Novel compound as 17-beta-hydroxysteroid dehydrogenase 13 (HSD17b13) inhibitor and pharmaceutical composition comprising same

Abstract

The present invention relates to a novel compound as an HSD17B13 inhibitor, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, and a pharmaceutical composition comprising same, which can be used for preventing or treating HSD17B13-mediated diseases such as nonalcoholic steatohepatitis (NASH). <Chemical Formula I>

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003] Novel compounds as HSD17B13 (17-beta-hydroxysteroid dehydrogenase 13) inhibitors and pharmaceutical compositions comprising the same [Technical field] The present invention relates to novel compounds as HSD17B13 inhibitors, stereoisomers thereof, pharmaceutically acceptable salts thereof, or solvates or hydrates thereof, and pharmaceutical compositions comprising the same.

[0004]

Background Technology

[0005] 17-beta-hydroxysteroid dehydrogenase (HSD17B) comprises a large family of 15 members, some of which are known to be involved in sex hormone metabolism. Some HSD17B enzymes also play key roles in cholesterol and fatty acid metabolism. HSD17B13, an enzyme with unknown biological function, has been identified as a novel liver-specific lipid droplet-associated protein in mice and humans, and its expression is significantly upregulated in patients and mice with nonalcoholic fatty liver disease (NAFLD). Overexpression of HSD17B13 in the liver promotes lipid accumulation in the liver. HSD17B13 can be used as a biomarker of chronic liver diseases, such as Alcoholic Liver Disease (ALD), nonalcoholic fatty liver disease (e.g., steatosis, nonalcoholic steatohepatitis (NASH), NASH-fibrosis or cirrhosis), steatohepatitis and / or liver cancer. Furthermore, inhibition of HSD17B13 activity can be used for the treatment and / or prevention of these liver diseases. Among nonalcoholic fatty liver diseases, nonalcoholic steatohepatitis, in particular, is accompanied by intralobular inflammation and ballooning degeneration of hepatocytes, unlike simple steatosis in which only hepatic steatosis is observed, and can lead to cirrhosis and hepatocellular carcinoma and can cause death from liver-related diseases. Therefore, the development of an effective pharmacological treatment for non-alcoholic steatohepatitis is necessary. The research on the present invention was conducted with the support of the Korea Institute for Advancement of Technology (KIAT)'s Small and Medium Enterprise Re-leap Support Project funded by the Ministry of Trade, Industry and Energy of the Republic of Korea (Project Unique Number: 1415189468, Project Number: P0022999).

[0006]

Contents of the invention

[0007]

Technical Problem

[0008] Technical Solution

[0009] (1) The present invention provides a compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof.

[0010] <Chemical Formula 1> In chemical formula I,

[0011] Xi, X2 and X3 are each independently N, 0 or S, and - each independently represents a single bond or a double bond; Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and S, wherein one or more of the 6- to 14-membered aryl or the 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and S may each independently be unsubstituted or substituted with halogen, -ORi, -CN, -CFs, or C1-C3 alkyl,

[0012] Ri is H or C1-C3 alkyl, wherein one or more of the C1-C3 alkyl groups may be independently substituted or unsubstituted with halogen;

[0013] Yi, Y2, YS and Y4 are each independently CR2 or N,

[0014] R2 is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of H, halogen, CN, C1-C3 alkyl, 6- to 14-membered aryl, N, 0, and - C(=0)- R a i, -(C1-C4 alkylene) - C(=0)- R a 2, -CF3, - N(》, -OR b i, -SR b2 , - S(=0)『 NR c iRdi, -NHC(=0)R b3 or - NR C2Rd2, wherein one or more of C1-C3 alkyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0, and S may be independently substituted or unsubstituted with halogen,

[0015] Rai and Ra2 are each independently - 0Rb3 or - NR c It's 3Rd3,

[0016] Rbi, Rb2 and Rb3 are each independently H or C1-C6 alkyl, wherein at least one of the C1-C6 alkyl groups may be independently substituted or unsubstituted with a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl group containing at least one heteroatom selected from the group consisting of N, 0 and S, wherein at least one H of the 6- to 14-membered aryl or the 5- to 12-membered heteroaryl group containing at least one heteroatom selected from the group consisting of N, 0 and S may each independently be substituted or unsubstituted with halogen, -CF3 or C1-C3 alkyl,

[0017] Rd, RC2, RC3, Rdi, Rd2 and Rd3 are each independently H, 0, C1-C6 alkyl or 6- to 14-membered aryl, wherein one or more of the C1-C6 alkyl or 6- to 14-membered aryl groups may be independently substituted or unsubstituted with 6- to 14-membered aryl or CN; L is - R e - N(Rf )- and ,

[0018] R e is a single bond or C1-C3 alkylene,

[0019] Rf is H or C1-C3 alkyl;

[0020] A2 is H, 6-14 membered aryl, 5-12 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S. and wherein 6 to 14-membered aryl, 5 to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, or 3 to 8-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S One or more of each independently selected from the group consisting of halogen, - CF3, C1-C3 alkyl, - C(=0)- ORgi, -

[0021] 0Rg2, - NR ga R g b, - NHC(=0)R g 3, - C(=O)NRg C Rgd or - S(0)『 R g 4 can be substituted or unsubstituted, R g i, Rg2, R g3 , R ga , Rgb, Rgc, Rgd and R g4 are each independently H, 0 or C1-C4 alkyl, wherein one or more of the C1-C4 alkyl groups may be independently substituted or unsubstituted with halogen. In the present invention, the term “Cm-Cn” (wherein m and n are each independently an integer greater than or equal to 1, and m < n) means the number of carbons, for example, ‘C1-C5 alkyl’ means alkyl having 1 to 5 carbons. In the present invention, “a-b membered” (wherein a and n are each independently an integer greater than or equal to 1, and a < b) means the number of atoms forming a ring, for example, ‘4-12 membered ring’ means that the ring is 4- to 12-membered. For example, 6- to 12-membered aryl means an aromatic hydrocarbon group forming a 6- to 12-membered ring. For example, a 4- to 12-membered heterocycloalkyl is a ring forming a 4- to 12-membered member, and the atoms forming the ring may include not only carbon but also one or more heteroatoms such as N, 0, and S. In the present invention, “substitution” or “substituted with ~” is defined as including the implicit condition that such substitution is in accordance with the allowable valency of the substituted atom and the substituent, and that the substitution induces a stable compound, for example, a compound that is not naturally transformed by rearrangement, cyclization, elimination, etc. In the present invention, “single bond” means a case where adjacent atoms or atomic groups are directly bonded. For example, in a chemical structure represented by xyz, if y is a single bond, it means “x-z” as a structure in which x and z are directly chemically bonded. In the present invention, unless otherwise specified, “alkyl” means a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group.Examples of alkyl include, but are not limited to, one or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl. In the present invention, unless otherwise stated, “alkylene” means a divalent functional group derived from alkyl defined as above. In the present invention, unless otherwise stated, “alkynylene” means a divalent functional group derived from alkyl containing at least one carbon-carbon triple bond in the alkyl. Examples of alkynylene include, However, the present invention is not limited thereto. In the present invention, unless otherwise stated, “alkenyl” means an unsaturated hydrocarbon group containing at least one carbon-carbon double bond in the alkyl. In the present invention, unless otherwise stated, “alkoxy” means a 1 7} group derived from a straight or branched saturated hydrocarbon moiety represented by - 0- CnH2n+l. Examples of alkoxy include, but are not limited to, one or more selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy, etc. Unless otherwise stated, “cycloalkyl” in the present invention means a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. It also includes all double ring structures such as bridged ring or spiro structure. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, spiro [4.4]nonanyl, spiro [3.3]heptanyl, bicyclo [3.1. dihexanyl, bicyclo [3.1. 1]heptanyl and bicyclo [2.2. 1]heptanyl, adamantyl. However, the present invention is not limited thereto. In the present invention, unless otherwise stated, “cycloalkenyl” means a cyclic group including at least one carbon-carbon double bond in the cycloalkyl, and the cycloalkenyl is not an aromatic ring. Examples of the cycloalkenyl may include at least one selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl, but is not limited thereto. In the present invention, unless otherwise stated, “heterocycloalkyl” means a cyclic group in which at least one carbon atom forming the ring in the cycloalkyl is independently substituted with a heteroatom or functional group selected from the group consisting of N, 0, S, SO, and S02. Examples of heterocycloalkyl include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, oxepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, aziridinyl, , but is not limited thereto. In the present invention, unless otherwise stated, “heterocycloalkenyl” means a cyclic group in which at least one carbon atom forming the ring in the cycloalkenyl is independently substituted with a heteroatom or functional group selected from the group consisting of N, 0, S, S0 and S02, and the heterocycloalkenyl is not an aromatic ring. Examples of heterocycloalkenyl include, and But are not limited thereto. In the present invention, unless otherwise stated, “heterocycloalkenylene” means a divalent functional group derived from a heterocycloalkenyl as defined above. In the present invention, unless otherwise stated, “aryl” means a monocyclic or polycyclic aromatic cyclic group having one or more aromatic rings, which are fused or non-fused. Examples of aryl include, but are not limited to, one or more selected from phenyl, biphenyl, naphthalenyl, tetrahydronaphthyl, indenyl, and anthracenyl. In the present invention, unless otherwise stated, “arylene” means a divalent functional group derived from an aryl as defined above. In the present invention, unless otherwise stated, “heteroaryl” means a monocyclic or polycyclic aromatic heterocycle containing at least one heteroatom selected from the group consisting of N, 0 and S within the ring and having one or more fused or non-fused aromatic rings. Examples of heteroaryl include, but are not limited to, one or more selected from thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, and purinyl. In the present invention, “heteroarylene” means a divalent functional group derived from heteroaryl as defined above, unless otherwise stated. In the present invention, “halogen” may be F, Cl, Br, or I, unless otherwise stated. In addition, terms and abbreviations used in this specification have their original meanings unless otherwise defined.In the present invention, the symbol “三 =三 “ represents a single bond or a double bond. Whether “三 =三” is a single bond or a double bond can be determined according to the allowable valence of the atoms connected to each other through “三 =三”. That is, in the formula I above.

[0022] “三= 三” can be determined according to X1, X2 and X3. For example, in the above formula In one embodiment, the case where Xi, X2 and X3 are simultaneously N in the formula I can be excluded. That is, Xi, X2 and X3 in the formula I may not all be N simultaneously. In one embodiment, two selected from X1, X2 and X3 in the formula I may be N, and the remaining one may be 0 or 으, and 三=三 is determined according to the chemical bond that satisfies the valence of the atoms. and X3 are each independently N, and X2 is 0 or S), each is 시, and X3 is 0 or S) each is N,

[0023] X1 may be 0 or S). It may be one.

[0024] (2) In the above (1), according to one embodiment, the formula I and X3 are each independently 시, and X2 is 0

[0025] Ai is an aryl having 6 to 14 members, wherein one or more Hs of the aryl having 6 to 14 members may each independently be substituted or unsubstituted with halogen, -ORi, or -CF3,

[0026] Ri may be H.

[0027] (3) In the above (1) or (2), according to one embodiment of the present invention, Yi, Y2, YS and Y4 of the formula I are each independently CR2 or 시,

[0028] R2 is H, halogen, C1-C3 alkyl, - C(=0)- R a i, -(C1-C4 alkylene) - C(=0)- R, - CF3, -N02, -ORbi, or - NR C It's 2Rd2,

[0029] Rai and Ra2 are each independently - 0Rb3 or - NR c It's 3Rd3,

[0030] Rbi and Rb3 are each independently H or C1-C6 alkyl, wherein one or more of the C1-C3 alkyl groups may be independently substituted or unsubstituted with a 6- to 14-membered aryl group, wherein one or more H groups of the 6- to 14-membered aryl group may each independently be substituted or unsubstituted with a halogen or -CF3,

[0031] RC2 and Rc3 are each independently H,

[0032] R d2 And Rd3 are each independently C1-C6 alkyl or 6- to 14-membered aryl, wherein at least one group of C1-C6 alkyl or 6- to 14-membered aryl may be independently substituted or unsubstituted with 6- to 14-membered aryl or CN. (4) In any one of (1) to (3), A2 of chemical formula I according to one embodiment of the present invention is H, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0, and C3-

[0033] 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of C15 cycloalkyl, N, 0 and S and wherein 6 to 14-membered aryl, 5 to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, 3 to 8-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S One or more of which may be independently substituted or unsubstituted with halogen, - CF3, C1-C3 alkyl, - C(=0)- ORgi, - 0Rg2, or - S(0)『 Rg4,

[0034] Rgi, R g2 and R g 4 are each independently H or C1-C4 alkyl, wherein one or more H of the C1-C4 alkyl may be independently substituted or unsubstituted with halogen.

[0035] (5) In any one of the above (1) to (4), the compound represented by the chemical formula I according to one embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof may include a compound represented by the following chemical formula la or chemical formula lb, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof.

[0036] <Chemical Formula Ia> In the chemical formula la, Xi to X3, Ai, Yi to Y4, R f And A2 are each the same as defined in Chemical Formula I, so redundant descriptions are omitted. In Chemical Formula lb, Xi to X3, Ai and Yi to Y4 are each the same as defined in Chemical Formula I, so redundant descriptions are omitted.

[0037] (6) In any one of the above (1) to (5), in the chemical formula I according to one embodiment of the present invention,

[0038] Xi, X2, and X3 are each independently N, 0, or S, and each of ═══ represents a single bond or a double bond; Ai is an aryl having 6 to 14 carbon atoms, where one or more Hs of the aryl having 6 to 14 carbon atoms can each independently be substituted or unsubstituted with a halogen, -ORi, or -CF3, and Ri is H; Yi, Y2, YS, and Y4 are each independently CR2 or N,

[0039] R2 is H, a halogen, C1-C3 alkyl, -C(═0)-R a i, -(C1-C4 alkylene)-C(═0)-R a 2, -CF3, -NO2, -ORbi, or -NRc2Rd2,

[0040] Rai and Ra2 are each independently -ORb3 or -NR c 3Rd3,

[0041] Rbi and Rb3 are each independently H or C1-C6 alkyl, where one or more Hs of the C1-C3 alkyl can each independently be substituted or unsubstituted with an aryl having 6 to 14 carbon atoms, and in this case, one or more Hs of the aryl having 6 to 14 carbon atoms can each independently be substituted or unsubstituted with a halogen or -CF3,

[0042] RC2 and Rc3 are each independently H,

[0043] R d2 and Rd3 are each independently C1-C6 alkyl or an aryl having 6 to 14 carbon atoms, where one or more Hs of the C1-C6 alkyl or the aryl having 6 to 14 carbon atoms can each independently be substituted or unsubstituted with an aryl having 6 to 14 carbon atoms or CN;

[0044] L is -R e -N(Rf)-,

[0045] Re is a single bond or C1-C3 alkylene,

[0046] Rf is H or C1-C3 alkyl;

[0047] A2 is H, 6-14 membered aryl, 5-12 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S. and wherein 6 to 14-membered aryl, 5 to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, or 3 to 8-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S One or more H may be independently substituted or unsubstituted with halogen, - CF3, C1-C3 alkyl, - C(=0)- ORgi, - 0Rg2, or - S(0)『 Rg4,

[0048] Rgi, R g2 and R g 4 are each independently H or C1-C4 alkyl, wherein at least one H of the C1-C4 alkyl may be independently substituted or unsubstituted with halogen. (7) In any one of the above (1) to (6), Ai of the above chemical formula I according to one embodiment of the present invention is each independently halogen, CN or -

[0049] It may be a phenol group substituted with CF3.

[0050] (8) In any one of the above (1) to (7), in the chemical formula I according to one embodiment of the present invention, Xi, X2 and X3 are each independently N, 0 or S (provided that Xi, X2 and X3 are not simultaneously N). Rh, R>, Rj, and Rk are each independently H, halogen, -CN, -CF3, or C1-C3 alkyl,

[0051] Yi, Y2, YS and Y4 are each independently CR2 or N,

[0052] R2 is H, halogen, Ci-C3 alkyl, - C(=0)- R a i, -(C1-C4 alkylene) - C(=0)- R a 2, -CF3, -N02, -ORbi, or -NRc2Rd2,

[0053] Rai and Ra2 are each independently - 0Rb3 or - NR c It's 3Rd3,

[0054] Rbi and Rb3 are each independently H or C1-C6 alkyl, wherein one or more of the C1-C3 alkyl groups may be independently substituted or unsubstituted with a 6- to 14-membered aryl group, wherein one or more H groups of the 6- to 14-membered aryl group may each independently be substituted or unsubstituted with a halogen or -CF3,

[0055] RC2 and Rc3 appear to be independent,

[0056] Rd2 and Rd3 are each independently C1-C6 alkyl or 6- to 14-membered aryl, wherein one or more of the C1-C3 alkyl or 6- to 14-membered aryl groups may be independently substituted or unsubstituted with 6- to 14-membered aryl or CN; L is - R e - N(Rf )- and ,

[0057] R e is a single bond or C1-C3 alkylene,

[0058] Rf is H or C1-C3 alkyl;

[0059] A2 is H, 6-14 membered aryl, 5-12 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S. and wherein one or more of 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, or 3- to 8-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S may be independently substituted or unsubstituted with halogen, - CF3, C1-C3 alkyl, - C(=0)- ORgi, - 0Rg2, or - S(0)『 Rg4,

[0060] Rgi, R g2 and R g 4 are each independently H or C1-C4 alkyl, wherein one or more of the C1-C4 alkyl groups may be independently substituted or unsubstituted with halogen.

[0061] (9) In any one of the above (1) to (8), the compound represented by the chemical formula I according to one embodiment of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof may include a compound represented by the following chemical formula Ila or chemical formula lib, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof.

