TW201245187A - Pyrazole derivatives - Google Patents

Abstract

A compound represented by formula [I] [wherein R1 represents an alkyl group or the like; R2 represents a hydrogen atom or the like; the ring A represents a phenyl group or the like; R3 represents a hydrogen atom or the like; R4 represents -CONRaRb or the like; Ra and Rb independently represent a hydrogen atom or the like; Y1 represents -(CH2)n-O- or -(CH2)m-; n represents an integer of 1 to 6; m represents an integer of 0 to 6; Y2 represents a heteroaryl group or the like; and Y3 represents a five-membered heteroarylene] or a pharmaceutically acceptable salt thereof, which is a novel compound having an antagonistic activity on group-II metabotropic glutamate (mGlu) receptors or a pharmaceutically acceptable salt thereof and is suitable for a prophylactic or therapeutic agent for diseases including mood disorders (depressionic disorders, bipolar disorders, etc), anxiety disorders (generalized anxiety disorders, panic disorders, obsessive-compulsive disorders, social anxiety disorders, post-traumatic stress disorders, a specific phobia, acute stress disorders, etc), schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsion, tremor, pain and sleep disorders which contains the compound or the pharmaceutically acceptable salt thereof as an active ingredient.

Description

201245187 VI. Description of the Invention: [Technical Field] The present invention relates to a novel compound having an antagonistic effect on a type II metabotropic glutamate (mGlu) receptor or a pharmaceutically acceptable salt thereof; A preventive or therapeutic agent for each of the following diseases as an active ingredient: mood disorder (depression, bipolar disorder, etc.), anxiety disorder (general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Fear, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, paralysis, tremors, pain, and sleep disorders. [Prior Art] Glutamate is known to be one of the main neurogenic excitatory substances for regulating high-order functions such as memory/learning in the mammalian central nervous system. The glutamate receptor can be roughly classified into an ionotropic glutamate receptor (iGIu receptor) and a metabotropic glutamate receptor (G-protein coupled receptor (GPCR)). mGlu receptor) 2 species. The iGIu receptor is classified as N-methyl-D-aspartate (NMDA) receptor, α-amino 3-hydroxy-5-methyl based on its agonist specificity. -4-Iso-3-oxo-5-methyl-4-isoxazolepropionic acid (AMP A) receptor and red alginate receptor. On the other hand, mGlu is present in the system. There are 8 subtypes (mGlul~8) ' can be classified into type I (mGlul, mGlu5), type 201245187 type II (mGlu2, mGlu3) and type III (mGlu4) by coupling signal transmission system and pharmacological properties. mGlu6, mGlu7, mGlu8). Type II and type III mGlu are expressed mainly as nerve receptors as autoreceptors or allogeneic receptors, and inhibit adenylate cyclase through Gi protein to regulate specific K + or Ca2+ channel activity. In recent years, there have been reports of changes in glutamate concentration in cerebrospinal fluid and plasma in patients with mental disorders such as mood disorders, anxiety disorders and schizophrenia, suggesting that mental illness Glutamic acid neurological dysfunction. Among the glutamate receptors, especially the type II mGlu receptor anti-reagent, in various animal models It shows antidepressant/anti-anxiety effects (Non-Patent Document 1), and suggests that the type II mGlu receptor antagonist may become a novel antidepressant/anxiolytic drug. Further, it also suggests type II. The efficacy of the mGlu receptor antagonist as a cognitive function enhancer (dementia, Alzheimer's disease) (Non-Patent Document 2). Recently, the type II mGlu receptor has been reported in Patent Documents 1 to 5 and the like. Antagonistic compounds. However, there are no compounds which have a heteroaryl-pyrazole skeleton disclosed or suggested in the patent documents. [Prior Art Document] [Patent Literature] [Patent Document 1] WO2008/128889 International Publication (Patent) Document 2] WO2008/119689 International Publication (Patent Document 3) WO2007/039439 International Publication (Patent Document 4) WO2006/084634 International Publication (Patent Document 5) WO2001/029012 International Publication No. 201245187 [Non-Patent Document] [Non- Patent Document 1] Biochemical Pharmacology 2008 75 997-1006 [Non-Patent Document 2] Neuropharmacology 2004 46 907- 9 17 [Summary of the Invention] [Hands to solve the problem] The present inventors have found that a compound represented by the following formula [Ϊ] or a pharmaceutically acceptable salt thereof can solve the above problems, and completed the present invention. That is, the present invention is (1) a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof;

[I] [In the formula [I], R1 represents a hydrogen atom or a C!·6 alkyl group (wherein the CU6 group may be substituted to 3 halogen atoms), and R2 represents a hydrogen atom or an alkyl group (herein Ci_6 can be substituted to 3 halogen atoms), ring A represents phenyl, heteroaryl, porphyrin-2-keto-5-easter, heteronymous late 201245187 quinone-1-one-5-yl, Isoindolin-1-one-6-yl, benzo[d]imidazol-2-one-5-yl or pyridone, ring A is porphyrin-2-one-5-yl, isoindole When the oxa-1-one-5-yl, isoindolin-1-one-6-yl or benzo[d]imidazol-2-one-5-yl group, R3 and R4 are the same or differently represent a hydrogen atom , a halogen atom or a ¢^-6 alkyl group, when ring A is a phenyl group, a heteroaryl group or a pyridone group, R3 represents a hydrogen atom, a dentate atom, a Ci.6-yard oxy group or a Ci-6 yard group (this Wherein the Cu alkoxy or CU6 alkyl group may be substituted by 1 to 3 halogen atoms), and R 4 represents a Cu alkyl group, a Cu alkoxy group (here, the C, -6 alkyl group or the Ci-6 alkoxy group) CONRaRb, -COR°, cyano or hydroxy substituted), -CONRaRb ' -0-CONRaRb, -NRalRbl, _CORc, cyano, -NRdCORe or -NRdS02Re,

Ra and Rb represent the same or different hydrogen atom, Cl_6 alkyl {wherein the CU6 alkyl group may be via a hydroxyl group, a _ atom,

Ci.6 alkoxy (here the CU6 alkoxy group may be substituted by 1 to 2 hydroxy groups), -CONRfRg, amine group, mono-C 1 -6 amine group, di-Cu alkylamino group, -8- 201245187 Morpholinyl, piperidino, pyrr〇Iidino, azetidino, 1,3-dioxan-2-yl, 1,3-di Oster-2-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl and 5,7-dioxaspiro[2.5]octane-6-yl (wherein the morpholine Base, piperidinyl, pyrrole steep, nitrogen chrysanthemum, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 2-oxa[3.3]heptane-6- And 5,7-dioxaspiro[2.5]octane-ί to 2 halogen atoms substituted) 1 to 3 substituents selected in the group consisting of} Ci·6 醯 、, oxetane Ordinary, tetrahydrofuranmethanyl, or, 1 and Rb may be bonded to the bonded nitrogen atom - 'further forming 4 to 6 members which may contain more than one nitrogen atom, saturated or unsaturated oxygen cap a ring (wherein the saturated or two to six membered ring ' may be substituted with one to two substituents selected from the group consisting of C, -6 alkyl, pendant oxy and hydroxy),

Ral and Rbl are formed in one step together with the bonded nitrogen atom to form a ring of 4 to 6 members which may contain more than one nitrogen atom, oxygen atom or ® and or unsaturated (here the saturated or unsaturated member ring) The group consisting of a C.6 alkyl group, a pendant oxy group and a hydroxyl group may be formed by a ratio of 1 or tetrahydroanthracene or a sulfur atom saturation. Formation, into the atomic 4 to 6 group selection -9- 201245187 1 to 2 substituents),

Re represents a Cu alkyl group, a hydroxyl group or a Cu alkoxy group,

Rd represents a hydrogen atom or a Cu alkyl group,

Re represents a Ci_6 alkoxy group, an amine group, a mono-Cu alkylamino group or a di-Cm alkylamino group. And Rg are the same or differently represented by a hydrogen atom or (^.6 alkyl, Y1 represents -(CH2)n-0- or -(CH2)m-, η represents an integer of 1 to 6, and m represents 0 to 6 Integer, Y2 represents aryl or heteroaryl {wherein the aryl or heteroaryl, may be via Ci-6 alkyl, C3.6 cycloalkyl, Ci.6 alkoxy (here the Ci. 6 alkane a group of C3-6 cycloalkyl or Cu alkoxy groups may be substituted by 1 to 3 halogen atoms), a group of cyano groups and a halogen atom may be substituted with 1 to 3 substituents} j Y3 represents a 5-member heterosis (2) A compound according to (1) or a pharmaceutically acceptable salt thereof, wherein, in the formula [I], R1 represents a hydrogen atom or a Cu alkyl group (wherein the Cu alkyl group may have 1 to 3 halogens) Atom substituted), R2 represents a hydrogen atom or a Cu alkyl group (wherein the alkyl group may be substituted by 1 to 3 halogen atoms), ring A represents a phenyl group or a heteroaryl group, and R3 represents a gas atom, a halogen atom or a Ch6 yard group. (here, the Cl.6 alkyl group may be substituted by 1 to 3 halogen atoms), -10- 201245187 R4 represents a Ci-6 yard group, a Ci.6 hospital oxy group (here the Cl. 6 fluorenyl group or C! .6 alkoxy is via -CONRaRb, -(:011 °cyano substitution), -CONRaRb,-0-C0NRaRb, -COR15 or cyano,

Ra and Rb are the same or different and represent a hydrogen atom, C..6 alkyl, (wherein the C.6 alkyl group may be via an amine group, a mono-Cu alkylamino group, a di-Cu alkylamino group, and a hydroxyl group). 1 to 2 substituents which are selected as a group to be substituted), oxetanyl group, tetrahydrofuranyl group or tetrahydropyranyl group, or Ra and Rb may be formed together with the bonded nitrogen atom, further A saturated or unsaturated 5 or 6 membered ring which may contain more than one nitrogen atom, oxygen atom or sulfur atom, f represents a hydroxyl group or a Cu alkoxy group, and Y1 represents -(ch2) no- or -(ch2) m -, η represents an integer from 1 to 6, m represents an integer from 0 to 6, and Y2 represents an aryl or heteroaryl group. Here, the aryl or heteroaryl group may be via a Ci-6, a C3.6 ring a group selected from the group consisting of Ci-6, a thiol group (wherein the Ci-6, a C3_6 cycloalkyl or a Cu alkoxy group may be substituted by 1 to 3 halogen atoms), a cyano group and a halogen atom 3 substituents} Y3 represents a 5-membered heteroaryl group. (3) A compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a 6-membered heteroaryl group. (4) A compound according to (3) or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a pyridyl group. The compound of any one of (1) to (4) or a pharmaceutically acceptable salt thereof, wherein Y1 is -CH2-0-. (6) A compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof, wherein Y2 is a phenyl or pyridyl group (wherein the phenyl or pyridyl group may be via a Cu alkyl group, C3. 6 cycloalkyl, Cu alkoxy (here, the C.6 alkyl, C3-6 cycloalkyl or (^.6 alkoxy may be substituted by 1 to 3 halogen atoms), an aryl group and a halogen atom (1) The compound of any one of (1) to (6) or a pharmaceutically acceptable salt thereof, wherein Y3 is a structure represented by the formula [II] Any one of them;

(8) A compound according to any one of (1) to (7), wherein R3 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (9) A pharmaceutical composition comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient. (10) The pharmaceutical of (9), which is a type II metabotropic glutamate receptor antagonist. And (1 1 ) a preventive or therapeutic agent for mood disorders, anxiety disorders, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, paralysis, tremors, pain, or sleep disorders, The compound of the present invention or a pharmaceutically acceptable salt thereof is used as an active ingredient. [Effect of the invention] The compound of the present invention and a pharmaceutically acceptable salt thereof have been found. The present invention will be described in more detail below. The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. <^.6 alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a different alkyl group. Propyl, isobutyl, tert-butyl, sec-butyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, etc. "1-6 alkoxy" Refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group and an ethoxy group. , propoxy, butoxy, pentyloxy, hexyloxy, isopropoxy, isobutoxy 'tert-butoxy, sec-butoxy, isopentyloxy, neopentyloxy a group, a tert-pentyloxy group, a 1,2-dimethylpropoxy group, etc. "mono-(:, .6 alkylamino group) means an amine group substituted with one C^6 alkyl group, which can be enumerated For example, methylamino, ethylamino, propylamino, butylamino, pentylamino 'hexylamino, isopropylamino, isobutylamino, tert-butylamino, sec - butylamino group, isoamylamino group, neopentylamino group, -13-201245187 tert-pentylamino group, 1,2-dimethylpropylamino group, etc. "Di-Cu alkylamino group" It means an amine group substituted with two independently Cu alkyl groups, and examples thereof include a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group, a diamylamino group, and two Hexylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, di-sec-butylamino, di-isoamylamino, di-p-pentylamine Base, di-tert.pentylamino, bis-1,2-dimethylpropylamino, ethylmethylamino, isopropylmethylamino, Isobutyl isopropylamino group, etc. "C,_6 alkylalkyl" means a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include a methyl group and an ethyl group. , propyl fluorenyl, butyl sulfhydryl, isobutyl decyl, pentylene, hexyl decyl, trimethyl ethyl, etc. "Aryl j means a monocyclic to 4-cyclic aromatic ring composed of 6 to 18 carbon atoms. Examples of the carbocyclic group include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a condensed tetraphenyl group, a fluorenyl group and the like. "Heteroaryl group" means a monocyclic or condensed cyclic aromatic heterocyclic group. For example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, dioxin Azyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4,triazolyl, tetrazolyl, quinolyl, isoquinolinyl, naphthyridinyl , quinazolinyl, benzofuranyl, benzothienyl, fluorenyl, benzoxazolyl, benzisoxazolyl, 1H-carbazolyl, 2H-carbazolyl, benzimidazolyl, Benzooxadiazolyl, benzothiadiazolyl, pyridazinyl, benzene And furazolyl, thienopyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyrazinyl, pyrazolopyrimidinyl, triazolopyrimidinyl, thienothiophenyl-14-201245187, imidazo Thiazolyl and the like. The "6-membered heteroaryl group" means a 6-membered cyclic aromatic heterocyclic group, and examples thereof include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group. The "5-membered heteroaryl group" means a 5-membered cyclic aromatic heterocyclic group, and examples thereof include a thienyl 'pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, and a different Oxazolyl, oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, and the like. The "C3.6 cycloalkyl group" means a cycloalkyl group having 3 to 6 carbon atoms, which means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. The "5-membered heteroaryl group" means a divalent group obtained by further removing any one hydrogen atom from the above "5-membered heteroaryl group". "It may be formed together with a nitrogen atom to be bonded, and may further contain a saturated or unsaturated 5 or 6 membered ring of one or more nitrogen atoms, oxygen atoms or sulfur atoms", and examples thereof include pyrrolidinyl and piperidine. Base, piperazino, morpholinyl, thiomorpholinyl, 1,2,3,6-tetragen 卩J±D-1-ol. "It may be formed together with the nitrogen atom to be bonded, and may further contain a saturated or unsaturated 4 to 6 membered ring of one or more nitrogen atoms, oxygen atoms or sulfur atoms", and examples thereof include azetidinyl group, Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,2,3,6-tetrahydropyridin-1-yl and the like. "C丨·6伸院基" means a divalent group obtained by further removing any one hydrogen atom from the above "C丨.6 alkyl group". The "Ch6oxyalkylene group" means a divalent group obtained by removing any one hydrogen atom from the above "(^.6 alkoxy group) into a-15-201245187 step. The preferred form of the compound of the present invention is as follows. In the formula [I], R1 is preferably a hydrogen atom or a C,·6 alkyl group, more preferably a Ci 6 fluorenyl group. Particularly preferably R1 is a methyl group. Preferably, R2 is a hydrogen atom. Preferred ring A is a phenyl group. Or a 6-membered heteroaryl group, more preferably a phenyl group or a pyridyl group. Preferably, R is a hydrogen atom, a halogen atom or a CU6 group (wherein the Cm alkyl group may be substituted by 1 to 3 halogen atoms), more preferably Halogen atom. Preferably, the size 4 is a Ci.3 alkyl group, a Cl.3 courtyard group (wherein the Ci 3 or Cu.3 alkoxy group is substituted with -CONRaRb or a hydroxyl group), _c〇NRaRb, NRdCORe or -NRdS02Re (wherein Ra, Rb, Rd and Re are synonymous with the above). Preferably Y1 is -ch2_o-. Preferably Y2 is phenyl or pyridyl {here the phenyl or pyridyl group may be via Ci .6 alkyl, C3-6 cycloalkyl, Cu alkoxy (here the C, -6 alkyl, c3-6 cycloalkyl or Cu alkoxy may be substituted by 1 to 3 halogen atoms), cyano and One to three substitutions for group selection of halogen atoms Y3 is preferably a substituted} ° formula [II] is any one of not configured. -16- [II] 201245187

[Chemical 3 I

A preferred embodiment of the formula [I] is: R1 is a hydrogen atom or a Ci6 group (wherein the ci.6 may be substituted by a halogen atom) 'R2 is a hydrogen atom or a C,.6 alkyl group (here, the CU6 fluorenyl group may be substituted by a halogen atom) 'Ring A is a phenyl group or a 6-membered heteroaryl group' R3 is a hydrogen atom, a halogen atom or a Ci·6 alkyl group (here, the carboxyl group may be 1 to 3) A halogen atom is substituted), and is c, -6 alkyl, Cu alkoxy (here, the Ci 6 an alkoxy group is substituted by -CONRaRb, -CORe or a cyano group), ·, -0-C0NRaRb, -COR45 Or a cyano group, 113 and Rb are the same or different hydrogen atoms, and the Cu alkyl group may be selected from the group consisting of an amine group, a mono-C!.6 alkylamino group, a diyl group and a hydroxyl group. a cyclic ether group to two substituent substituents, or 1 and Rb may be further substituted with the bonded nitrogen atom to form one or more nitrogen atoms, saturated or unsaturated oxygen atoms 5 or 6-member ring,

Re is hydroxy or C,.6 alkoxy, Y1 is -CH2-0-, after 1 to 3 via 1 to 3 芝C 乙6院: base or C!. CONRaRb base, (this Cu alkylamine) or 4 Formed from ~6 or a sulfur atom-17- 201245187 γ2 is a phenyl or pyridyl group. Here, the phenyl or pyridyl group can be via (^.6 alkyl, C3-6 cycloalkyl, C丨6 alkoxy) One to three substitutions of the group consisting of a group (wherein the Cu alkyl group, C3.6 cycloalkyl group or c^6 alkoxy group may be substituted by 1 to 3 halogen atoms), a prison group and a dentate atom Further, Y3 is a 5-membered heteroaryl group. In the formula [I], another preferred embodiment 'is a compound represented by the following formula [m].

