benzoate (2.033 mL, 11.46 mmol) was dissolved in MeOH (10 mL), and hydrazine hydrate (1.671 mL, 27.5 mmol) was added at 0° C., followed by stirring 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 the mixture to obtain compound b-1 (2.21 g, 10.83 mmol).

[0159] Step 2: Preparation of ethyl 2-oxo-2-(2-(4-(trifluoromethyl)benzoyl)hydrazine mono)acetate (c-1) [ka]

[0160] 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, yield 85%), which was used in the next step without further purification.

[0161] Step 3: Preparation of ethyl 5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-1) [ka]

[0162] 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, the mixture was filtered through celite, washed with NaHCO3, and the organic layer was dried over anhydrous MgSO4. The residue was concentrated under reduced pressure and purified by MPLC (silica gel, 0-25%, EtOAc / Hexane) to obtain compound d-1 (0.88 g, yield 89%).

[0163] ESI LC / MS:m / z calcd.for C 12 H 10 F3N2O2S[M+H] + :303.04;found 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).

[0164] Step 4: Preparation of 5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-1) [ka]

[0165] Compound d-1 (0.8 g, 2.64 mmol) was dissolved in methanol, and sodium borohydride (0.31 g, 7.94 mmol) was gradually added at 0°C, followed by stirring at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with an aqueous solution of NH4Cl, concentrated under reduced pressure, extracted with ethyl acetate, and dried over anhydrous Na2SO4. The residue obtained 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, yield 89%) as a pale yellow solid.

[0166] ESI LC / MS:m / z calcd.for C 10 H8F3N2OS[M+H]+ :261.03;found 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.

[0167] Step 5: Preparation of 2-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (f-1) [ka]

[0168] Compound e-1 (1 g, 3.84 mmol) was dissolved in CH2Cl2 (10 mL), triphenylporphine (1.2 g, 4.61 mmol) and isothiocyanic acid (NCS) (0.616 g, 4.61 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was washed with water and brine, and dried over anhydrous MgSO4. The mixture was concentrated under reduced pressure to remove volatile substances, and the resulting residue was purified by MPLC (silica gel, 0-20%, EtOAc / Hexane) to obtain compound f-1 (0.203 g, yield 19%).

[0169] ESI LC / MS:m / z calcd.for C 10 H7ClF3N2S[M+H] + :279.01;found 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). 13 C NMR (CD3OD, 100MHz) δ169.38, 168.29, 133.05, 132.48, 128.20, 128.06, 125.98, 125.14, 122.45, 37.42.

[0170] Step 6: Preparation of 2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-1) [ka]

[0171] 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 dropwise and stirred at room temperature for 2 hours. The solvent was removed by concentrating under reduced pressure, and the mixture was extracted with ethyl acetate and dried over anhydrous Na2SO4. The residue obtained 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, yield 85%).

[0172] ESI LC / MS:m / z calcd.for C 17 H 14 F3N2OS2[M+H] + :383.04;found 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.

[0173] 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) [ka]

[0174] Compound g-1 (0.3 g, 0.78 mmol) was dissolved in acetonitrile (5 mL), and cesium carbonate (0.38 g, 1.17 mmol) and methyl 2-bromoacetate (0.9 mL, 0.94 mmol) were added dropwise and stirred at room temperature for 1 hour and 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure to remove acetonitrile, washed with water and brine, extracted with EtOAc, and dried over anhydrous Na2SO4. The residue obtained 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, yield 96%).

[0175] Step 8: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (1) [ka]

[0176] Compound h-1 (0.32 g, 0.7 mmol) was dissolved in tetrahydrofuran, and then 2M lithium hydroxide aqueous solution (1.5 mL) was added at 0°C and stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with water and acidified with 1N HCl. After that, the mixture 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%).

[0177] ESI LC / MS:m / z calcd.for C 19 H 16 F3N2O3S2[M+H] + :441.06;found 441.1. 1H 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 C NMR (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.

[0178] <Example 2> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid

[0179] Step 1: Preparation of ethyl 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thiophenoxy)propanoate (i-1) [ka]

[0180] Compound i-1 (59 mg, yield 94%) was obtained in the same manner as in Example 1, except that ethyl 2-bromopropanoate was used instead of methyl 2-bromoacetate in step 7.

[0181] Step 2: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thiophenoxy)propanoic acid (2) [ka]

[0182] Compound 2 (46 mg, yield 83%) was obtained in the same manner as in Example 1, except that compound i-1 was used instead of compound h-1 in step 8.

[0183] ESI LC / MS:m / z calcd.for C 20 H 18 F3N2O3S2[M+H] + :455.07;found 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.

[0184] <Example 3> Preparation of 2-methyl-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid

[0185] 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) [ka]

[0186] Compound j-1 (18 mg, yield 28%) was obtained in the same manner as in Example 1, except that ethyl-2-bromo-2-methylpropanoate was used instead of methyl-2-bromoacetate in step 7 of Example 1.

[0187] 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) [ka]

[0188] Compound 3 (9 mg, yield 64%) was obtained in the same manner as in Example 1, except that compound j-1 was used instead of compound h-1 in step 8.

[0189] ESI LC / MS:m / z calcd.for C 21 H 20 F3N2O3S2[M+H] + :469.09;found 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 C NMR (CD3OD, 100MHz) δ177.71, 172.53, 169.65, 155.73, 136.30, 131.93, 131 .88, 129.51, 127.49, 127.45, 125.90, 118.15, 80.33, 34.91, 25.83, 16.87.

[0190] <Example 4> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetonitrile [ka]

[0191] Compound 4 (0.163 g, yield 67%) was obtained in the same manner as in Example 1, except that 2-bromoacetonitrile was used instead of methyl 2-bromoacetate in Step 7.

[0192] 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).

[0193] <Example 5> Preparation of 2-(((4-((2H-tetrazol-5-yl)methoxy)-3-methylphenyl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole [ka]

[0194] 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, yield 41%).

[0195] 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).