[0062] <Chemical Formula IIa>

[0063] In chemical formula Ila, Xi to X3, Yi to Y4, Rf and A2 are each the same as defined in chemical formula I, so redundant description is omitted, and Wi to W5 are each independently H, halogen or 0H. For example, at least three or more of Wi to W5 may be halogen or 0H. In chemical formula lib, Xi to X3 and Yi to Y4 are each the same as defined in chemical formula I, so redundant description is omitted, and Wi to W5 are each independently H, halogen or 0H. For example, at least three or more of Wi to W5 may be halogen or 0H.

[0064] (10) The present invention provides a compound described in Table 1 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof.

[0065] [Table 1]

[0066] (11) In any one of the above (1) to (9), the compound having a novel structure according to the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate or a hydrate thereof may be a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate or a hydrate thereof shown in Table 1. In the present invention, "stereoisomer" includes diastereomers and optical isomers, and includes a single enantiomeric isomer, a mixture of enantiomeric isomers including a racemic mixture, a single diastereoisomer and a mixture of diastereoisomers. Such isomers can be separated by resolution using a conventional technique, for example, column chromatography or HPLC. Alternatively, they can be stereospecifically synthesized using optically pure starting materials and / or reagents of a known arrangement. Specifically, the isomer may be an optical isomer. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and, when administered to a subject, does not typically cause allergic reactions such as gastrointestinal upset, dizziness, or similar reactions.In the present invention, "pharmaceutically acceptable salt" means a salt commonly used in the pharmaceutical industry, and for example, an inorganic ionic salt manufactured with calcium, potassium, sodium or magnesium, etc.; an inorganic acid salt manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; an organic acid salt manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, spartic acid, ascorbic acid, carbonic acid or vanillic acid, etc.; a sulfonic acid salt manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc. Amino acid salts made of glycine, arginine or lysine, etc.; and amine salts made of trimethylamine, triethylamine, ammonia, pyridine or picoline, etc., but the types of salts meant in the present invention are not limited by these listed salts. The pharmaceutically acceptable salts of the present invention can be prepared by a conventional method known to those skilled in the art. The "hydrate" of the present invention is a compound described above or a pharmaceutically acceptable salt thereof and water are bound by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc. The "solvate" of the present invention is a compound described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a solvent other than water, which are bound by non-covalent intermolecular forces, and may contain the solvent in a stoichiometric or non-stoichiometric amount. Specifically, the solvate contains about 0.001% of solvent molecules per 1 mole of the active ingredient.It can be included in a ratio of about 25 mol to about 10 mol, and more specifically, it can be included in a ratio of about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc. The present invention provides a pharmaceutical composition comprising (as an active ingredient) a compound having a novel structure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. Hereinafter, the “compound having a novel structure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof” according to the present invention may be a compound according to any one selected from (1) to (11), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive. The pharmaceutically acceptable additive is an additive commonly used in the pharmaceutical field and can be appropriately selected by a person skilled in the art. For example, the pharmaceutically acceptable additives include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the additives may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like. The compound represented by the above chemical formula I, the compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising at least one of these (as an active ingredient) exhibits HSD17B13 inhibitory activity and may be used for the prevention or treatment of HSD17B13-mediated diseases.In one embodiment, the HSD17B13-mediated disease may include nonalcoholic steatohepatitis (NASH). The compound represented by the above formula I, the compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising at least one or more thereof (as an active ingredient) may be used for the prevention or treatment of nonalcoholic steatohepatitis (NASH). In the present invention, “nonalcoholic steatohepatitis (NASH)” may be substantially the same as metabolic dysfunction associated steatohepatitis (NLASH). In the present invention, "prevention" means any act of inhibiting or delaying the onset of HSD17B13-mediated disease or nonalcoholic steatohepatitis (NASH) by administering a compound represented by the above chemical formula I according to the present invention, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising (as an active ingredient) at least one of them. In the present invention, "treatment" means any act of improving or beneficially changing the symptoms of HSD17B13-mediated disease or nonalcoholic steatohepatitis (NASH) by administering a compound represented by the above chemical formula I according to the present invention, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising (as an active ingredient) at least one of them. The present invention provides a method for preventing or treating HSD17B13-mediated disease or non-alcoholic steatohepatitis (NASH), which comprises administering a compound represented by the above chemical formula I, a compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising at least one or more of these (as an active ingredient).The present invention provides a use of a compound represented by the above formula I, a compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising at least one or more thereof (as an active ingredient) for preventing or treating HSD17B13-mediated disease or nonalcoholic steatohepatitis (NASH). The present invention provides a use of a compound represented by the above formula I, a compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising at least one or more thereof (as an active ingredient) for the manufacture of a medicament for preventing or treating HSD17B13-mediated disease or nonalcoholic steatohepatitis (NASH).

[0067] (12) The present invention provides a method for preventing or treating HSD17B13-mediated disease or non-alcoholic steatohepatitis (NASH), comprising administering a compound according to any one selected from (1) to (11), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof. (13) The present invention provides a use of a compound according to any one selected from (1) to (11), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, for preventing or treating HSD17B13-mediated disease or non-alcoholic steatohepatitis (NASH).

[0068] (14) The present invention provides the use of a compound according to any one of (1) to (11), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, for the manufacture of a medicament for preventing or treating HSD17B13-mediated disease or non-alcoholic steatohepatitis (NASH).

[0069]

Effect of the invention

[0070]

Form for carrying out the invention

[0071] Mass (Waters, SQD2 or Agi lent, LC / MSD) analysis was performed to confirm the results. Manufacturing examples: Preparation of compounds of Examples 1 to 52 Example 1 Preparation of 2,6-difluoro-4-(3-(2-((4-fluorobenzyl)amino)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif 1 uor o-4-(3-(2-((4-f luorobenzyl)amino)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol 1)

[0072] (4-Fluorophenyl)methanamine, 2-chloro-6-methylpyrimidine-4-carbonitrile, potassium carbonate (K2CO3), and dimethyl formamide (DMF) were stirred at 140°C for 4 hours. Water was added to the reaction solution to precipitate the compound, and the solid was filtered to obtain it. The obtained solid was purified by column chromatography to obtain 2-

[0073] ((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)— 6— methylpyrimidine— 4— carbonitrile) was obtained. [Step 2]

[0074] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl )amino)-6-methylpyrimidine-4-carbonitrile), 50% hydroxylamine solution (Hydroxyl amine solution 50 wt . % in H2O, 50% NHROH^HRO), ethanol (ethanol,

[0075] EtOH) was stirred at 100°C for 2 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure to obtain 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide. [Step 3]

[0076] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide, 3,5-difluoro-4-hydroxybenzoic acid, hydroxybenzotriazole (HOBt), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) e After dissolving HCl in DMF, N,N-diisopropylethylamine (N,N- Di isopropylethylamine, DIPEA) was added and stirred at 140°C for 6 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate (EA). The combined organic layers of the extracts were washed with water, dried over magnesium sulfate (MgS04), and concentrated under reduced pressure. The above concentrated material was purified by column chromatography to obtain the title compound 2,6-difluoro-4-(3-(2-((4-fluorobenzyl)amino)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-4-(3-(2-((4- f luorobenzyl )amino)— 6— methylpyrimidin— 4— yl )— 1,2,4— oxadi azo 1—5— yl )phenol ). Example 2

[0077] 2,3,6-Trifluoro-4-(3-(2-((4-fluorobenzyl)amino)-6-methylpyrimidine-

[0078] Preparation of 4-yl)-1,2,4-oxadiazol-5-yl)phenol (2,3,6-tr if luoro-4-(3-(2-((4-f luorobenzyl)amino)-6-methyl pyr imidi n-4-y 1)-1,2,4-oxadi azo 1-5-yl)pheno 1) 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitr i le) was synthesized using the same method as in step 1 of Example 1.

[0079] [Step 2] 2-((4-f luorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide was synthesized using the same method as in step 2 of Example 1.

[0080] [Step 3]

[0081] The title compound 2,3,6-trifluoro-4-(3-(2-((4-fluorobenzyl)amino)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol was prepared in substantially the same manner as described in step 3 of Example 1, except that 2,3,5-trifluoro-4-hydroxybenzoic acid was used instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide. methylpyr imidin-4-yl )- 1,2,4- oxadi azo 1-5- yl )phenol ) was synthesized. Example 3

[0082] 2, 3, 6 -trifluoro- 4- (3- (2- ( ( (5 -fluoropyridin- 2- yl)methyl)amino)pyrimidin- 4 -yl)- 1,2, 4 -oxadiazol- 5 -yl)phenol (2, 3, 6- tr if luoro- 4- (3— (2— (((5— f luoropyridin— 2— yl)methyl)amino)pyrimidin— 4— yl)— 1,2, 4— oxadiazol—

[0083] Preparation of 5-yl)phenol) 2-(((5-fluoropyridin-2-yl)methyl)amino)pyrimidine-4-carbonitrile(2-) was prepared in substantially the same manner as described in Step 1 of Example 1, except that (5-fluoropyridin-2-yl)methanamine and 2-chloropyrimidine-4-carbonitrile(2-chloro-6-methylpyrimidine-4-carbonitrile) were used instead of (4-fluorophenyl)methanamine and 2-chloro-6-methylpyrimidine-4-carbonitrile(2-)

[0084] (((5— f luoropyridin— 2— yl )methyl )amino)pyrimidine— 4— carboni tri le) was synthesized.

[0085] [Step 2]

[0086] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl )amino)— 6— methylpyrimidine— 4— carbonitr i le) instead of 2—(((5— fluoropyridin- 2 -yl)methyl)amino)pyrimidine- 4 -carbonitr i le)

[0087] 2-(((5-fluoropyridin-2-yl)methyl)amino)-N'-hydroxypyrimidine-4-carboxymidamide (2-(((5-fluoropyridin-2-yl)methyl)amino)-N'- hydr oxypyrimidine-4-carboxymidamide)# was synthesized in substantially the same manner as described in step 2 of Example 1, except that 2-(((5-fluoropyridin-2-yl)methyl)amino)-N'- hydr oxypyrimidine-4-carboxymidamide was used.

[0088] [Step 3]

[0089] 2-((4-fluorobenzyl)amino)-N'-hydroxy- 6-methylpyrimidine-4-carboxymidamide

[0090] 2,3,6-Trifluoro-4-(3-(2-(((5-fluoropyridin-2-yl)methyl)amino)pyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol was synthesized in substantially the same manner as described in Step 3 of Example 1, except that 2-(((5-fluoropyridin-2-yl)methyl)amino)-N'-hydroxypyrimidine-4-carboximidamide and 2,3,5-trifluoro-4-hydroxybenzoic acid were used instead of 4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid. Example 4

[0091] Preparation of 2,6-dichloro-4-(3-(2-((4-fluorobenzyl)amino)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol 2-((4-Fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile was synthesized in the same manner as in Step 1 of Example 1.

[0092] [Step 2] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide was synthesized using the same method as step 2 of example 1. [Step 3]

[0093] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-dichloro-4-hydroxybenzoic acid The title compound 2,6-dichloro-4-(3-(2-((4-fluorobenzyl)amino)-6-methylpyrimidin-4-yl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6—di chloro 0—4— (3— (2— ((4— fluorobenzyl )amino)— 6— methylpyrimidin— 4— yl )- 1,2,4- oxadiazol- 5- yl )phenol ) was synthesized in substantially the same manner as described in step 3 of Example 1, except that o-4-hydr oxybenz oic acid was used. Example 5

[0094] Preparation of 2,6-difluoro-4-(3-(3-((4-fluorobenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif 1 uoro-4-(3-(3-((4-f 1 uorobenzyl)amino)-4-methyl phenyl)-1,2,4-oxadiazol-5-yl)phenol)

[0095] (4-fluorophenyl)methanamine and 2-chloro-6-methylpyrimidine-4-carbonitrile instead of 1-(chloromethyl)-4-fluorobenzene and

[0096] 3-((4-fluorobenzyl)amino)-4-methylbenzonitrile was synthesized in substantially the same manner as described in Step 1 of Example 1, except that 3-amino-4-methylbenzonitrile was used. [Step 2] 3-((4-Fluorobenzyl)amino)-N’-hydroxy-4-methylbenzimidamide was synthesized in substantially the same manner as described in Step 2 of Example 1, except that 3-((4-fluorobenzyl)amino)-4-methylbenzonitrile was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile.

[0097] [Step 3]

[0098] The title compound 2,6-difluoro-4-(3-(3-((4-fluorobenzyl)amino)-4-methylphenyl)- was prepared in substantially the same manner as described in step 3 of Example 1, except that 3-((4-fluorobenzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3—((4—f 1 uor obenzy 1 ) am i no )-N ' -hydr oxy-4- methylbenzimidamide) was used instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carbox imi dami de ) l,2,4-Oxadiazol-5-yl)phenol (2,6-difluoro-4- (3—(3—((4—fluorobenzyl)amino)— 4— methyl phenyl )— 1,2,4— oxadi azo 1—5— yl)phenol) was synthesized. Example 6 Preparation of 2,6-difluoro- 4- (3- (3- ( (4-fluorobenzyl)amino) -4-methoxyphenyl)- 1,2,4-oxadiazol- 5 -yl)phenol (2,6-dif 1 uoro-4- ( 3- ( 3- ( ( 4- f 1 uorobenzyl ) amino) - 4- methoxyphenyl )-1,2,4-oxadiazol-5-yl ) pheno 1 )

[0099] 1-(Chloromethyl)-4-fluorobenzene, 3-amino-4-methoxybenzonitrile, and K2CO3 were dissolved in DMF and stirred at 140°C for 16 hours. The mixture after the reaction was diluted with water and extracted with EA. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to synthesize 3-((4-fluorobenzyl)amino)-4-methoxybenzonitrile.

[0100] [Step 2]

[0101] 3-((4-fluorobenzyl)amino)-N'-hydroxy-4-methoxybenzimidamide was synthesized in the same manner as described in Step 2 of Example 1, except that 3-((4-f luorobenzyl)amino)-4-methoxybenzonitrile was used instead of 2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile.

[0102] [Step 3]

[0103] 2-((4-fluorobenzyl)amino)-N'-hydroxy- 6-methylpyrimidine-4-carboxymidamide

[0104] The title compound 2,6-difluoro-4-(3-(3-((4-fluorobenzyl)amino)-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenol was prepared in substantially the same manner as described in step 3 of Example 1 except that 3-((4-fluorobenzyl)amino)-N'-hydroxy-4-methoxybenzimidamide was used instead of 4-carboxylic acid imi dami de )

[0105] 5- yl)phenol) was synthesized. Example 7 Preparation of 2,6-difluoro-4-(5-(3-((4-fluorobenzyl)amino)-4-methylphenyl)-1,3,4-thiadiazol-2-yl)phenol (2,6-di f luoro-4-(5-(3-((4-f luorobenzyl)amino)-4-methylphenyl)-1,3,4-thiadiazol-2-yl)phenol)

[0106] Methyl 3-((4-fluorobenzyl)amino)-4-methylbenzoate was synthesized in substantially the same manner as described in step 1 of Example 6, except that methyl 3-amino-4-methylbenzoate was used instead of 3-amino-4-methoxybenzonitrile.

[0107] [Step 2] Methyl 3-((4-f luorobenzyl)amino)-4-methylbenzoate was dissolved in EtOH, 50% hydrazine hydrate was added, and the mixture was stirred at 100°C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 3-((4-f luorobenzyl)amino)-4-methylbenzohydrazide.

[0108] [Step 3] 3-((4-fluorobenzyl)amino)-4-methylbenzohydrazide, 3,5-difluoro-4-hydroxybenzoic acid, HOBt, and EDOHC1

[0109] After dissolving in DMF, it was stirred at 140°C for 6 hours. After the reaction, the mixture was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgSCU, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain 3,5-difluoro- N ' -(3-( (4-fluorobenzyl )amino) -4-methylbenzoyl )-4-hydroxybenzohydrazide (3,5-di f luoro-N ' -(3-( (4- f luorobenzyl ) amino) -4-methyl benzoyl ) — 4— hydr oxybenzohydr az i de ).

[0110] [Step 4]

[0111] 3,5-difluoro-N'-(3-((4-fluorobenzyl)amino)-4-methylbenzoyl)-4-hydroxybenzohydrazide and Lawesson's Reagent

[0112] 1,4-Dioxane was dissolved and stirred at 120°C for 16 hours. The mixture after the reaction was diluted with water and extracted with sesame oil. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated. The concentrated material was purified by column chromatography to obtain the title compound 2,6-difluoro-4-(5-(3-((4-fluorobenzyl)amino)-4-methylphenyl)-1,3,4-thiadiazol-2-yl)phenol. Example 8

[0113] Preparation of 2,6-difluoro-4-(5-(3-((4-fluorobenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-3-yl)phenol (2,6-d if 1 uoro-4-(5-(3-((4-f 1 uorobenzyl)amino)~4~ methyl phenyl)-1,2,4- oxadiazol-3- yl)phenol) Methyl 3-((4-fluorobenzyl)amino)-4-methylbenzoate was synthesized in substantially the same manner as described in Step 1 of Example 6, except that methyl 3-amino-4-methylbenzoate was used instead of 3-amino-4-methoxybenzonitrile. [Step 2] Methyl 3-((4-fluorobenzyl)amino)-4-methylbenzoate (methyl 3-((4-f luorobenzyl )amino)— 4— methylbenzoate)O} IM lithium hydroxide (IM LiOH) was dissolved in tetrahydrofuran (THF) and stirred at 110 °C.