(wherein 'rings A, R3, R4 and γ2 are synonymous with the foregoing). Another preferred embodiment of the formula [I] is a compound represented by the following formula [IV]. 【化5】 Μ

"18- 201245187 (wherein 'ring A, R3 'R4 and Y2 are synonymous with the above) ^ stereoisomers and optical isomers such as tautomers and geometric isomers may exist in the compounds of the present invention, The invention also includes such. Further, various hydrates, solvates and crystalline polymorphs of the inventive compound and its salts are also included. Further, the compound [I] of the present invention can also be an isotope (for example, D, 3 η, 13 C, 1 4 C, 15 N, 31 P, 3 2 P, 3 5 S, 18 F, 1 2 51 , etc.) Logo. In the present invention, a pharmaceutically acceptable salt means a pharmaceutically acceptable salt. These may, for example, be combined with acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, malonic acid, lactobionic acid, glucose. Acid, glucose heptanoic acid, benzoic acid, methanesulfonic acid, glycolic acid, 2-hydroxyethanolsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (toluenesulfonic acid), lauryl sulfate, malic acid, aspartic acid, Gluten, adipic acid, cysteine, Ν-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid thiocyanate, Acid salts such as undecanoic acid, acrylic acid polymer and carboxyvinyl polymer: salts with inorganic salts such as lithium salts, sodium salts, potassium salts and calcium salts; organic amines such as morpholine and piperidine; and amino acids salt. The compound [I] of the present invention or a pharmaceutically acceptable salt can be formulated, either directly or in combination with a pharmaceutically acceptable carrier, according to a method known per se. The pharmaceutically acceptable carrier may be exemplified by various organic or inorganic carrier materials conventionally used as a preparation material, such as excipients in solid preparations (for example, lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light). Anhydrous citric acid, etc.), lubricants (such as magnesium stearate, calcium stearate, -19-201245187 talc, colloidal cerium oxide, etc.), binders (such as crystalline cellulose, white sugar, D-mannitol, paste Fine, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), disintegrants (eg starch, carboxymethyl) Cellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, etc., or a solvent in a liquid preparation (for example, water for injection, alcohol, Propylene glycol, polyethylene glycol, sesame oil, corn oil, etc.), dissolution aids (eg polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triamine methane, cholesterol, triethanolamine, carbonic acid) , sodium citrate, etc., suspending agent (such as stearyl triethanolamine, sodium lauryl sulfate, lauryl alanine, lecithin, chlorinated alginate, Benzethonium chloride, a surfactant such as glyceryl monostearate; or a hydrophilic polymer such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose or hydroxypropylcellulose; Isotonic agent (such as glucose, D. sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffer (such as phosphate, acetate, carbonate, citrate, etc.), painless agent ( For example, benzyl alcohol, etc.). Further, when formulating, a preservative (for example, paraben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, etc.) or an antioxidant (for example, sulfite, ascorbic acid) may be used as needed. Etc.), colorants, sweeteners, adsorbents, wetting agents, etc. The compound [I] of the present invention or a pharmaceutically acceptable salt can be administered orally or parenterally (e.g., intravenously, topically, rectally, etc.). The dosage form for administration is, for example, a tablet (including a sugar-coated tablet, a coated tablet), a powder, a granule, a -20-201245187 powder, a tablet, a capsule (including a soft capsule), a liquid, an injection (for example, a subcutaneous injection, a vein). Intra-injection, intramuscular injection, intraperitoneal injection, etc.) 'external preparation (for example, nasal administration, preparation, transdermal preparation, ointment, emulsion, etc.), suppository (for example, rectal suppository, vaginal suppository, etc.), sustained release agent (for example) The sustained release microcapsules and the like, the nine doses, the drip, and the like can be produced by a conventional preparation technique (for example, the method described in the Japanese Pharmacopoeia, the fifth modification). The compound [I] of the present invention or a pharmaceutically acceptable salt can be appropriately selected depending on the subject, the route of administration, the disease, the age, weight and symptoms of the patient. For example, in the case of treating an adult patient, the amount administered is 1 曰 1 to 2 000 mg, and this amount is administered once a day or divided into several times. When the type II mGlu receptor antagonist is used as a pharmaceutically active ingredient, it can be used not only for humans but also for animals other than humans (cats, dogs, cows, chickens, fish, etc.). The compound of the present invention and a pharmaceutically acceptable salt thereof can be synthesized by, for example, the method shown below, but the method for producing the compound of the present invention is not limited thereto. The "inactive solvent" means an aromatic solvent such as benzene, toluene, xylene or pyridine; a hydrocarbon solvent such as hexane, pentane or cyclohexane; dichloromethane, chloroform or 1,2-dichloroethanol; Halogenated hydrocarbon solvent such as carbon tetrachloride; ether solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethanol or 1,4-dioxane; ester system such as ethyl acetate or ethyl formate Solvent; alcoholic solvent such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol; ketone solvent such as acetone or methyl ethyl ketone; N, N-dimethylformamide, N- Methylpyrrole-21 - 201245187 Alkyl ketone such as alkyl ketone or N,N-dimethylacetamide; sub-grinding solvent; nitrile solvent such as acetonitrile or propionitrile; water, homogenous and heterogeneous mixed solvent Wait. Such inactivity is suitably selected in the art to which those skilled in the art are well aware. "Alkali" means, for example, a hydrogenated product of lithium hydride, sodium hydride, an alkali metal or an alkaline earth metal; lithium decylamine, sodium propyl decylamine, lithium dicyclohexyl decylamine, lithium hexamethyldimethylhexamethyl Amidoxime, a potassium hexamethyldiamine, an alkalinized metal decylamine; sodium methoxide, sodium ethoxide, a lower alkoxide of an alkali or alkaline earth metal; butyllithium, tert-butyl An alkyl lithium such as lithium or methyl lithium; an alkali metal or an alkaline earth such as potassium hydroxide, lithium hydroxide or barium hydroxide; an alkali metal or alkali acid salt such as sodium carbonate, potassium carbonate or carbonic acid; sodium hydrogencarbonate or carbonic acid; Alkali metal or alkaline earth hydrogen salt such as potassium hydrogen: an amine such as triethylamine, N-methylmorpholine or N,N-diiso N,N-dimethylaniline; tetra-n-butylammonium fluoride 4-grade ammonium salt such as trimethylammonium; pyridine, imidazole, 2,6-1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)bicyclo[4.3.0]one-5- The base such as a basic heterocyclic ring such as a olefin (DBN) is appropriately selected in accordance with the reaction conditions of the general knowledge in the art. "Acid j means, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, inorganic acid and hydrazine-toluenesulfonic acid, methanesulfonic acid, dimethyl hydrazine trifluoroacetate, etc., and the like solvents can be potassium according to the reaction conditions. An alkali metal such as calcium hydride such as hydrazine hydride, lithium diisoammine or sodium, or a carbonic acid propyl group of tert-butyric potassium hydride, sodium sec-butylate or metal hydroxide of a metal hydroxide Ethylamine, benzoquinone quinolate, quinolate, 1,5-diaza compound, etc., such as nitric acid, phosphoric acid, etc., organic acids such as formic acid and acetic acid • 22-201245187. The acid is appropriately selected according to various reaction conditions known to those skilled in the art. [Production Method 1] The compound [II] of the present invention can be produced by the following method. [Chemical 6] <Process 1 &gt ;

In the formula, the rings A, Ri, R2, R3, R4, γ1 and γ2 are synonymous with the above. R5 represents a protecting group of a carboxyl group such as a methyl group, an ethyl group, a tert-butyl group or a benzyl group (refer to Protective Groups in Organic Synthesis 4th edition; John Wiley & Sons, INC.) or a hydrogen atom. Step 1: The compound [II] of the present invention can be condensed with the compound (2) by a protecting group wherein R5 is a carboxyl group, which is well known to those skilled in the art, in the presence of a base in an inert solvent. The reaction is followed by an intramolecular cyclization reaction (see Comprehensive Organic Transformations Second Edition 1 999; John Wiley & Sons, INC.). Alternatively, the compound [II] of the present invention can be amidated in the inactive solvent by the compound (1) and the compound (2) wherein R5 is a hydrogen atom as known in the art. After the reaction, 'manufactured by intramolecular cyclization reaction (refer to Comprehensive Organic Transformations Second Edition 1999; John Wiley & Sons, INC.). Here, the compound (1) and the compound (2) can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound or various organic synthesis methods known to those skilled in the art. Here, the hydrazylation reaction means that, for example, in an inert solvent, in the presence or absence of a base, 〇-(7-azabenzotriazol-1-yl)-N,N,N', N,·tetramethylurea cation hexafluorophosphate (HATU), 〇-(benzotriazol-1-yl)-N,N,N',N'·tetramethylurea cation hexafluorophosphate (HBTU), N,N,-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), II a condensation reaction of a condensing agent such as phenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI); using a mixed acid anhydride such as ethyl chloroformate, isobutyl chloroformate or trimethylethenyl chloride Condensation reaction: a condensation reaction using an acid halide such as sulfinyl chloride, chlorinated sulfonium chloride or 1-chloro-N,N,2-trimethyl-1-propenylamine, etc. Here, when an amidation reaction using a condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt) or hydroxy amber succinimide (HOSu) may be used as needed. Here, the intramolecular cyclization reaction is carried out. Means, for example, in an inactive solvent, heating The cyclization reaction under non-heating conditions' used as desired acid or base Amides of the compounds. -24-201245187 [Production Method 2] The compound [I-II] of the present invention can be produced by the following method

[Chemical 7 I < Process 2 >

In the formula, ring Λ, R1, R2, R3, R4, R5, γι and Υ2 are synonymous with the above. Step 2: Compound (4) can be produced by an amidation reaction of compound (1) with compound (3) wherein R5 is a hydrogen atom known to those skilled in the art in an inactive solvent. (See Comprehensive Organic Transformations Second Edition 1999; John Wiley & Sons, INC.). Here, as the compound (1) and the compound (3), a commercially available compound, a known compound, or a compound synthesized from a commercially available compound or a known compound by various organic synthetic methods known to those skilled in the art can be used. Here, the hydrazide reaction means, for example, in the presence of an inactive solvent, in the presence or absence of a base, 〇·(7-azabenzotriazol-1-yl)-fluorene, hydrazine, hydrazine, Ν'-Tetramethylurea cation hexafluorophosphate (HATU), 0-(benzotriazol-1.yl)_N,N,N',N'-tetramethylurea cation hexafluorophosphate (HBTU), N,N,-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylamino-25-201245187 propyl)carbodiimide hydrochloride (EDC. Condensation reaction of a condensing agent such as HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI); using ethyl chloroformate, isobutyl chloroformate or trimethyl ethane chloride a condensation reaction of a mixed acid anhydride; condensation of an acid halide using a sulfinyl chloride group, a chlorinated sulfonium group, a 1-chloro-indole, an anthracene, a 2-trimethyl-1-propenylamine or the like Reaction, etc. Here, when a guanidine reaction of a condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt) or hydroxy amber succinimide (HOSu) may be used as needed. Step 3: The compound [I-II] of the present invention can be produced by intramolecular cyclization of the compound (4) in an inert solvent. In this step, for example, toluenesulfonyl chloride, sulfinyl chloride, phosphorus oxychloride, Burgess Reagent, methyl methacrylate-N-(triethyl) can be used as needed. Activator such as sulfonate). (reference

Comprehensive Organic Transformations Second Edition 1 999; J〇hn Wi 1 ey & Sοns, INC.) 0 Further, for example, the compound (4) can be produced by the following method. [Chemical 8] <Process 3>

In the formula, rings A, R1, R2, R3, R4, R5, Y1 and Y2 are synonymous with the former -26-201245187. R6 represents methoxymethyl, trimethyldecyl ethoxymethyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzyl, trityl, methanesulfonyl A protecting group for an amine group such as a benzenesulfonyl group or a p_tosylsulfonyl group (refer to Protective Groups in Organic Synthesis 4th edition; John Wiley & Sons, INC.) or a hydrogen atom. Step 4: Compound (6) can be produced from the compound (1) and the compound (5) wherein R5 is a hydrogen atom by the same procedure as in Step 2 of <Scheme 2>. Where R6 is a protecting group for an amine group, the compound (6) can be obtained by using various organic synthesis methods well known to those skilled in the art (refer to Protective Groups in Organic Synthesis 4th edition; John Wiley & Sons, INC.) The protective group R6 is removed for manufacture. Alternatively, the compound (6) can be condensed by a compound (1) wherein R5 is a protecting group of a carboxyl group, which is known to those skilled in the art, in an inactive solvent, and a compound (5) wherein R6 is a hydrogen atom. The reaction was made (see Comprehensive Organic Transformations Second Edition 1999; John Wiley & Sons, INC.). Here, the compound (1) and the compound (5) can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound, or various organic synthesis methods known to those skilled in the art. Step 5: Compound (4) can be produced from Compound (6) and Compound (7) by the same procedure as in Step 2 of <Scheme 2>. Here, the compound (7) can be a compound synthesized from a commercially available compound or a known compound using a commercially available compound, a known compound, or a variety of organic synthesis methods known to those skilled in the art. -27-201245187 [Production Method 3] The compound [I-IV] of the present invention can be produced by the following method. [Chemical 9] <Process 4 >

In the formula, rings A, R1, R2, R3, Ra, Rb, γ1, γ2 and γ3 are synonymous with the above. R7 represents a bond, a Ci6 alkyl group or a Ci6oxyalkyl group. Step 6: The compound [bIV] of the present invention can be produced from the compound [] and the compound (8) of the present invention by the same procedure as in the step 2 of <Scheme 2>. Here, the compound (8) can be a compound synthesized from a commercially available compound or a known compound using a commercially available compound, a known compound, or a variety of organic synthesis methods known to those skilled in the art. [Production Method 4] The compound [I-V] of the present invention can be produced by the following method. -28- 201245187 【化1 〇】 <Process 5 >

In the formula, 'ring A, R1, R2, R3, R7, Ra, Rb, γ1, γ2 and Y3 are synonymous with the above. R8 represents Cu alkyl group, and R9 represents Cu alkyl group. Step 7: The compound [iv] of the present invention can be known by those skilled in the art by the presence of an acid and a reducing agent in an inactive solvent. The compound (8) is produced by a reductive amination reaction of the compound (9) (refer to Comprehensive Organic Transformations Second Edition 1 999; John Wiley & Sons, INC.). Here, as the compound (8) and the compound (9), a compound synthesized from a commercially available compound or a known compound can be used, using a commercially available compound, a known compound, or a variety of organic synthesis methods known to those skilled in the art. Here, examples of the acid include inorganic acids such as hydrochloric acid hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as P-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid. Further, the reducing agent used in the reductive amination reaction is a reagent which can be converted into an amine group by a cyclic imine group, and examples thereof include sodium borohydride, sodium borohydride triethoxy hydride, and boron cyanoborohydride. Sodium, borane, borane·pyridine, borane-methylpyridine, and the like. -29 - 201245187 [Production Method 5] The compound [I-VII] of the present invention can be produced by the following method. [Chemical 1 1] <Process 6 >

In the formula, the rings A, R1, R2, R3, R7, Ra, Rb, Y1, Y2 and Y3 are synonymous with the above. Step 8: The compound [I-VII] of the present invention can be produced by a hydration reaction known to those skilled in the art of the compound [I-VI] of the present invention (refer to Comprehensive Organic Transformations Second Edition 1999). ;John Wiley & Sons, INC.). For example, the compound represented by the formula (1-1) or the formula (1-2) of the compound (1) can be produced by the following method. -30- .R2, co2r5

(1-2) 201245187 [Chemical 1 2] <Process 7 >

R1-N (CH2)n HO (10) wherein n, R1, R2, R5 and Y2 are synonymous with the above. And R1()'' is the same or different, and represents a hydrogen atom, a 0.6 alkyl group, a group, a Cu alkoxy group (wherein the Cu alkyl group, the C3_6 cycloalkyloxy group may be substituted by 1 to 3 halogen atoms), The cyano group and the halogen represent a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom. Step 9: Compound (1-1) can be produced by reacting inactive solvate (10) with compound (11) to produce "(10) and (11), commercially available compounds, or The retardation reaction synthesized by a commercially available compound or a known compound using an organic synthesis method which is generally known in the art can be exemplified by using, for example, triphenylphosphine, tributylphosphine, and azodicarboxylic acid. Ester, diisopropyl azodicarboxylate

Rio, Rl〇' C3-6 naphthenic or. The 6-alkane atom, in X1, is compounded into various compounds which are known and known. a method of organic phosphating, an azo compound such as azodi-31 - 201245187 carboxylic acid di tert-butyl ester; or a phosphorous ylide reagent such as cyanomethyltributylphosphorane Method (Ref. chem. Rev. 2009. 1 09, 25 5 1 -265 1 ). Step 1 : Compound (1-2) can be compounded by the presence or absence of a palladium catalyst ligand in the presence or absence of a base, in the presence or absence of a palladium catalyst, or in the absence of a palladium catalyst ligand ( 10) Manufactured by reacting with the compound (12) (refer to C〇mprehensive Organic Transformations Second Edition 1999; John Wiley & Sons, INC.). Here, the compound (10) and the compound (12) can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound, or various organic synthetic methods known to those skilled in the art. Here, examples of the base include sodium carbonate, potassium carbonate, carbonic acid planing, triethylamine 'diisopropylethylamine, lithium hydride, sodium hydride, potassium hydride, lithium diisopropyl decylamine, and lithium hexamethyl. Diamine amide, sodium hexamethyldiamine, sodium methoxide, sodium ethoxide, tert-butoxide, butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, Sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. The palladium catalyst may, for example, be palladium(II) acetate, dichlorobistriphenylphosphine palladium (II), dichlorobisacetonitrile palladium (ruthenium) or ruthenium triphenylphosphine palladium (ruthenium). The ligand may, for example, be rac-2-(di-t-butylphosphino)binaphthalene, triphenylphosphine, tributylphosphine, 2,2-bis(diphenylphosphino)-1,1- Binapthenes (BINAP), 2-(di-tert-butylphosphino)biphenyl, 1,1 bis(diphenylphosphino)ferrocene (dppf), 1,3-bis(diphenylphosphino) ) Propane (dppp) and the like. -32- 201245187 For example, the compound represented by the formula (1 ο-1 ) of the compound (1 ο ) can be produced by the following method. [Chemical 1 3] <Process 8 >