[0196] <Example 6> Preparation of N-hydroxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide [ka]

[0197] Compound 1 (3.7 mg, 0.008 mmol) was dissolved in 1 mL of THF, and 1,1'-carbonyldiimidazole (3.4 mg, 0.021 mmol) was added and reacted at room temperature for 1 hour. Hydroxylamine hydrochloride (1.5 mg, 0.021 mmol) was added to the reaction mixture, and the mixture was further reacted at room temperature for 16 hours. Potassium hydrogen sulfate (5.7 mg, 0.042 mmol) was added to the mixture, and 0.5 mL of distilled water was added and the mixture was further reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and compound 6 (2.7 mg, yield 69%) was obtained by separation using Prep-HPLC.

[0198] 1H 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).

[0199] <Example 7> Preparation of N-methoxy-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide [ka]

[0200] Compound 7 (9.2 Mg, yield 85%) was obtained in the same manner as in Example 6, except that O-methylhydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride.

[0201] 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).

[0202] <Example 8> Preparation of N-cyano-2-(2-methyl-4-(((5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetamide [ka]

[0203] Compound 8 (14 mg, yield 42%) was obtained in the same manner as in Example 6, except that cyanamide was used instead of hydroxylamine hydrochloride.

[0204] 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).

[0205] <Example 9> Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0206] Step 1: Preparation of 4-fluorobenzohydrazide (b-2) [ka]

[0207] Compound b-2 (1.03 g, yield 67%) was obtained in the same manner as in Example 1, except that compound a-2 was used instead of compound a-1 in step 1.

[0208] Step 2: Preparation of ethyl 2-(2-(4-fluorobenzoyl)hydrazine-1)-2-oxoacetate (c-2) [ka]

[0209] Compound c-2 (0.236 g, yield 93%) was obtained in the same manner as in Example 1, except that compound b-2 was used instead of compound b-1 in step 2.

[0210] Step 3: Preparation of ethyl 5-(4-propylphenyl)-1,3,4-thiadiazole-2-carboxylate (d-2) [ka]

[0211] Compound d-2 (0.256 g, yield 78%) was obtained in the same manner as in Example 1, except that compound c-2 was used instead of compound c-1 in step 3.

[0212] Step 4: Preparation of (5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-2) [ka]

[0213] Compound e-2 (0.185 g, yield 88%) was obtained in the same manner as in Example 1, except that compound d-2 was used instead of compound d-1 in step 4.

[0214] Step 5: Preparation of (5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (f-2) [ka]

[0215] Compound f-2 (0.178 g, yield 78%) was obtained in the same manner as in Example 1, except that compound e-2 was used instead of compound e-1 in step 5.

[0216] Step 6: Preparation of 4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio-2-methylphenol (g-2) [ka]

[0217] Compound g-2 (0.332 g, yield 97%) was obtained in the same manner as in Example 1, except that compound f-2 was used instead of compound f-1 in step 6.

[0218] Step 7: Preparation of methyl 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetate (h-2) [ka]

[0219] Compound h-2 (0.340 g, yield 84%) was obtained in the same manner as in Example 1, except that compound g-2 was used instead of compound g-1 in step 7.

[0220] Step 8: Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (9) [ka]

[0221] Compound 9 (0.363 g, yield 93%) was obtained in the same manner as in Example 1, except that compound h-2 was used instead of compound h-1 in step 8.

[0222] ESI LC / MS:m / z calcd.for C18 H 16 FN2O3S2[M+H] + :391.06;found 391. 1 H 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 C NMR (100MHz, CDCl3) δ171.38, 169.49, 168.57, 164.44 (d, JCF=251.2Hz), 156.14, 134.76 , 130.75, 129.85, 128.60, 126.11, 124.51, 116.28, 112.21, 60.50, 34.28, 16.13, 14.20.

[0223] <Example 10> Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0224] Step 1: Preparation of ethyl 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoate (i-2) [ka]

[0225] Compound i-2 (0.320 g, yield 74%) was obtained in the same manner as in Example 1, except that compound g-2 was used instead of compound g-1 in step 7 and ethyl 2-bromopropanoate was used instead of methyl 2-bromoacetate.

[0226] Step 2: Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (10) [ka]

[0227] Compound 10 (0.259 g, yield 64%) was obtained in the same manner as in Example 1, except that compound i-2 was used instead of compound h-1 in step 8.

[0228] ESI LC / MS:m / z calcd.for C 19 H 18 FN2O3S2[M+H] + :405.08;found 405. 1 H 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.

[0229] <Example 11> Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0230] Step 1: Preparation of ethyl 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoate (j-2) [ka]

[0231] Compound j-2 (0.174 g, yield 39%) was obtained in the same manner as in Example 1, except that compound g-2 was used instead of compound g-1 in step 7 and ethyl 2-bromo-2-methylpropanoate was used instead of methyl 2-bromoacetate.

[0232] Step 2: Preparation of 2-(4-(((5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (11) [ka]

[0233] Compound 11 (0.167 g, yield 40%) was obtained in the same manner as in Example 1, except that compound j-2 was used instead of compound h-1 in step 8.

[0234] ESI LC / MS:m / z calcd.for C 20 H 20 FN2O3S2[M+H] + :419.09;found 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). 13C 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.

[0235] <Example 12> Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0236] Step 1: Preparation of 3,4-difluorobenzohydrazide (b-3) [ka]

[0237] Compound b-3 (0.34 g, yield 73.5%) was obtained in the same manner as in Example 1, except that compound a-3 was used instead of compound a-1 in step 1.

[0238] Step 2: Preparation of ethyl 2-(2-(3,4-difluorobenzoyl)hydrazine-1)-2-oxoacetate (c-3) [ka]

[0239] Compound c-3 (0.36 g, yield 67%) was obtained in the same manner as in Example 1, except that compound b-3 was used instead of compound b-1 in step 2.

[0240] Step 3: Preparation of ethyl 5-(3,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-3) [ka]

[0241] Compound d-3 (54 mg, yield 34%) was obtained in the same manner as in Example 1, except that compound c-3 was used instead of compound c-1 in step 3.