[0114] The mixture was stirred for 4 hours. After the reaction, the mixture was diluted with water and extracted with EA. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain 3-((4-f luorobenzyl)amino)-4-methylbenzoic acid.

[0115] [Step 3]

[0116] 3,5-difluoro-N',4-dihydroxybenzimidamide was synthesized in the same manner as described in Step 2 of Example 1, except that 3,5-difluoro-4-hydroxybenzonitrile was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile. [Step 4]

[0117] Instead of 2-((4-fluorobenzyl)amino)-N’-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid, 3-((4-fluorobenzyl)amino)-4-methylbenzoic acid and 3,5-difluoro-N’,4-dihydroxybenzimidamide were used, and the title compound 2,6-difluoro-4-(5-(3-((4-fluorobenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-3-yl)phenol was synthesized in substantially the same manner as described in Step 3 of Example 1. Example 9

[0118] 2,6-difluoro-4-(3-(3-((4-fluoro-3-

[0119] (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro—4—(3—(3—((4—fluoro—3—(trifluoromethyl)benzyl)amino)—4—methylphenyl)-1,2,4-oxadiazol-5-yl)phenol) Preparation

[0120]

[0121] 3-amino-4-methylbenzonitrile, 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene, 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene

[0122] 2-(trifluoromethyl)benzene, K2CO3, and DMF were stirred at 120°C for 18 hours. The mixture after reaction was diluted with water and extracted with a solvent. The combined organic layers of the extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((4-f luoro-3-

[0123] (tri fluoromethyl )benzyl ) am i no ) -4-me t hy 1 benzon itri le) was obtained.

[0124] [Step 2]

[0125] 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((4— fluoro— 3— (tri fluoromethyl)benzyl)amino)— 4— methylbenzonitrile), 50% hydroxylamine solution (50% NH20H in H20 solution), and EtOH were stirred at 100°C for 3 hours. After the reaction, the mixture was diluted with water and extracted with Toyo. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The above-mentioned thick substance was purified by column chromatography to obtain 3-( (4-fluoro-3-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-( (4- f luoro-3- (tr if luoromethyl)benzyl)amino)-N'- hydr oxy— 4— me t hy 1 benz imi dam i de ).

[0126] [Step 3]

[0127] 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide, 3,5-difluoro-4-hydroxybenzoic acid, HOBt, and EDOHC1 were dissolved in DMF, DIPEA was added, and the mixture was stirred at 120°C for 3 hours. After the reaction was completed, the mixture was diluted with water and extracted with EA. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The above concentrated material was purified by column chromatography to obtain the title compound 2,6-difluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-4-(3-(3-((4- f luoro-3-( tr if luoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)pheno 1). Example 10

[0128] Preparation of 2,6-difluoro-4-(3-(4-methyl-3-(( (1-methyl-3-(trifluoromethyl)-lH-pyrazol—4-yl)methyl)amino)phenyl)- 1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-4-(3-(4-methy 1-3-( ( (1-methy 1-3-( tri if luoromethy 1 )-lH-pyrazol-4- yl)methyl)amino)phenyl)- 1,2,4-oxadiazol-5-yl)phenol)

[0129] 1-(Chloromethyl)-4-fluorobenzene and

[0130] 4-(Chloromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole and 3-amino-4-methylbenzonitrile were used instead of 3-amino-4-methoxybenzonitrile, and 4-methyl-3-(((1-methyl-3-

[0131] (Trifluoromethyl)-1H-pyrazol-4-yl)methyl)amino)benzonitrile was synthesized in substantially the same manner as described in Step 1 of Example 6.

[0132] [Step 2] 2-((4-Fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile was replaced by 4-methyl-3-

[0133] Except for using ((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)amino)benzonitrile (4-methyl—3—(((1—methyl—3—(trifluoromethyl)-lH-pyrazol-4-yl)methyl)amino)benzonitrile), N'-hydroxy-4-methyl-3-(((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)amino)benzimidamide (1'-hydroxy—4—methyl—3—(((1—methyl—3—(trifluoromethyl)—1H—pyrazol—4—yl)methyl)amino)benzimidamide) was synthesized in substantially the same manner as described in Step 2 of Example 1.

[0134] [Step 3]

[0135] Except for using 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide (2-((4-fluorobenzyl)amino)-N’-hydroxy-6-methylpyrimidine-4-carboximidamide) instead of N'-hydroxy-4-methyl-3-(((1-methyl-3-

[0136] (trifluoromethyl)-1H-pyrazol-4-yl)methyl)amino)benzimidamide (1'-hydroxy—4—methyl—3—(((1—methyl—3—(trifluoromethyl)—1H—pyrazol—4—yl)methyl)amino)benzimidamide), Step

[0137] The title compound 2,6-difluoro-4-(3-(4-methyl-3-(((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di fluoro-4-(3-(4-methyl— 3— (((1— methyl— 3— (tri fluoromethyl)— 1H— pyrazol— 4— yl)methyl)amino)phenyl)-1,2,4- oxadiazol-5-yl)phenol) was synthesized in substantially the same manner as described in 3. Example 11 Methyl 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-

[0138] Preparation of ((4-fluorobenzyl)amino)benzoate (methyl 4-(5-(3,5-difluoro-4-hydroxyphenyl)- 1,2,4- oxadiazol- 3- y 1 )-2-( (4-fluorobenzyl )amino)benzoate)

[0139] 4-Fluorobenzoyl chloride and methyl 2-amino-4-cyanobenzoate were dissolved in acetic acid (AcOH), sodium borohydride (NaBH4) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction, the mixture was diluted with water and extracted with distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain methyl 4-cyano-2-((4-fluorobenzyl)amino)benzoate (methyl 4-cyano-

[0140] 2-((4-f luorobenzyl )amino)benzoate) was obtained.

[0141] [Step 2]

[0142] The steps of Example 1 were repeated except that methyl 4-cyano-2-((4-fluorobenzyl)amino)benzoate was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile.

[0143] Methyl-2-((4-fluorobenzyl)amino)-4-(N'-hydroxycarbamimidoyl)benzoate (methyl-2-) was prepared in substantially the same manner as described in 2.

[0144] ((4-f luorobenzyl )amino)-4-(N' -hydroxycarbamimidoyl )benzoate) was synthesized.

[0145] [Step 3]

[0146] HOBt

[0147] 2-((4-fluorobenzyl)amino)-N'-hydroxy- 6-methylpyrimidine-4-carboxymidamide

[0148] Instead of 4-carboximidami de, methyl- 2-((4-fluorobenzyl)amino)- 4-(N’ - hydroxycarbamimidoyl)benzoate was used, and the title compound methyl 4-(5-(3,5 - difluor o-4-hydroxypheny 1)- 1,2,4 -oxadiazol- 3 -yl)-2-((4 - fluorobenzyl)amino)benzoate was obtained in substantially the same manner as described in Step 3 of Example 1

[0149] 1,2,4 -oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)benzoate). Example 12

[0150] 4- (3- (3- ((4 -fluoro- 3-(trifluoromethyl)benzyl)amino) -4 -methylphenyl)-

[0151] 1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)phenol(4-(3-(3-((4-fluoro-3-

[0152] (trifluoromethyl)benzyl)amino)— 4— methylphenyl)— 1,2,4— oxadiazol—5— yl)—2 — (trifluoromethyl)phenol) Preparation <​​​2-(trifluoromethyl)benzene), K2CO3, and DMF were stirred at 120°C for 18 hours. The mixture was diluted with water and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgSO', and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((4-f luoro-3-

[0155] (tr if luoromethyl )benzyl ) am i no ) -4-me t hy 1 benzon itri le) was obtained.

[0156] [Step 2] 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-

[0157] ( (4— f luoro— 3— (tr if luoromethyl ) benzyl )amino)— 4— methylbenzoni tr i le) , 50% hydroxylamine solution (50% NH20H in H20 solut ion), and EtOH were stirred at 100°C for 3 hours. After the reaction, the mixture was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The above concentrated material was purified by column chromatography to obtain 3-( (4-fluoro-3-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-( (4- f luoro-3-( tri f luoromethyl)benzyl)amino)-N'- hydr oxy— 4— me t hy 1 benz imi dam i de ).

[0158] [Step 3]

[0159] 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide, 4-hydroxy-3-(trifluoromethyl)benzoic acid, HOBt, and EDOHC1 were dissolved in DMF, DIPEA was added, and the mixture was stirred at 120°C for 18 hours. After the reaction was completed, the mixture was diluted with water and extracted with EA and THF. The combined organic layers of the extracts were washed with water, dried over MgSO, and concentrated under reduced pressure. The above concentrated material was purified by column chromatography to give the title compound 4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2-

[0160] (Trifluoromethyl)phenol (4- (3- (3-((4- f luoro- 3- (tr if luoromethyl )benzyl )amino)-

[0161] 4-methylphenyl)- 1,2,4-oxadiazol- 5- y 1)-2- (trifluoromethyl)phenol) was obtained. Example 13 2,3, 6 -trifluoro- 4- (3- (3- ( (4 -fluoro- 3-

[0162] (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,3,6-trifluoro-4-(3-(3-((4-fluoro-3-

[0163] Preparation of (tri fluoromethyl ) benzyl ) am i no ) -4-me t hy 1 pheny 1 )— 1,2,4— oxadi azo 1—5 — yl)phenol) 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitr i le) was synthesized using the same method as step 1 of Example 9.

[0164] [Step 2] 3-((4-fluoro-3-) in the same manner as step 2 of Example 9

[0165] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 3— (tr if luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz i midamide) was synthesized.

[0166] [Step 3]

[0167] The title compound 2,3,6-trifluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol was synthesized in substantially the same manner as described in step 3 of Example 9, except that 2,3,5-trifluoro-4-hydroxybenzoic acid was used instead of 3,5-difluoro-4-hydroxybenzoic acid. Example 14

[0168] Preparation of 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)benzoic acid Methyl 4-cyano-2-((4-fluorobenzyl)amino)benzoate was synthesized in the same manner as in step 1 of Example 11.

[0169] [Step 2] Methyl 2-((4-fluorobenzyl)amino)-4-(N'-hydroxycarbamimidoyl)benzoate was prepared in the same manner as in step 2 of Example 11

[0170] ((4-f luorobenzyl )amino)-4-(N'- hydroxycarbamimidoyl )benzoate) was synthesized. [Step 3]

[0171] Methyl 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide was prepared in substantially the same manner as described in step 3 of Example 1, except that methyl-2-((4-fluorobenzyl)amino)-4-(N'-hydroxycarbamimidoyl)benzoate was used instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide. Fluorobenzyl)amino)benzoate (methyl 4- (5- (3 ,5- di f 1 uor o-4-hydr oxypheny 1 )-

[0172] 1,2,4-oxadiazol-1-3-yl)-2-((4-f luorobenzyl)amino)benzoate) was synthesized.

[0173] [Step 4] The title compound 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-f luorobenzyl)amino)benzoate was prepared in substantially the same manner as described in step 2 of Example 8, except that methyl 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-f luorobenzyl)amino)benzoate was used instead of methyl 3-((4-f luorobenzyl)amino)-4-methylbenzoate. -Hydroxyphenyl)- 1,2,4-oxadiazol- 3 -yl)- 2- ((4-fluorobenzyl)amino)benzoic acid (4- (5-(3,5~di f 1 uor o-4-hydr oxypheny 1 )-l,2,4- oxadi azo 1-3-yl )-2-((4-f luorobenzyl )amino)benzoic acid) was synthesized. Example 15

[0174] 2, 3, 5, 6 -Tetrafluoro- 4- (3- (3- ((4 -fluoro- 3-

[0175] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2, 3, 5, 6-tetrafluoro-4- (3- (3- ((4-fluoro-3- (tri fluoromethyl ) benzyl ) am i no )-4-meth y 1 pheny 1 )— 1,2,4— oxadi azo 1—5— yl)phenol) 3-((4-fluoro-3-) in the same manner as step 1 of Example 12

[0176] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile(3-((4-£11101'0-3-

[0177] (tri fluoromethyl )benzyl )amino)- 4-methylbenzonitrile) was synthesized.

[0178] [Step 2] 3-((4-fluoro-3-) in the same manner as step 2 of Example 12

[0179] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 3— (tr if luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz i midamide) was synthesized.

[0180] [Step 3]

[0181] 4-hydroxy-3-(trifluoromethyl)benzoic acid (4-hydroxy- 3-

[0182] The title compound 2, 3, 5, 6-tetrafluoro-4-hydroxybenzoic acid was prepared in substantially the same manner as described in step 3 of Example 12, except that 2, 3, 5, 6-tetrafluoro-4- (3- (3- ( (4-fluoro-3-

[0183] (Trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2, 3, 5, 6-tetrafluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)—4—methyl t hy 1 pheny 1)— 1,2,4—oxadiazol— 5—yl)phenol) was synthesized. Example 16 N-(3-cyanophenyl)-4-(5-(3, 5-difluoro-4-hydroxyphenyl)-1, 2, 4-oxadiazol- 3 -yl)-2-((4-fluorobenzyl)amino)benzamide (N-(3-cyanophenyl)-4-

[0184] Preparation of (5-(3, 5~dif 1 uoro-4-hydr oxyphenyl )-1,2, 4-oxad i azo 1 —3— y 1 ) —2—( (4— f luorobenzyl )amino)benzamide) Methyl 4— cyano— 2— ((4— f luorobenzyl )amino) benzoate was synthesized using the same method as step 1 of Example 11.

[0185] [Step 2] Step 2 of Example 11 {Methyl-2-((4-fluorobenzyl)amino)-4-(N'-hydroxycarbamimidoyl)benzoate (methyl-2-

[0186] ( (4-f luorobenzyl ) am i no ) -4- ( N ' -hydr oxy car bam imi doy 1 )benzoate) was synthesized. [Step 3]

[0187] Methyl 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide was prepared in substantially the same manner as described in step 3 of Example 1, except that methyl-2-((4-fluorobenzyl)amino)-4-(N'-hydroxycarbamimidoyl)benzoate was used instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide. Fluorobenzyl)amino)benzoate (methyl 4- (5- (3 ,5- di f 1 uor o-4-hydr oxypheny 1 )- 1,2,4— oxadi azo 1—3— yl )-2-( (4-f luorobenzyl )amino)benzoate) was obtained.

[0188] [Step 4] A method substantially the same as that described in step 2 of Example 8 was carried out except that methyl 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)benzoate was used instead of methyl 3-((4-f luorobenzyl)amino)-4-methylbenzoate.

[0189] (5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)benzoic acid (4-(5-(3,5~di f 1 uor o-4-hydr oxypheny 1)-l,2,4- oxadi azo 1-3-yl)-2-((4-f luorobenzyl )amino)benzoic acid) was synthesized.

[0190] [Step 5]

[0191] 4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)benzoic acid, 3-aminobenzonitrile, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-

[0192] [Bis(dimethylamino)methylene]— 1H— 1,2,3— tri azol o[ 4,5— b] pyridinium 3-Oxide

[0193] Hexafluorophosphate, HATU) and DIPEA were dissolved in THF and stirred at 120°C for 16 hours. The mixture was diluted with water and extracted with ethanol. The mixed organic layers of the extracts were washed with water, dried over MgSO, and concentrated under reduced pressure. The above concentrated material was purified by column chromatography to synthesize the title compound N-(3-cyanophenyl)-4-(5-(3,5-difluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluorobenzyl)amino)benzamide (N-(3-cyanophenyl)-4-(5-(3,5-di f luoro-4- hydr oxyphenyl)— 1,2,4— oxadi azo 1—3— yl)-2-((4-f luorobenzyl)amino)benzamide). Example 17

[0194] 3 , 5 -Difluoro- 4- (3- (3- ( (4 -fluoro- 3-

[0195] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (3, 5- dif luoro— 4— (3— (3— ((4— f luoro— 3— (trif luoromethyl)benzyl)amino)— 4 — methyl phenyl )- 1,2,4- oxadiazol- 5- yl )phenol ) 3-((4-fluoro-3-) in the same manner as step 1 of Example 9

[0196] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile(3-((4-£11101'0-3-

[0197] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile) was synthesized.

[0198] [Step 2] 3-((4-fluoro-3-) in the same manner as step 2 of Example 9

[0199] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 3—( tri f luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz imidamide) was synthesized. [Step 3]

[0200] The method described in step 3 of Example 9 was substantially the same as that described in step 3 of Example 9, except that 2,6-difluoro-4-hydroxybenzoic acid was used instead of 3,5-difluoro-4-hydroxybenzoic acid, to obtain the title compound 3,5-difluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol-5-yl)phenol (3,5-difluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol-5-yl)phenol 1-5- yl)phenol ) was synthesized. Example 18

[0201] 2, 3 -Difluoro- 4- (3- (3- ( (4 -fluoro- 3-

[0202] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,3- dif luoro— 4— (3— (3— ((4— f luoro— 3— (trif luoromethyl)benzyl)amino)— 4 — methyl phenyl )- 1,2,4- oxadiazol- 5- yl )phenol )

[0203] [Step 1] Ro- 3-

[0204] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-( (4- f luoro-3-

[0205] (trif luoromethyl )benzyl ) am i no ) -4-me t hy 1 benzon itri le) was synthesized.

[0206] [Step 2] 3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 3— (tri if luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz i midamide) was synthesized using the same method as in step 2 of Example 12.