(10-1) wherein R1 'R2 and R5 are the same as defined above. Step 1 1 : The compound (1 4 ) can be produced by reacting the compound (13) with N,N-dimethylformamide or the like in an inactive solvent in the presence of a base. The compound (13) can be a compound synthesized from a commercially available compound or a known compound using a commercially available compound, a known compound or a known organic synthesis method known to those skilled in the art. Step 12: Compound (10-1) can be produced by reacting a reducing agent with compound (14) in an inert solvent. (Refer to Comprehensive Organic Transformations Second Edition 1 999; John Wiley & Sons, INC.). Here, the reducing agent is a reagent capable of reducing a formazan group and converting it into a hydroxyl group, and examples thereof include lithium borohydride, sodium borohydride, calcium borohydride, zinc borohydride, lithium aluminum hydride, sodium aluminum hydride, and diisobutyl hydride. Base aluminum and so on. For example, the compound (2) can be produced by the following method. -33- 201245187 [Chemical 1 4] <Process 9 >

In the formula, rings A, X1, R3 and R4 are synonymous with the above. Step 13: Compound (16) can be compounded by the presence or absence of a palladium catalyst ligand in the presence or absence of a base, in the presence or absence of a base, in the presence or absence of a palladium catalyst, or in the absence of a palladium catalyst ligand. 15) Manufactured by reacting with a suitable cyanating agent. The compound (15) can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound, or various organic synthetic methods known to those skilled in the art. Here, as the appropriate sizing agent, for example, zinc cyanide, copper cyanide, potassium hydride or an aromatic pin can be cited. Step 14: The compound (2) can be produced by an addition reaction of the compound (16) with a hydroxylamine or a salt thereof in an inactive solvent, in the presence or absence of a base. In addition to the synthesis of the compound (16), the compound (16) can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound, or various organic synthetic methods known to those skilled in the art. For example, the compound (3) can be produced by the following method. -34- 201245187 [Chemical 1 5] <Process 10 > ? H2N-N_Re 0 II (5) ^R4 R3 Step 15 R3 (17) (3) where, Rings A, R3, R4, R5 and R6 are as described above Synonymous. Step 15: Compound (3) can be produced from Compound (17) and Compound (5) by the same procedure as in Step 4 of <Scheme 3>. Here, the compound (17) and the compound (5) can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound, or various organic synthetic methods known to those skilled in the art. [Examples] Next, the present invention will be described in more detail by way of Production Examples, Examples and Test Examples. However, the present invention is not limited by the Examples, Examples and Test Examples, and without departing from the scope of the present invention. In the production example and the examples, when the column chromatography method is used for purification, the following commercially available ones are used: "NH2 dioxide gel" is Biotage (registered trademark) SNAPCartridge KP manufactured by Biotage. -NH, "Silica dioxide gel" is made of Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil, and "cerium oxide gel 60 N" is a cerium oxide gel manufactured by Kanto Chemical Co., Ltd. 60 N, "Chromatorex NH" uses Chromatorex (registered trademark) NH manufactured by Fuji Silysia Chemical Co., Ltd. Refining using reverse phase column chromatography -35- 201245187 "CAPCELL PAK" uses the CAPCELL PAK (registered trademark) C18 TYPE MGII manufactured by Shiseido Co., Ltd. In the case of TLC purification, TLC (cerium oxide gel sheet) was made using Silica gel 60F254 (Merck) and TLC (NH2 cerium oxide gel sheet) using TLC plate NH (Fuj i Silysia). The respective instrument data described in the production examples and the examples were measured by the following measuring instruments. Microwave reactor: Initiator (Biotage AB) LCMS Spectra: Shimadzu LCMS-IT-TOF, Shimadzu LCMS-2010EV, micromass Platform LC, micromass GCT, Agilent 6150, Agilent 1 2 9 0 I nf in ity and Agilent 1100 NMR spectrum: iH-NMR] 600MHz: JNM-ECA600 (Japan Electronics), 500MHz: JNM-ECA5 00 (Japan Electronics), 300MHz: UNITYNOVA3 00 (Varian Inc.), 200MHz: GEMINI2000/200 (Varian Inc.) The compound names in the examples are named by ACD/Name (ACD/Labs 12.0, Advanced Chemistry Development Inc.). The RT (holding time) of the LCMS in the production examples and the examples was measured using any of the conditions shown below.

Condition A measuring machine: Agilent Agilent 1290 Infinity and Agilent 6150 Column: Waters Acquity CSH €Μ8,1·7μηι, φ2.1χ -36 - 201245187 5 0mm Solvent: Liquid A; Contains 0 · 1 % formic acid water, B Liquid; acetonitrile with 0.1% formic acid

Gradient: 〇 point (A liquid / B liquid = 80/2 0), 1.2-1.4 points (A liquid / B liquid = 1 / 99)

Flow rate: 0.8 mL/min, detection method: 254 nm C ondition B Measuring machine: Shimadzu Corporation LCMS-2010EV Column: Shimpack XR-〇DS, 2.2 pm, <i) 2.0 x 30 mm Solvent: Liquid A; 0.1% formic acid water , liquid B: acetonitrile gradient with 0.1% formic acid: 〇 (A liquid / B liquid = 90/10), 3 points (A liquid / B liquid = 0 / 100)

Flow rate: 0.6 mL/min' Detection method: 254 nm Condition C

Measuring instruments: Agilent Agilent 1100 and Micromass Platform LC column: Waters Sun-Fire C18, 2.5 μm; φ 4.6 x 50 mm Solvent: solution A; 0.1% trifluoroacetic acid in water, solution B; containing 0.1% trifluoro Acetonitrile gradient of acetic acid: 〇 (A liquid / B liquid = 90/10), 0.5 points (A liquid / B liquid = 90/10), 5.5 points (A liquid / B liquid = 20/80), 6.0 points ( A liquid / B liquid = 1 / 99), 6_3 minutes (A liquid / B liquid = 1 / 99) Flow rate: 1 m L / mi η, detection method: 2 5 4 nm -37- 201245187 Manufacturing example and example The nucleus of the nuclear magnetic resonance (NMR) spectrum used is as follows. s : singlet (singlet), d: doublet (doublet), t: triplet (triplet), q: quartet (quartet), dd: double doublet (double doublet), dt: double triplet (double triplet) ), dq : double quartet, double: double double doublet, m: multiplet, br : broad, J · coupling constant, Hz: Hertz, DMSO -d6: heavy hydrogenated dimethyl hydrazine production example 1 ethyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-4-carboxylate 1) ethyl 5-carbamid-1- Methyl-1H-pyrazole-4-carboxylate was added to a solution of diisopropylamine (27.6 g) in tetrahydrofuran (400 mL), and η-butyllithium (105 mL, 2.60 M hexane solution), stirring for 1 hour. After the reaction mixture was cooled to -78 °C, a solution of ethyl 1-methyl-1H-pyrazole-4·carboxylate (20.0 g) in tetrahydrofuran (100 mL) was added and stirred for 2 hours. N,N-dimethylformamide (79.7 g) was added dropwise to the reaction mixture at -7 8 ° C, and after stirring for 1 hour, a 2M aqueous solution of hydrogen chloride was added. The reaction solution was made acidic with a 5 Μ aqueous solution of hydrogen chloride and then extracted three times with ethyl acetate. The combined organic layers were washed twice with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (jjjjjjlili -38- 201245187 2) Ethyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-4-carboxylate under ice-cooling 'ethyl 5-methylmercapto-1-methyl- To a solution of 1H-pyrazole-4-carboxylate (23.0 g) in methanol (300 mL), sodium borohydride (5.25 g) was added and stirred for 1 hour. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was diluted with water, and then extracted three times with ethyl acetate. The combined organic layer was washed with EtOAc EtOAc m. 1H NMR (200 MHz, DMSO-d6) δ ppm 1.27 (t, J = 7.03 Hz, 3 Η) 3.87 ( s, 3 H) 4.2 1 ( q, J = 7.03 Hz, 2 H ) 4.81 ( d, J = 5.71 Hz, 2 H) 5.26 - 5.41 ( m, 1 H) 7.75 ( s, 1 H) Production Example 2 Ethyl 1·methyl-5-{4-(trifluoromethyl)phenoxy]methyl } -1 Η-pyrazole-4-carboxylate in ethyl 5-(hydroxymethyl)-1-methyl-1Η-pyrazole-4-carboxylate (5.00 g), 4-hydroxybenzotriene A solution of fluoride (6.60 g) and triphenylphosphine (9.11 g) in tetrahydrofuran (25 mL) was added dropwise to diisopropyl azodicarboxylate (7.60 mL) at room temperature for 3 hours. The solvent was distilled off under reduced pressure, diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to column chromatography {(NH cerium dioxide gel, hexane: ethyl acetate = 90: 10 to 75:25) and (cerium oxide gel, hexane: ethyl acetate = 80) : 20 ) Refining to give the title compound (7.36 g). -39- 201245187

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.35 ( t, J = 7.25 Hz, 3 H) 3.97 ( s, 3 H) 4.32 ( q, J = 7.03 Hz, 2 H )5.54 ( s, 2 H ) 7.10 ( d, J = 8.79 Hz, 2 H) 7.56 ( d, J = 8.35 Hz, 2 H ) 7.88 ( s, 1 H ) ; MS ( ESI neg. ) m/z : 327 C MH ]- In the same way The following compounds were synthesized. Ethyl 5-[(4-fluorophenoxy)methyl]-1-methyl-1H·pyrazole-4-carboxylate

1H NMR ( 600 MHz, CHLOROFORM-d) δ ppm 1.33 ( t, J = 7.30 Hz, 3 H) 3.96 ( s, 3 H) 4.30 ( q, J = 6.88 Hz, 2 H )5.44 ( s, 2 H) 6.88 - 7.00 ( m, 4 H ) 7.86 ( s, 1 H) Ethyl 5-[(3,4-difluorophenoxy)methyl]-1-methyl-1H-pyrazole-4-carboxylic acid Ester MS ( ESI/APCI Dual pos. ) m/z : 297 [ M + H] + ethyl 5-{ 〔(6-fluoropyridin-3-yl)oxy]methyl} -1-methyl-1H -pyrazole-4-carboxylate MS ( ESI/APCI Dual pos. ) m/z : 280 [ M + H ) + Preparation Example 3 ethyl 5-([ 5-fluoropyridin-2-yl)oxy Ethylmethyl}-methyl-1H-pyrazole-4-carboxylate ethyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-4-carboxylate (300 mg) '2-Chloro-5-fluoropyridine (322 mg), palladium(II) acetate (37 mg), carbonic acid (797 mg) 'rac-2-(1-t-butylphosphino)· The mixture of 1,1'-binaphthyl (65 mg) and 1,4-dioxane (16 mL) was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate. EtOAc was evaporated. The residue was purified by column chromatography (yield: EtOAc: EtOAc: EtOAc: EtOAc: 1H NMR (200 MHz, CHLOROFORM-d) <5 ppm 1.26 - 1.38 (m, 3 Η) 3.95 ( s, 3 Η ) 4.29 ( q, J = 7.18 Hz, 2 H) 5.68 ( s, 2 H ) 6.75 ( dd, J = 9.67, 3.52 Hz, 1 H ) 7.36 ( ddd, J = 9.1 2, 7.58, 3.08 Hz, 1 H ) 7.90 ( s, 1 H ) 8.0 1 ( d, J = 3.08 Hz, 1 H ) MS (ESI pos.) m/z: 280 [M + H]+ The following compound was synthesized in the same manner. Ethyl 1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4-carboxylate MS ( ESI pos. ) m /z : 3 3 0 [ M + H]+ ethyl 1-methyl- 5-( {[ 4-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole- 4-carboxylate MS ( ESI/APCI Dual pos.) m/z : 330 ( M + H) + ethyl 1-methyl-5- {[(5-methylpyridin-2-yl)oxy] Methyl}-1H-pyrazole-4-carboxylate MS ( ESI/APCI Dual pos. ) m/z : 276 [ M + H] + Production Example 4 1-methyl-5- ( { [ 5-( Trifluoromethyl)pyridine·2·yl]oxy}methyl)-1Η-pyrazole-4-carboxylic acid ethyl 1-methyl-5-( { 〔5-(trifluoromethyl)pyridine- 2-yl]oxy}methyl)-1Η-indole 哩-4-residual acid vinegar (249 mg), 2M hydroxide-41 - 201245187 sodium aqueous solution (1.13 mL), tetrahydrofuran (4.0 mL) and methanol (2.0 The mixture of the mixture was heated to reflux for 1 hour. After the mixture was adjusted to pH 6 with citric acid aqueous solution, it was extracted with chloroform three times. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The title compound (188 mg) was obtained as a colorless solid. NMR ( 600 MHz, CHLOROFORM-d ) <5 ppm 3.97 (s, 3 Η) 5.74 ( s, 2 Η) 6.87 ( d, J = 8.67 Hz, 1 H) 7.82 ( dd, J = 8.67, 2.48 Hz, 1 H) 7.96 ( s, 1 H) 8.46 ( s, 1 H) ; MS (ESI s.) m/z: 300 [ MH] - The following compound was synthesized in the same manner: 1-methyl- 5-{ [4 -(Trifluoromethyl)phenoxy]methyl}-1H-pyrazole-4-carboxylic acid MS (ESI pos.) m/z : 301 [ M + H] + 5-[(4-fluorophenoxy) Methyl]-1-methyl-1H-pyrazole-4-carboxylic acid MS ( ESI pos. ) m/z : 25 1 [M + H] + 5- { 〔 ( 5-fluoropyridine·2- (oxy)methyl}-1-methyl-1H-pyrazole-4-carboxylic acid MS (ESI pos.) m/z : 252 [M + H] + 5-[ (3,4-difluoro Phenoxy)methyl]-1-methyl-1H-pyrazole·4-carboxylic acid MS ( ESI/APCI Dual pos. ) m/z : 269 [ M + H]+ 1-methyl-5-( {[4-(Trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H·pyrazole-4-carboxylic acid MS ( ESI/APCI Dual pos. ) m/z : 302 [ M + H ] + -42- 201245187 5- { 〔(5-Chloropyridin-2-yl)oxy]methyl}-1-methyl-1H-pyrazole-4-carboxylic acid MS ( ESI/APCI Dual pos. ) m/z : 290 [ M + Na]+ 5-{ [(6-Methoxypyridin-3-yl)oxy]methyl} -1-methyl·1H-pyrazole-4-carboxylic acid MS ( ESI/APCI Dual neg.) m/z: 2 62 〔 MH]- 5· ( {[ 5-(Difluoromethyl)pyridin-2-yl)oxy}methyl)-1-methyl-1H-pyrazole-4-carboxylic acid MS ( ESI/APCI D ua 1 neg.) m/z : 282 C MH - 1-methyl-5- {((5-methylpyran-2-yl)oxy]methyl} -i H-pyrazole-4-carboxylate Acid 1H NMR (600 MHz, DMSO-d6) δ ppm 2.19 - 2.25 ( m, i H ) 3.86 -3. 90 ( m,3 H ) 5 · 60 ( s, 2 H) 6. 79 ( d, J = 8. 26 Hz, 1 H ) 7. 57 ( dd, J = 8 • 46, 2.27 Hz, 1 H ) 7.8 1 ( s, 1 H ) 8.02 ( dd, J=1.65, 0.83 Hz, 1 H ) 1 2 • 42 - 1 2.57 ( m, 1 H) 5- { 〔( 5-cyclopropylpyridin-2-yl)oxy]methylindole-1-methyl-1H-pyrazole-4-carboxylic acid MS ( ESI/APCI Dual pos.) m/z : 2 74 [ M + H]+ Production Example 5 2-[ 4-( Ν'-hydroxymethylmethyl)phenyl]acetamidamine {i.e. 2-[4-( N5-hydroxycarbamimidoyl ) phenyl] acetamide } -43- 201245187 1 ) 2-( 4-cyanophenyl)acetamidine in the presence of (4-cyanophenyl)acetic acid (500) To a solution of chloroform (6.0 mL) in EtOAc (3 mL), EtOAc (EtOAc) The reaction solution was concentrated under reduced pressure. After adding 28% aqueous ammonia (3.00 mL) to a suspension of tetrahydrofuran (7.0 mL), the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained solid was washed with diisopropyl ether to give the title compound (3 50 mg). 2) 2-[4-(N'-hydroxymethylindenyl)phenyl]acetamidine 2-(4-cyanophenyl)acetamide (350 mg), 50% aqueous hydroxylamine solution (160 μί) A mixture of ethanol (1.5 mL) was heated to reflux for 12 hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssss 7.22 ( d, J = 8.25 Hz, 2 H) 7.43 ( br. s., 1 H) 7.56 ( d, J = 8.25 Hz, 2 H) 9.53 ( s, 1 H) The following compounds were synthesized in the same manner. 2-[ 3-( Ν'·hydroxymethylindenyl)phenyl]acetamidamine MS ( ESI pos.) m/z : 194 [ M + H] + 4- ( Ν '-hydroxymethyl decyl) benzoate Indoleamine-44 - 201245187 1 H NMR (200 MHz, DMSO-d6) <5 ppm 5.88 ( s, 2 H ) 7.38 ( br. s., 1 H) 7.73 ( d, J = 8.35 Hz, 2 H) 7.86 ( d, J = 8.35 Hz, 2 H) 7.97 (br. s., 1 H) 9.78 (s, 1 H) 3-( Ν'-hydroxymethylmethyl)benzamide 1 NMR (200 MHz, DMSO-d6) δ ppm 5.85 ( s, 2 Η ) 7.26 - 7.52 (m, 2H) 7.72 - 7.8 9 (m, 2H) 7.96 (br. s·, 1 H ) 8.15 ( s,1 H ) 9.68 ( s , 1 H ) 4-( Ν'-hydroxymethylmethyl)-3-methylbenzamide MS ( ESI pos. ) m/z : 194 [ M + H] + 4-fluoro-3-(N' -hydroxymercapto)benzamide MS ( ESI pos. ) m/z : 198 [ M + H]+ N-[ 2-(dimethylamino)ethyl]-3-( Ν'-hydroxyl Benzylamine 1 NMR ( 200 MHz, DMSO-d6) δ ppm 2.18 ( s, 6 H ) 2.40 ( t, J = 6.81 Hz, 2 H) 3.3 2 - 3.43 ( m, 2 H) 5.86 ( s, 2 H) 7.39 - 7.51 (m, 1 H) 7.74 - 7.84 (m, 2 H) 8.12 (s, 1 H) 8.33 - 8.43 (m, 1 H) 9.69 (s, 1 H) 2- 〔 3-(N'-hydroxymethyl fluorenyl Phenoxy]acetamide 1H NMR (600 MHz, DMSO-d6) δ ppm 4.40 ( s, 2 Η ) 5.75 (s, 2 H) 6.86 - 6.96 (m, 1 H) 7.19 - 7.28 (m, 3 H 7.33 ( br. s·,1 H) 7.47 ( br. s·,1 H) 9.59 ( s,1 H) 3- (N'-hydroxymethylindenyl)-N-(oxetane-3 -yl)benzamide MS ( ESI pos. ) m/z : 2 3 6 [ M + H]+ -45- 201245187 6-(N'-hydroxymethylindenyl)pyridine-3-carboxamide MS ( ESI/APCI Dual pos. ) m/z : 181 [ M + H]+ N-[2-(dimethylamino)ethyl]-4-(N'-hydroxymethylindenyl)benzamide 1H NMR ( 200 MHz, DMS0-d6) δ ppm 2.12 ( s, 9 Η ) 2.28 - 2.44 (m, 2 H) 3.18 - 3.53 (m, 2 H) 5.86 (s, 2 H) 7.32 - 8.54 (m, 5 H) 9.69 (s, 1 H) 3-fluoro·4·(Ν'·hydroxymethylmethyl)benzamide MS ( ESI/APCI Dual pos. ) m/z : 198 [ M + H]+ 3- ( Ν '-hydroxymethyl decyl)-4-methylbenzamide MS ( ESI/APCI Dual pos. ) m/z : 194 [ M + H ) + 4- ( Ν '-hydroxymethyl fluorenyl)- N-methylbenzamide MS ( ESI/APCI Dual pos.) m/z : 194 [ M + H] + 4- ( Ν '-hydroxymethylmethyl) benzoic acid 1 NMR ( 200 MHz, DMSO-d6 ) δ Pept 5.67 - 8.2 5 ( m, 7 H ) 3-( Ν'-hydroxymethylindenyl)benzoic acid 1 NMR ( 200 MHz, DMSO-d6) δ ppm 5.65 - 8.32 ( m, 7 H ) [4- ( Ν '-Hydroxymethylindenyl)phenyl]acetic acid [3-( Ν'-hydroxymethylindenyl)phenyl]acetic acid 6-(Ν'-hydroxymethylindenyl)pyridine·2-carboxamide Η 1 NMR ( 200 MHz , DMS0-d6) δ ppm 6.39 ( br. s., 2 H) 7.52 - 7.70(m, 1 H) 7.86 - 8.09(m, 3 H) 8.82( -46 - 201245187 br. s., 1 Η ) 9.93 ( s, 1 Η ) 4- (Ν'-hydroxymethylindenyl)phenylcarbamate 1 H NMR ( 200 MHz, DMSO-d6 ) <5 ppm 5.5 6 - 9.69 ( m, 9 Η ) 3 -(N'-hydroxymethylmethyl)-N-methylbenzimidamide 2-[3-( Ν'-hydroxymethylmethyl)phenoxy]acetamide