[0242] Step 4: Preparation of (5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (e-3) [ka]

[0243] Compound e-3 (45 mg, yield 99%) was obtained in the same manner as in Example 1, except that compound d-3 was used instead of compound d-1 in step 4.

[0244] Step 5: Preparation of 2-(chloromethyl)-5-(3,4-difluorophenyl)-1,3,4-thiadiazole (f-3) [ka]

[0245] Compound f-3 (36 mg, yield 74%) was obtained in the same manner as in Example 1, except that compound e-3 was used instead of compound e-1 in step 5.

[0246] Step 6: Preparation of 4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenol (g-3) [ka]

[0247] Compound g-3 (50 mg, yield 98%) was obtained in the same manner as in Example 1, except that compound f-3 was used instead of compound f-1 in step 6.

[0248] 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) [ka]

[0249] Compound h-3 (64 mg, yield 99%) was obtained in the same manner as in Example 1, except that compound g-3 was used instead of compound g-1 in step 7.

[0250] Step 8: Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (12) [ka]

[0251] Compound 12 (25 mg, yield 39.8%) was obtained in the same manner as in Example 1, except that compound h-3 was used instead of compound h-1 in step 8.

[0252] ESI LC / MS:m / z calcd.for C 18 H 15 F2N2O3S2[M+H] + :409.05;found 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).

[0253] <Example 13> Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0254] Step 1: Preparation of ethyl 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoate (i-3) [ka]

[0255] Compound i-3 (67 mg, yield 97%) was obtained in the same manner as in Example 1, except that compound g-3 was used instead of compound g-1 in step 7 and 2-bromopropanoic acid was used instead of methyl 2-bromoacetate.

[0256] Step 2: Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (13) [ka]

[0257] Compound 13 (3 mg, yield 5%) was obtained in the same manner as in Example 1, except that compound i-3 was used instead of compound h-1 in step 8.

[0258] ESI LC / MS:m / z calcd.for C 19 H 18 FN2O3S2[M+H] + :423.07;found 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).

[0259] <Example 14> Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0260] 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) [ka]

[0261] Compound j-3 (33 mg, yield 50%) was obtained in the same manner as in Example 1, except that compound g-3 was used instead of compound g-1 in step 7 and ethyl 2-bromo-2-methylpropanoate was used instead of methyl 2-bromoacetate.

[0262] Step 2: Preparation of 2-(4-(((5-(3,4-difluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (14) [ka]

[0263] Compound 14 (12 Mg, yield 38%) was obtained in the same manner as in Example 1, except that compound j-3 was used instead of compound h-1 in step 8.

[0264] ESI LC / MS:m / z calcd.for C 19 H 18 FN2O3S2[M+H] + :437.08;found 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). 13 C 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.

[0265] <Example 15> Preparation of 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0266] Step 1: Preparation of 3,4,5-trifluorobenzohydrazide (b-4) [ka]

[0267] Compound b-4 (0.74 g, yield 39%) was obtained in the same manner as in Example 1, except that compound a-4 was used instead of compound a-1 in step 1 of Example 1.

[0268] Step 2: Preparation of ethyl 2-oxo-2-(2-(3,4,5-trifluorobenzoyl)hydrazine mono)acetate (c-4) [ka]

[0269] Compound c-4 (0.209 g, yield 72%) was obtained in the same manner as in Example 1, except that compound b-4 was used instead of compound b-1 in step 2.

[0270] Step 3: Preparation of ethyl 5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-4) [ka]

[0271] Compound d-4 (0.21 g, yield 56%) was obtained in the same manner as in Example 1, except that compound c-4 was used instead of compound c-1 in step 3.

[0272] Step 4: Preparation of (5-3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (e-4) [ka]

[0273] Compound e-4 (0.24 g, yield 99%) was obtained in the same manner as in Example 1, except that compound d-4 was used instead of compound d-1 in step 4.

[0274] Step 5: Preparation of 2-(chloromethyl)-5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazole (f-4) [ka]

[0275] Compound f-4 (0.18 g, yield 68%) was obtained in the same manner as in Example 1, except that compound e-4 was used instead of compound e-1 in step 5.

[0276] Step 6: Preparation of 2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-4) [ka]

[0277] Compound g-4 (0.368 g, yield 99%) was obtained in the same manner as in Example 1, except that compound f-4 was used instead of compound f-1 in step 6.

[0278] 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) [ka]

[0279] Compound h-4 (0.247 g, yield 56%) was obtained in the same manner as in Example 1, except that compound g-4 was used instead of compound g-1 in step 7.

[0280] Step 8: 2-(2-methyl-4-(((5-(3,4,5-trifluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (15) [ka]

[0281] Compound 15 (64 mg, yield 15%) was obtained in the same manner as in Example 1, except that compound h-4 was used instead of compound h-1 in step 8 of Example 1.

[0282] ESI LC / MS:m / z calcd.for C 18 H 14 F3N2O3S2[M+H] + :427.04;found 427. 1 H 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). <Example 16> Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0283] Step 1: Preparation of 3-chloro-4-fluorobenzohydrazide (b-5) [ka]

[0284] Compound b-5 (0.60 g, yield 88%) was obtained in the same manner as in Example 1, except that compound a-5 was used instead of compound a-1 in step 1 of Example 1.

[0285] Step 2: Preparation of ethyl 2-(2-(3-chloro-4-fluorobenzoyl)hydrazine-1)-2-oxoacetate (c-5) [ka]

[0286] Compound c-5 (0.60 g, yield 88%) was obtained in the same manner as in Example 1, except that compound b-5 was used instead of compound b-1 in step 2.

[0287] Step 3: Preparation of ethyl 5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazole-2-carboxylate (d-5) [ka]

[0288] Compound d-5 (0.556 g, yield 60%) was obtained in the same manner as in Example 1, except that compound c-5 was used instead of compound c-1 in step 3.