[0207] [Step 3]

[0208] 4-hydroxy-3-(trifluoromethyl)benzoic acid (4-hydroxy- 3-

[0209] (tr if luoromethyl )benzoic acid) instead of 2, 3 -difluoro- 4 -hydroxybenzoic acid

[0210] The title compound 2,3-difluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol was synthesized in substantially the same manner as described in step 3 of Example 12, except that (2,3-difluoro-4-hydr oxybenzo ic acid) was used. Example 19

[0211] 2 , 5 -Difluoro- 4- (3- (3- ( (4 -fluoro- 3-

[0212] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,5- dif luoro— 4— (3— (3— ((4— fluoro— 3— ( tri fluoromethyl )benzyl)amino)— 4— methyl phenyl )- 1,2,4- oxadiazol- 5- yl )phenol ) 3-((4-fluoro-3-) in the same manner as step 1 of Example 12

[0213] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile(3-((4-£11101'0-3-

[0214] (tri fluoromethyl )benzyl )amino)- 4-methylbenzonitrile) was synthesized.

[0215] [Step 2] 3-((4-fluoro-3-) in the same manner as step 2 of Example 12

[0216] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide) was synthesized.

[0217] [Step 3] 4-Hydroxy-3-(trifluoromethyl)benzoic acid (4-hydroxy-3-(trifluoromethyl)benzoic acid)

[0218] (trifluoromethyl)benzoic acid) was replaced with 2,5-difluoro-4-hydroxybenzoic acid (2,5-difluoro-4-hydroxybenzoic acid), and the title compound 2,5-difluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,5-difluoro-4-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol) was synthesized in substantially the same manner as described in Step 3 of Example 12. Example 20 5-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-

[0219] 1,2,4-oxadiazol-5-yl)-2-hydroxybenzonitrile (5-(3-(3-((4-fluoro-3-

[0220] (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2-hydroxybenzonitrile) Preparation [Step 1] In the same manner as in Step 1 of Example 12, 3-((4-fluoro-3-

[0221] (Trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((4- f luoro-3- (trif luoromethyl)benzyl)aiiiino)- 4-methylbenzonitrile) was synthesized.

[0222] [Step 2] 3-((4-fluoro-3-) in the same manner as step 2 of Example 12

[0223] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 3— (tr if luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz i midamide) was synthesized.

[0224] [Step 3]

[0225] 4-hydroxy-3-(trifluoromethyl)benzoic acid instead of 3-cyano-4-hydroxybenzoic acid

[0226] The title compound 5-(3-(3-((4-fluoro-3-) was prepared in substantially the same manner as described in step 3 of Example 12, except that 4-hydroxybenzoic acid) was used.

[0227] (Trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2-hydroxybenzonitrile (5-(3-(3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2-hydroxybenzonitrile) was synthesized. Example 21 2,6-Difluoro-4-(3-(3-((3-fluoro-5-

[0228] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- difluoro— 4— (3— (3— ((3— fluoro— 5— (tri fluoromethyl )benzyl)amino)— 4— methyl phenyl )- 1,2,4- oxadiazol- 5- yl )phenol )

[0229] Instead of 1-(chloromethyl)-4-fluorobenzene and 3-amino-4-methoxybenzonitrile, 1-

[0230] 3-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((3-fluoro-5-(trifluoromethyl)benzene) and 3-amino-4-methylbenzonitrile) were prepared in substantially the same manner as described in step 1 of Example 6, except that (bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene and 3-amino-4-methylbenzonitrile were used.

[0231] (tr if luoromethyl )benzyl ) am i no ) -4-me t hy 1 benzon itri le) was synthesized.

[0232] [Step 2] 3-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((3-f luoro-5-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile) was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)— 6— methylpyrimidine— 4— carbonitrile) in a manner substantially the same as that described in step 2 of example 1, except that 3-((3-f luoro-5-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile) was used to prepare 3-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((3-f luoro-5-(trifluoromethyl)benzyl)amino)-N' - hydroxy- 4- methyl benz i midamide) was synthesized.

[0233] [Step 3] 2-( (4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide ( 2- ( (4- f 1 uor obenzy 1 ) am i no )- N'-hydr oxy- 6- me t hy 1 py r imidine-

[0234] 3-((3-fluoro-5-(trifluoromethyl)benzyl)amino)- instead of 4-carboximidamide)

[0235] N' -Hydroxy-4-methylbenzimidamide (3-( (3- f luoro-5-

[0236] The title compound 2,6-difluoro-4-(3-(3-((3-fluoro-5-)-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methyl-1-benzimidam i de) was prepared in substantially the same manner as described in step 3 of Example 1, except that (trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methyl-1-benzimidam i de) was used.

[0237] (Trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- dif luoro— 4— (3— (3— ((3— fluoro— 5—( tri f luoromethyl )benzyl) ami no )—4— methyl phenyl )- 1,2,4- oxadi azo 1-5- yl)phenol ) was synthesized. Example 22

[0238] 2 , 6 -Difluoro- 4- (3- (3- ( (4 -fluoro- 2-

[0239] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-4-(3-(3-((4-fluoro-2-(tri fluoromethyl )benzyl)amino)-4-methyl phenyl )-1,2,4-oxadiazol-5-yl )phenol )

[0240] 1-(chloromethyl)-4-fluorobenzene and

[0241] 3-amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) instead of 1-

[0242] (Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (1-(you0111006shi71)-4-fluoro- 2-(trifluoromethyl)benzene) and 3-amino-4-methylbenzonitrile (3-amino-4-methylbenzonitrile) were used, and in a substantially the same manner as described in Step 1 of Example 6, 3-((4-fluoro-2-

[0243] (Trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((4-fluoro-2-

[0244] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile) was synthesized.

[0245] [Step 2]

[0246] Instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-fluorobenzyl)amino)—6—methylpyrimidine—4—carbonitrile), in a substantially the same manner as described in Step 2 of Example 1, 3-

[0247] ((4-Fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide) was synthesized.

[0248] ((4-Fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide) was synthesized.

[0249] [Step 3]

[0250] 2-( (4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide ( 2- ( (4- f 1 uor obenzy 1 ) am i no )- N'-hydr oxy- 6- me t hy 1 py r imidine-

[0251] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)- instead of 4-carboximidamide)

[0252] The title compound 2,6-difluoro-4-(3-(3-((4-f luoro-2-(trif luoromethyl)benzyl)amino)— N' —hydroxy— 4— methyl benz i midamide) was prepared in substantially the same manner as described in step 3 of Example 1, except that N' -hydroxy-4-methylbenzimidamide (3-( (4-f luoro-2- (trif luoromethyl)benzyl)amino)— N' —hydroxy— 4— methyl benz i midamide) was used.

[0253] (Trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- difluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol) was synthesized. Example 23

[0254] 2,6-Difluoro-3-(3-(3-(4-fluoro-3-

[0255] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- dif luoro— 3— (3— (3— ((4— f luoro— 3— (trif luoromethyl)benzyl)amino)— 4 — methyl phenyl )- 1,2,4- oxadiazol- 5- yl )phenol ) 3-((4-fluoro-3-) in the same manner as step 1 of Example 12

[0256] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile(3-((4-£11101'0-3-

[0257] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile) was synthesized.

[0258] [Step 2] 3-((4-fluoro-3-) in the same manner as step 2 of Example 12

[0259] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 3— (tr if luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz i midamide) was synthesized.

[0260] [Step 3]

[0261] 4-hydroxy-3-(trifluoromethyl)benzoic acid (4-hydroxy- 3-

[0262] The title compound 2,6-difluoro-3-(3-(3-((4-fluoro-3-) ...

[0263] (Trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- di f luoro— 3— (3— (3—( (4— f luoro— 3— (trifluoromethyl )benzyl )amino)— 4— methylphenyl)- 1,2,4- oxadiazol- 5- yl)phenol) was synthesized. Example 24

[0264] 2 , 6 -Difluoro- 4- (3- (3- ( (3 -fluoro- 4-

[0265] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- dif luoro— 4— (3— (3— ((3— fluoro— 4—( tri fluoromethyl )benzyl)amino)— 4— methyl phenyl )- 1,2,4- oxadiazol- 5- yl )phenol )

[0266] 3-amino-4-methylbenzonitrile, 4-

[0267] (Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (4-(bromomethyl)-2-f luoro-l-(tri if luoromethyl)benzene), K2CO3, and DMF were stirred at 80°C for 18 hours. The mixture after the reaction was diluted with water and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgSO', and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((3-£11101'0-4- (tri fluoromethyl )benzyl )amino)-4-methylbenzonitrile).

[0268] [Step 2]

[0269] 3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile(3-

[0270] ((3— fluoro— 4— (trifluoromethyl )benzyl)amino)— 4— methylbenzonitrile) , 50% NH2OH in H2O solution, and EtOH were stirred at 80°C for 2 hours. The mixture was diluted with water and extracted with distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated. The concentrated material was purified by column chromatography to give compound 3- ((3 -fluoro- 4-

[0271] (Trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((3-fluoro— 4— (trifl uoromethyl )benzyl )amino)-N' -hydr oxy— 4— me t hy 1 benz imi dam i de ) was obtained.

[0272] [Step 3]

[0273] 3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide, 3,5-difluoro-4-hydroxybenzoic acid, HOBt, and EDOHC1 were dissolved in DMF, followed by addition of DIPEA and stirring at 80°C for 18 h. The above mixture after reaction was concentrated and purified by column chromatography to obtain the title compound 2,6-difluoro-4-(3-(3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-4-(3-(3-((3- f luoro-4-( tr if 1 uoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol). Example 25

[0274] 2,6-Difluoro-4-(3-(4-fluoro-3-((4-flu 9.lu-- 3-

[0275] (trifluoromethyl)benzyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro— 4— (3— (4— f luoro— 3— ( (4-f luoro-3-

[0276] Preparation of (trif luoromethyl)benzyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)phenol)

[0277] 1-(chloromethyl)-4-fluorobenzene and

[0278] 3-amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) instead of 4-

[0279] (Bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (4-(bromomethyl)-1-f luoro-

[0280] 4-Fluoro-3-((4-fluoro-3-)benzene) and 3-amino-4-fluorobenzonitrile were prepared in substantially the same manner as described in step 1 of Example 6, except that 2-(trifluoromethyl)benzene and 3-amino-4-fluorobenzonitrile were used.

[0281] (trifluoromethyl)benzyl)amino)benzonitrile(4-£11101'0-3-((4-£11101'0-3-

[0282] (tri fluoromethyl )benzyl )amino)benzonitrile) was synthesized.

[0283] [Step 2]

[0284] 4-Fluoro-3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)benzonitrile) was prepared in substantially the same manner as described in step 2 of Example 1, except that 4-fluoro-3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)benzonitrile was used instead of 2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile) 4-fluoro-3-((4-fluoro-3-(trifluoromethyl)benzyl)amino)benzonitrile)

[0285] (trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide) was synthesized.

[0286] [Step 3]

[0287] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide instead of 4-fluoro-3-((4-fluoro-3-

[0288] (trifluoromethyl)benzyl)amino) -N'-hydroxybenzimidamide (4-fluoro- 3-((4- f luoro— 3—( tri f luoromethyl )benzyl ) am i no ) -N ' -hydr oxybenz imi dam i de ) Compound 2,6-Difluoro-4-(3-(4-fluoro-3-( (4-fluoro-3-) was prepared in substantially the same manner as described in step 3 of Example 1, except that

[0289] (trifluoromethyl)benzyl)amino)phenyl)- 1,2,4 -oxadiazol- 5 -yl)phenol (2,6- di f luoro— 4— (3—(4— f luoro— 3—( (4— f luoro-3-

[0290] (trifluoromethyl)benzyl)amino)phenyl)— 1,2,4— oxadiazol— 5— yl)phenol) was synthesized. Example 26

[0291] 2 , 6 -Difluoro- 3-(3-(3-((4 -fluoro- 2-

[0292] Preparation of (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-3-(3-(3-((4-f luoro-2-( tr if luoromethyl )benzyl )amino)-4-methyl phenyl )-1,2,4-oxadiazol-5-yl )phenol ) 3-((4-fluoro-2- in the same manner as step 1 of Example 22

[0293] (trifluoromethyl)benzyl)amino) -4-methylbenzonitrile(3-((4- f luoro-2-

[0294] (tr if luoromethyl )benzyl ) am i no ) -4-me t hy 1 benzon itri le) was synthesized.

[0295] [Step 2] 3-((4-fluoro-2- in the same manner as step 2 of Example 22

[0296] (trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 2— (trifluoromethyl )benzyl )amino)-N'-hydr oxy— 4— me t hy 1 benz imi dam i de ) was synthesized. [Step 3]

[0297] The method described in step 3 of Example 22 was substantially the same as that described in step 3 of Example 22 except that 2,4-difluoro-3-hydroxybenzoic acid was used instead of 3,5-di f luoro-4-hydroxybenzoic acid, thereby obtaining the title compound 2,6-difluoro-3-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-4-(3-(4-f luoro-3-( (4-f luoro-3-

[0298] (trifluoromethyl)benzyl)amino)phenyl)— 1,2,4— oxadiazol— 5— yl)phenol) was synthesized. Example 27

[0299] 2 , 6 -Difluoro- 4- (3- (3- ( (4 -fluoro- 2-

[0300] (trifluoromethyl)benzyl)amino)- 2,4-dimethylphenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6- dif luoro- 4- (3- (3- ((4-fluoro- 2- (tri fluoromethyl )benzyl)amino)-

[0301] Preparation of 2,4-dimethylphenyl)-1,2,4-oxadiazol-5-yl)phenol)

[0302] [Step 1]

[0303] Instead of 1-(chloromethyl)-4-fluorobenzene and 3-amino-4-methoxybenzonitrile, 1-

[0304] 3-((4-fluoro-2-trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene) and 3-amino-2,4-dimethylbenzonitrile (3-amino-2,4-dimethylbenzonitrile) were used in substantially the same manner as described in step 1 of Example 6.

[0305] (Trifluoromethyl)benzyl)amino)-2,4-dimethylbenzonitrile (3-((4-fluoro-2- (trifluoromethyl )benzyl )amino)-2,4-dimethylbenzonitrile) was synthesized. [Step 2]

[0306] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-2,4-dimethylbenzonitrile was prepared in substantially the same manner as described in step 2 of Example 1, except that 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-2,4-dimethylbenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'- hydr oxy-2, 4-dimethylbenzi mi dam i de ) was synthesized. [Step 3]

[0307] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide) Instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide, use 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-2,4-dimethylbenzimidamide

[0308] The title compound 2,6-difluoro-4-(3-(3-((4-fluoro-2-

[0309] (Trifluoromethyl)benzyl)amino)-2,4-dimethylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro-0-4-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-

[0310] 2,4-dimethylphenyl)-1,2,4-oxadiazol-5-yl)phenol) was synthesized. Example 28

[0311] 2,6-difluoro-3-(3-(3-((3-fluoro-5-

[0312] (Trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro—3—(3—(3—((3—fluoro—5—(trifluoromethyl)benzyl)amino)—4—methylphenyl)-1,2,4-oxadiazol-5-yl)phenol) Preparation [Step 1]

[0313] 1-(Chloromethyl)-4-fluorobenzene (1-(chloromethyl)-4-fluorobenzene) and

[0314] 3-Amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) was replaced with 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene(1-(bromomethyl)-3-fluoro-5-

[0315] 5-(trifluoromethyl)benzene) and 3-amino-4-methylbenzonitrile (3-amino-4-methylbenzonitrile) were used, except that the method described in Step 1 of Example 6 was substantially the same as 3-((3-fluoro-5-

[0316] (Trifluoromethyl)benzyl)amino)-4-methylbenzonitrile (3-((3-fluoro-5-(tri fluoromethyl )benzyl )amino)-4-methylbenzonitrile) was synthesized.

[0317] [Step 2]

[0318] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile(2-((4-f luorobenzyl )amino)— 6— methylpyrimidine— 4— carbonitrile) instead of 3-((3-fluoro-5- (trifluoromethyl)benzyl)amino)- 4-methylbenzonitrile(3-((3-£11101'0-5-

[0319] 3-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((3-f luoro-5-(tri f luoromethyl)benzyl)amino)-N'-hydr oxy-4- methylbenzimidamide) was synthesized in substantially the same manner as described in step 2 of Example 1, except that (tri fluoromethyl )benzyl )amino)-4-methylbenzonitrile) was used.

[0320] [Step 3]

[0321] 2-((4-fluorobenzyl)amino)-N'-hydroxy- 6-methylpyrimidine-4-carboxymidamide

[0322] 4-carbox imi dami de ) and 3 , 5 -difluoro-4 -hydroxybenzoic acid (3 , 5- di f luoro-4- hydroxybenzoic acid) instead of 3- ((3 -fluoro- 5-

[0323] The title compound 2,6-difluoro-3-(3-(3-((3-f luoro— 5— (trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((3-f luoro— 5— (trifluoromethyl)benzyl)am i no )-N'-hydr oxy-4-methyl benzimi dam i de ) and 2,4-difluoro-3-hydroxybenzoic acid were used, but the method was substantially the same as that described in Step 3 of Example 1, except that 2,4-difluoro-3-hydroxybenzoic acid was used.

[0324] (trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro—3—(3—(3—((3—fluoro—5—(tri f luoromethyl )benzyl)amino )—4—methyl phenyl )-1,2,4-oxadiazol-5-yl)phenol ) was synthesized. Example 29

[0325] 2 , 6 -Difluoro- 3-(3-(3-((4 -fluoro- 2-

[0326] (trifluoromethyl)benzyl)amino)-4-(phenylamino)phenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-3- (3- (3- ((4- f luoro-2-( tri f luoromethyl )benzyl )amino)-4-

[0327] Preparation of ( pheny 1 am i no ) pheny 1 )— 1,2,4— oxadiazol— 5— yl )phenol )

[0328] 3-amino-4-methylbenzonitrile and 4-

[0329] Instead of (bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene), 3-amino-4-(phenylamino)benzonitrile (3-amino-4-(pheny 1 am i no ) benz on itri le) and 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-

[0330] 3-((4-fluoro-2-)benzene) was prepared in substantially the same manner as described in step 1 of Example 24, except that (tr if luoromethyl )benzene) was used.