1 NMR ( 600 MHz, DMSO-d6) δ ppm 4.20 - 4.62 ( m, 2 H) 5.75 (s, 2 H) 6.78 - 7.59 (m, 6 H) 9.59 (s, 1 H ) 3- (Ν'- Hydroxymercapto)-N-(2-hydroxyethyl)benzamide 1H NMR (200 MHz, DMSO-d6) δ ppm 3.42 - 3.61 ( m, 2 H) 4.59 - 4.91 (m, 1 H) 5.86 (s, 2 H) 7.32 - 8.48 (m, 7 H ) 9.69 ( s, 1 H ) tert-butyl 3-( Ν'-hydroxymethyl decyl) benzoate 1 NMR ( 200 MHz, DMSO-d6 <5 ppm 1.56 ( s, 9 Η ) 5.72 - 9.84 ( m, 7 Η ) 5- (N'-hydroxymethylindenyl)pyridine-3-carboxamide MS ( ESI/APCI Dual pos. ) m/ z : 181 [ M + H] + 2-[ 2-bromo-4-( Ν'-hydroxymethylindenyl)phenyl]acetamide 1 NMR ( 600 MHz, DMSO-d6) δ ppm 5.75 - 5.92 ( m , 2 H) 6.88 - 8.10 (m, 7 H) 9.68 ( s, 1 H) 2-[ 4-fluoro-3-( Ν'-hydroxymethylmethyl)phenyl]acetamide 1 NMR (200 MHz, DMS0-d6) <5 ppm 3.33 ( s, 2 Η ) 6.73 - 8.20 ( m, 8 Η ) -47- 201245187 2-Fluoro-4-(Ν'-hydroxymethylmethyl)benzamide MS ( ESI /APCI Dual pos. ) m/z : 198( M + H ) + 2-[3-Fluoro-5-(N'-hydroxymethylindenyl)phenyl]acetamimid MS ( ESI/APCI Dual pos. ) m/z : 23 4 [ M + Na]+ 2-[3-Fluoro-4-(N'-hydroxymethylindenyl)phenyl]acetamimid MS ( ESI/APCI Dual pos. ) m /z : 212[ M + H]+ 5-(N'-hydroxymethylindenyl)pyridine-2-carboxamide ESI MS ( ESI/APCI Dual pos. ) m/z : 181 [ M + H]+ 2- [2-Fluoro-3-(indolyl-hydroxymethyl)phenyl]acetamidamine MS ( ESI/APCI Dual pos.) m/z : 212 [ M + H]+ 2-[2-fluoro-4 -(N'-hydroxymethylindenyl)phenyl]acetamidamine MS ( ESI/APCI Dual pos. ) m/z : 212 [ M + H] + 2-[2-chloro-5- (Ν'-hydroxyl Methyl phenyl acetamide MS ( ESI/APCI Dual pos. ) m/z : 22 8 [ M + H ] + 5-(N'-hydroxymethylindenyl)-2-methylbenzamide Amine MS ( ESI/APCI Dual pos. ) m/z : 194 [ M + H] + 2-[5-(Ν'-hydroxymethylmethyl)-2-methylphenyl]acetamide MS ( ESI / APCI Dual pos. ) m/z : 208 [ M + H] 2-chloro-4-( N'·hydroxymethylmethyl)benzamide MS ( ESI/APCI Dual pos. ) m/z : 214 [ M + H]+ 3-chloro-4-(N'-hydroxymethylindenyl)benzamide MS ( ESI/APCI Dual pos. ) m/z : 2 14( M + H ) + 4- (N'- Hydroxymethyl)-2- Benzomethionine MS ( ESI/APCI Dual pos. ) m/z : 194 [ M + H] + -48- 201245187 2-[2-Chloro-4-(N'-hydroxymethylindenyl)phenyl] Acetamine MS ( ESI/APCI Dual pos.) m/z : 228 [ M + H] + 2-[4-(N'-hydroxymethylmethyl)-2-methylphenyl]acetamide MS ( ESI/APCI Dual pos. ) m/z : 208 [ M + H] + 2-[4-(N'-hydroxymethylmethyl)-3-methylphenyl]acetamimid MS ( ESI/APCI Dual pos m/z : 208 [ M + H] + Ν '-hydroxy-3-[( 3 - oxoperpiperazin-1-yl)carbonyl]benzamide: benzenecarboximidamide ) MS ( ESI/APCI Dual pos. m/z : 263 [ M + H] + 2-fluoro-3-(N'-hydroxymethylindenyl)benzamide MS ( ESI/APCI Dual pos. ) m/z : 198 [ M + H ) + 3-[3-(N'-hydroxymethylindenyl)phenyl]propane decylamine 1H NMR (200 MHz, DMSO-d6) <5 ppm 2.68 -m, 3 H) 3.33 (br. s., 1 H) 5.75 (s, 2 H) 6.76 (b H) 7.10 - 7.62 (m, 5 H) 9.57 (s, 1 H) 2- [4-( Ν'-hydroxymethylmethyl)phenyl]-2- Methylpropane 醯1Η NMR (200 MHz, DMSO-d6) δ ppm 1.43 ( ) 5.76 ( s, 2 Η) 6.90 ( s, 2 Η) 7.32 ( d, J = 8.4 Hz, 7.6 1 ( d, J = 8.4 Hz, 2 H) 9.57 ( s, 1 H) 3-Ethyl-anthracene-hydroxybenzoic acid 1 NMR ( 600 MHz, DMSO-d6 ) δ ppm 2.i J = 3.7 , 1.9 Hz, 3 H) 5.68 ( s, 2 H) 6.69 ( s, 2 H ) d, J = 5.0 Hz, 1 H) 8.20 ( d, J = 5.4 Hz, 1 H) 10.14 ( 眯 (benzene 2.91 ( r · s ·,1 amine s, 6 Η 2 Η ) Π ( dt, 6.92 ( s, 1 Η -49- 201245187 2-fluoro-5-(N'-hydroxymethyl decyl) benzoguanamine MS ( ESI /APCI Dual pos. ) m/z : 198 [ M + H]+ 3-fluoro-5-(N'-hydroxymethylindenyl)benzamide MS ( ESI pos. ) m/z : 198 [ M + H]+ 4-(N'-hydroxymethylindenyl)-3-methoxybenzamide MS ( ESI pos. ) m/z : 210 [M + H]+ 5- (N'-hydroxyformamidine 1) methoxybenzamide 1H NMR (600 MHz, DMS0-d6) δ ppm 3.90 ( s, 3 Η ) 5.77 ( s, 2 Η) 7.12 ( d, J = 9.1 Hz, 1 H) 7.49 - 7.5 8 ( m, 1 H) 7.59 - 7.67 ( m, 1 H ) 7.74 ( dd, J = 8.7, 2.48 Hz, 1 H ) 8.11 ( d, J = 2.5 Hz, 1 H) 9.51 ( s, 1 H) 3-(N'-hydroxymethylindenyl)-4-methoxybenzimidamide 1H NMR (600 MHz, DMS0-d6) <5 ppm 3.84 ( s, 3 H )5.54 - 5.69 ( m, 2 H) 7.06 - 7.22 ( m, 2 H) 7.81 - 7.95 (m, 3 H ) 9.39 ( s, 1 H ) 3-(N'-hydroxycarbamimidyl)-2-methoxybenzamide 1H NMR (600 MHz, DMS0-d6) δ Ppm 4.05 ( s, 2 Η ) 5.91 - 5.97 (m, 1 H) 7.06 - 8.29 (m, 7 H) 8.63 - 8.72 (m, 1 H) N-(2-Amino-2-oxoethyl) -3- (Ν'-hydroxymethylmethyl)benzamide

1 H NMR (600 MHz, DMS0-d6) <5 ppm 3.83 ( d, J = 5.78 Hz, 2 H) 5.86 (s, 2 H) 7.04 (br. s., 1 H) 7.38 ( br. s. , 1 H) 7.47 ( t, J = 7.8 Hz, 1 H) 7.74 - 7.90 ( m, 2 H -50- 201245187 ) 8.18 (t, J = 1.7 Hz, 1 Η) 8.65 (t, J = 5.8 Hz, 1 Η) 9.70 ( s, 1 H) N-(2-Amino-2-oxoethyl)-4-( Ν'-hydroxymethylmethyl)benzamide 1 NMR ( 600 MHz, DMSO-d6 δ ppm 3.79 - 3.85 ( m, 2 H) 5.89 ( s, 2 H) 7.37 ( br. s., 1 H) 7.73 - 7.81 ( m, 2 H) 7.87 ( d, J = 8.7 Hz, 2 H) 7.94 - 8.06 ( m, 1 H) 8.68 (s, 1 H) 9.78 ( s, 1 H ) 2-[3-chloro-4-(Ν'-hydroxymethylmethyl)phenyl]acetamidamine 2- 〔 3-Chloro-5-(Ν'-hydroxymethylindenyl)phenyl]acetamido 3-chloro-5-(Ν'·hydroxymethylmethyl)benzamide 2-[6-(Ν'-hydroxyl Methyl thiopyran-3-yl]acetamidamine MS ( ESI/APCI Dual pos.) m/z '· 19 5 ( Μ + Η } + 2-[2-fluoro-5-(Ν'-hydroxyl Methyl phenyl acetamide MS ( ESI/APCI Dual pos. ) m/z : 212 [ M + H] + 2-[ 5-( Ν'-hydroxymethylmethyl)pyridin-2-yl] Acetamine MS ( ESI/APCI Dual pos. ) m/z : 195 (M + H ) + Ν'-hydroxy-4-(2-hydroxyethyl)benzhydrazide 1H NMR ( 200 MHz, CHLOROFORM-d ) ¢5 ppm 1.27 -1.44 (m, 2 H) 4.21 - 4.49 (m , 2 H) 5.57 (s, 1 H) 6.98 -8.00 ( m, 7 H ) Ν'-hydroxy-2-(hydroxymethyl)pyridine-4-carboxamidine (carboximidamide) Ν'-hydroxy-3 -(2-hydroxypropan-2-yl)benzhydrazide-51 - 201245187 1H NMR (200 MHz, DMSO-d6) <5 ppm 1.42 ( s, ) 3.32 (s, 1 H) 5.01 (s, 1 H ) 5.76(s, 1 H) 7.19 -(m, 1 H) 7.41 - 7.56 ( m, 2 H ) 7.76 ( t, J=1.5 Hz, 1 9.55 ( s, 1 H ) Ν'-hydroxy-4-( 2-Hydroxypropan-2-yl)benzhydrazide 1H NMR (200 MHz, DMSO-d6) <5 ppm 1.42 ( s, ) 3.33 ( s, 1 Η) 5.02 ( s, 1 Η) 5.74 ( s, 1 Η) 7.32 -(m, 2 Η) 7.52 - 7.66 ( m, 2 Η) 9.54 ( s, 1 Η) Ν '-Hydroxy-4-(hydroxymethyl) benzamidine MS ( ESI/APCI Dual pos. ) m/z : 167( M + H ) + 4-[aminomethylmethyl (amino)amino]-Ν'-hydroxybenzhydrazide MS ( ESI/APCI Dual pos. ) m/z : 209 [ M + H] + 4-(Aminomethylamino)-Ν'-hydroxybenzhydrazide 1 NMR (200 MHz, DMSO-d6) δ ppm 5.67 ( s, ) 5.87 ( s, 2 H) 7.26 - 7.62 (m, 4 H) 8.60 ( s, 1 H) (s, 1 H ) 3-(Aminomethylamino)-Ν'-hydroxybenzhydrazide 1H NMR ( 600 MHz, DMSO-d6 ) δ ppm 3.08 J = 5.4 Hz, 1 H) 5.59 ( s, 2 H) 5.74 ( s, 1 H) 7.01 - (m, 2 H) 7.31 - 7.40 (m, 1 H) 7.57 (t, J=1.9 Hz, 1 8.45 ( s, 1 H ) 9.47 ( s, 1 H ) N'·hydroxy-4-[(methylamine-mercapto)amino]benzamide 1 H NMR ( 600 MHz, DMSO-d6 ) δ ppm 2.64 J = 4.5 Hz, 3 H) 5.66 ( s, 2 H) 6.03 ( d, J = 4.5 Hz, 1 6 H 7.37 H) 6 H 7.49 2 H 9.42 (d, 7.17 H) (d, H) -52- 201245187 7.37 (d, J = 8.7 Hz, 2 H) 7.47 - 7.55 (m, 2 H) 8.58 ( s, 1 H) 9.4 1 ( s, 1 H ) Ν'-hydroxy-3-[(methylaminecarboxamide) Amino]benzamide 1H NMR (200 MHz, DMSO-d6) δ ppm 2.63 ( d, J = 4.4 Hz, 3 H) 5.68 ( s, 2 H) 5.99 ( d, J = 4.4 Hz, 1 H ) . . . . . . . . . . . . . . -(N'-hydroxymethylindenyl)phenyl]carbamate-hydroxy-; 1-oxo-2,3-dihydro-1^isoindole-5-formamidine MS (ESI/APCI Dual pos. ) m/z : 192 [ M + H]+ Ν'- Hydroxy-3-oxo-2,3-dihydro-1H-isoindole-5-formaldehyde MS ( ESI/APCI Dual pos. ) m/z : 192 [ M + H]+ ^^'-hydroxy- 2-Side oxy-2,3-dihydro-1^1-indol-5- formazan 1H NMR (600 MHz, DMSO-d6) δ ppm 3.48 ( s, 2 H ) 5.68 ( s, 2 H) 6.78 ( d, J = 8.3 Hz, 1 H) 7.42 - 7.61 ( m, 2 H ) 9.43 ( s, 1 H) 10.45 ( s, 1 H) Ν '-hydroxy-2-side oxy-2,3-dihydro -1H-benzimidazole-5-formamidine 1H NMR (200 MHz, DMSO-d6) δ ppm 4.34 ( br. s., 2 H) 5.69 ( s, 2 H) 6.77 - 7.01 (m, 1 H) 7.15 - 7.63 (m, 3 H ) 1 0.69 ( br. s·, 2 H ) Ν'-hydroxy-4-(2-oxo-imidazolidine-1-yl)benzhydrazide 1H NMR (600 MHz, DMSO-d6 δ ppm 3.3 7 - 3.5 0 ( m, 2 H) 3.85 ( dd, J = 8.9, 7.22 Hz, 2 H) 5.72 ( s, 2 H) 7.00 ( s, 1 H) 7.47 - 7.65 ( m, 4 H 9.47 ( s, 1 H) -53- 201245187 Ν'-Hydroxy-3-(2-oxo-imidazolidine-1-yl)benzamide 1H NMR (600 MHz, DMSO-d6) δ ppm 3.3 6 - 3.45 (m,2H) 3.81 - 3.92(m,2H) 5.76(s,2H) 6.96(s,1 Η )7.24 - 7.3 2 ( m, 2 H) 7.63 - 7.78 ( m, 2 H) 9.60 ( s, 1 H) Ν'-Hydroxy-4-(2-oxo-oxypyrrolidin-1-yl)benzamide 1H NMR ( 600 MHz, DMSO-d6 ) <5 ppm 2.06 ( quin, J = 7.53 Hz, 2 H ) 2.40 - 2.57 ( m, 2 H ) 3.84 ( t, J = 7.02