[0289] Step 4: Preparation of (5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol (e-5) [ka]

[0290] Compound e-5 (0.451 g, yield 87%) was obtained in the same manner as in Example 1, except that compound d-5 was used instead of compound d-1 in Step 4.

[0291] 1 H 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).

[0292] Step 5: Preparation of 2-(3-chloro-4-fluorophenyl)-5-(chloromethyl)-1,3,4-thiadiazole (f-5) [ka]

[0293] Compound f-5 (0.259 g, yield 53%) was obtained in the same manner as in Example 1, except that compound e-5 was used instead of compound e-1 in step 5.

[0294] 1H 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).

[0295] Step 6: Preparation of 4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenol (g-5) [ka]

[0296] Compound g-5 (69 mg, yield 97%) was obtained in the same manner as in Example 1, except that compound f-5 was used instead of compound f-1 in step 6.

[0297] 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) [ka]

[0298] Compound H-5 (74 mg, yield 89%) was obtained in the same manner as in Example 1, except that compound G-5 was used instead of compound G-1 in step 7.

[0299] 1 H 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).

[0300] Step 8: Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid (16) [ka]

[0301] Compound 16 (44 mg, yield 88%) was obtained in the same manner as in Example 1, except that compound h-5 was used instead of compound h-1 in step 8 of Example 1.

[0302] ESI LC / MS:m / z calcd.for C 18 H 15 ClFN2O3S2[M+H] + :425.02;found 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.

[0303] <Example 17> Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0304] 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) [ka]

[0305] Compound i-5 (74.8 mg, yield 70.2%) was obtained in the same manner as in Example 1, except that compound g-5 was used instead of compound g-1 in step 7 and compound ethyl 2-bromopropanoate was used instead of methyl 2-bromoacetate.

[0306] 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).

[0307] Step 2: Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid (17) [ka]

[0308] Compound 17 (33 mg, yield 85%) was obtained in the same manner as in Example 1, except that compound i-5 was used instead of compound h-1 in step 8.

[0309] 1H 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). 13 C 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.

[0310] <Example 18> Preparation of 2-(4-(((5-(3-chloro-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid

[0311] 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) [ka]

[0312] Compound j-5 (12 Mg, yield 13%) was obtained in the same manner as in Example 1, except that compound g-5 was used instead of compound g-1 in step 7 and compound ethyl 2-bromo-2-methylpropanoate was used instead of methyl 2-bromoacetate.

[0313] 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) [ka]

[0314] Compound 18 (3 mg, yield 26%) was obtained in the same manner as in Example 1, except that compound j-5 was used instead of compound h-1 in step 8.

[0315] ESI LC / MS:m / z calcd.for C 20 H 19 ClFN2O3S2[M+H] + :453.05;found 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.

[0316] <Example 19> Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)acetic acid

[0317] Step 1: Preparation of 3-fluoro-4-(trifluoromethyl)benzohydrazide (b-6) [ka]

[0318] Compound b-6 (2.044 g, yield 92%) was obtained in the same manner as in Example 1, except that compound a-6 was used instead of compound a-1 in step 1 of Example 1.

[0319] Step 2: Preparation of ethyl 2-(2-(3-fluoro-4-(trifluoromethyl)benzoyl)hydrazine-1)-2-oxoacetate (c-6) [ka]

[0320] Compound c-6 (0.139 g, yield 43%) was obtained in the same manner as in Example 1, except that compound b-6 was used instead of compound b-1 in step 2.

[0321] Step 3: Preparation of ethyl 5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole-2-carboxylate (d-6) [ka]

[0322] Compound d-6 (0.371 g, yield 89%) was obtained in the same manner as in Example 1, except that compound c-6 was used instead of compound c-1 in step 3.

[0323] Step 4: Preparation of (5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-6) [ka]

[0324] Compound e-6 (0.253 g, yield 91%) was obtained in the same manner as in Example 1, except that compound d-6 was used instead of compound d-1 in step 4.

[0325] Step 5: Preparation of 2-(chloromethyl)-5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (f-6) [ka]

[0326] Compound f-6 (0.234 g, yield 79%) was obtained in the same manner as in Example 1, except that compound e-6 was used instead of compound e-1 in step 5.

[0327] Step 6: Preparation of 4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenol (g-6) [ka]

[0328] Compound g-6 (0.401 g, yield 97%) was prepared in the same manner as in Example 1, except that compound f-6 was used instead of compound f-1 in step 6.

[0329] 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) [ka]

[0330] Compound h-6 (0.421 g, yield 89%) was obtained in the same manner as in Example 1, except that compound g-6 was used instead of compound g-1 in step 7.

[0331] 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) [ka]

[0332] Compound 19 (0.264 g, yield 60%) was obtained in the same manner as in Example 1, except that compound h-6 was used instead of compound h-1 in step 8 of Example 1.

[0333] 1 H 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 C NMR (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.

[0334] <Example 20> Preparation of 2-(4-(((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)-2-methylphenoxy)propanoic acid

[0335] 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) [ka]

[0336] Compound i-6 (0.360 g, 72%) was obtained in the same manner as in Example 1, except that compound g-6 was used instead of compound g-1 in step 7 and compound ethyl 2-bromopropanoate was used instead of compound methyl 2-bromoacetate in step 7.

[0337] 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) [ka]

[0338] Compound 20 (0.300 g, yield 66%) was obtained in the same manner as in Example 1, except that compound i-6 was used instead of compound h-1 in step 8.

[0339] 1 H 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). 13C 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.

[0340] <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

[0341] 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) [ka]

[0342] Compound j-6 (52 Mg, yield 10%) was obtained in the same manner as in Example 1, except that compound g-6 was used instead of compound g-1 in step 7 and ethyl 2-bromo-2-methylpropanoate was used instead of methyl 2-bromoacetate.

[0343] 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) [ka]

[0344] Compound 21 (80 mg, yield 17%) was obtained in the same manner as in Example 1, except that compound j-6 was used instead of compound h-1 in step 8.

[0345] 1 H 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).