[0331] (trifluoromethyl)benzyl)amino)-4-(phenylamino)benzonitrile(3-( (4-£ 11101'0-2-

[0332] (tr if luoromethyl )benzyl ) am i no ) -4 - ( pheny 1 am i no ) benz on itri le) was synthesized. [Step 2]

[0333] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-

[0334] (Phenylamino)benzonitrile (3-( (4- f luoro- 2- (tr if luoromethyl )benzyl )amino)-4-

[0335] (phenylamino)benzonitrile) and 50% NH2OH in H2O solution, EtOH were stirred at room temperature for 18 hours. The mixture was diluted with water and extracted with EA after the reaction was completed. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure to give 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-(phenylamino)benzimidamide (3-( (4- f luoro-2-

[0336] (trif 1 uoromethyl )benzyl )amino)-N' -hydr oxy-4 - ( pheny 1 am i no ) benz i 111 i dam i de ) was obtained.

[0337] [Step 3]

[0338] 3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((3-f luoro-4-(tri f luoromethyl)benzyl)amino)-N'- hydr oxy-4-me t hy 1 benz imi dam i de ) and 3,5-di f luoro-4-hydroxybenzoic acid (3,5-di f luoro-4-hydroxybenzoic acid) instead of 3-((4-fluoro-2-

[0339] (trifluoromethyl)benzyl)amino)-N'-hydroxy-4-(phenylamino)benzimidamide (3-((4- f luoro- 2- (tr if luoromethyl )benzyl )amino)-

[0340] The title compound 2,6-difluoro-3-(3-(3-((4-fluoro-2-(N'— hydroxy— 4— (phenyl ami no )benzi midamide)O} 2,4-difluoro-3-hydroxybenzoic acid was prepared in substantially the same manner as described in Step 3 of Example 24, except that 2,4-di fluor 0-3- hydroxybenzoic acid was used.

[0341] (trifluoromethyl)benzyl)amino)-4-(phenylamino)phenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-3- (3- (3- ((4-fluoro-2- (trif luoromethyl )benzyl) ami no )-4-

[0342] ( pheny 1 am i no ) pheny 1 )- 1,2,4- oxadi azo 1-5- yl )phenol ) was synthesized. Example 30

[0343] 3- (3- (4-(benzylamino)- 3- ((4 -fluoro- 2-

[0344] (Trifluoromethyl)benzyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol(3-(3-(4-a*1127121111du110)-3-((4-ho11101'0-2-

[0345] Preparation of (trif luoromethyl)benzyl)amino)phenyl)— 1,2,4— oxadiazol— 5— yl)— 2,6— di fluorophenol)

[0346] [Step 1]

[0347] 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene, 3-amino-4-(benzylamino)benzonitrile, and K2CO3 were dissolved in DMF and stirred at 60°C for 16 hours. The reaction mixture was diluted with water and extracted with distilled water. The combined organic layers of the extracts were washed with water, dried over MgSO, and concentrated under reduced pressure. The above concentrated material was purified by column chromatography to obtain 4-(benzylamino)-3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide (4-(benzylamino)-3-((4- f luoro-2- (trif luoromethyl )benzyl) ami no)— N'—hydroxybenzimidamide).

[0348] [Step 2]

[0349] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile(2-((4-f luorobenzyl )amino)— 6— methylpyrimidine— 4— carbonitrile) instead of 4-(benzylamino)- 3-((4-fluoro- 2-(trifluoromethyl)benzyl)amino) -N'- hydroxybenzimidamide (4-(benzylamino)- 3-((4-f luoro-2-

[0350] 4 - (trif luoromethyl )benzyl ) am i no ) -N ' -hydr oxybenz imi dam ide)# was used in substantially the same manner as described in step 2 of example 1, except that

[0351] (Benzylamino)-3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide (4-(benzylamino)-3-((4-fluoro-2-

[0352] (trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide) was synthesized. [Step 3]

[0353] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide (2-((4-fluorobenzyl)amino)-N’-hydroxy-6-methylpyrimidine-4-carboximidamide) and 3,5-difluoro-4-hydroxybenzoic acid (3,5-difluoro-4-hydroxybenzoic acid) were replaced with 4-(benzylamino)-3-((4-fluoro-2-

[0354] (trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide (4-(benzylamino)-3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide) and

[0355] 2,4-difluoro-3-hydroxybenzoic acid (2,4-difluoro-3-hydroxybenzoic acid). The title compound 3-(3-(4-(benzylamino)-3-((4-fluoro-2-

[0356] (Trifluoromethyl)benzyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol (3-(3-(4-(benzylamino)-3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)phenyl)—1,2,4—oxadiazol—5—yl)—2,6—difluorophenol) was synthesized. Example 31

[0357] 3-(3-(3-Amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)phenyl)-

[0358] 1,2,4-Oxadiazol-5-yl)-2,6-difluorophenol (3-(3-(3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)phenyl)—1,2,4—oxadiazol—5—yl)—2,6—difluorophenol) Preparation 3-Amino-4-methylbenzonitrile (3-amino-4-methylbenzonitrile) and 4-

[0359] (Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (4-(bromomethyl)-2-fluoromethyl)benzene) Instead, 3-amino-4-hydroxybenzonitrile(3-hex0 yuan10-

[0360] 4-hydroxybenzonitrile) and 1-(bromomethyl)-4-fluoro-2-

[0361] (Trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene) was used in substantially the same manner as described in Step 1 of Example 24 except that 3-amino-4-((4-fluoro-2-

[0362] (Trifluoromethyl)benzyl)oxy)benzonitrile (3-amino-4-((4-fluoro-2-

[0363] (Trifluoromethyl)benzyl)oxy)benzonitrile was synthesized. [Step 2]

[0364] 3-((4-Fluoro-2-(trifluoromethyl)benzyl)amino)-4-

[0365] (Phenylamino)benzonitrile (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-(phenylamino)benzonitrile) was used instead of 3-amino-4-((4-fluoro-2-

[0366] (Trifluoromethyl)benzyl)oxy)benzonitrile(3-ai shi 0-4-((4-fluoro-2-

[0367] (Trifluoromethyl)benzyl)oxy)benzonitrile was used, except that 3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)-N'-hydroxybenzimidamide (3-amino—4—((4—fluoro—2—(trifluoromethyl)benzyl)oxy)-N’—hydroxybenzimidamide) was synthesized in substantially the same manner as described in Step 2 of Example

[0368] 29.

[0369] [Step 3]

[0370] It should be noted that there may be some unclear or incorrect expressions in the original text (such as "3-애辻0" which seems to be an error), and the translation is done as accurately as possible based on the existing content.3 - ((3 - fluoro - 4 - (trifluoromethyl)benzyl)amino)-N'-hydroxy - 4 - methylbenzimidamide and 3,5 - difluoro - 4 - hydroxybenzoic acid were replaced by 3 - amino - 4 - ((4 - fluoro - 2 -

[0371] (trifluoromethyl)benzyloxy)-N'-hydroxybenzimidamide and 2,4 - difluoro - 3 - hydroxybenzoic acid. The title compound 3 - (3 - (3 - amino - 4 - ((4 - fluoro - 2 - (trifluoromethyl)benzyloxy)phenyl)-1,2,4 - oxadiazol - 5 - yl)-2,6 - difluorophenol

[0372] (3-(3-(3 - amino - 4 - ((4 - fluoro - 2 - (trifluoromethyl)benzyloxy)phenyl)-1,2,4 - oxadiazol - 5 - yl)-2,6 - difluorophenol) was synthesized in substantially the same manner as described in Step 3 of Example 24. Example 32

[0373] 2,3,6 - trifluoro - 5 - (3 - (3 - ((4 - fluoro - 2 -

[0374] (trifluoromethyl)benzyl)amino)-4 - methylphenyl)-1,2,4 - oxadiazol - 5 - yl)phenol (2,3,6 - trifluoro - 5 - (3 - (3 - ((4 - fluoro - 2 -

[0375] Preparation of (tri fluoromethyl ) benzyl ) am i no ) -4-me t hy 1 pheny 1 )— 1,2,4— oxadi azo 1—5— yl)phenol) 3-((4-fluoro-2-) in the same manner as step 1 of Example 22

[0376] (trifluoromethyl)benzyl)amino)-4-methylbenzonitrile(3-((4-£11101'0-2-

[0377] (tri fluoromethyl )benzyl )amino)- 4-methylbenzonitrile) was synthesized.

[0378] [Step 2] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4- f luoro— 2— (tri if luoromethyl )benzyl )amino)— N' —hydroxy— 4— methyl benz i midamide) was synthesized using the same method as in step 2 of Example 22. [Step 3]

[0379] The title compound 2,3,6-trifluoro-5-(3-) was prepared in substantially the same manner as described in step 3 of Example 22, except that 2,4,5-trifluoro-3-hydroxybenzoic acid was used instead of 3,5-difluoro-4-hydroxybenzoic acid.

[0380] (3- ((4-fluoro-2-(trifluoromethyl)benzyl)amino) -4-methylphenyl)- 1,2,4-oxadiazol- 5 -yl)phenol (2 , 3 , 6- tr if luoro- 5- (3- (3-( (4- f luoro- 2-

[0381] (trifluoromethyl)benzyl)amino)— 4— methylphenyl)— 1,2,4— oxadiazol— 5— yl)phenol) was synthesized. Example 33

[0382] 2,6-Difluoro- 3- (3- (4-fluoro- 3- ( (4-fluoro- 2-

[0383] (trifluoromethyl)benzyl)amino)phenyl)- 1,2,4 -oxadiazol- 5 -yl)phenol (2,6- di f luoro- 3- (3- (4- f luoro- 3- ( (4- f luoro- 2 -

[0384] Preparation of (trif luoromethyl)benzyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)phenol) 1-(chloromethyl)-4-fluorobenzene and

[0385] 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene) instead of 3-amino-4-methoxybenzonitrile

[0386] 4-Fluoro-3-((4-fluoro-2-)benzene) and 3-amino-4-fluorobenzonitrile (3-amino-4-fluorobenzonitrile) were prepared in substantially the same manner as described in step 1 of Example 6, except that 2-(trifluoromethyl)benzene and 3-amino-4-fluorobenzonitrile were used.

[0387] (trifluoromethyl)benzyl)amino)benzonitrile(4-£11101'0-3-((4-£11101'0-2-

[0388] (tri fluoromethyl )benzyl )amino)benzonitrile) was synthesized.

[0389] [Step 2]

[0390] 4-Fluoro-3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)benzonitrile) was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile) in a manner substantially the same as that described in step 2 of Example 1, except that 4-fluoro-3-((4-f luoro-2-(trifluoromethyl)benzyl)amino)benzonitrile) was used. 4-Fluoro-3-((4-f luoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide (4-f luoro-3-((4-f luoro-2-

[0391] ( trif 1 uor ome t hy 1 ) benzy 1 ) am i no ) -N ' -hydr oxybenz imi dam ide)# was synthesized. [Step 3]

[0392] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 4-fluoro-3-((4-fluoro-2-

[0393] The title compound 2,6-difluoro-3-(3-(4-fluoro-3-((4-fluoro-2-(4-fluoro-2-((4-fluoromethyl)benzyl)amino)-N'-hydroxybenzimidamide (4-£11101'0-3-((4-f 1 uor 0-2-( trif 1 uor ome t hy 1 ) benzy 1 ) am i no )-N'-hydr oxybenz imi dam i de ) and 2,4-difluoro-3-hydroxybenzoic acid (2,4~di f 1 uor o-3-hydr oxybenzo ic acid) were prepared in substantially the same manner as described in step 3 of Example 1, except that

[0394] (trifluoromethyl)benzyl)amino)phenyl)- 1,2,4 -oxadiazol- 5 -yl)phenol (2,6- di f luoro— 3— (3— (4— f luoro— 3— ( (4— f luoro-2-

[0395] (trifluoromethyl)benzyl)amino)phenyl)— 1,2,4— oxadiazol— 5— yl)phenol) was synthesized. Example 34

[0396] 3- (3- (3 -amino- 4- ((4 -fluoro- 2- (trifluoromethyl)benzyl) oxy) phenyl) -

[0397] Preparation of 1,2, 4-oxadiazol- 5 -yl)- 2, 5, 6-trifluorophenol (3- (3- (3-amino- 4- ((4- fluoro- 2- (trif luoromethyl )benzyl)oxy)phenyl )-1,2, 4-oxadiazol-5-yl )-2, 5,6- trif 1 uor opheno 1 ) 3-amino-4-methylbenzonitrile and 4-

[0398] (Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene) was replaced with 3-amino-4-hydroxybenzonitrile (3-amino-4-hydroxybenzonitrile), and 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene) was used. Otherwise, in substantially the same manner as described in Step 1 of Example 24, 3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile (3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile) was synthesized.

[0399] 4-hydroxybenzonitrile) and 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene) were used. Otherwise, in substantially the same manner as described in Step 1 of Example 24, 3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile (3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile) was synthesized.

[0400] (trifluoromethyl)benzene) were used. Otherwise, in substantially the same manner as described in Step 1 of Example 24, 3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile (3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile) was synthesized.

[0401] (trifluoromethyl)benzyl)oxy)benzonitrile (3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile) was synthesized.

[0402] [Step 2]

[0403] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-

[0404] (phenylamino)benzonitrile (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-(phenylamino)benzonitrile) was replaced with 3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile (3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile). Otherwise, in substantially the same manner as described in Example

[0405] (trifluoromethyl)benzyl)oxy)benzonitrile(3-amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)benzonitrile) was used. Otherwise, in substantially the same manner as described in Example

[0406] (trifluoromethyl)benzyl)oxy)benzonitrile) was used. Otherwise, in substantially the same manner as described in Example

[0407] 3-Amino-4-((4-fluoro-2-(trifluoromethyl)benzyl)oxy)-N'-hydroxybenzimidamide was synthesized in substantially the same manner as described in step 2 of 29.

[0408] [Step 3] 3-((3-Fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide and 3,5-difluoro-4-hydroxybenzoic acid were replaced with 3-amino-4-((4-fluoro-2-

[0409] (Trifluoromethyl)benzyl)oxy)-N'-hydroxybenzimidamide and 2,4,5-trifluoro-3-hydroxybenzoic acid. The title compound 3-(3-(3-amino-4-((4-fluoro-2-

[0410] (Trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenol (3-(3-(3-amino-4-((4-fluoro-2-

[0411] (Trifluoromethyl)benzyl Doxy)phenyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenol was synthesized. Example 35

[0412] 2,3,6-Trifluoro-5-(3-(3-((4-Fluoro-2-

[0413] (Trifluoromethoxy)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,3,6-Trifluoro-5-(3-(3-((4-Fluoro-2-

[0414] (Trifluoromethoxy)benzylamino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol Preparation

[0415]

[0416] 1-(Chloromethyl)-4-fluorobenzene (1-(chloromethyl)-4-fluorobenzene) and

[0417] 3-Amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) instead of 3-Amino-

[0418] 4-Methylbenzonitrile (3-amino-4-methylbenzonitrile) and 1-(Bromomethyl)-4-fluoro-2-(trifluoromethoxy)benzene (1-(Bromomethyl)-4-fluoro-2-

[0419] (Trifluoromethoxy)benzene) was used, and 3-((4-Fluoro-2-

[0420] (Trifluoromethoxy)benzyl)amino)-4-methylbenzonitrile (3-((4-Fluoro-2-

[0421] (Trifluoromethoxy)benzyl)amino)—4—methylbenzonitrile was synthesized.

[0422] [Step 2]

[0423] Instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-fluorobenzyl)amino)—6—methylpyrimidine—4—carbonitrile), 3-((4-fluoro-2-(trifluoromethoxy)benzyl)amino)-4-methylbenzonitrile was used, and 3- was synthesized in substantially the same manner as described in Step 2 of Example 1, except that

[0424] ((4-fluoro-2-(trifluoromethoxy)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro-2-(trifluoromethoxy)benzyl)amino)-N’-hydroxy—4—methylbenzimidamide) was synthesized.

[0425]

[0426] [Step three]

[0427] Instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide (2-((4-fluorobenzyl)amino)-N’-hydroxy-\\(6\\)-methylpyrimidine-\\(4\\)-carboximidamide) and 3,5-difluoro-4-hydroxybenzoic acid (3,5-difluoro-4-hydroxybenzoic acid), 3-((4-fluoro-2-

[0428] ​(Trifluoromethoxy)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro—2—(trifluoromethoxy)benzyl)amino)-N’-hydroxy-4-methylbenzimidamide) and 2,4,5-trifluoro-3-hydroxybenzoic acid (2,4,5-trifluoro-3-hydroxybenzoic acid) were used, and the title compound 2,3,6-trifluoro-5-(3-(3-((4-fluoro-2-(trifluoromethoxy)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,3,6-trifluoro-5-(3-(3-((4-fluoro-2-(trifluoromethoxy)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol) was synthesized in substantially the same manner as described in Step 3 of Example 1, except for using the above. Example 36

[0429] Preparation of 3-(3-(3-((Adamantan-1-ylmethyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol (3-(3-(3-((Adamantan-1-ylmethyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol)

[0430] 1-(Chloromethyl)-4-fluorobenzene (1-(chloromethyl)-4-fluorobenzene) and

[0431] 3-amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) was replaced with 1-

[0432] 3-((adamantane-1-ylmethyl)amino)-4-methylbenzonitrile was synthesized by a method substantially the same as described in step 1 of Example 6, except that 1-(bromomethyl)adamantine and 3-amino-4-methylbenzonitrile were used.