Hz, 2 H) 5.77 ( s, 2 H) 7.5 6 - 7.76 ( m, 4 H) 9.56 ( s, 1 H) Ν'-hydroxy-3-(2-oxopyrrolidin-1-yl)benzene脒1H NMR (600 MHz, DMSO-d6) &lt;5 ppm 2.03 - 2.12 (m, 2 Η) 2.46 - 2.55 (m, 2 Η) 3.80 - 3.90 (m, 2 Η) 5.81 (s, 2 Η) 7.3 2 - 8.04 ( m, 4 Η) 9.65 ( s, 1 Η) N-(2,2-Dimethoxyethyl)-3-(Ν'-hydroxymethylmethyl)benzamide MS ( ESI/ APCI Dual pos. ) m/z : 26 8 [ M + H]+ N'-hydroxy-2-oxo-oxo-1,2-dihydropyridine-4-carboindole MS ( ESI/APCI Dual pos. ) m/ z : 154 [ M + H] + Ν '-hydroxy-6-oxo-oxy-1,6-dihydropyridine-3-carboxamidine MS ( ESI/APCI Dual pos. ) m/z : 154 [ M + H] + 3-Amino-N'-hydroxybenzimidamide Production Example 6 4-(Cyanomethyl)benzoindole-54- 201245187 Methyl 4-(cyanomethyl)benzoate (1.00 g A mixture of hydrazine-hydrate (2.86 g) and methanol (20 mL) was heated to reflux for 2 hours. The reaction mixture was stirred with EtOAc EtOAc EtOAc. 1H NMR (200 MHz, DMSO-d6) &lt;5 ppm 4.11 ( s, 2 Η ) 4.49 ( br. s., 2 H) 7.42 ( d, J = 7.91 Hz, 2 H) 7.84 ( d, J = 7.91 Hz, 2 H ) 9.79 ( s, 1 H ); MS (ESI ESI) m/z: 1 74 (MH) - The following compound was synthesized in the same manner. 3-(Cyanomethyl)benzoindole MS (ESIneg.) m/z: 174 [MH]- 4-cyanobenzoindole 1H NMR (600 MHz, DMSO-d6) &lt;5 ppm 4.56 ( Br. s., 2 H) 7.87 - 7.95 ( m, 4 H) 10.00 (br. s., 1 H) 3-cyanobenzopyrene MS ( ESI neg.) m/z : 160 [ MH ]- Production Example 7 Ν'-[4-(Cyanomethyl)benzylidene]-1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl -1H-pyrazole-4-carbazide in the presence of 1-methyl-5-({[5-(trifluoromethyl)pyridine-2-yl)oxy}methyl)-1H-pyridyl Add 4-(cyanomethyl)benzo-55-201245187 hydrazine (23 mg), diisopropylethyl at room temperature in a solution of azole-4-carboxylic acid (26 mg) in tetrahydrofuran (0.40 mL) Amine (31 μιη) and 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea cation hexafluorophosphate (HATU) (49 mg), stirred 14 hours. Water was added to the reaction mixture, followed by extraction with chloroform / methanol (5 / 1). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (jjjjjjjjjjjjj 1H NMR ( 600 MHz, METHAN0L-d3 ) δ ppm 3.98 ( s,3 Η) 3.99 ( s,2 Η) 5.83 ( s,2 Η) 6.99 ( d,J = 9.08 Hz, 1 H) 7.49 ( d, J </ RTI> <RTIgt; N'-[3-(Cyanomethyl)benzylidenyl]-1·methyl-5·( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)·1 Η-pyrazole-4-carbazide MS ( ESI neg.) m/z : 4 5 7 [ Μ - Η ]- Production Example 8 methyl ({4-[ 5-(1-methyl- 5-{ 〔 4-(Trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-yl]phenyl}ethenyl)amino Formate 1 ) tert-butyl 2-[(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)carbonyl] Amine carboxylic acid ester in 1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-poridazole-4-carboxylic acid (500 mg) in chloroform (5. In a solution of mL), under ice cooling, chlorinated thiol (254 mg) and N,N-dimethylformamide-56-201245187 (1 drop) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Pyridine (260 mg) and tert-butyl hydrazine carboxylate (264 mg) were added to a suspension of the residue in tetrahydrofuran (5·0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, crystals crystals crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal 2) 1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole-4-carboate hydrochloride will be tert-butyl 2-[(1· Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)carbonyl]diamine carboxylate (690 mg), chloroform (7.0 mL) A mixture of hydrogen chloride solution (1.25 mL, 4 M dioxane solution) was stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness crystals crystals 3) 2-[4-( {2-[(1-Methyl-5-{[4-(trifluoromethyl)phenoxy)methyl}-1H-pyrazol-4-yl)carbonyl] Amino}carbonyl)phenyl]acetamide in a solution of 4-(2-amino-2-oxoethyl)benzoic acid (188 mg) in N,N-dimethylformamide (3.0 mL) After adding 1,1'-carbonyldiimidazole (193 mg) at room temperature, the mixture was stirred at 40 ° C for 1 hour. Add 1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole-4-carboate hydrochloride (300 mg) to the reaction solution at 40 Stir at °C for 5 hours. Water was added to the reaction mixture at -57-201245187, and extracted with chloroform. The organic layer was concentrated under reduced pressure. EtOAc m. 4) Methyl ({4-[5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,3 4-[4-( {2-[ (1-methyl-5-{ 〔4] under the nitrogen environment of 4-oxathiazol-2-yl]phenyl hydrazinyl) carbazate -(trifluoromethyl)phenoxy]methylindole-1H-pyrazol-4-yl)carbonyl] hydrazino} carbonyl)phenyl]acetamide (180 mg), tetrahydrofuran (3.8 mL), and Burgess A mixture of the reagent (451 mg) was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 1H NMR (600 MHz, DMSO-d6) δ ppm 3.68 ( s, 3 H) 3.92 ( s, 3 H) 4.35 ( s, 2 H) 5.54 ( s, 2 H) 7.20 ( d, J = 8.67 Hz, 2 H) 7.40 ( d, J = 8.67 Hz, 2 H ) 7.65 ( d, J = 8.67 Hz, 2 H ) 7.78 ( d, J = 8.26 Hz, 2 H) 7.97 ( s, 1 H) 10.92 ( s, 1 H); MS (ESI pos.) m/z: 516 [M + H] + EMI99.2 Ethyl 5-(5-(2-(difluoromethyl)pyridin-2-yl)oxy}methyl) 1-methyl-1H-pyrazole-4-carboxylate ethyl 5-(hydroxymethyl)-1-methyl--58-201245187 1 Η-pyrazole-4- obtained in Production Example 1. Carboxylic ester (1.69 g) and 2-chloro-5-(difluoromethyl)pyridine (1.32 g) in hydrazine, dimethyl dimethylformamide (20 mL), cooled in ice bath, a little After adding sodium hydride (60%, 380 mg, a little while, stirring at the same temperature for 1 hr, stirring at room temperature for 18 hours. Water (100 mL) was added to the reaction mixture, and the crystals were separated by filtration to give the title. Compound (1.99 g) as a colorless solid. MS ( ESI/APCI Dual pos.) m/z: 312 [M + H]+ The following compound was synthesized in the same manner: ethyl 5-{[(5-chloropyridine-2- Alkyloxy]methyl}-1-methyl-1H-pyrazole-4- Carboxylic acid ethyl 5-{[(5-iodopyridin-2-yl)oxy]methyl}-1-methyl-1H-pyrazole-4-carboxylate MS ( ESI/APCI Dual pos.) m/z : 3 8 8 [ M + H]+ Production Example 10 Methyl 5-{[(6-methoxypyridin-3-yl)oxy]methyl}-1-methyl-1H·pyrazole -4-carboxylate Ethyl 5-([(6-fluoropyridin-3-yl)oxy)methyl}-1-methyl-1H-indole 哩-4 - xiang obtained in Production Example 2 A mixture of vinegar (_'2 66 mg), sodium methoxide (28%/methanol, 550 μm) and methanol (2.0 mL) was stirred under microwave irradiation at 1 50 ° C for 1 hour. After concentrating, the residue was purified by column chromatography (jjjjjjjjjjjjjjjjjjjjj Dual pos.) m/z : 2 7 8 [ M + H]+ -59- 201245187 Production Example 1 1 ethyl 5-{[( 5-cyclopropylpyridine-2.yl)oxy]methyl} - 1-Methyl-1H-pyrazole-4-carboxylate Ethyl 5-{[[5-iodopyridin-2-yl)oxy]methylindole-1-methyl group obtained in Production Example 9 - 1H-pyrazole-4-carboxylate (2.00 g), bromine Cyclopropyl zinc (II) (0.5M / THF, 1 5.5 mL), the mixture store triphenylphosphine palladium (497 mg), and tetrahydrofuran (20 mL), the under nitrogen atmosphere, 60 ° C for 1 hour. Water was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (yield: hexane: ethyl acetate = 90: 10 to 50: 50). Compound (510 mg) as a yellow solid. MS ( ESI/APCI Dual pos. ) m/z : 302 [ M + H] + Example 1 2- ( 4- { 5 · [ 1-methyl-5-( { [ 5-(trifluoromethyl)) Pyridin-2-yl]oxy}methyl)_1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)acetamide [Chem. 1 6] Μ

1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazole-4-carboxyl obtained in Production Example 4 under nitrogen atmosphere To a solution of N-N-dimethylformamide (2.0 mL) in acid-60-201245187 (100 mg), 1,1'-carbonyldiimidazole (1 〇8 mg) was added at room temperature for 3 hours. 2-[4-(Ν'-hydroxymethylindenyl)phenyl]acetamide (128 mg) obtained in Production Example 5 was added to the reaction mixture, and stirred at 80 ° C for 2 hours, then acetic acid (2.0) was added. (mL) and concentrated at 8 (TC for 12' hours), the reaction mixture was concentrated under reduced pressure, and then extracted with chloroform / methanol (9 / 1) three times. After the organic layer was washed with water, The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) (g) s. ( d, J = 8.67 Hz, 1 H) 7.32 ( d, J = 8.26 Hz, 2 H) 7.44 ( br. s., 1 H) 7.76 ( d, J = 8.26 Hz, 2 H) 8.04 ( dd, J = 9.08, 2.48 Hz, 1 H) 8.16(s, 1 H) 8.61(s, 1 H) ; MS ( ESI pos.) m/z : 4 5 9 [ M + H]+ Use the same as in Example 1. According to the method, the compounds of Example 2 to Example 4 described in Table 1_丨 to Table 1-3 were obtained. -61 - 201245187 [Table 1 - 1imm Structural Machine Data

1H NMR (600 MHz, DMS 〇-d6) δ ppm 4.01 (st 3 H) 5.91 (s, 2 H) 7.08 (d, J = 8.67 Hz, 1 H) 7.49 (br. s. , 1 H) 7.89 - 8.14 (m, 6 H) 8.23 (s, IH) 8.65 (s, 1 H); MS (ESI pos. ) m/z 445 [M+H]+

1H NMR (600 MHz, DMS 〇-d6) δ ppm 4.01 (s, 3 H) 5.93 (s, 2 H) 7.08 (d, J = 9.08 Hz, 1 H) 7.49 (st 1 H) 7.58 (t, J =7.84 Hz, 1 H) 7.98 8.02 (m, 1 H) 8· 02 - 8.06 (m· 1 H) 8. 09 (dd, J=8.88t 2.68 Hz, 1 H) 8.14 (br. s., 1 H) 8.24 (s, 1 H) 8.48 (s, 1 H) 8.65 (s, 1 H) ; MS (ESI pos.) ca/z : 445 [M+H] +

1H NMR ¢600 MHz, DUS〇-d6) δ ppm 3.43 (s, 2 H) 4.01 (s, 3 H) 5.91 (s( 2 H) 6.89 (br. s., 1 H) 7.07 (d, J= 8. 67 Hz, 1 H) 7.38 - 7.45 (m, 2 H) 7.51 (br. s., 1 H) 7.72 (dtt J=7. 33, _.70 Hz, 1 H) 7.87 (s, 1 H 8.09 (dd, J=8.88, 2.68 Hz, 1 H) 8.22 (s, 1 H) 8.65 (s. 1 H) ; MS (ESI pos.) m/z : 459 [M+H]+

1H NMR (600 MHz, DMS 〇-d6) δ ppm 3.96 (s· 3 H) 5.70 (s, 2 H) 7.27 (d, J = 8.67 Hz, 2 H) 7. 66 (d, J = 8.67 Hz, 2 H) 7.69 (s, 1 H) 8.06 (d, J=8.26 Hz, 1 H) 8. 20 - 8. 25 (m, 2 H) 8. 32 (dd, J=8.26, 2.48 Hz, 1 H ) 9. 11 (d, J=2.06 Hzt 1 H); MS (ESI pos.) m/z : 445 [M+H]+

1H NMR (600 MHz, DMS0-d6) δ ppm 2. M (s· 6 H) 2.33 - 2.40 Cm, 2 H) 3.31 - 3.37 (m, 2 H) 3.99 (s. 3 H) 5.73 (s, 2 H) 7.30 (d, J=8.67 Hz, 2 H) 7.69 (d, J=8.67 Hz, 2 H) 7.92 - 7. 96 (m, 2 H) 7.99 - 8.04 (o, 2 H) 8.24 (s, 1 H) 8. 51 (t, J=5.57 Hz, 1 H); MS (ESI pos.) m/z 515 [M+H]+

1H NMR (600 MHz, DMS0-d6) ό ppm 2· 54 (s, 3 H) 3.99 (s, 3 H) 5. 71 (s, 2 H) 7.28 (d, J=8.67 Hz, 2 H) 7.44 (s, 1 H) 7.68 (d, J=8.67 Hz, 2 H) 7.74 - 7.78 (m, 1 H) 7.85 (s, 1 H) 7.91 (d, J=7.84 Hz, 1 H) 8.02 (s, 1 H) 8.24 (s, 1 H); MS (ESI pos.) m/z : 458 [M+H]+ -62- 201245187 [Table 1 - 2] 8

1H NMR ¢600 MHz, DMS〇-d6) 6 ppm 3.99 (s, 3 H) 5.72- (s, 2 H) 7.29 (d, J=8.67 Hz, 2 H) 7.64 (s,1 H&gt; 7.68 (d , J=8_67 Hz, 2 H) 7.81 (dd, J=8.26, 1.65 Hz, 1 H) 7.85 (dd, J=11.56, 1.65 Hz, 1 H) 8.02 (t, J=7.64 Hz, 1 H) 8.15 (s, 1 H) 8.25 (s, 1 H); MS (ESI neg.) m/z : 460 [MH]- 9

1H NMR (600 MHz, DHS〇-d6) 6 ppm 3.96 (s, 3 H) 5.70 (s, 2 H) 7.27 (d, J = 8.67 Hz, 2 H) 7.47 - 7.51 (id, 2 H) 7.64 ( d, J=8. 67 Hz, 2 H) 8.03 - 8.09 (m, 1 H) 8.12 (br. s. , 1 H) 8.22 (s, 1 H) 8.52 (dd, J=6.81, 2.27 Hz, 1 H) ; MS (ESI neg.) m/z : 460 [MH]- 10

1H NMR (600 MHz, DMS0-d6) 6 ppm 2.53 (s. 3 H) 3.99 (s, 3 H) 5.73 (s, 2 H) 7.29 (d, J=8.67 Hz, 2 H) 7.41 (br. s ·, 1 H) 7.45 (d, J=7.84 Hz, 1 H) 7.67 (d, J=8.67 Hz, 2 H) 7.92 (dd, J=7.84, 2.06 Hz, 1 H) 8.04 (br. s., 1 H) 8.25 (s, 1 H) 8.43 (d, J=2.06 Hz, 1 H) ; MS (ESI neg.) a/z : 456 [MH]*· 11

1H NMR (600 MHz, DMS 〇-d6) δ ppm 2.77 (d, J=4.54 Hz, 3 H) 4.01 (s. 3 H) 5.91 (s, 2 H) 7.08 (d, J=8. 67 Hz, 1 H) 7.93 (d, J=8. 70 Hz, 2 H) 7.97 (d. J=8. 70 Hz, 2 H) 8.10 (dd, J=8. 88, 2. 68 Hz, 1 H) 8 . 23 (s, 1 H) 8. 56 (q, J=4.54 Hz, 1 H) 8.65 (s, 1 H) ; MS (ESI pos.) m/z * 459 [M+H]+ 12

1H NMR (600 MHz, DUS〇-d6) δ ppm 2.51 (s, 3 H) 4.01 (s, 3 H) 5.91 (s, 2 H) 7.07 (d, J = 8.67 Hz, 1 H) 7.39 (br. s., 1 H) 7.44 (d. J=7.84 Hz, 1 H) 7.91 (dd, J=7.84, 1.65 Hz, 1 H) 8.03 (br. s., 1 H) 8.08 (dd, J=8.67, 2.48 Hz, 1 H) 8.24 (s, l H&gt; 8.39 (d. J=2.06 Hz, 1 H) 8.62 (s, 1 H); MS (ESI pos.) m/z : 459 [M+H]+ 13

1H NMR (600 MHz, DMS 〇-d6) δ ppm 2.52 (s, 3 H) 4.02 (s, 3 H) 5.90 (s, 2 H) 7.07 (d, J = 8.67 Hz, 1 H) 7.44 (br. s., 1 H) 7.76 (dd, J=8.05, 1.45 Hz· 1 H) 7.83 - 7.88 (m, 2 H) 8.02 (s, 1 H) 8.09 (dd, J=8.67, 2.48 Hzt 1 H) 8.23 (s, 1 H) 8.63 (d, J=0.83 Hz, 1 H) ; MS (ESI pos.) m/z : 459 [M+H]+ -63- 201245187 [Table 1-3]

Example 2 4-{5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]- 1,2,4-oxadiazole-3-ylindolebenzamide Example 3 3-{5-[1-methyl- 5-({[[4-(trifluoromethyl))pyridine-2- Yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzimidamide Example 4 2-(3-(5-[ 1-methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadi Zyridin-3-ylindole phenyl)acetamide Example 5 6-[5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole 4-yl)-1,2,4-oxathiazol-3-yl]pyridine-3-carboxamide amide Example 6 N-[2-(dimethylamino)ethyl]-4-[ 5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3 -yl]benzamide-64 - 201245187 Example 7 3-Methyl-4-[ 5-(1-methyl- 5-{[4-(trifluoromethyl)phenoxy]methyl} - 1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidamide Example 8 3-Fluoro-4-[5-(bu methyl-5-{ [4- (trifluoromethyl) phenoxy ]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzamide Example 9 4-Fluoro-3-[5-(l-A 5-[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidazole Amine Example 1 4-Methyl-3-[ 5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl) -1,2,4_-oxadiazole-3-yl]benzimidamide Example 1 1 Ν-Methyl-4-{ 5-[1-methyl-5-( { [ 5-(trifluoro) Methyl)pyridin-2-yloxyoxindolemethyl)-1Η-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzimidamide Example 12 4- Methyl-3-{5-[1-methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]- 1,2,4-oxadiazol-3-yl}benzamide-9-201245187 Example 13 3-Methyl-4-{ 5-[1-methyl-5- ({[ 5-( Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzimidamide Example 14 4-fluoro-3-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazole·4-yl] -1,2,4-oxadi -3-ylbenzimidamide Example 152-{3-[5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole- 4-yl)-1,2,4-oxadiazole-3-yl]phenyl}acetamidamine [Chemical 1 7]