[0346] <Example 22> Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0347] Step 1: Preparation of 4-methylbenzohydrazide (b-7) [ka]

[0348] Compound b-7 (0.78 g, yield 85%) was obtained in the same manner as in Example 1, except that compound a-7 was used instead of compound a-1 in step 1 of Example 1.

[0349] Step 2: Preparation of ethyl 2-(2-(4-methylbenzoyl)hydrazine-1)-2-oxoacetate (c-7) [ka]

[0350] Compound c-7 (1.25 g, yield 96%) was obtained in the same manner as in Example 1, except that compound b-7 was used instead of compound b-1 in step 2.

[0351] Step 3: Preparation of ethyl 5-(p-tolyl)-1,3,4-thiadiazole-2-carboxylate (d-7) [ka]

[0352] Compound d-7 (0.840 g, yield 67.7%) was obtained in the same manner as in Example 1, except that compound c-7 was used instead of compound c-1 in step 3.

[0353] Step 4: Preparation of (5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methanol (e-7) [ka]

[0354] Compound e-7 (0.690 g, yield 99%) was obtained in the same manner as in Example 1, except that compound d-7 was used instead of compound d-1 in step 4.

[0355] Step 5: Preparation of 2-(chloromethyl)-5-(p-tolyl)-1,3,4-thiadiazole (f-7) [ka]

[0356] Compound f-7 (0.359 g, yield 47.8%) was obtained in the same manner as in Example 1, except that compound e-7 was used instead of compound e-1 in step 5.

[0357] Step 6: Preparation of 2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-7) [ka]

[0358] Compound g-7 (0.560 g, yield 97%) was obtained in the same manner as in Example 1, except that compound f-7 was used instead of compound f-1 in step 6.

[0359] Step 7: Preparation of methyl 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetate (h-7) [ka]

[0360] Compound h-7 (70 mg, yield 97%) was obtained in the same manner as in Example 1, except that compound g-7 was used instead of compound g-1 in step 7.

[0361] Step 8: Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (22) [ka]

[0362] Compound 22 (34 mg, yield 96%) was obtained in the same manner as in Example 1, except that compound h-7 was used instead of compound h-1 in step 8 of Example 1.

[0363] ESI LC / MS:m / z calcd.for C 19 H 19 N2O3S2[M+H] + :387.09;found 386.8. 1 H 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).

[0364] <Example 23> Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid

[0365] Step 1: Preparation of ethyl 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoate (i-7)

[0366] [ka]

[0367] Compound i-7 (0.100 g, yield 97%) was obtained in the same manner as in Example 1, except that compound g-7 was used instead of compound g-1 and ethyl 2-bromopropanoate was used instead of methyl 2-bromoacetate in step 7 of Example 1.

[0368] Step 2: Preparation of 2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (23)

[0369] [ka]

[0370] Compound 23 (34 mg, yield 35%) was obtained in the same manner as in Example 1, except that compound i-7 was used instead of compound h-1 in step 8.

[0371] ESI LC / MS:m / z calcd.for C 20 H 21 N2O3S2[M+H] + :401.10;found 401.1. 1H 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). 13 C 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.

[0372] <Example 24> Preparation of 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid Step 1: Preparation of ethyl 2-methyl-2-(2-methyl-4-(((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (j-7)

[0373] 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) [ka]

[0374] Compound j-7 (94 mg, yield 97%) was obtained in the same manner as in Example 1, except that compound g-7 was used instead of compound g-1 in step 7 and ethyl 2-bromo-2-methylpropanoate was used instead of methyl 2-bromoacetate.

[0375] 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) [ka]

[0376] Compound 24 (2Mg, yield 3%) was obtained in the same manner as in Example 1, except that compound j-7 was used instead of compound h-1 in step 8.

[0377] 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). 13 C 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.

[0378] <Example 25> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid

[0379] Step 1: Preparation of 4-(trifluoromethyl)benzohydrazide (b-8) [ka]

[0380] Compound b-8 (1.16 g, 53%) was obtained in the same manner as in Example 1, except that compound a-8 was used instead of compound a-1 in step 1.

[0381] Step 2: Preparation of ethyl 2-(2-(4-(fluorooxy)benzoyl)hydrazine-1)-2-oxoacetate (c-8) [ka]

[0382] Compound c-8 (0.275 g, yield 86%) was obtained in the same manner as in Example 1, except that compound b-8 was used instead of compound b-1 in step 2.

[0383] Step 3: Preparation of ethyl 5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole-2-carboxylate (d-8) [ka]

[0384] Compound d-8 (0.352 g, yield 85%) was obtained in the same manner as in Example 1, except that compound c-8 was used instead of compound c-1 in step 3.

[0385] Step 4: Preparation of (5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methanol (e-8) [ka]

[0386] Compound e-8 (0.249 g, yield 90%) was obtained in the same manner as in Example 1, except that compound d-8 was used instead of compound d-1 in step 4.

[0387] Step 5: Preparation of 2-(chloromethyl)-5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazole (f-8) [ka]

[0388] Compound f-8 (0.206 g, yield 70%) was obtained in the same manner as in Example 1, except that compound e-8 was used instead of compound e-1 in step 5.

[0389] Step 6: Preparation of 2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenol (g-8) [ka]

[0390] Compound g-8 (0.398 g, yield 97%) was obtained in the same manner as in Example 1, except that compound f-8 was used instead of compound f-1 in step 6.

[0391] 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) [ka]

[0392] Compound H-8 (0.409 g, yield 87%) was obtained in the same manner as in Example 1, except that compound G-8 was used instead of compound G-1 in step 7.

[0393] Step 8: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)acetic acid (25) [ka]

[0394] Compound 25 (0.393 g, yield 86%) was obtained in the same manner as in Example 1, except that compound h-8 was used instead of compound h-1 in step 8 of Example 1.

[0395] 1 H 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.

[0396] <Example 26> Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid

[0397] 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) [ka]

[0398] Compound i-8 (0.379 g, yield 76%) was obtained in the same manner as in Example 1, except that compound g-8 was used instead of compound g-1 in step 7 and compound ethyl 2-bromopropanoate was used instead of methyl 2-bromoacetate.