[0433] [Step 2]

[0434] 3-((adamantan-1-ylmethyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((adamantan-1-ylmethyl)amino)-N'-hydroxy-4-methylbenzimidamide) was prepared in substantially the same manner as described in step 2 of Example 1, except that 3-((adamantan-1-ylmethyl)amino)-4-methylbenzonitrile was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile).

[0435] 4-methylbenzimidamide) was synthesized.

[0436] [Step 3]

[0437] 2-((4-fluorobenzyl)amino)-N'-hydroxy- 6-methylpyrimidine-4-carboxymidamide

[0438] The title compound 3-((adamantan-1-ylmethyl)amino)-N'-hydroxy-4-methylbenzimidamide and 2,4-difluoro-3-hydroxybenzoic acid were used instead of 4-carboxylic acid and 3,5-difluoro-4-hydroxybenzoic acid, in substantially the same manner as described in step 3 of Example 1, except that 3-((adamantan-1-ylmethyl)amino)-N'-hydroxy-4-methylbenzimidamide and 2,4-difluoro-3-hydroxybenzoic acid were used, thereby obtaining the title compound 3-(3-(3-((adamantan-1-ylmethyl)amino)-4-methylphenyl)-1,2,4-oxadiazole-5 -1)- 2, 6 -difluorophenol(3-(3-

[0439] (3— ((adamantan— 1—ylmethyl ) am i no ) -4~me t hy 1 pheny 1 )— 1,2,4— oxadi azo 1—5— yl )-2, 6 - di f luorophenol ) was synthesized. Example 37 2, 6 -difluoro- 3- (3- (5-( (4 -fluoro- 2-

[0440] Preparation of (trifluoromethyl)benzyl)amino)-6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-3-(3-(5-((4-f luoro-2-(trif luoromethyl)benzyl)amino)-6-methylpyr idin-3-yl)-1,2,4-oxadiazol-5-yl)phenol)

[0441] Instead of 4-fluorobenzoyl chloride and methyl 2-amino-4-cyanobenzoate, 4-fluoro-2-(trifluoromethyl)benzaldehyde (4-f luoro-2-

[0442] 5-((4-fluoro-2-trifluoromethyl)benzaldehyde) and 5-amino-6-methylnicotinnitrile (5-amino-6-methylnicotinonitrile) were prepared in substantially the same manner as described in step 1 of Example 11, except that 5-((4-fluoro-2-trifluoromethyl)benzaldehyde) and 5-amino-6-methylnicotinnitrile were used.

[0443] (Trifluoromethyl)benzyl)amino)-6-methylnicotinonitrile (5-((4-£11101'0-2- (trif luoromethyl )benzyl) ami no )-6-methyl Nicotinonitrile) was synthesized.

[0444] [Step 2] 5-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-6-methylnicotinimidamide (5-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-6-methylnicotinonitrile) was prepared in substantially the same manner as described in step 2 of Example 1, except that 5-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-6-methylnicotinimidamide was used instead of 2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile) 6- methy Ini cot inimidami de) was synthesized.

[0445] [Step 3]

[0446] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 5-((4-fluoro-2-

[0447] The title compound 2,6-difluoro-3-(3-(5-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-6-methylnicotinimidamide (5-((4-f 1 fluoro-2-(trifluoromethyl)benzy 1)am i no ) — N'-hydr oxy-6-methylni cot inimidami de) and 2,4-difluoro-3-hydroxybenzoic acid were used in substantially the same manner as described in step 3 of Example 1, except that the title compound 2,6-difluoro-3-(3-(5-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol (2,6-di f luoro-3-(3-(5-( (4-f luoro-2-

[0448] (tri f luoromethyl )benzyl )amino)— 6— methylpyridin— 3— yl )— 1 ,2,4— oxadiazol— 5— yl )phenol ) was synthesized. Example 38 Preparation of tert-butyl 4- (((5- (5- (2,4- difluoro- 3 -hydroxyphenyl)- 1,2,4- oxadiazol- 3 -yl)- 2-methylphenyl)amino)methyl)piperidine- 1-carboxylate (tert- butyl 4- (((5- (5- (2,4- dif luoro- 3 - lydroxyphenyl )- 1,2,4- oxadiazol- 3- yl )- 2- methylphenyl )amino)methyl )piperidine—l— carboxylate)

[0449] 1-(chloromethyl)-4-fluorobenzene and

[0450] 3-amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) instead of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (tert-butyl 4-(bromomethyl)piperidine-

[0451] Tert-butyl 4-(((5-cyano-2-methylphenyl)amino)methyl)piperidine-!-carboxylate was synthesized in substantially the same manner as described in Step 1 of Example 6, except that tert-butyl 4-(((5-cyano-2-methylphenyl)amino)methyl)piperidine—l— carboxylate was used.

[0452] [Step 2] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl )amino)— 6— methylpyrimidine— 4— carbonitrile) instead of tert—butyl 4-

[0453] (((5-cyano-2-methylphenyl)amino)methyl)piperidine-1-carboxylate (tert-butyl 4-

[0454] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-( (4- f luoro-2- (tri if luoromethyl )benzyl )amino)- N'- hydr oxy- 4- me thylbenzi mi dam i de ) was synthesized in substantially the same manner as described in step 2 of Example 1, except that (((5— cyano— 2— methylphenyl )amino)methyl )piperidine—l— carboxylate) was used.

[0455] [Step 3] 2-((4-fluorobenzyl)amino)-N'-hydroxy- 6-methylpyrimidine-4-carboxymidamide

[0456] The title compound tert-butyl 4-(((5-(5-(2,4-difluoro-3-hydroxybenzoic acid) was prepared in substantially the same manner as described in step 3 of Example 1, except that 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide) and 2,4-difluoro-3-hydroxybenzoic acid were used instead of 4-carboxylic acid and 3,5-difluoro-4-hydroxybenzoic acid. 4-Difluoro-3-hydroxyphenyl)-

[0457] 1,2, 4-oxadiazol-3-yl)-2-methylphenyl)amino)methyl)piperidine-1-carboxylate (tert-butyl 4- ( ( (5- (5- (2 , 4- di f 1 uor o-3-hydr oxypheny 1 )-1 ,2,4- oxadiazol-3-yl )—2— methyl phenyl )amino)methyl )piperi dine— 1— carboxylate) was synthesized. Example 39

[0458] Preparation of 3-(3-(3-((2,4-bis(trifluoromethyl)benzyl)amino)-4-methylphenyl)- 1,2,4-oxadiazol-5-yl)-2,6-difluorophenol 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (4-(bromomethyl)-

[0459] Step 12 of Example 12 except that 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene was used instead of 1-f luoro-2-(trifluoromethyl)benzene.

[0460] 3-((2,4-bis(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile was synthesized in a manner substantially identical to that described in 1.

[0461] [Step 2]

[0462] 3-((2,4-bis(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide was synthesized in substantially the same manner as described in Step 2 of Example 1, except that 3-((2,4-bis(trifluoromethyl)benzyl)amino)-4-methylbenzonitrile was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile.

[0463] [Step 3] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 3-((2,4-bis(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide

[0464] The title compound 3-(3-(3-((2,4-bis(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol was synthesized in substantially the same manner as described in Step 3 of Example 1, except that N’-hydroxy-4-methylbenzimidamide and 2,4-difluoro-3-hydroxybenzoic acid were used. Example 40

[0465] Preparation of 2,6-difluoro-3-(5-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-methylphenyl)-1,3,4-oxadiazol-2-yl)phenol

[0466] [Step 1]

[0467] 4-(Bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (4-(bromomethyl)-

[0468] 1-fluoro-2-(trifluoromethyl)benzene) and 3-amino-4-methylbenzonitrile (3-hex111 yuan10-

[0469] Methyl 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-methylbenzoate was synthesized in substantially the same manner as described in Step 1 of Example 1, except that 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene and methyl 3-amino-4-methylbenzoate were used instead of 4-methylbenzonitrile.

[0470] [Step 2] Instead of methyl 3-((4-f luorobenzyl)amino)-4-methylbenzoate, use methyl 3-((4-f luoro-2-(trifluoromethyl)benzyl)amino)-4-methylbenzoate.

[0471] 3-((4-fluoro-2-(trifluoromethoxy)benzyl)amino)-4-methylbenzohydrazide (3-((4-f luoro— 2— (trifluoromethoxy)benzy 1 )amino)— 4— methylbenzohydrazide ) was synthesized in substantially the same manner as described in step 2 of Example 7, except that (trifluoromethoxy)benzyl)amino)-4-methylbenzoate) was used.

[0472] [Step 3]

[0473] 3 - ((4 - Fluoro - 2 - (trifluoromethoxy)benzyl)amino) - 4 - methylbenzohydrazide (3 - ((4 - fluoro - 2 - (trifluoromethoxy)benzyl)amino) - 4 - methylbenzohydrazide) and 2,4 - difluoro - 3 - hydroxybenzaldehyde were dissolved in phosphorus (V) oxide chloride (POCl3) and stirred at 120 °C for 16 hours. Water was added to the reaction solution to precipitate, and the solid was obtained by filtration. The obtained solid was purified by column chromatography to obtain the title compound 2,6 - difluoro - 3 - (5 - (3 - ((4 - fluoro - 2 -

[0474] (trifluoromethyl)benzyl)amino) - 4 - methylphenyl) - 1,3,4 - oxadiazol - 2 - yl)phenol (2,6 - difluoro - 3 - (5 - (3 - ((4 - fluoro - 2 - (trifluoromethyl)benzyl)amino) - 4 - methylphenyl) - 1,3,4 - oxadiazol - 2 - yl)phenol). Example 41

[0475] 2,6 - difluoro - 3 - (3 - (3 - ((4 - fluoro - 2 -

[0476] (trifluoromethyl)benzyl)amino) - 4 - nitrophenyl) - 1,2,4 - oxadiazol - 5 - yl)phenol (2,6 - difluoro - 3 - (3 - (3 - ((4 - fluoro - 2 - (trifluoromethyl)benzyl)amino) - 4 - nitrophenyl) - 1,2,4 - oxadiazol - 5 - yl)phenol) preparation

[0477]

[0478] 4-(Bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-methylbenzonitrile were replaced with 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-nitrobenzonitrile, and 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-nitrobenzonitrile was synthesized in substantially the same manner as described in Step 1 of Example 12, except that 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-nitrobenzonitrile were used instead of 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-methylbenzonitrile.

[0479] 4-methylbenzonitrile) were replaced with 1-(bromomethyl)-4-fluoro-2-

[0480] (trifluoromethyl)benzene and 3-amino-4-nitrobenzonitrile were used instead of 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-methylbenzonitrile, and 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-nitrobenzonitrile was synthesized in substantially the same manner as described in Step 1 of Example 12, except that 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-nitrobenzonitrile were used instead of 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene and 3-amino-4-methylbenzonitrile.

[0481] [Step 2]

[0482] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile was replaced with 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-nitrobenzonitrile, and 3-

[0483] ((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-nitrobenzimidamide (3-((4-fluoro-2-(tri fluoromethyl )benzyl)ami no)- N'- hydr oxy- 4-nitr obenz i mi dam i de ) was synthesized.

[0484] [Step 3]

[0485] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 3-((4-fluoro-2-

[0486] The title compound 2,6-difluoro-3-(3-(3-((4-f 1 uor 0-2- ( trif 1 uor ome t hy 1 ) benzy 1 ) am i no ) -N ' -hydr oxy-4-nitr obenz imi dam i de ) and 2,4-difluoro-3-hydroxybenzoic acid were used in a substantially the same manner as described in step 3 of Example 1, except that the

[0487] (Trifluoromethyl)benzyl)amino)-4-nitrophenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6-difluoro-3- (3- (3- ((4-fluoro- 2-(tri fluoromethyl )benzyl)amino )-4-nitrophenyl )— 1,2,4— oxadi azo 1—5— yl )phenol ) was synthesized. Example 42 2,6-difluoro- 3- (3- (3- ( (4-fluoro- 2-

[0488] Preparation of (trifluoromethyl)benzyl)amino)-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro-3-(3-(3-((4-fluoro-2-(tri fluoromethyl )benzyl)amino)-4-methoxyphenyl )-1,2,4-oxadiazol-5-yl ) pheno 1 )

[0489] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-methoxybenzonitrile was synthesized in substantially the same manner as described in Step 1 of Example 6, except that 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene was used instead of 1-(chloromethyl)-4-fluorobenzene.

[0490] [Step 2]

[0491] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile(2-((4-fluorobenzyl)amino)— 6—methylpyrimidine— 4—carbonitrile) instead of 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-methoxybenzonitrile(3-((4-£11101'0-

[0492] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methoxybenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'- hydr oxy-4- me t hoxybenz i mi dam i de ) was synthesized in substantially the same manner as described in step 2 of Example 1, except that 2-(tri fluoromethyl )benzyl)amino)-N'- hydr oxy-4- me t hoxybenz i mi dam i de was used.

[0493] [Step 3]

[0494] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 3-((4-fluoro-2-

[0495] The title compound 2,6-difluoro-3-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methoxybenzimidamide (3-((4-f luoro— 2— (trifluoromethyl)benzyl)am i no)-N'-hydr oxy-4-methoxybenzimi dam i de) and 2,4-difluoro-3-hydroxybenzoic acid were used in a substantially the same manner as described in Step 3 of Example 1, except that

[0496] (Trifluoromethyl)benzyl)amino)-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-3-(3-(3-((4-fluoro-2-(tri fluoromethyl )benzyl)amino)-4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenol) was synthesized. Example 43

[0497] 2, 6-Difluoro- 3- (3- (4-methyl- 3- ((4-(methylsulfonyl) -2-

[0498] (trifluoromethyl)benzyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)phenol(2,6-difluoro-3-(3-(4-methyl-3-((4-(methyl sulfonyl )-2-

[0499] Preparation of (trif luoromethyl)benzyl)amino)phenyl)— 1,2,4— oxadiazol— 5— yl)phenol)

[0500] 1- (bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene (1-

[0501] 4-methyl-3-((4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)amino)benzonitrile(4-methyl-3-((4-(methylsulfonyl)-2-(trifluoromethyl)benzene) was prepared in substantially the same manner as described in step 1 of Example 9, except that (bromomethyl)—4— (methyl sulfonyl)—2— (trifluoromethyl)benzene) was used.

[0502] (tri fluoromethyl )benzyl )amino)benzonitrile) was synthesized.

[0503] [Step 2]

[0504] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile) instead of 4-methyl-3-((4-

[0505] N'-Hydroxy-4-methyl-3-((4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)amino)benzonitrile (4-tau-3-((4-(methylsulfonyl)—2—(trifluoromethyl)benzyl)amino)benzonitrile) was prepared in substantially the same manner as described in step 2 of Example 1, except that O(methylsulfonyl)-2-(trifluoromethyl)benzyl)amino)benzonitrile (4-tau-3-((4-(methylsulfonyl)—2—(trifluoromethyl)benzyl)amino)benzonitrile) was used.

[0506] (Trifluoromethyl)benzyl)amino)benzimidamide (N'-hydroxy-4-methyl-3-((4- (methylsulfonyl )— 2— (trifluoromethyl )benzyl )amino)benzimidamide)-^ was synthesized.

[0507] [Step 3]

[0508] HOBt

[0509] Instead of 2 - ((4 - fluorobenzyl)amino)-N’- hydroxy - 6 - methylpyrimidine - 4 - carbox imi dami de and 3, 5 - di f luoro - 4 - hydr oxybenzoic acid, N’- hydroxy - 4 - methyl - 3 - ((4 - (methylsulfonyl)-2 -

[0510] (trifluoromethyl)benzyl)amino)benzimidamide and 2, 4 - di f luoro - 3 - hydroxybenzoic acid were used, and the title compound 2, 6 - di f luoro - 3 - (3 - (4 - methyl - 3 - ((4 - (methylsulfonyl)-2 - (trifluoromethyl)benzyl)amino)phenyl)-1,2,4 - oxadiazol - 5 - yl)phenol was prepared in substantially the same manner as described in Step 3 of Example 1, except that

[0511] (trifluoromethyl)benzyl)amino)pheny 1 )— 1 , 2 , 4— oxadiazol— 5— y 1 )pheno 1 ) was synthesized. Example 44 Preparation of 3- (3- (3- ((2-chloro- 4-fluorobenzyl)amino) -4-methylphenyl)- 1,2,4-oxadiazol- 5 -yl)- 2, 6 -difluorophenol (3- (3- (3- ((2-chloro- 4- f luorobenzyl )am i no ) -4-methyl t hy 1 pheny 1 )— 1,2,4— oxadiazol— 5— yl )—2,6— dif l uor opheno 1 )

[0512] 1-(chloromethyl)-4-fluorobenzene and

[0513] 3-amino-4-methoxybenzonitrile instead of 1-

[0514] 3-((2-chloro-4-fluorobenzyl)amino)-4-methylbenzonitrile was synthesized in substantially the same manner as described in Step 1 of Example 6, except that 1-(bromomethyl)-2-chloro-4-f luorobenzene and 3-amino-4-methylbenzonitrile were used. [Step 2]

[0515] 3-((2-chloro-4-fluorobenzyl)amino)-N'-hydroxy-4-methylbenzimidamide was synthesized in substantially the same manner as described in Step 2 of Example 1, except that 3-((2-chloro-4-f luorobenzyl)amino)-4-methylbenzonitrile was used instead of 2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile.