1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole-4-carboxylic acid (150 mg) obtained in Preparation Example 4, Production Example 5 2-[3-( Ν'-hydroxymethylindolyl)phenyl]acetamidamine (125 mg), 1,1'-carbonyldiimidazole (105 mg) and N,N-dimethylformamide A mixture of (1·〇mL) was stirred at 150 ° C for 30 minutes under microwave irradiation. After concentrating the reaction mixture under reduced pressure, the residue was subjected to reverse phase column chromatography (-66-201245187 CAPCELL PAK MG II, water containing 0.1% trifluoroacetic acid: containing 0.1% trifluoroacetic acid The title compound (44 mg) was obtained as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.43 ( s, 2 Η ): 3.99 ( s , 3 H) 5 72 ( s, 2 H ) 6.90 (b r. s ., 1 H )7. ( d, J-8.79 Hz , 2 H) 7.41 -7.45 ( m, 2 H ) 7.52 ( br. s .,1 Η) 7.69 ( d, J = 8 • 79 Hz,: 2 H) 7.76 - 7.80 ( m 5 1 H) 7.90 (s, 1 Η ) 8.24 ( s, 1 Η ) ; MS ( ESI pos. ) m/z : 45 8 [ M + H]+ The same procedure as in Example 15 was used to obtain Table 2 1 to the compounds of Example 16 to Example 31 described in Table 2-3. -67 - 201245187 [Table 2 - 1] Example Structured Machine Data 16 $\ F HO 1H NMR (600 UHz, DMS〇-d6) δ ppm 4.01 (s, 3 H) 5.75 (s, 2 H) 7.27 - 7.39 (m, 2 H) 7.60 -7.75 (m, 4 H) 8.05 - 8.21 (m, 2 H) 8.28 (s, 1 H) 8. 56 (t, J=1.60 Hz, 1 H); MS (ESI Pos.) m/z : 445 [M+H]+ 17 A oh 1H NMR (600 MHz ( DMS〇-d6) δ ppm 4.00 (s, 3 H) 5.73 (s, 2 H) 7.31 (d, J= 8. 71 Hz, 2 H) 7.58 - 7.66 (mt 1 H) 7.70 (d, J=8. 70 Hz, 2 H) 8.04 - 8.17 (a, 2 H) 8.26 (s, 1 H) 8.54 (m, J=1.60, 1.60 Hz, 1 H); MS (ESI pos.) ra/z : 445 [M+H3+ 18 $\ 1H NMR (500 MHz, DMS〇-d6) fi ppm 3.46 (st 2 H) 4.02 ( s, 3 H) 5.75 (st 2 H) 6.95 (br. s., 1 H&gt; 7.33 (d, J=8.58 Hz, 2 H) 7.42 (d, J=8.58 Hz, 2 H) 7.53 (br. s , 1 H) 7.72 (d, J=8.92 Hz, 2 H) 7.90 (d, J=8.23 Hz, 2 H) 8.26 (s, 1 H); MS (ESI pos.) m/z : 458 [M +H] + 19. Nine OH 1H NMR (500 MHz, DMS〇-d6) ό ppm 3.63 (s, 2 H) 3.99 (st 3 H) 5.72 (s, 2 H) 7. 30 (d, J=8.79 Hz, 2 H) 7.39 (d, J=8.41 Hz, 2 H) 7. 69 (d, J=8.79 Hz, 2 H) 7. 88 (s, 2 H) 8.23 (s, 1 H); MS ( ES I pos.) m/z : 459 [M+H] + 20 :^Τ&gt; 1H NMR ¢500 MHz, DMS〇-d6) 6 ppm 3.66 (s, 2 H) 4· 02 (s, 3 H) 5.75 (s, 2 H) 7· 33 (d, J=8.41 Hz, 2 H) 7.46 - 7.49 (mt 2 H) 7.72 (d, J=8. 79 Hz, 2 H) 7.81 - 7.85 (m, 1 H 7.91 (s, 1 H) 8.27 (s, 1 H); MS (ESI pos.) m/z : 459 CM+H] + 21 p tv 4 〇1H NMR ¢600 MHz, DMS〇-d6) δ ppm 4.02 (s, 3 H) 5.77 (s, 2 H) 7.31 - 7.35 (m, 2 H) 7.68 -7. 72 (mf 2 H) 7.86 (br. s., 1 H) 7.90 (br. s, 1 H) 8.15 - 8.21 (m, 3 H) 8.29 (s, 1 H) ; MS (ESI pos.) m/z : 445 [M+H]+ -68- 201245187 [Table 2 — 2] 22 /V, F 1H NMR (600 MHz, DMS0-J6) δ ppm 3.48 (s( 2 H) 4.00 (s, 3 H) 5.63 Cs( 2 H) 6.94 (br. s. f 1 H) 7.12 - 7. 17 (m , 4 H) 7.46 - 7.49 (nt 2 H) 7.55 (br. s. f 1 H) 7.85 (s, 1 H) 7.94 (s, 1 H&gt; 8.23 (s, 1 H); MS (ESI pos.) m/z : 408 [M+H] + 23 NH, 1H NMR (600 MHz, DMS 〇-d6) δ ppm 3.47 (s, 2 H) 4. 01 (s, 3 H) 5.64 (s, 2 H) 6.94 (br. s., 1 H) 7. 14 - 7. 18 (mf 4 H) 7.44 (d, J=8. 26 Hz, 2 H) 7.53 (br. s. t 1 H) 7.93 (d, J=8.26 Hz, 2 H) 8.23 (s, 1 H MS (ESI pos. ) m/z : 408 [M+H]+ 24 ¢) 〇^hF 1H NMR (600 MHz, DMS〇-d6) 6 ppm 3.47 (s, 2 H) 4.02 (s, 3 H) 5.82 (s, 2 H) 6.90 - 6.99 (m, 2 H) 7.44 - 7.49 (ra, 2 H) 7.55 (br. s., 1 H) 7. 70 - 7.76 (m, 1 H) 7. 78 - 7. 83 (m, 1 H) 7.90 (s, 1 H) 8.20 - 8.24 (m, 2 H) ; MS (ESI pos.) m/z : 409 [M+H] + 25 Orders \ NHa 1H NMR (600 MHz ( DMS 〇-d6) 6 ppm 3.46 (s, 2 H) 4.02 (s, 3 H) 5.82 (s, 2 H) 6.90 - 6.98 (m, 2 H) 7.42 (d, J = 8.26 Hz , 2 H) 7. 53 (br. s. , 1 H) 7.71 - 7.76 (m, 1 H) 7.88 (d, J=8. 26 Hz, 2 H) 8.22 (S&gt; 2 H) ; MS (ESI Pos.) o/z : 409 [M+H]+ 26 FT Oaa^ NH, 1H NMR (600 MHz. DMS〇-d6) δ ppm 3.98 (st 3 H) 5.70 (s, 2 H) 6.74 - 6.88 ( In, 3 H) 7.29 (s, 2 H) 7. 51 - 7.59 (m, 1 H) 7. 65 - 7.77 (ro, 4 H) 8. 19 (s, 1 H) 27 1H NMR (600 MHz, DMSO~d6) 6 ppm 2. 14 (s, 6 H) 2.35 - 2.41 (m, 2 H) 3.31 - 3.40 (ra, 2 H) 3.99 (s, 3 H) 5.74 (s, 2 H) 7.31 (d , J=8.67 Hz, 2 H) 7.60 (t, J=7.84 Hi, 1 H) 7.69 (d, J=8. 67 Hz, 2 H) 7.94 - 8.09 (m, 2 H) 8.25 (s, 1 H 8.41 - 8.49 (ra, 1 H) 8. 55 - 8.65 (m, 1 H); MS (ESI pos.) m/z : 515 [M+H]+ -69- 201245187 [Table 2 — 3]

Example 16 4-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4 -oxathiazol-3-yl]benzoic acid Example 17 3-[5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole 4-yl)-1,2,4-oxadiazol-3-yl]benzoic acid Example 182-{4-[5-(1-methyl-5-{[4-(trifluoromethyl) Phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl}acetamidamine-70-201245187 Example 19 { 4- [ 5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole- 3-yl]phenyl}acetic acid Example 20 { 3-[ 5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole-4- -1,2,4-oxathiazol-3-yl]phenyl}acetic acid Example 21 6-[5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy) Methyl}methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]pyridine-2-carboxamide 222-[3-(5-{5 -[(4-fluorophenoxy)methyl]-1-methyl-1H-pyrazol-4-ylindole-1,2,4-oxadiazole-3-yl)phenyl]acetamide real Example 232-[4-(5-{5-[(4-Fluorophenoxy)methyl]-1-methyl-1H-pyrazol-4-yl}-1,2,4-oxadiyl Zyrid-3-yl)phenyl]acetamidine Example 24 2- { 3 -[ 5-( 5- {[(5-fluoropyridin-2-yl)oxy)methyl}-1-methyl- 111-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl}acetamidamine-71 - 201245187 Example 252-{4-[5-(5-{ 〔 (5-fluoropyridin-2-yl)oxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl hydrazine Indoleamine Example 26 4-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2 , 4-oxathiazol-3-yl]phenylcarbamate Example 27 N-[2-(Dimethylamino)ethyl]-3-[5-(l-methyl- 5 -{[4-(Trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidamide Example 28N-Methyl-3-{5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl -1,2,4-oxadiazol-3-yl}benzamide 292-{3-[5-(1-methyl-5-{[4-(trifluoromethyl)benzene) Oxy oxy -1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenoxy}acetamidine Example 30 N-(2-hydroxyethyl)-3- [ 5- ( 1-Methyl-5- {[ 4-(trifluoromethyl)phenoxy]methyl} -1H-pyrazol-4-yl)-1,2,4·oxadiazole- 3-yl]benzimidamide Example 31 3-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1Η-pyrazol-4-yl -1,2,4-oxathiazol-3-yl]-oxime--72- 201245187 (oxetan-3-yl)benzamide Example 32 3-[5-(1- Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl]benzoate Guanamine [Chemical 1 8]

Ethyl 1-methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole-4-carboxylate (100 mg) obtained in Preparation Example 2 and its manufacture Sodium methoxide (1 3 4 pL, 28% methanol) was added to the suspension of 3-( Ν'-hydroxymethyl decyl)benzamide (66 mg) in ethanol (1 . 5 mL) obtained in Example 5. The solution was stirred at 150 ° C for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure. Residue was purified by reverse phase column chromatography (CAPCELL PAK MG II, water containing 0.1% trifluoroacetic acid: hydrazine containing trifluoroacetic acid acetonitrile = 90: 10 to 10: 90) to give the title compound ( 2&lt;1 mg) of a pale yellow solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 4.00 ( s, 3 H) 5.73 (s, 2 H) 7.23 - 7.36 (m, 2 H) 7.49 (br. s., 1 H) 7.62 - 7.77 ( m , 2 H) 7.93 - 8.04 ( m, 4 H) 8.08 ( s, 1 H ) 8.25 (s, 1 H), MS ( ESI pos. ) m/z : 444 [ M + H] + used and Example 32 In the same manner, the compounds of Examples 33 to 4 described in Table 3-2 were obtained. -73- 201245187 [Table 3 - 1 Example Structured Machine Data 33

1H NMR (200 MHz, CHL0R0F0RM-d) δ ppm 1.54 (s, 9 H) 4.07 (s, 3 H) 5.74 (s, 2 H) 7.12 -7.23 (ra, 2 H) 7.50 - 7.65 (m, 3 H 8.08 -8.18 (m, 2 H) 8.20 - 8.28 (m, 1 H) 8.71 (s, H); MS (ESI pos.) m/z : 501 [M+H]+

34 1H NMR (600 MHz. DMS〇-d6) δ ppn 4.00 Cs, H) 5. 75 (s· 2 H&gt; 7. 24 - 7. 37 (ra. 2 H) 7. 50 (s, 1 H) 7.57 - 7.61 (m, 1 H) 7.69 (d, J=8.71 Hz, 2 H) 8.01 - 8.07 (〇, 1 H) 8.16 (st 1 H) .25 (s, 1 H) 8.51 (s, 1 H ) ; MS (ESI pos.) m/z : 444 [M+H]+

35 1H NMR (600 MHz, DM5〇-d6) δ ppm 4.03 (s, H) 5.84 (s, 2 H) 6.95 - 6.99 (m. 1 H) 7.53 (br. s.( 1 H) 7.64 (t, J=7.57 Hz, 1 H) 7.71 -7.76 (m, 1 H) 8.05 - 8.10 (in, 2 H) 8.18 (br. 1 H) 8.22 (d, J=2.75 Hz, 1 H) 8.25 (s, 1 H) 8.51 (s, 1 H); MS (ESI pos.) nj/z : 395 [M+H]+ NH,

36 1H NMR (600 MHz, DMS0-d6) δ ppm 4.03 (s, 3 H) 5.83 (s, 2 H) 6.95 - 6.99 (m, 1 H) 7.53 (br. s., 1 H) 7.72 - 7.77 ( Ra, 1 H) 8.03 (s, 4 H) 8. 12 (br. s, 1 H) 8.23 (s, 1 H&gt; 8.24 (s, H>; MS (ESI pos·) m/z : 395 [M +H]+

37 1H NMR ¢600 MHz. DMS〇-d6) δ ppm 3.98 {s, 3 H) 5.60 (s, 2 H) 7.08 - 7.15 &lt;m, 4 H) 7.49 (s, 1 H) 7.97 - 8.01 (m , 2 H) 8.01 - 8.05 (n&gt;( H) 8.09 (s, 1 H) 8.21 (s, 1 H) ; MS (ESI pos.) ra/z : 394 [M+H]+ 38

1H NMR ¢600 MHz, DMS〇-d6) δ ppm 3.98 (s, 3 H) 5.62 (s, 2 H) 7.14 (d, J=6. 42 Hz, 4 H) 51 (br. s., 1 H 7.62 (t, J=7.79 Hzr 1 H) 04 - 8.07 (m, 1 H) 8.08 - 8. 12 (m, 1 H) 8.17 (s, 1 H) 8.23 (s, 1 H) 8.51 (s, 1 H) ; MS (ESI pos.) m/z : 394 [M+H]+ -74- 201245187 [Table 3 — 2] 39

1H NMR (500 MHz, DMS 〇-d6) δ ppm 4.00 (s, 3 Η) 5.75 (s, 2 Η) 7.31 (d, J=8.92 Hz, 2 H) 7.68 (d, J=8.92 Hz, 2 H 7.75 (br. s., 1 H) 8.27 (sr 1 H) 8.36 (br. s., 1 H) 8.73 - 8.78 (m, 1 H) 9.18 (d, J=2.06 Hz, 1 H) 9.23 ( d, J=2. 06 Hz, 1 H); MS (ESI pos.) m/z : 445 [M+H3+ 40

1H NMR (500 MHz, DMS 〇-d6) δ ppm 2. 78 (d, J=4. 20 Hz, 3 H) 3.99 (s, 3 H) 5.74 (s, 2 H) 7.31 (d, J=8.79 Hz, 2 H) 7.59 (t, J=7.64 Hz, 1 H) 7. 69 (d, J=8. 79 Hz, 2 H) 7.95 - 8.08 (m. 2 H) 8.25 (s, 1 H) 8.41 - 8.50 (m, 1 H) 8.56 -8. 70 (m, 1 H) ; MS (ESI pos.) m/z : 458 [M+H]+ 41

1H NMR (600 MHz, DMS 〇-d6) δ ppm 2. 77 (d, J=4. 54 Hz, 3 H) 3.99 {s, 3 H) 5.73 (s, 2 H) 7.30 (d, J=8 · 67 Hz, 2 H) 7,69 (d, J=8.67 Hz, 2 H) 7.94 (d, J=8. 70 Hz, 2 H) 8.02 (d, J=8.67 Hz, 2 H) 8.24 (s , 1 H) 8.56 (q, J=4. 13 Hz, 1 H); MS (ESI pos.) m/z · 458 [M+H]+ Example 33 tert-butyl 3 -[ 5 - ( 1 -methyl-5 - { 〔 4 -(trifluoromethyl)phenoxy]methyl} -1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzene Formate Example 34 4-[ 5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2 , 4-oxathiazol-3-yl]benzimidamide Example 3 5 3 -[ 5-(5-{[(5-fluoropyridin-2-yl)oxy)methyl}-1-) -1-1H-pyrazol-4-yl)-1,2,4-oxathiazol-3-yl]benzamide-9-201245187 Example 36 4-[ 5- ( 5- { [ ( 5 -Fluoropyridin-2-yl)oxy]methyl}-1-methyl-114-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzamide Example 37 4-(5-{5-[(4-Fluorophenoxy)methyl]-1-methyl-1H-pyrazol-4-yl}-1,2,4-oxadiazole-3 -based) benzamide 38 3-(5-{5-[(4-Fluorophenoxy)methyl]-1-methyl-1H-pyrazol-4-yl}-1,2,4-oxadiazole-3- Benzobenzamide 0 Example 39 5-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl) -1,2,4-oxathiazol-3-yl]pyridine-3-carboxamide oxime Example 40 N-Methyl-3-[5-(l-methyl-5-{[4-(trifluoro) Methyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidamide Example 41 N-Methyl-4- [5·(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methylindole-1Η-pyrazol-4-yl)-1,2,4-oxadiazole- 3-yl]benzamide amide Example 42 (4-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)_1H- Pyrazol-4-yl]-1,3,4-oxadi-76- 201245187 oxazol-2-yl}phenyl)acetonitrile [Chemical 19]

N,-[4-)benzylidenyl]-1-methyl-5-({[5-(trifluoromethyl: oxy)methyl)_1H obtained in Production Example 7 under nitrogen atmosphere _Pyrazole-4_carboate (35 mg) in a suspension of 76 mL) was added to the Burgess test at room temperature for 1 hour at 50 °C. The reaction solution was concentrated under reduced pressure by column chromatography ((cerium dioxide gel, chloroform: methyl ketone: 3) and (NH cerium dioxide gel, chloroform)} refined compound (21 mg) colorless Amorphous. 1H NMR ( 600 MHz, CHLOROFORM-d ) &lt;5 s, 2 Η) 4.06 ( s, 3 Η) 5.92 ( s, 2 Η) 6.86 ( d, 1 Η) 7.48 ( d, J = 8.67 Hz, 2 H 7.80 ( dd, J Hz, 1 H) 8.05 ( s, 1 H) 8.07 ( d, J = 8.67 Hz,: 8.47 ( m, 1 H) ; MS ( ESI pos. ) m/z : 441 Example 4 3 2 - ( 4 - { 5 -[ 1 -methyl-5 - ( { [ 5 - ) pyridin-2-yl )oxy}methyl) 1 H-pyrazole-4-yl] oxazol-2-yl丨Phenyl)acetamide (cyanomethyl)pyridine-2·yltetrahydrofuran (:(55 mg). The residue was taken to be 1 = 99: 1 to 97 to give the titled ppm 3.83 (J = 8.67 Hz, = 8.67, 2.06 2 Η ) 8.42 - [Μ + Η]+ (trifluoromethyl-1,3,4-oxa-77- 201245187 [Chemical 2 Ο]