[0399] Step 2: Preparation of 2-(2-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)thio)phenoxy)propanoic acid (26) [ka]

[0400] Compound 26 (0.409 g, yield 87%) was obtained in the same manner as in Example 1, except that compound i-8 was used instead of compound h-1 in step 8.

[0401] 1 H 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.

[0402] <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

[0403] 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) [ka]

[0404] Compound j-8 (0.179 g, yield 35%) was obtained in the same manner as in Example 1, except that compound g-8 was used instead of compound g-1 in step 7 and compound ethyl 2-bromo-2-methylpropanoate was used instead of methyl 2-bromoacetate.

[0405] 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) [ka]

[0406] Compound 27 (0.170 g, yield 35%) was obtained in the same manner as in Example 1, except that compound j-8 was used instead of compound h-1 in step 8.

[0407] ESI LC / MS:m / z calcd.for C 21 H 20 F3N2O4S2[M+H] + :485.08;found 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.

[0408] The compounds of Examples 1 to 27 are summarized in Tables 1 and 2 below.

[0409] [Table 1]

[0410] [Table 2]

[0411] <Experimental Method>

[0412] 1.Animals Specific pathogen-free, 6-week-old immunocompetent C57BL / 6 mice were obtained from SLC, Inc. (Shizuoka, Japan). All animal experimental procedures were performed in strict compliance with the Institutional Guidelines for Animal Research. The protocol was approved by the Animal Experiment Ethics Committee of Kyungpook National University, Republic of Korea (approval number: KNU 2012-43).

[0413] 2.Cell culture Macrophage RAW 264.7 cells were used, provided by the Korea Cell Line Bank, and cultured in a culture medium containing DMEM supplemented with 100mg / mL inactivated fetal bovine serum and 10mg / mL penicillin-streptomycin at 37℃ and 5% CO2. All cells in the experimental process were subcultured when they grew at a density of about 80~90%, and only cells that had not been used for more than 20 passages were used.

[0414] 3. Measurement of Cytotoxicity To evaluate the cytotoxicity of the samples, cell proliferation was examined using a cell counting kit [CCK-8; Dojindo Laboratories (Tokyo, Japan)]. RAW 264.7 cells 1 × 10 4 After pre-incubation for 20 hours, 1μg / mL LPS and the compound of the embodiment were added at different concentrations and incubated at 37℃ in a 5% CO2 incubator for 24 hours. After incubation, 10μL of CCK-8 reagent was added and incubated again for 1-2 hours, and the absorbance was measured. The absorbance was measured at 450nm using a microplate reader [BMG Labtech (Offenburg, Germany)].

[0415] 4. Measurement of Nitric Oxide (NO) production The NO concentration was measured by measuring the concentration of nitrite in the culture medium using the Griess Reagent System (Promega). 5After adjusting the concentration to cells / mL, the cells were seeded into a 24-well plate and pre-cultured in a 5% CO2 incubator for 20 hours. The cells were treated with 1 μg / mL LPS and various concentrations of the compound of the embodiment and then re-cultured for 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 (Offenburg, Germany)]. The NO concentration in the cell culture medium was calculated by comparing with a standard curve for each concentration of sodium nitrite (NaNO2).

[0416] 5. Measurement of inflammation-related cytokine ratios The supernatant was aliquoted in the same manner as for measuring NO. The amounts of TNF-α and IL-6 in the supernatant were quantified using a multiplex bead-based immunoassay technique (BD™ Cytometric Bead Array) system and flow cytometry (BD Biosciences).

[0417] 6. Luciferase Analysis Raw264.7 / NF-kb-luc cells were treated with 1mg / mL LPS and various concentrations of compounds in the same manner as for measuring NO. After 16 hours, D-luciferin solution was added to the cells, and luminescence images were obtained using IVIS Lummina III. Luminescence image quantification was performed using Living imaging software.

[0418] 7. Western blot 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 the lysate was separated by 10% SDS-PAGE. The separated proteins were transferred to a polyvinylidene difluoride (PVDF) membrane (Biorad, CA, USA) at 70 mA for 1 hour and 30 minutes, and then blocked with TBST (tris buffered saline; pH 7.5) solution containing 50 mg / mL skim milk at room temperature for 2 hours. Anti-iNOS, pIKKαβ antibodies were used to examine the expression levels of iNOS, pIKKαβ, diluted 1:1000, and incubated at room temperature for 2 hours, followed by washing three times with TBST. Secondary antibodies, horse radish peroxidase (HRP)-conjugated anti-mouse IgG and anti-rabbit IgG, were diluted 1:2000 and incubated 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.

[0419] 8. Macrophage Image Analysis 2mL of thioglycollate medium (BD, USA) was injected into the abdominal cavity of C57Bl / 6 mice, and 3 days later, the mice were decapitated and 8mL of Dulbecco's modified Eagle's medium (DMEM) was injected into the abdominal cavity to collect cells. After centrifugation, the cells were suspended in DMEM containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin, and then cultured for 2 hours in a 37℃, 5% CO2 incubator. Non-adherent cells were removed and the cells were used for cell experiments.

[0420] The acute inflammation suppression ability of the compounds of the examples was evaluated using a macrophage tracking technique using fluorescent images. Macrophages extracted from the abdominal cavity of mice were incubated with Vybrant TMAfter labeling with DiD Cell-Labeling Solution, the cells were delivered to the mice via intravenous injection. The following day, 50 mg / kg of the compound of the embodiment was orally administered, and one hour later, 0.1% Carrageenan (CG) solution or PBS was subcutaneously injected into the sole of the right or left foot of the mice. Fluorescence images were obtained using IVIS Lumina III at the designated times.

[0421] 9.Statistical analysis All data are presented as the mean ± standard deviation (SD) from at least three independent experiments, and the statistical significance of differences was determined by unpaired Student's test using GrahPad Prism 5. P values ​​less than 0.05 were considered statistically significant.