[0516] [Step 3]

[0517] The title compound 3-(3-(3-((2-chloro-4-fluorobenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol (3-(3-(3-((2-chloro-4-fluorobenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol) was synthesized in substantially the same manner as described in Step 3 of Example 1, except that 3-((2-chloro-4-fluorobenzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((2-chloro-4-fluorobenzyl)amino)-N'-hydroxy-4-methylbenzimidamide) and 2,4-difluoro-3-hydroxybenzoic acid (2,4-difluoro-3-hydroxybenzoic acid) were used instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide (2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide) and 3,5-difluoro-4-hydroxybenzoic acid (3,5-difluoro-4-hydroxybenzoic acid). Example 45 Preparation of 3-(3-(3-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol (3-(3-(3-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,6-difluorophenol)

[0518] 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxin (6-(chloromethyl)-

[0519] Step 9 of Example 9 except that 2,3-dihydrobenzo[b][l,4]dioxine) was used.

[0520] 3-(((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)amino)-4-methylbenzonitrile (3-(((2,3-dihydrobenzotb] [1,4] di ox in— 6— yl )methyl )amino)— 4— methylbenzoni tr i le) was synthesized by a method substantially identical to that described in 1.

[0521] [Step 2]

[0522] 3-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-4-methylbenzonitrile was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile, but the process was carried out substantially the same way as described in step 2 of Example 1, except that 3-(((2,3-dihydrobenzotb][1,4]dioxin-6-yl)methyl)amino)-4-methylbenzonitrile was used to prepare 3-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-N'-hydroxy-4-methylbenzimidamide (3- (((2,3- di hydrobenzo [b] [l,4]dioxin- 6- yl )methyl )amino)- N' -hydroxy- 4- methyl benz i midamide) was synthesized.

[0523] [Step 3]

[0524] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 3-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-N'-hydroxy-4-methylbenzimidamide — N' -hydr oxy-4- methylbenzimidamide) and 2,4-difluoro-3-hydroxybenzoic acid were used, but the same procedure was followed as described in step 3 of Example 1 to obtain the title compound 3-(3-(3-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-4-methylphenyl)-1,2,4-oxadiazole-

[0525] 5-yl)-2,6-difluorophenol(3-(3-(3-(((2,3-dihydrobenzo[b] [l,4]dioxin-6- yl)methyl)amino)— 4— methyl phenyl )— 1,2,4— oxadiazol— 5— yl )-2, 6 - di f luorophenol ) was synthesized. Example 46

[0526] Preparation of 2,6-difluoro-3-(3-(3-((4-fluoro-2-hydroxybenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-3-(3-(3-((4-f luoro-2-hydroxybenzyl)am i no )-4-meth y 1 pheny 1 )— 1,2,4— ox ad i azo 1—5— yl ) phenol )

[0527] 3-((4-fluoro-2-hydroxybenzyl)amino)-4-methylbenzonitrile (3-((4-f 1 uor o-2-hydr oxybenzy 1 )amino)-4-methylbenzonitrile) was synthesized in substantially the same manner as described in step 1 of Example 9, except that 2-(bromomethyl )-5-fluorophenol was used.

[0528] [Step 2] Example 1 except that 3-((4-fluoro-2-hydroxybenzyl)amino)-4-methylbenzonitrile (Z^a-fluoro-R-hydroxybenzyl)amino)-4-methylbenzonitrile) was used instead of 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)—6—methylpyrimidine—4—carbonitrile)

[0529] 3-((4-fluoro-2-hydroxybenzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((4-fluoro-2-hydr oxybenzy 1 ) am i no ) — N ' -hydr oxy— 4— me t hy 1 benz imi dam i de ) was synthesized in substantially the same manner as described in step 2 of 1.

[0530] [Step 3]

[0531] Except for using 3-((4-fluoro-2-hydroxybenzyl)amino)-N'-hydroxy-4-methylbenzimidamide and 2,4-difluoro-3-hydroxybenzoic acid instead of 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid, the procedure in Example 1

[0532] was substantially the same as that described in Step 3 to synthesize the title compound 2,6-difluoro-3-(3-

[0533] (3-((4-fluoro-2-hydroxybenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro-3-(3-(3-((4-fluoro-2-hydroxybenzyl)amino)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)phenol). Example 47

[0534] 2,6-difluoro-3-(3-(3-((4-fluoro-2-

[0535] (Trifluoromethyl)benzyl)amino)-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro-3-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)phenol) Preparation 3 - Amino - 4 - methylbenzonitrile (3 - amino - 4 - methylbenzonitrile) and 4 -

[0536] (Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene) was replaced with 3 - amino - 4 - hydroxybenzonitrile(3 - amino - 4 - hydroxybenzonitrile)

[0537] 4 - hydroxybenzonitrile) and 1 - (bromomethyl)-4 - fluoro - 2 - (trifluoromethyl)benzene (1 - (bromomethyl)-4 - fluoro - 2 -

[0538] (trifluoromethyl)benzene)was used, and 3 - ((4 - fluoro - 2 -

[0539] (trifluoromethyl)benzyl)amino) - 4 - hydroxybenzonitrile(3 - ((4 - fluoro - 2 -

[0540] (trifluoromethyl)benzyl)amino) — 4— hydroxybenzonitrile) was synthesized in substantially the same manner as described in Step 1 of Example 24.

[0541] [Step 2]

[0542] 3 - ((4 - fluoro - 2 - (trifluoromethyl)benzyl)amino) - 4 -

[0543] (Phenylamino)benzonitrile (3- ((4- f luoro- 2- (tri f luoromethyl )benzyl )amino)- 4-

[0544] ( pheny 1 ami no) benzon itr i le) instead of 3-((4 -fluoro- 2-

[0545] (trifluoromethyl)benzyl)amino) -4-hydroxybenzonitrile (3-((4- f luoro- 2-

[0546] (tri f luoromethyl )benzyl ) am i no ) -4-hydr oxybenzon itri le) was used, but in a substantially the same manner as described in step 2 of Example 29.

[0547] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N',4-dihydroxybenzimidamide (3-((4- f luoro-2-(tr if 1 uoromethyl )benzyl )amino)-

[0548] N',4-di hydr oxybenzi midamide) was synthesized.

[0549] [Step 3] 3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-( (3- f luoro- 4- (tr if luoromethyl )benzyl )amino)-N'- hydr oxy-4-meth y l benz imi dam i de ) and 3 , 5 -difluoro-4-hydroxybenzoic acid (3 , 5- di f luoro-4-hydroxybenzoic acid) instead of 3- ( (4 -fluoro- 2-

[0550] The title compound 2,6-difluoro-3-(3-(3-((4-f luoro— 2— (tri fluoromethyl )benzyl) ami no)— N' ,4-di hydr oxybenzi midamide)o} was prepared in substantially the same manner as described in step 3 of Example 24, except that 2,4-difluoro-3-hydroxybenzoic acid was used.

[0551] (Trifluoromethyl)benzyl)amino)-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-dif luoro-3-(3-(3-((4-fluoro-2-(tri fluoromethyl )benzyl)amino)-4-hydroxyphenyl )-1,2,4-oxadiazol-5-yl )phenol ) was synthesized. Example 48

[0552] 2,3, 6 -trifluoro- 5- (3- (3- ( (4 -fluoro- 2-

[0553] (trifluoromethyl)benzyl)amino)-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)phenol(2,3,6-nu]Shimho11101'0-5-(3-(3-((4-bu11101"0-2-

[0554] Preparation of (trifl uor omethyDbenzy Damino) -4-hydr oxypheny 1)-1, 2, 4-oxad iazol -5 - yl) phenol) [Step 1]

[0555] 3-amino-4-methylbenzonitrile and 4-

[0556] (Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene) was replaced with 3-amino-4-hydroxybenzonitrile (3-amino-4-hydroxybenzonitrile), and 1-(bromomethyl)-4-fluoro-2-

[0557] 4-hydroxybenzonitrile) and 1-(bromomethyl)-4-fluoro-2-

[0558] (trifluoromethyl)benzene (1-(bromomethyl)-4-fluoro-2-

[0559] (trifluoromethyl)benzene) were used. 3-((4-Fluoro-2-(trifluoromethyl)benzyl)amino)-4-hydroxybenzonitrile (3-((4-fluoro-2-

[0560] (trifluoromethyl)benzyl)amino)-4-hydroxybenzonitrile) was synthesized in substantially the same manner as described in Step 1 of Example 24.

[0561] [Step 2]

[0562] 3-((4-Fluoro-2-(trifluoromethyl)benzyl)amino)-4-(phenylamino)benzonitrile (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-

[0563] (phenylamino)benzonitrile) was replaced with 3-((4-fluoro-2-

[0564] (trifluoromethyl)benzyl)amino)-4-hydroxybenzonitrile (3-((4-fluoro-2-

[0565] In substantially the same manner as described in Step 2 of Example 29, except using ((trifluoromethyl)benzyl)amino)-4-hydroxybenzonitrile

[0566] 3-((4-Fluoro-2-(trifluoromethyl)benzyl)amino)-N',4-dihydroxybenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-

[0567] N',4-(1H,1'H-bis(imidazole-1-carboxamide)) was synthesized.

[0568] [Step 3]

[0569] Instead of 3-((3-Fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide) and 3,5-difluoro-4-hydroxybenzoic acid (3,5-difluoro-4-hydroxybenzoic acid), 3-((4-Fluoro-2-

[0570] (Trifluoromethyl)benzyl)amino)-N',4-dihydroxybenzimidamide (3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N',4-dihydroxybenzimidamide) was used

[0571] The title compound 2,3,6-trifluoro-5-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)phenol(2,3,6-chloro-11101'0-5-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-hydroxyphenyl)-11101'0-5-(3-(3-((4-:〔11101'0-2-

[0572] (tri f luoromethyl )benzyl )ami no )-4~hydr oxyphenyl )-1 ,2, 4-oxadi azol -5- yl )phenol ) was synthesized. Example 49

[0573] 2 , 6 -Difluoro- 3-(3-(3-((4 -fluoro- 2-

[0574] (trifluoromethyl)benzyl)amino)-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-

[0575] Preparation of 5-yl)phenol (2,6-dif luoro-3-(3-(3-((4-f luoro-2-(trif luoromethyl)benzyl)amino)-4-(trif luoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)phenol)

[0576] 3-amino-4-(trifluoromethyl)benzonitrile (3-amino-4-(trifluoromethyl)benzonitrile), sodium hydride (NaH) and DMF were stirred at room temperature for 30 minutes to obtain 1-(bromomethyl)-4-fluoro-2-

[0577] (Trifluoromethyl)benzene(1-(bromomethyl)- 4- f luoro-2 -

[0578] (trifluoromethyl)benzene) was added and stirred at room temperature for 18 hours. The mixture after the reaction was diluted with water and extracted with sesame oil. The combined organic layers of the extracts were washed with water, dried over MgSO, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-(trifluoromethyl)benzonitrile(3-((4-£11101'0-2-

[0579] (trif luoromethyl)benzyl)amino)-4-(tr if luoromethyDbenzoni tri le) was obtained. [Step 2]

[0580] 3- ((4-fluoro-2-(trifluoromethyl)benzyl)amino) -4-

[0581] (Phenylamino)benzonitrile (3- ((4-fluoro- 2-( tri fluor omethyl)benzyl) ami no )-4- ( pheny 1 am i no ) benz on itri le) instead of 3- ((4 -fluoro- 2-

[0582] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-(trifluoromethyl)benzimidamide (3-((4-£11101'0-2- (tri fluor omethyl)benzyl)ami no )-4-(tri fluor omethyl)benzonitrile) was prepared in substantially the same manner as described in step 2 of Example 29, except that 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-(trifluoromethyl)benzimidamide (3-((4-£11101'0-2-

[0583] (trifl uoromethyl )benzy 1 ) am i no ) — N ' -hydr oxy-4-

[0584] (trif 1 uoromethyl )benzimidamide) was synthesized.

[0585] [Step 3] 3-((3-fluoro-4-(trifluoromethyl)benzyl)amino)-N'-hydroxy-4-methylbenzimidamide (3-( (3- f luoro-4- (tr if 1 uoromethyl )benzyl )amino)-N'- hydr oxy-4-meth y 1 benz imi dam i de ) and 3 , 5 -difluoro-4-hydroxybenzoic acid (3 , 5- di f luoro-4-hydroxybenzoic acid) instead of 3- ( (4 -fluoro- 2-

[0586] (trifluoromethyl)benzyl)amino)-N'-hydroxy-4-(trifluoromethyl)benzimidamide (3-((4-f luoro-2-

[0587] The title compound 2,6-difluoro-3-(3-(3-((4-fluoro-2-)-(trifluoromethyl)benzyl)amido)-N'-hydr oxy-4-(trifluoromethyl)benzimidamide) and 2,4-difluoro-3-hydroxybenzoic acid were prepared in substantially the same manner as described in Step 3 of Example 24, except that 2,4-difluoro-3-hydroxybenzoic acid was used.

[0588] (trifluoromethyl)benzyl)amino)-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-

[0589] 5-yl)phenol (2,6-difluor 0-3- (3- (3- ((4-fluoro- 2- (tri fluoromethyl )benzyl) ami no)-

[0590] 4- (trifluoromethyl)phenyl)- 1,2,4- oxadiazol- 5- yl)phenol) was synthesized. Example 50 Ethyl 4- (4- (5- (2, 4 -difluoro- 3 -hydroxyphenyl)- 1,2, 4 -oxadiazol- 3 -yl)-

[0591] 2-((4-fluoro-2-(trifluoromethyl)benzyl)amino)phenyl)butanoate (ethyl 4-

[0592] (4- (5- (2,4- dif luoro- 3- hydroxyphenyl)- 1,2,4- oxadiazol- 3- yl)- 2- ((4- f luoro- 2 -

[0593] Preparation of (trifl uor omethyDbenzy 1 )amino)phenyl )but anoat e )

[0594] [Step 1]

[0595]

[0596] Instead of 1-(chloromethyl)-4-fluorobenzene and 3-amino-4-methoxybenzonitrile, 1-

[0597] Ethyl 4-(4-cyano-2-((4-fluoro-2-trifluoromethyl)benzene (1-(bromomethyl)-4-f luoro-2-(trifluoromethyl)benzene) and ethyl 4-(2-amino-4-cyanophenyl)butanoate were used in substantially the same manner as described in step 1 of Example 6.

[0598] (Trifluoromethyl)benzyl)amino)phenyl)butanoate (ethyl 4-(4-cyano-2-((4- f luoro— 2— (trifluoromethyl)benzyl)amino)phenyl)butanoate) was synthesized.

[0599] [Step 2]

[0600] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile) instead of ethyl 4-(4-cyano-2-((4-fluoro-2-

[0601] Ethyl-4-(2-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-(N'-hydroxycarbamimidoyl)phenyl)butanoate was synthesized in substantially the same manner as described in Step 2 of Example 1, except that ethyl 4-(4—cyano—2—((4-f luoro—2—(trifluoromethyl)benzyl)amino)-4-(N'-hydroxycarbamimidoyl)phenyl)butanoate was used.

[0602] [Step 3]

[0603] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine- 4-carboxymidamide

[0604] 4-Carbox imi dami de ) and 3 , 5 -difluoro - 4 -hydroxybenzoic acid (3 , 5 - di f luoro-4- hydr oxybenzoic acid) instead of ethyl - 4- (2- ((4 -fluoro - 2-

[0605] The title compound ethyl 4-(4-(5-(2,4-difluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)-2-((4-fluoro-2-(trifluoromethyl)benzyl)amino)phenyl)butanoate (ethyl-4-(2-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-(N'-hydroxycarbamimidoyl)phenyl)butanoate) and 2,4-difluoro-3-hydroxybenzoic acid were used in a substantially the same manner as described in step 3 of Example 1, except that (4- (5-(2, 4- di f 1 uor o-3-hydr oxypheny 1 )—1,2, 4— oxadi azol— 3— yl )— 2— ( (4— f luoro-2-

[0606] (trif luoromethyl )benzyl )amino)phenyl )butanoate) was synthesized. Example 51

[0607] 2 , 6 -Difluoro- 3- (3- (3- ( (4-fluoro- 2-

[0608] (trifluoromethyl)benzyl)amino)-4- ((4-fluoro-2-

[0609] Preparation of (trifluoromethyl)benzyl)oxy)phenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6-difluoro- 3- (3- (3-( (4- f luoro- 2- ( trif luoromethyl )benzyl )amino)- 4- ( (4- f luoro- 2- (trif luoromethyl )benzyl )oxy)pheny 1)-1,2,4- oxadiazol- 5- yl)phenol)

[0610] Instead of 1-(chloromethyl)-4-fluorobenzene and 3-amino-4-methoxybenzonitrile, 1-

[0611] (Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (1- (bromomethyl)-4-fluoro-

[0612] 3-((4-fluoro-2-)benzene) and 3-amino-4-hydroxybenzonitrile were prepared in substantially the same manner as described in step 1 of Example 6, except that 2-((4-fluoro-2-)benzene and 3-amino-4-hydroxybenzonitrile were used.

[0613] (trifluoromethyl)benzyl)amino)-4- ((4-fluoro-2-

[0614] (trifluoromethyl)benzyl)oxy)benzonitrile (3- ((4-fluoro-2-

[0615] (trif luoromethyl )benzyl )amino)— 4—((4— f luoro-2-

[0616] (tri fluoromethyl )benzyl )oxy)benzonitr i le) was synthesized.