(4-{ 5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-1H-pyrazole obtained in Example 42 -4-yl]-1,3,4·oxadiazole-2-ylindole phenyl)acetonitrile (30 mg) in tetrahydrofuran/water (0.68 mL, 3/1) suspension, added at room temperature Acetamide (18 mg) and palladium chloride (II) (1.2 mg) were stirred for 12 hours. Palladium chloride (11) (121^) was added to the reaction mixture at room temperature, and the mixture was stirred for 2.5 days. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted twice with chloroform/methanol/tetrahydrofuran. The organic layer was combined, dried over anhydrous sodium sulfate and evaporated. The residue was diluted with chloroform / methanol / tetrahydrofuran, and the residue was filtered. The residue was purified by column chromatography (cerium oxide gel, chloroform:methanol = 9 9:1 to 9 6: 4) and TLC (cerium oxide gel, chloroform:methanol = 1 : 1). The title compound (3.1 mg) was obtained as a colorless solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 3.44 ( s, 2 Η ) 4.00 ( s, 3 Η) 5.86 ( s, 2 Η) 6.91 ( br. s.,1 Η) 7.07 ( d, J = 8.67 Hz, 1 H) 7.41 ( d, J = 8.26 Hz, 2 H) 7.50 ( br. s·, 1 H) 7.86 ( d, J = 8.26 Hz, 2 H ) 8.09 ( dd, J = 8.67, 2.48

Hz, 1 H ) 8. 13 ( s, 1 H ) 8.63 ( s, 1 H ) ; MS ( ESI pos. -78- 201245187 ) m/z : 45 9 [ M + H] + Example 44 2-( 3-{5-[l-methyl-5-({[[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1Η-1 azole...-4-yl]-1, 3,4-oxathiazol-2-yl}phenyl)acetamide [Chemical 2 1] Μ

1) (3- { 5-[ 1-methyl-5-( { 〔 5-(trifluoromethyl)pyridine-2-yl)oxy}methyl)-1Η-pyrazol-4-yl]- 1,3,4-oxadiazol-2-yl}phenyl)acetonitrile Ν'-[3-(cyanomethyl)benzamide obtained in Production Example 7 was used in the same manner as in Example 42. 1-yl-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4-carbazide (3 67 mg) Compound (22 5 mg) as a colorless solid. MS ( ESI neg. ) m / z : 439 [ MH ] - 2) 2-(3-{5-[l-methyl-5-([(trifluoromethyl)pyridin-2-yl]]] Oxy}methyl)-1H-pyrazol-4-yl]-1,3,4-oxadiazol-2-yl}phenyl)acetamidine in (3-{5-[1-methyl - 5-( { 〔5-(Trifluoromethyl).pyridine-2-79-201245187 yloxy}methyl)-1H-pyrazole-4-yl]-1,3,4-oxa In a solution of oxazol-2-yl}phenyl)acetonitrile (119 mg) in N,N-methylformamide (3.0 mL), 35% hydrogen peroxide (2 6 1 μL) was added at room temperature. After stirring for 1 hour, the mixture was stirred at 40 ° C for 4 hours and at room temperature for 12 hours. After adding 35% hydrogen peroxide water (261 μί) to the reaction solution at room temperature, the mixture was stirred at 60 ° C for 2 hours. Water and a 1% by weight aqueous sodium thiosulfate solution were added to the reaction mixture, and the resulting solid was collected by filtration. The obtained solid was purified by reverse phase column chromatography (CAPCELL PAK MG II, water containing 0.1% trifluoroacetic acid: acetonitrile containing 〇.1% = fluoroacetic acid = 90:10 to 10:90) to obtain the title. Compound (56 mg) as a colorless solid. 1H NMR (600 MHz, DMSO-d6) &lt;5 ppm 3.44 ( s, 2 ) 4.00 ( s, 3 H) 5.86 ( s, 2 H) 6.91 ( br. s·, 1 H) 7.07 ( d 1 = 8.67 Hz, 1 H) 7.41 - 7.48 ( m, 2 H ) 7.52 ( br. s., 1 H) 7.76 ( dt, J = 6.71, 2.01 Hz, 1 H) 7.90 ( s,1 H) 8.08 ( dd

1 = 8.67, 2.48 Hz, 1 H) 8.13 ( s, 1 H) 8.63 ( d, J = 2.48 H 1 H) ; MS ( ESI pos. ) m/z : 45 9 [ M + H]+ Use and implementation The compound of Example 45 to Example 49 shown in Table 4 was obtained in the same manner as in Example 44. -80- 201245187 [Table 4] Example Structured Machine Data 45 1H NMR (600 MHzf DMS0-d6) δ ppm 3.47 (s, 2 H) 4.00 (s, 3 H) 5.69 (s, 2 H) 6.94 (br s., 1 H) 7.31 (s, 2 H) 7.44 - 7.51 (m, 2 H) 7,54 (br. s. , 1 H) 7.72 (s, 2 H) 7.79 (s, 1 H) 7.93 (s, 1 H) 8.18 (s, 1 H) ; MS (ESI pos.) m/z : 458 [M+H3+ 46 ψ % 0 1H NMR (600 MHz, DMS〇-d6) fi ppm 4. 00 ( s, 3 H) 5.87 (s, 2 H) 7.07 (d, J=8.67 Hz, 1 H) 7.52 (s, 1 H) 8.01 (d, J=1.65 Hz, 4 H) 8.06 -8.13 (m, 2 H) 8.16 (s, 1 H) 3.63 (st 1 H) ; MS (ESI pos.) m/z : 445 [M+H] + 47 f%. F-^ NH* 1H NMR (600 MHz, DMS0-d6) δ ppm 3.96 (s, 3 H) 5. 55 - 5, 75 (m, 2 H) 7. 15 - 7.34 (ta, 2 H) 7.50 - 7.55 (m, 1 H) 7.56 - 7.62 (m, 1 H) 7.64 - 7.72 (m, 2 H) 7.93 - 8.06 (a, 2 H) 8.09 - 8.22 (m, 2 H) 8.40 - 8.55 (m, 1 H) ; MS (ESI pos.) m/z : 444 [M+H] + 48 A 1H NMR ¢ 600 MHz, DMS0-d6) 6 ppm 3.95 (s, 3 H) 5.64 (s, 2 H) 7.25 ( d, J=8. 67 Hz, 1 H)' 7.49 (br. s. , 1 H) 7.66 (d, J=8.67 Hz, 1 H) 7.93 - 8.02 (m, 4 H) 8.08 (br. s. , 1 H) 8.15 (s, 1 H); MS (ESI pos. > m/z : 444 [M+H] + 49 /^. 1H NMR (600MHz, DMS0-d6) δ ppm 4.01 (s, 3 H ) 5.88 (s, 2 H) 7.07 (d· J=8.67 Hz, 1 H) 7.55 (br. s. , 1 H) 7.62 (t, J=7.84 Hz, 1 H) 8.03 - 8.19 (m, 5 H 8.47 - 8.51 (m, 1 H) 8.62 (s, 1 H); MS (ESI pos.) m/z : 445 [M+H] + Example 45 2- {3 -[ 5-(1-A -5-[4-(Trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-yl]phenyl} Indoleamine Example 46 4-{5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4- Base]-1,3,4-oxadi-81 - 201245187 oxazol-2-yl}benzimidamide Example 47 3-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazole 4-yl)-1,3,4-oxadiazole-2-yl]benzimidamide Example 48 4-[5-(1-methyl-5-{[4-(trifluoromethyl) Phenoxy]methyl}-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-yl]benzimidamide Example 49 3-{5-[1-A 5-(5-(5-(Trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,3,4-oxadiazole-2 -yl}benzimidamide Example 50 4-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl) -1,2,4-oxadiazole-3-yl]-N-(oxetan-3-yl)benzamide [2 2] N.

-82- 201245187 4-[5-(1-Methyl-5-{[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl group obtained in Example 16 a solution of -1,2,4-oxadiazol-3-yl]benzoic acid (22 mg) in tetrahydrofuran (2.0 mL), diisopropylethylamine (17 μ! Urea fluorophosphate cation 2-(1Η-7-azabenzotriazol-1·yl)-1,1,3,3-tetramethylmethaneamine salt (HATU) (28 mg) and oxetane Alkyl-3-ylamine hydrochloride (8.1 mg), stirred for 4 hours. After adding water to the reaction mixture, it was extracted with chloroform/methanol (9/1) three times. The organic layer was washed with saturated aqueous sodium hydrogen carbonate. The mixture was dried over anhydrous magnesium sulfate (MgSO4). Solids 1H NMR (600 MHz, DMSO-d6) δ ppm 3.99 ( s, 3 Η ) 4.57 ( t, J = 6.61 Hz, 2 H) 4.75 ( t, J = 7.〇2 Hz, 2 H) 4.92 - 5.07 ( m, 1 H) 5.73 ( s, 2 H) 7.30 ( d, J = 8.67 Hz, 2 H) 7.69 ( d, J = 8.67 Hz, 2 H) 7.98 - 8.01 ( m, 2 H) 8.02 -8.05 ( m, 2 H) 8.25 ( s, 1 H) 9.23 ( d, J = 6.61 Hz, 1 H); MS ( ESI pos.) m/z : 500 [M + H] + Example 51 N -Methyl - 2-{3- [5-(l-Methyl-5-[4-(trifluoromethyl)phenoxy]methyl}-1H-pyrazol-4-yl)-l,2,4-oxadiazole- 3-yl]phenyl}acetamidamine-83- 201245187 [Chemical 2 3]

Using the same procedure as in Example 50, {3-[5-(1-methyl-5-{[4-(trifluoromethyl)phenoxy]]: 1H-pyrazole- 4-Methyl-1,2,4-oxadiazol-3-yl]phenyl}acetic acid () and methylamine (7 EtOAc, EtOAc) 1 H NMR ( 600 MHz, DMSO-d6 ) &lt;5 ppm 2.53 J = 4.54 Hz, 3 H) 3.45 ( s, 2 H) 3.99 ( s, 3H) 5.72 ( s ) 7.30 ( d, J = 8.67 Hz, 2 H ) 7.39 - 7.44 ( m, 2 H ) 7 d, J = 8.67 Hz, 2 H) 7.75 - 7.79 ( m, 1 H) 7.89 ( s, 1 7.98 ( d, J = 4.54 Hz, 1 H) 8.23 (s, 1 H); MS neg.) m/z: 470 [MH] - Example 52 2-{4-[5-(l-methyl-5-{[4-(trifluoromethylphenyl)] Methyl}-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-phenyl}acetamide to the base}-4 3 mg compound (d, , 2 Η . 69 ( Η) (ESI base) base] -84- 201245187 [Chem. 2 4]

The methyl ({4-[ 5-(1-methyl4-(trifluoromethyl)phenoxy)methyl}-1H-pyrazol-4-yl)-heterodiazole obtained in Preparation Example 8 -2-yl]phenyl}ethinyl)carbamate (no ethanol (2.2 mL) and 3M aqueous sodium hydroxide (0.21 m) was stirred at room temperature for 20 hours. ϋ After being acidic, it is extracted with chloroform. The organic layer is subjected to concentrated column chromatography under reduced pressure (cerium dioxide gel, chloroform~chloroform:methanol) and TLC (cerium oxide gel, chloroform:methanol =9 : 1 ) The title compound (22 mg) was obtained as a colourless solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 3.96 ) 4.35 ( s, 2 Η) 5.59 ( s, 2 Η) 7.24 ( s, 2 Η 7 s.,1 Η) 7.39 ( s,2 Η) 7.69 ( s,2 Η) 7·83 ( s,2 (br. s.,1 H ) 8.00 ( s, 1 H ) ; MS ( ESI pos 458 [ M + H]+ Using the same procedure as in Example 1, the compounds of Examples 53 to 128 described in Tables 5-1 to Table were obtained. Mixture of 1,3,4-oxo mg), L) After the reaction solution ί, refined with =90:10, (s, 3 Η .34 ( br. Η ) 7.93 ) m / z : 5 -1 3 -85- 201245187 [Table 5 — 1] Example Structured Machine Data 53 MS (ESI/APCI Dua丨pos.> m/z: 463 [M+H]+ RT=1. 76 (Condition B) 54 Λ ΝΗ, MS (ESI pos.) ra /z: 538 [M+H]+ HT=2. 41 (Condition C) 55 — γ MS (ESI pos.) m/z: 489 [M+H]+ RT=2.23 (Condition C) 56 (&gt; =Ν ^/ΝΗ: MS (ESI pos.) m/z: 477 [M+H]+ RT=0.924 (Condition A) 57 MS (ESI pos.) rn/z: 463 [M+H] + ?T =0. 980 (Condition A) 58 -r/'S Jry 'AS (ESI pos.) ra/z: 477 [M+H] + RT=0. 979 (Condition A) -86- 201245187 [Table 5- 2] 59 NH, MS (ESI pos.) m/z: 459 [M+H]+ RT=0.927(Condition A) 60 A 0^H. MS (ESI pos.) n/z- 459 [H+H ]+ RT=0.942 (Condition A) 61 0 MS (ESI pos.) m/z: 426 [M+H]+ RT=0.895 (Condition A) 62 -Λ j\y F MS (ESI pos.) m/ z: 426 [M+H]+ RT=0.914 (Condition A) 63 MS (ESI/APCI Dual pos.) ra/z: 475 [M+H]+ ^T=1.79 (Condition B) 64 ,Λ&gt; NH , MS (ESI pos.) m/z: 477 [M+H]+ IT= 0.91 (Condition A) -87- 201245187 [Table 5 - 3] 65 ojxy 夕\. F, Η, Ν MS (ESI/APCI Dual pos.) m/z: 446 [M+H]+ RT=1.77 (Condition B) 66 MS (ESI pos.) n/z: 477 [M+H]+ RT= 0.92 (Condition A) 67 MS (ESI pos.) m/z: 477 [H+H]+ RT= 0.95 (Condition A) 68 α / 〇MS (ESI pos.) m/z: 443 [M+ H]+ RT= 0. 93 (Condition A) 69 -Λ 〇τν&gt; 0 0^, &lt; α〇MS (ESI pos. ) n/z: 493 [M+H] + RT= 1.00 (Condition A) 70 MS (ESI pos.) m/z: 459 [M+H]+ RT= 0. 96 (Condition A) -88- 201245187

[Table 5 - 4 I 71 MS (ESI pos.) m/z: 473 [U+H]+ RT = 0.97 (Condition A) 72 θ \. \ NHj MS (ESI pos.) m/z· 421 [M+H]+ RT= 0.75 (Condition A) 73 long time \ MS (ESI pos·) m/z: 479 [M+H]+ RT= 0.97 ( Condition A) 74 Take \ 0 MS (ESI pos.) m/z: 445 [M+H]+ RT= 0.94 (Condition A) 75 for a long time. &gt; ό i /^ΗΙ rfS (ESI pos.) m/z: 461 [M+H]+ ίϊΤ= 0.89 (Condition A) 76 MS (ESI pos.) m/z: 459 [M+H] + RT = 0.94 (Condition A) -89- 201245187 [Table 5 - 5] 77 A; MS (ESI pos.) m/z: 493 [M+H]+ RT= 0.99 (Condition A) 78 A; MS (ESI pos .) m/z: 473 [M+H]+ RT= 0.95 (Condition A) 79 A; MS (ESI pos.) ra/z: 473 [M+H] + RT= 0.96 (Condition A) .80 MS (ESI pos.) ra/z: 478 [M+H]+ RT= 0.75 (Condition A) 81 H^i&gt;&gt;1S (ESI pos.) m/z: 474 [M+H] + ?T= 0.82 (Condition A) 82 US (ESI pos.) m/z: 510 [M+H]+ RT= 0.79 (Condition A) -90- 201245187 [Table 5 - 6 83

MS (ESI pos.) tn/z: 463 [M+H] + RT= 0.93 (Condition A) 84

1H NMR (600 MHz, DMS〇-d6) δ ppm 2. 38 (t, 3=7. 6 Hz, 2 H) 2. 87 (t, J=7. 6 Hz, 2 H) 4. 05 (s , 3 H) 5· 94 (s, 2 H) 6. 76 (br. s., IH) 7.11 (d, J=8.7 Hz, 1 H) 7.29 (br. s., 1 H) 7.41 - 7.45 ( m, 2 H) 7.69 - 7.73 (m, 1 H) .82 (s, 1 H) 8.13 (dd, J=8.7, 2.48 Hz, 1 H) 8.25 (s, 1 H) 8.67 - 8.71 (ro, 1 H): MS (ESI pos.) m/z: 473 [M+H] + RT= 0.98 (Condition A) 85

1H NMR (600 MHz, DMS0~d6) δ ppm 1.46 (s, 6 H) 4.05 (s, 3 H) 5.94 (s, 2 H) 6.95 (d, J = 7.8 Hz, 2 H) 7.10 (d, J =8. 7 Hz, 1 H) 7.45 - 7.49 (in, 2 H) 7.81 - 7.85 (m, 2 H) 8.11 - 8.15 (m( H) 8. 25 (s, 1 H) 8. 69 - 8. 72 (a, 1 H) ; MS (ESI pos.) cn/z: 487 [M+H] + RT= 1.04 (Condition A) 86

1H NMR ¢600 MHz, DMS〇-d6) δ ppm 2.62 (s, 3 H) 4.06 (s, 3 H) 5.96 (S&gt; 2 H) 7.11 (d, J=8. 7 Hz, IH) 7.70 (t , J=7.6 Hz. 1 H) 8.10 - 8.20 (m, 3 H) 8.29 (s, 1 H) 8.46 - 8.49 1 H) .69 (s, 1 H) ;MS (ESI pos.) m/z: 444 [M+H] + RT= 1. 18 (Condition A) 87