[0422] <Experimental Example 1> Enzyme activity (EC 50 ) Analysis In order to confirm the effect of the compound of the embodiment on PPARδ activation, the following experiment was carried out. First, the compound of the embodiment was diluted in DMSO to 100X the final concentration, and then 1 / 50 was diluted in assay buffer and placed in a 384-well plate in an amount of 10 μL each. GST-bound PPARδ LBD (ligand-binding domain) was added to a final concentration of 5 nM, and fluorescien-conjugated C33 coactivator peptide and Tb-α-GST antibody were added to a final concentration of 100 nM and 10 nM, respectively. The final volume of each test system was 20 μL, and the test for each concentration was carried out twice. After the reaction, the binding activity was measured by the TR-FRET method. That is, the excitation was performed at 340 nm, and the emission values ​​were measured at 495 nm and 520 nm, respectively, and the results were analyzed as 490 nm measurement value / 520 nm measurement value, and the EC 50 The values ​​were calculated using the analysis program Prism 6. The results are summarized in Table 2 below.

[0423] The principle of this test method is as follows: When a GST antibody binds to GST fused to PPARδ LBD, it is kept in an inactive state, and when an agent is bound to it, a conformational change in the LBD protein is induced. At this time, the fluorescent energy donor bound to the GST antibody transfers energy to the fluorescent energy acceptor (fluorescine) bound to the PPARδ substrate (C33 peptide), resulting in the emission of fluorescent energy, and the degree of PPARδ activation can be measured by measuring this value.

[0424] Meanwhile, the known PPARδ agonist compound GW501516 was used as the test substance. 50 The value was 15.5 nM.

[0425] [Table 3]

[0426] <Experimental Example 2> Cytotoxicity Analysis To evaluate the cytotoxicity of the compound of Example 1, the compound of Example 1 was treated at concentrations of 0, 12 μM, 25 μM, and 50 μM in Raw264.7 cells, a macrophage cell line, and then the CCK8 assay was performed according to the above-mentioned experimental method 3. The results of the CCK8 assay showed that no cytotoxicity was observed at any concentration (FIG. 1). Specifically, even at the maximum concentration of 50 μM, cell proliferation was similar to that of the vehicle group, and no significance was detected.

[0427] <Experimental Example 3> Analysis of Nitric Oxide (NO) Production

[0428] NO is produced from L-arginine by nitric oxide synthase (NOS) present in various tissues. There are three types of NOS, including neuronal NOS, endothelial NOS, and inducible NOS (iNOS). Among them, iNOS, also called NOS-2, is expressed in various cells including macrophages by inflammatory stimuli such as toxins in bacteria and various inflammatory cytokines during bacterial infection, and once iNOS is expressed, a large amount of NO is produced for a long period of time, which is involved in cytotoxicity during inflammation. In order to analyze the amount of nitric oxide produced by the compound of Example 1, the following experiment was performed.

[0429] 1mg / mL lipopolysaccharide (LPS) and 0, 12μM, 25μM, and 50μM of the compound of Example 1 were added to Raw264.7 cells and cultured for 24 hours, and the change in NO concentration in the culture supernatant was analyzed. As a result of the analysis, the NO concentration secreted from LPS-stimulated Raw264.7 decreased depending on the concentration of the compound of Example 1, and specifically, the NO concentrations generated by LPS-stimulated Raw26.7+0μM, LPS-stimulated Raw26.7+12.5μM, LPS-stimulated Raw26.7+25μM, and LPS-stimulated Raw26.7+50μM were 22.8±1.3μM, 18.9±0.3μM, 14.8±0.54μM, and 2.41±0.24μM, respectively (Figure 2).

[0430] <Experimental Example 4> Analysis of the effect of suppressing iNOS protein expression (Western blot) In order to confirm whether the NO production inhibitory effect of the compound of Example 1 is due to the inhibition of iNOS protein expression, 1mg / mL LPS and 0, 12μM, 25μM, and 50μM concentrations of the compound of Example 1 were added to Raw264.7 cells, and the effect on iNOS protein expression was evaluated by the method of Experimental Method 7. As a result, it was confirmed that Raw264.7 cells without LPS did not express iNOS protein, and that Raw264.7 cells with 1mg / mL LPS showed high iNOS protein expression. It was also confirmed that when the compound of Example 1 was treated, the iNOS protein expression of LPS-stimulated Raw264.7 was significantly inhibited (Figure 3).

[0431] <Experimental Example 5> Analysis of the inhibitory effect on the production of inflammation-related factors LPS, a well-known endotoxin present in the 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). To analyze the effect of the compound of Example 1 in inhibiting the secretion of the cytokines, RAW264.7 cells were cultured for 24 hours with 1 mg / mL LPS and the compound of Example 1 at concentrations of 0, 12 μM, 25 μM, and 50 μM, and the concentrations of IL-6 and TNFα 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 statistical significance was confirmed compared to the vehicle group (FIG. 4).

[0432] Nuclear factor-kappa B (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 is composed of p50 and p65, and acts as a transcription factor in the nucleus to synthesize iNOS, COX-2, and inflammation-related cytokines. In general, the action of NF-κB is inhibited by binding to inhibitor NF-κBα (IκBα) in the cytoplasm. In order to confirm whether NF-κb-related cell signaling induced in Raw264.7 cells is affected by the compound of Example 1, NF-κb promoter-luciferase analysis and pIKKαβ expression change analysis were performed in Raw264.7 cells using 1 mg / mL LPS and the compound of Example 1 at concentrations of 0, 12 μM, 25 μM, and 50 μM. As a result, when 1 mg / ml LPS was treated in Raw264.7 / NF-κb-luciferase cells, strong luminescent signals were generated, but when treated with the compound of Example 1, the luminescent signals were reduced in a concentration-dependent manner, and statistical significance was confirmed when compared with the vehicle group (Figure 5). It was also confirmed that the compound of Example 1 effectively reduced pIKKαβ protein expression (Figure 6).