[0617] [Step 2]

[0618] 2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-f luorobenzyl )amino)— 6— methylpyrimidine— 4— carbonitrile) instead of 3-((4-fluoro- 2-(trifluoromethyl)benzyl)amino)- 4- ((4-fluoro- 2-

[0619] (trifluoromethyl)benzyl)oxy)benzonitrile (3- ((4-fluoro-2-

[0620] (trif luoromethyl )benzyl )amino)— 4—((4— f luoro-2 -

[0621] Examples except that (tr if luoromethyl )benzyl)oxy)benzoni tri le) was used

[0622] 3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)-4-((4-fluoro-2-

[0623] (trifluoromethyl)benzyl)oxy)- N'-hydroxybenzimidamide (3- ((4-fluoro- 2- (trif luoromethyl )benzyl )amino)— 4—((4— f luoro— 2— (tr if luoromethyl )benzyl )oxy)-

[0624] N ' -hydr oxybenz imi dam i de ) was synthesized.

[0625] [Step 3] HOBt

[0626] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of 3-((4-fluoro-2-

[0627] (trifluoromethyl)benzyl)amino)-4- ((4-fluoro-2-

[0628] The title compound 2,6-difluoro-3-(3-(3-((4-fluoro-2-(trifluoromethyl)benzyl)amino)- 4 ...

[0629] (Trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)phenol (ethyl 4- (4- (5- (2,4~di f 1 uor o-3-hydr oxypheny 1 )—1,2,4— oxadi azol— 3— yl )— 2— ( (4— f luoro-2- (trif luoromethyl )benzyl )amino)phenyl )but anoate) was synthesized. Example 52

[0630] 2,6-Difluoro-3-(3-(4-methyl-3-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)phenyl)-1,2,4-oxadiazol-5-yl)phenol (2,6-difluoro-3-(3-(4-methyl—3—(((1—methyl—1H—pyrazol—4—yl)methyl)amino)phenyl)—1,2,4—oxadiazol—

[0631] 5-yl)phenol) Preparation

[0632] 1-(Chloromethyl)-4-fluorobenzene (1-(chloromethyl)-4-fluorobenzene) and

[0633] 3-Amino-4-methoxybenzonitrile (3-amino-4-methoxybenzonitrile) instead of 4-

[0634] (Bromomethyl)-1-methyl-1H-pyrazole (4-(bromomethyl)-1-methyl-1H-pyrazole) and 3-amino-4-methylbenzonitrile (3-amino-4-methylbenzonitrile) were used, and 4-methyl-3-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzonitrile (4-06na1dao-3-(((1-methyl - 1H-pyr azo 1 -4-y 1 )methyl)amino)benzonitrile) was synthesized in substantially the same manner as described in Step 1 of Example 6, except for this.

[0635] [Step 2] 2-((4-Fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile (2-((4-fluorobenzyl)amino)-6-methylpyrimidine-4-carbonitrile) instead of 4-methyl-3-

[0636] N'-Hydroxy-4-methyl-3-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzimidamide was synthesized in substantially the same manner as described in Step 2 of Example 1, except that ((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzonitrile (4-methyl-3-(((1-methyl-1H-pyrazol-1-4-yl)methyl)amino)benzonitrile) was used.

[0637] [Step 3]

[0638] 2-((4-fluorobenzyl)amino)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide and 3,5-difluoro-4-hydroxybenzoic acid instead of N'-hydroxy-4-methyl-3-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzimidamide and 2,4-difluoro-3 The title compound 2,6-difluoro-3-(3-(4-methyl-3-(((1-methyl- 1H-pyrazol- 4-yl)methyl)amino)phenyl)- 1,2,4-oxadiazol- 5-yl)phenol (2,6-difluoro-3-(3-(4-methyl- 3-(((1-methyl- 1H-pyrazol- 4-yl)methyl)amino)phenyl)- 1,2,4-oxadiazol- 5-yl)phenol) was synthesized in substantially the same manner as described in step 3 of Example 1, except that 2,4-difluoro-3-hydroxybenzoic acid was used. The NMR of the above-mentioned prepared compounds is shown in Table 2 below. [Table 2] Experimental Example Experimental Example 1: Evaluation of 17-beta-hydroxysteroid dehydrogenase 13 enzyme activity inhibition ability (in vitro HSD17 P 13 enzyme assay) To evaluate the enzyme activity inhibition ability of each compound, 20 uL of 50 nM hHSD17pi3 (0rigene, Cat. No. TP313132) recombinant protein and 2.5 uL of 10 concentrations of 10x evaluation substances were placed in a PerkinElmer 384-well plate (PerkinElmer 384-well plate (Cat. No. 6057480)) and reacted at room temperature for 30 minutes. Afterwards, 2.5 uL of 10x NAD (Sigma Aldrich, Cat. No. NAD100-RO) and leukotriene B4 (leukotrienB4 (Cayman chemical, Cat. No. 20110)) were added to final concentrations of 0.5 mM and 10 uM, respectively, and the reaction was incubated at 37°C for 3 hours. The final buffer was 50 mM Tris-HCl, 0.01% BSA, 0.002% Tween-20, pH 7.4. The products were then measured using the Promega NAD(P)H-Glo™ Detection System (Cat. No. G9062). Specifically, an equal amount of NAD(P)H-Glo™ detection reagent was added, and the sample was incubated at 25°C for 1 hour. The luminescence of the sample was measured using a Tecan SPARK 10M micro reader. The data were obtained by confirming the RLU (relative 1 light unit) value of the measured luminescence.Experimental Example 2: Evaluation of 17-beta-hydroxysteroid dehydrogenase 11 enzyme activity inhibition ability (in vitro HSD17 P 11 enzyme assay) To evaluate the enzyme activity inhibition ability of each compound, 20 uL of 50 nM hHSD17pil (Origene, Cat. No. TP305941) recombinant protein and 2.5 uL of 10 concentrations of 10x evaluation substances were placed in a PerkinElmer 384-well plate (PerkinElmer 384-well plate (Cat. No. 6057480)) and reacted at room temperature for 30 minutes. Afterwards, 2.5 uL of 10x NAD (Sigma Aldrich, Cat. No. NAD100-R0) and estradiol (Sigma Aldrich, Cat. No. E8875) were added to the final concentrations of 0.5 mM and 25 uM, respectively, and the reaction was incubated at 37°C for 90 min. The final buffer was 50 mM Tris-HCl, 0.01% BSA, 0.002% Tween-20, pH 7.4. The product was then analyzed using the Promega NAD(P)H-Glo™ Detection System (Promega.

[0639] The luminescence of the sample was measured using the NAD(P)H-Glo™ Detection System (Cat. No. G9062). Specifically, an equal amount of NAD(P)H-Glo™ detection reagent was added, reacted at 25°C for 1 hour, and then the luminescence of the sample was measured using a Tecan SPARK 10M micro reader. The data was obtained by confirming the RLU (relative 1 ight unit) value of the measured luminescence. Experimental Example 3: Evaluation of 17-beta-hydroxysteroid dehydrogenase 1 enzyme activity inhibition ability (in vitro HSD17 P 1 enzyme assay) To evaluate the enzyme activity inhibition ability of each compound, 20 uL of 50 nM hHSD17pi (Origene, Cat. No. TP311135) recombinant protein and 2.5 uL of 10 concentrations of 10x evaluation substances were placed in a PerkinElmer 384-well plate (PerkinElmer 384-well plate (Cat. No. 6057480)) and reacted at room temperature for 30 minutes. Afterwards, 2.5 uL of 10x NAD (Sigma Aldrich, Cat. No. NAD100-R0) and estradiol (Sigma Aldrich, Cat. No. E8875) were added to final concentrations of 0.5 mM and 10 uM, respectively, and the reaction was incubated at 37°C for 40 min. The final buffer was 50 mM Tris-HCl, 0.01% BSA, 0.002% Tween-20, pH 7.4. The products were then measured using a Promega NAD(P)H-Glo™ Detection System (Cat. No. G9062).Specifically, an equal amount of NAD(P)H-Glo™ detection reagent was added, and the sample was incubated at 25°C for 1 hour. The luminescence of the sample was measured using a Tecan SPARK 10M micro reader. The data were obtained by confirming the RLU (relative 1 light unit) value of the measured luminescence. Experimental Example 4: Evaluation of 17-beta-hydroxysteroid dehydrogenase 2 enzyme activity inhibition ability (in vitro HSD17 P 1 enzyme assay) To evaluate the enzyme activity inhibition ability of each compound, 20 uL of 25 nM hHSD17p2 (Origene, Cat. No. TP303293) recombinant protein and 2.5 uL of 10 concentrations of 10x evaluation substances were placed in a PerkinElmer 384-well plate (PerkinElmer 384-well plate (Cat. No. 6057480)) and reacted at room temperature for 30 minutes. Afterwards, 2.5 uL of 10x NAD (Sigma Aldrich, Cat. No. NAD100—R0) and estradiol (Sigma Aldrich, Cat. No. E8875) were added to a final concentration of 0.6 and 5 mM, respectively, and the reaction was incubated at 37°C for 40 min. The final buffer was 50 mM Tris-HCl, 0.01% BSA, 0.01% Tween-20, pH 7.4. The products were then measured using a Promega NAD(P)H-Glo™ Detection System (Cat. No. G9062). Specifically, an equal amount of NAD(P)H-Glo™ detection reagent was added, reacted at room temperature for 1 hour, and then the luminescence of the sample was measured using a SPARK 10M micro reader from Tecan.Data was obtained by checking the RLU (relative 1 light unit) value of the measured luminescence. Experimental Example 5: LC-MS / MS Estrone Detension Assay (Estrone detection assay) 1 Ox NAD-O} estradiol (Estradiol (Sigma Aldrich, Cat. No. E8875)) was added to the mixture of recombinant proteins (hHSD17pi3, hHSD17pil, hHSD17pi, 11HSD17P2) and the test substance to a final concentration of 0.5 mM and 25 uM, respectively, and the reaction was performed at 37°C for 3 hours. Afterwards, the product, estrone, was measured using UPLC-MS / MS (ACQUITY UPLC I- Class-Xevo TQ-S micro Triple Quadrupole). Based on the concentration of the treated compound and the measured product value, nonlinear regression (four parameters) of Prism was used to obtain the curve fitting and IC50. Experimental results - Data analysis Based on the data obtained in Experimental Examples 1 to 5, nonlinear regression (four parameters) of Prism was used to obtain the % inhibitory efficacy of the example compounds, and then curve fitting and IC50. The % inhibitory efficacy of the compound was calculated by the following formula. Compound % inhibitory efficacy = -100 x ((RLUtest- RLU. min ) / (RLU max - RLU min )) Here, RLUtest is the luminescence value of the reaction sample to which each compound was added, RLU max is the luminescence value, RLU, of the reaction sample with 5% DMSO added instead of 10x compound. min is the luminescence value of a sample without added substrate or reactant.

[0640] IC 50 The results are shown in Table 3 below.

[0641] [Table 3]

[0642] *: IC50 (uM) measured by E2 LC-MS / MSO||

[0643] A: IC50 < 0.3 uM (0.3 uM or less)

[0644] B: 0.3 uM < IC50 < 1 uM (0.3 uM or more and 1 uM or less)

[0645] C: 1 uM < IC50 < 3 uM (more than 1 uM and less than or equal to 3 uM)

[0646] D: 3 uM < IC50 (more than 3 uM) According to the above results, the selectivity for the target was confirmed in the evaluated compounds, and it was confirmed that the compounds according to the present invention have excellent enzyme activity inhibition ability of HSD17B13 (17-beta-hydroxyster 0 id dehydrogenase 13). Therefore, it can be seen that the compound of the present invention can be useful for the prevention or treatment of NASH. Although the present invention has been described above with reference to preferred embodiments, those skilled in the art will understand that the present invention can be variously modified and changed within the spirit and scope of the present invention as set forth in the following claims.

Claims

【Scope of Claims】 【 Claim 11 A compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof; <화학식 1> Xi, X2 and X3 are each independently N, 0 or S, and - each independently represents a single bond or a double bond; Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, 0 and S, wherein one or more of the 6- to 14-membered aryl or a 5- to 12-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, 0 and S may each independently be substituted or unsubstituted with halogen, -ORi, -CN, -CFs, or C1-C3 alkyl, Ri is H or C1-C3 alkyl, wherein one or more of the C1-C3 alkyl groups may be independently substituted or unsubstituted with halogen; Yi, Y2, YS and Y4 are each independently CR2 or N, R2 is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of H, halogen, CN, C1-C3 alkyl, 6- to 14-membered aryl, N, 0, and - C(=0)- R a i, -(C1-C4 alkylene) - C(=0)- R a 2, -CF3, -N02, -ORbi, -SR b2 , -S(=0)『NRciRdi, -NHC(=0)R b3 or - NR C 2Rd2, wherein one or more of C1-C3 alkyl, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0, and S may be independently substituted or unsubstituted with halogen, Rai and Ra2 are each independently - 0Rb3 or - NR c It's 3Rd3, Rbi, R b2 And Rb3 are each independently H or C1-C6 alkyl, wherein at least one H of the C1-C6 alkyl may be independently substituted or unsubstituted with a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , wherein at least one H of the 6- to 14-membered aryl or a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and S may each independently be substituted or unsubstituted with halogen, -CF3 or C1-C3 alkyl, Rd, RC2, Res, Rdi, R d2 and Rd3 are each independently H, 0, C1-C6 alkyl or 6- to 14-membered aryl, wherein one or more of the C1-C6 alkyl or 6- to 14-membered aryl groups may be independently substituted or unsubstituted with a 6- to 14-membered aryl or CN; L is - R e - N(Rf )- and , Re is a single bond or C1-C3 alkylene, Rf is H or C1-C3 alkyl; A2 is H, 6-14 membered aryl, 5-12 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S. and wherein 6 to 14-membered aryl, 5 to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, or 3 to 8-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S One or more H are each independently a halogen - NRg a Rgb, - NHC(=0)R g 3, -C(=O)NR gc R gd Or - S(0)『 can be substituted or unsubstituted with Rg4 Rgi, R g 2, Rg3, Rga, Rgb, Rgc, R g d and R g 4 are each independently H, 0 or C1-C4 alkyl, wherein one or more of the C1-C4 alkyl groups may be independently substituted or unsubstituted with halogen. 【In the claim 1, The above chemical formula I Each is independently a poem, and X2 is 0 or S), and X2 are N, respectively, X3 is 0 or S) and X3 are respectively, and Xi is 0 or S is ), Ai is a 6- to 14-membered aryl, wherein one or more of the 6- to 14-membered aryl groups may be independently substituted or unsubstituted with halogen, -ORi, or -CF3, Ri is H, a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. 【

3. In claim 1, Yi, Y2, YS and Y4 of the chemical formula I are each independently CR2 or N, R2 is H, halogen, C1-C3 alkyl, - C(=0)- R a i, -(C1-C4 alkylene) - C(=0)- R a 2, - CF3, - NO2, -ORbi, or - NRc2Rd2, Rai and Ra2 are each independently - 0Rb3 or - NR c It's 3Rd3, Rbi and Rb3 are each independently H or C1-C6 alkyl, wherein one or more of the C1-C3 alkyl groups are each independently substituted with a 6- to 14-membered aryl group or It may be unsubstituted, and in this case, one or more H of the 6- to 14-membered aryl may be independently substituted or unsubstituted with halogen or -CF3, RC2 and Rc3 are each independently H, R d2 And Rd3 are each independently C1-C6 alkyl or 6- to 14-membered aryl, wherein one or more of the C1-C6 alkyl or 6- to 14-membered aryl groups may be independently substituted or unsubstituted with a 6- to 14-membered aryl or CN, a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. 【

4. In claim 1, A2 of the formula I is H, 6-14 membered aryl, 5-12 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and , C3-C15 cycloalkyl, 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, 0 and S or and wherein 6 to 14 membered aryl, 5 to 12 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, 0 and C3-C15 cycloalkyl, N, 0 and S. 3- to 8-membered heterocycloalkyl One or more of the following independently represent halogen, - CF3, C1-C3 alkyl, - C(=0)- ORgi, - 0Rg2, or - S(0)『 can be substituted or unsubstituted with Rg4, Rgi, R g2 and R g 4 is each independently H or C1-C4 alkyl, wherein one or more of the C1-C4 alkyl groups may be independently substituted or unsubstituted with halogen, a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. 【

5. A compound according to claim 1, comprising a compound represented by the following chemical formula la or chemical formula lb, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof; <화학식 Ib> In the chemical formula la, Xi to X3, Ai, Yi to Y4, R f and A2 are each the same as defined in Chemical Formula I, and in Chemical Formula lb, Xi to X3, Ai and Yi to Y4 are each the same as defined in Chemical Formula I. 【

6. A compound selected from the compounds shown in the table below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof:

7. A composition comprising a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient. A pharmaceutical composition for preventing or treating a disease mediated by HSD17B13 (17-beta-hydr oxys ter oid dehydrogenase 13).

8. A pharmaceutical composition according to claim 7, wherein the HSD17B13-mediated disease comprises non-alcoholic steatohepatitis (NASH). 【The claim comprises a step of administering a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. Method for preventing or treating HSD17B13 (17-beta-hydroxys ter oid dehydrogenase 13) mediated disease.

10. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof for the prevention or treatment of a disease mediated by HSD17B13 (17-beta-hydroxysteroid dehydrogenase 13). Claim 11】 Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, for the manufacture of a medicament for the prevention or treatment of a disease mediated by HSD17B13 (17-beta-hydroxys ter oid dehydrogenase 13).

Images