[0433] This indicates that the compound of Example 1 is an effective PPARδ agonist that regulates NF-κb cell signaling in macrophages and is therefore effective in regulating inflammatory cytokines.

[0434] <Experimental Example 6> Image analysis of macrophages The inflammation model induced by λ-carrageenan in the paw of mice is an acute arthritis model and is useful for confirming the inhibitory effect on edema caused by osteoarthritis. To confirm the acute inflammation inhibitory effect of the compound of Example 1, an experiment was conducted using the macrophage tracking technique (FIG. 7) and the above-mentioned Experimental Method 8.

[0435] As a result, before the induction of inflammation, no fluorescent signal was observed in the sole of any experimental group injected with 0.1% CG. Meanwhile, 6 hours after the induction of inflammation, a strong fluorescent signal was observed in the sole of the vehicle group injected with 0.1% CG. Meanwhile, a lower fluorescent signal was observed in the sole of the vehicle group injected with 0.1% CG in the group treated with 50 mg / kg of the compound of Example 1, and statistical significance was also detected (FIGS. 8 and 9).

[0436] Through this, it was confirmed that the compound of Example 1, which is a PPARδ agonist, has no cytotoxicity and is effective in suppressing inflammatory cytokines and NO production by regulating NF-κb cell signaling in macrophages, and is also effective in preventing macrophage infiltration into acute inflammation sites.

[0437] Although the present invention has been described in detail through preferred embodiments and experimental examples, the scope of the present invention is not limited to the specific embodiments, but should be interpreted according to the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof: 【Chemistry 1】 In the above Chemical Formula 1, R １ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl, C １－５ Alkoxy or C １－５ haloalkoxy; R ２ are each independently -H, C １－５ Alkyl or -O-R ２１ and The R ２１ Cyano C １－５ Heteroaryl C of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S １－５ Alkyl or 【Chemistry 2】 and The R ２１１ and R ２１２ are each independently -H or C １－５ alkyl, and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, The R ２１４ is -H or C １－５ is alkyl; and x and y each independently represent an integer of 1 to 5.

2. The compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 2 below. The compound according to claim 1, its stereoisomer, its hydrate, or a salt thereof: 【Chemistry 3】 In the above Chemical Formula 2, R １１ , R １２ and R １３ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl or C １－５ haloalkoxy; R ２２ is -H or C １－５ is alkyl; and R ２１ Cyano C １－５ Heteroaryl C of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S １－５ Alkyl or 【Chemistry 4】 and The R ２１１ and R ２１２ are each independently -H or C １－５ alkyl, and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, The R ２１４ is -H or C １－５ It is an alkyl.

3. The compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 3 below. The compound according to claim 1, its stereoisomer, its hydrate, or a salt thereof: 【Chemistry 5】 In the above Chemical Formula 3, R １１ , R １２ and R １３ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl or C １－５ haloalkoxy; R ２１１ and R ２１２ are each independently -H or C １－５ is alkyl; and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, wherein R ２１４ is -H or C １－５ It is an alkyl.

4. The R ２１ teeth, 【Chemistry 6】 The compound according to claim 1, its stereoisomer, its hydrate or a salt thereof,

5. The R １ are each independently -H, a halogen, or -CH ３ , -CF ３ Or -OCF ３ The compound according to claim 1, its stereoisomer, its hydrate or a salt thereof,

6. The compound represented by Chemical Formula 1 is any one selected from the following compound group, a stereoisomer thereof, a hydrate thereof, or a salt thereof according to claim 1 : (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-tetrazol-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, comprising as an active ingredient a compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof: 【Chemistry 7】 In the above Chemical Formula 1, R １ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl, C １－５ Alkoxy or C １－５ haloalkoxy; R ２ are each independently -H, C １－５ Alkyl or -O-R ２１ and The R ２１ Cyano C １－５ Heteroaryl C of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S １－５ Alkyl or 【Chemistry 8】 and The R ２１１ and R ２１２ are each independently -H or C １－５ alkyl, and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, The R ２１４ is -H or C １－５ is alkyl; and x and y each independently represent an integer of 1 to 5.

8. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 7, wherein the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 2: 【Chemistry 9】 In the above Chemical Formula 2, R １１ , R １２ and R １３ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl or C １－５ haloalkoxy; R ２２ is -H or C １－５ is alkyl; and R ２１ Cyano C １－５ Heteroaryl C of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S １－５ Alkyl or 【Chemistry 10】 and The R ２１１ and R ２１２ are each independently -H or C １－５ alkyl, and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, The R ２１４ is -H or C １－５ It is an alkyl.

9. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 7, wherein the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 3: 【Chemistry 11】 In the above Chemical Formula 3, R １１ , R １２ and R １３ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl or C １－５ haloalkoxy; R ２１１ and R ２１２ are each independently -H or C １－５ is alkyl; and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, wherein R ２１４ is -H or C １－５ It is an alkyl.

10. The R ２１ teeth, 【Chemistry 12】 The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 7,

11. The R １ are each independently -H, a halogen, or -CH ３ , -CF ３ Or -OCF ３ The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 7,

12. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 7, wherein the compound represented by Chemical Formula 1 is any one selected from the following compound group: (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-tetrazol-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 for preventing or treating an inflammatory disease 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 functional health food composition for preventing or improving an inflammatory disease, comprising as an active ingredient a compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof: 【Chemistry 13】 In the above Chemical Formula 1, R １ are each independently -H, halogen, or C １－５ Alkyl, C １－５ Haloalkyl, C １－５ Alkoxy or C １－５ haloalkoxy; R ２ are each independently -H, C １－５ Alkyl or -O-R ２１ and The R ２１ Cyano C １－５ Heteroaryl C of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of alkyl, N, O, and S １－５ Alkyl or 【Chemistry 14】 and The R ２１１ and R ２１２ are each independently -H or C １－５ alkyl, and R ２１３ is -OH, -NH ２ , -NHOR ２１４ or -NHCN, The R ２１４ is -H or C １－５ is alkyl; and x and y each independently represent an integer of 1 to 5.

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