MS (ESI/APCI Dual pos.) m/z: 463 [M+H]+ RT=1.80 (Condition B) 88

1H NMR (600 MHz, DMS 〇-d6) δ ppm 3.46 (s, 2 H) 4.03 (s, 3 H) 5.91 (s, 2 H) 6.91 - 6.96 (m, 1 H) 7.10 (t, J=55 7 Hz, 1 H) 7.02 - 7.05 (m, 1 H) 7.42 (d, J=8.3 Hz, 2 H) 7.52 (br. 1 H) 7.86 (d, J=8.3 Hz, 2 H) 7.95 (dd , J=8. 7, 2.48 Hz, 1 H) 8.23 (s, 1 H) 8.46 (d, J=1.7 Hz, 1 H) ;MS (ESI pos.) m/z: 441 [M+H3 + RT = 0.85 (Condition A) -91 - 201245187 [Table 5 - 7] 89 ΝΗ, MS (ESI pos.) m/z: 405 [M+H]+ RT= 0.82 (Condition A) 90 -Λ MS (ESI pos .) m/z:. 463 [M+H] + RT= 1.00 (Condition A) 91 $\ / &gt; MS (ESI pos.) m/z: 475 [M+H]+ RT= 0.88 (Condition A 92 ^ V 7% ; ° ^ MS (ESI pos.) m/z: 475 [M+H]+ RT= 0.97 (Condition A) 93 4S (ESI pos.) m/z: 475 [M+H] + RT = 0.87 (Condition A) 94 A. ilS (ESI pos.) m/z: 431 [M+H] + U= 0.90 (Condition A) -92- 201245187 [Table 5 - 8] 95 MS (ESI pos.) m/z: 475 [WH] * · RT= 0 94 (Condition A) 96 Λ ^ % MS (ESI pos.) m/z: 502 [M+H]+ RT= 0.87 (Condition A) 97 A $ \ a . ~ NH, MS (ESI pos.) m/z: 502 [M+H]+ RT= 0.85 (Condition A) 98 〆, 〇^ΝΗ, MS (ESI/APCI Dual pos.) m/z: 479 [M +H]+ RT=1.79 (Condition B) 99 NH, liS (ESI pos.) m/z: 493 [M+H] + ϊΤ=〇. 951 (Condition A) 100 ^r&gt; NH, iS (ESI/ APCI Dual pos.) m/z'· 443 [M+H] + iT=1.63 (Condition B) -93- 201245187 [Table 5-9] 101 0 7S α, MS (ESI pos.) n/z: 493 [M+H] + RT=1. 03 (Condition A) 102 A MS (ESI pos.) m/z: 479 [M+H]+ RT=1. 06 (Condition A) 103 1H NMR (600 MHz, DUS0-d6) δ ppm 3.50 (s, 2 H) 4.00 (s, 3 H) 5.90 (sr 2 H) 7.00 (br. s., 1 H) 7.08 (d, J=8.7 Hz( 1 H) 7.57 ( Br. s., IH) 7. 78 - 7. 84 (m, 1 H) 7. 86 - 7. 90 (a, 1 H)' 8.09 (dd, J=9. 1, 2.5 Hz, 1 H) 8.23 (s, 1 H) 8.58 (d, J=1.7 Hz, 1 H) 8.64 (s, 1 H) ; MS (ESI/APCI Dual pos.) m/z: 460 [M+H]+ 104 - Ϋύ MS (ESI/APCI Dual pos.) m/z: 477 [M+H]+ RT=1. 78 (Condition B) 105 ^ X dS (ESI/APCI Dual pos.) m/z: 460 [M+ H]+ RT=1.61 (Condition B) 106 交\ CH US (ESI/APCI Dual pos.) m/z·' 446 [M+H] + RT=1.90 (Condit Ion B) -94- 201245187 [Table 5 - 1 Ο] 107 —A MS (ESI pos.) m/z: 433 [M+H]+ RT=0. 87 (Condition A) 108 $ V 1H NMR (600 MHz, CHLOROFORM-d) δ ppro 1.58 -1.67 (m, 6 H) 4. 06 (s· 3 H) 5.96 (s, 2 H) 6.88 (d, J=8.7 Hzt 1 H) 7.26 (s, 3 H 7.45 (t, J=7.8 Hz, 1 H) 7. 66 (d, J=7. 8 Hz, 1 H) 7.82 (dd, J=8.7, 2.5 Hz, 1 H) 7.91 - 7.99 (m, 1 H) 8. 16 (s, 1 H) 8. 19 - 8.24 (m, 1 H) 8.45 -8.53 (m, 1 H) ; MS (ESI/APCI Dual pos.) m/z: 460 [H+H ] + 109 1H NUR (600 UHz, DMS0-d6) δ ppm 1.44 &lt;s, 6 H) 4.05 (s, 3 H) 5.16 (s, 1 H) 5.94 (s, 2 H) 7.10 (d( J= 8.7 Hz, 1 H) 7.60 (d, J=8.7 Hz, 2 H) 7.82 (d, J=8.3 Hz, 2 H) 8.09 - 8.17 (m, 1 H) 8.25 (s, 1 H) 8. 71 ( s, 1 H) ; MS (ESI/APCI Dual pos.) m/z: 460 [M+H]+ 110 MS (ESI/APCI Dual pos.) m/z* 432 [M+H]+ RT=1.86 (Condition B) 111 _Cl, 〇$ \ NH, MS (ESI/APCI Dual pos.) m/z: 474 [M+H]+ RT=2.03 (Condition B) 112 ~py〇A. NH^° NH, 1H NMR (600 MHz, DMS〇-d6) δ ppm 3. 99 - 4. 04 (m, 3 H) 5.79 - 5.83 (m, 2 H) 6. 00 (br. s., 2 H) 6.96 (dd, J=9. 1,3.30 Hz, 1 H) 7.53 - 7.58 (m, 2 H) 7.71 - 7.76 (m, 1 H) 7.77 - 7.82 Cm, 2 H) 8.20 (s, 1 H 8.23 (d, J=3.3 Hz, 1 H) 8.90 (s, 1 H) : MS (ESI/APCI Dual pos.) n/z: 410 [M+H]+ -95- 201245187 [Table 5 - 1 1] 113

1H NMR ¢600 MHz, DUS〇-d6) 6 ppm 4.01 (s, H) 5.82 &lt;s, 2 H) 5.92 (br. st 2 H) 6.97 (dd, J=9. 1, 3.72 Hz, 1 H 7.35 - 7.42 (m, 1 H) 7.47 (d, J=7. 4 Hz, 1 H) 7.55 - 7.61 (m, 1 H) 7.74 (s, 1 H) 8.14 (s, 1 H) 8.18 - 8.25 (n, 2 H) 8.83 (s, 1 H) ; MS (ESI/APCI Dual pos.) m/z: 410 [M+H]+ 114

1H NMR ¢600 MHzr DMS〇-d6) δ ppm 4.04 (s, 3 H) 5.87 - 5.97 (m, 4 H) 7.11 (d, J=8. 7 Hz, 1 H) 7.31 - 7.38 (m, 1 H ) 7.39 - 7.45 (m, 1 H) 7.54 - 7. 60 (m, 1 H) 8.08 - 8. 17 (m, 2 H) 8.24 (s, 1 H) 8.68 (d, J=1.7 Hz, 1 H ) 8.83 (s, 1 H) ; MS (ESI/APCI Dual ροέ.) m/z: 460 [M+H]+ 115

MS (ESI pos.) m/z: 460 [M+H]+ RT= 2.25 (Condition C) 116

1H NMR (600 MHz, DMS 〇-d6) δ ppm 2.62 (dt J=5.0 Hz, 3 H) 3.98 (st 3 H) 5.78 (s, 2 H) 6.14 (d, J=4.5 Hz, 1 H) 6.93 (dd, J=9. 1, 3. Hz, 1 H) 7.49 - 7.55 (m, 2 H) 7.68 - 7.73 (m, H) 7.73 - 7.79 (m, 2 H) 8.17 (s, 1 H) 8.19 (d, J=3.3 Hz, IH) 8. 88 (s, 1 H) ; MS (ESI/APCI Dual pos.) m/z* 424 [M+H]+ 117

1H NMR (600 MHz, DMS0-d6) 6 ppn 2.66 (d, J=5.0 Hz, 3 H) 4.02 (s. 4 H) 5.82 (s. 3 H) 03 - 6. 11 (m, 1 H) 6.92 - 7.01 (m, 1 H) 7.34 - 7.41 (m, 1 H) 7.44 - 7. 50 (m, 1 H) 7. 54 - 7. 62 (mr 1 H) 7. 69 - 7, 79 (m, 1 H) 8. 11 - 8. 17 (in, 1 H) 8. 18 - 8. 24 (m, 2 H) 8.83 (s, 1 H) ; MS (ESI/APCI Dual pos.) m/z: 424 [M+H] + 118

1H NMR (600 MHz, DMS0-d6) δ ppm 2. 65 (d. J=4. 5 Hz, 3 H) 4.04 (s, 3 H) 5.95 (s, 2 H) 6.04 - 6.12 (m, 1 H 7.11 (d, ;=8. 7 Hz, 1 H) 7.29 - 7.38 (m, 1 H) 7.41 (s, 1 H) 7.50 - .60 (m, 1 H) 8.06 - 8.15 (id, 1 H) 8.17 (s, H) 8.24 (s, 1 H) 8.69 (s, 1 H) 8.79 - 8.87 (m, 1 H) -96- 201245187 [Table 5 — 1 2] 119 NH^. 1H NUR ¢600 MHz. DMS〇-d6) δ ppm 2. 65 (d, J=4.5 Hz, 3 H) 4.04 (s, 3 H) 5.93 (s, 2 H) 6.11 - 6.19 (m, 1 H) 7. Π (d, J=8.7 Hz, 1 H) 7.54 (d, J=8.7 Hz, 2 H) 7.71 - 7.81 (m, 2 H) 8. 07 - 8. 18 (m, 1 H) 8. 22 (s, 1 H 8. 66 -8.73 (a, 1 H) 8. 88 (s, 1 H) 120 0N QF , 〇 ^ 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 3. 88 -3.96 (o, 3 H) 4.02 (s, 3 H) 5.83 (s, 2 H) 6. 67 - 6. 78 (m, 3 H) 7. 32 - 7. 38 (m, 1 H) 7.82 · 7.90 (m, 2 H&gt; 7.96 - 8. 04 (o, 1 H) 8. 07 - 8. 13 (m, 1 H) 121 Water Γ MS (ESI/APCI Dual pos.) m/z: 457 [M+H]+ RT=1.75 ( Condition B) 122 -v'S MS (ESI/APCI Dual pos,) m/z: 457 [M+H]+ RT=1.77 (Condition B) 123 夕 \ MS (ESI pos.) m/z: 457 [M+ H]+ RT= 0.98 (Condition A) 124 -r/, 夕 \ 1H NMR (600 MHz, DMS0-d6) δ ppm 4.04 (s, 3 H) 5.95 (s, 2 H) 7.03 (d. J=8.3 Hz, 1 H) 7. 11 (d, J=8.7 Hz, 1 H) 7.46 - 7.61 (tn, 2 H) 8.06 -8.19 (m, 1 H) 8.23 (s, 1 H) 8.71 (s, 1 H) 10.76 - 11.07 (m, 2 H) -97- 201245187 [Table 5 — 1 3] 125

MS (ESI pos.) m/z: 486 [M+H]+ RT= 1.01 (Condition A) 126

MS (ESI pos.) m/z: 485 [M+H]+ RT= 1.03 (Condition A) 127

1H NMR ¢600 MHz, DMS〇-d6) δ ppm 2.09 (t, J=7.4 Hz, 2 H) 2.54 (t, J=8.1 Hzt 2 H) 3.87 (t, J=7.2 Hz, 2 H) 4.05 (s, 3 H) 5.94 (s, 2 H) 7.11 (d, J=8.7 Hz, 1 H) 7.81 - 7.85 (m,; H) 7.87 - 7.92 (m, 2 H) 8.13 (dd, J= 8. 7, 2.48 Hz, 1 H) 8.24 (s, 1 H) 8.70 (st 1 H) ; MS (ESI pos.) m/z· 485 [U+H] + 128

1H NMR (600 MHz, DMS〇-d6) 6 ppm 2.04-2.11 (m, 2 H) 2.50 - 2.55 (m, 2 H) 3.85 (t, J=7.0 Hz, 2 H) 4.05 (s, 3 H) 5.94 (s, 2 H) 7.11 (d, J=8. 7 Hz, 1 H) 7. 52 (t, J=8. 1 Hz, 1 H) 7.66 (d, J=7.4 Hz, 1 H) 7.78 (dd, J=8. 3, 1.65 Hz, 1 H) 8.13 (dd, J=8.7P 2.5 Hz, 1 H) 8.26 (s, 1 H) 8.36 - 8.39 (m, 1 H) 8.68 (s, 1 H); MS (ESI pos.) m/z: 495 [M+H] + </ </RTI> </RTI> </ RTI> </ RTI> 3-fluoro-4-{5-[l-methyl- 5-({[[ Pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzamide 实施 Example 54 2-(2 -Bromo-4-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]- 1,2,4-oxathiazol-3-ylindole phenyl)acetamide Example 55 N-(2-hydroxyethyl)-3- { 5-[ 1-methyl-5- ( { [ 5-(Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazole-4-yl]-1,2,4-oxadiazol-3-yl}benzamide -98- 201245187 Example 56 2-(4-Fluoro-3-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl) -1 Η-pyrazol-4-yl]-1,2,4-oxadiazole-3 -yl}phenyl)acetamide Example 57 2-Fluoro-4-{5-[1-methyl- 5-({[[4-(trifluoromethyl)pyridin-2-yl]oxy}) -1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindole benzamide Example 5 8 2-(3-fluoro-5- { 5-[ 1 -methyl-5-( { [ 5-(trifluoromethyl)pyridine-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole -3-yl}phenyl)acetamide Example 592-(4-(5-[1-methyl·5·({[4-(trifluoromethyl)pyridin-2-yl)oxy}) Base)-1Η-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)acetamide Example 602-(3·{5-[1-methyl- 5-(丨[4-(Trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl }phenyl)acetamide Example 61 2-[4-(5-{5-[(3,4-Difluorophenoxy)methyl]-1-methyl-1H-pyrazol-4-yl } -1,2,4-oxadiazol-3-yl)phenyl]acetamide-99-201245187 Example 62 2-[ 3- ( 5- { 5-[(3,4-difluorobenzene) Oxy)methyl]-1-methyl-1H-pyrazol-4-yl}-1,2,4-oxadiazol-3-yl)phenyl]acetamide Example 6 3 2- ( 3 - { 5-[ 1-Methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4- Oxodioxazol-3-yl}phenoxy)acetamide Example 64 2-(3-Fluoro-4-{5-[1-methyl-5-({[5-(trifluoromethyl))) Pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetamide Example 65 5-{ 5-[1-Methyl-5-(5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4- Oxodioxazol-3-yl}pyridine-2-carboxamide oxime Example 66 2-(2-Fluoro-3-{5-[1-methyl-5-({[5-(trifluoromethyl))) Pyridin-2-yloxyoxindolemethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)acetamide Example 67 2-( 2-fluoro-4-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl] -1,2,4-oxadiazole-3-yl}phenyl)acetamidamine-100-201245187 Example 68 2- { 3-[ 5- ( 5- {[ (5-chloropyrene ratio D Ding-2-yl)oxy]methyl}-1-methyl-1H-pyrazol-4-yl)·l,2,4-oxadiazole-3-yl]-5-fluorophenyl} Acetamide Example 69 2-(2-Chloro-5-{5-[l- Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole- 3-yl}phenyl)acetamide Example 70 2-Methyl-5-indole-5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy) }Methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}benzimidamide Example 71 2-(2-methyl-5-{5- [l-Methyl-5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxa Oxazol-3-ylindole phenyl)acetamide Example 72 2-{4-[5-(5-{[(6-methoxypyridin-3-yl)oxy]methyl} -1- Methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl oxime oxime Example 73 2-chloro-4-{5-[l-- 5-(5-(5-(Trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3 -yl}benzamide-101 - 201245187 Example 74 3-Chloro-4-[ 5-(5-{[(5-chloropyridin-2-yl)oxy)methyl}-1-methyl- 1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidamide Example 75 3-Chloro-4-{5-[5-( { 〔5-( Difluoromethyl)pyridine 2-yloxy]methyl)-1-methyl-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}benzimidamide Example 76 2 -Methyl-4-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl] -1,2,4-oxadiazole-3-yl}benzamide amide Example 77 2-(2-Chloro-4-{5-[1-methyl-5-({[5-(three) Example of fluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)acetamide 78 2-(2-Methyl-4-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole 4-yl]-1,2,4-oxathiazol-3-yl}phenyl)acetamide Example 79 2-(3-Methyl-4-{5-[1-methyl-5 -({[5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl} Phenyl)acetamide-102-201245187 Example 80 4-{3-[ 5-(5-{[(5-fluoropyridin-2-yl)oxy)methyl}-1-methyl-1H- Pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidyl}piperazin-2-one - Example 81 4- { 3-[ 5- ( 5- { [(5-chloropyridin-2-yl)oxy Methyl}-1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]benzimidyl}piperazin-2-one Example 82 4- (3- { 5-[ 5-( { 〔5-(Difluoromethyl)pyridin-2-yl)oxy}methyl)-1-methyl-1H-pyrazol-4-yl]-1, 2,4-oxadiazole-3-yl}benzylidene)piperazin-2-one Example 83 2 -Fluoro-3-{5-[l-methyl-5-({[[- Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzimidamide Example 843 -(3-( 5-[1-methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1 , 2,4-oxathiazol-3-yl}phenyl)propane decylamine Example 85 2-Methyl-2-(4-{5-[l-methyl- 5-({[[- Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)propane decylamine- 103- 201245187 Example 861-(3-(5-[1-methyl- 5-({[5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-1H-pyrazole- 4-yl]-1,2,4-oxadiazole-3-yl}phenyl)ethanone Example 87 2-Fluoro-5-{5-[1-methyl-5-({[5- (trifluoromethyl)pyridin-2-yl] Oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindolebenzamide Example 8 8 2- (4- { 5-[ 5 - ( { [(5-(Difluoromethyl)pyridin-2-yl)oxy}methyl)-1-methyl-111-pyrazol-4-yl]-1,2,4-oxadiazole -3-yl}phenyl)acetamide Example 89 2-{4-[5-(1-methyl-5-{[(5-methylpyridin-2-yl)oxy]methylhydrazine- 1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl}acetamide Example 90 3-Fluoro-5-{5-[1-Methyl-5 -( { 〔5-(Trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl} Benzamide Example 91 3-methoxy-4-{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)- 1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzamide-104-201245187 Example 92 2-Methoxy-5-{5-[1- Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)_1H-pyrazol-4-yl]-1,2,4-oxadiazole-3 -yl}benzamide oxime Example 93 4-methoxy-3-{5-[l-methyl-5-({[[4-(trifluoromethyl)pyridin-2-yl]oxy}) Base)-1H-pyrazole- 4-yl]-1,2,4-oxadiazole-3-yl}benzimidamide Example 94 2- { 4-[ 5- ( 5- {[( 5-cyclopropionidin-2-) Ethyloxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl}acetamide Example 95 2- Methoxy-3-{5-[l-methyl-5-({[[5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl] -1,2,4-oxadiazole-3-yl}benzamide amide Example 96 N-(2-Amino-2-oxoethyl)-3 - { 5-[1-methyl- 5-( { 〔 5-(Trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl Benzylguanamine Example 97 N-(2-Amino-2-oxoethyl)-4-{ 5-[1-methyl-5-({[5-(trifluoromethyl)pyridine)- 2-yloxy]methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindolebenamide-105-201245187 Example 98 3-Chlorine 4-{5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1, 2,4-oxathiazol-3-yl}benzimidamide Example 99 2-(3-Chloro-4-{5-[1-methyl-5-({[5-(trifluoromethyl) Pyridin-2-yloxy} -1H-pyrazol-4-yl]-1,2,4-oxathiazol-3-yl}phenyl)acetamide Example 100 2-{3-chloro-4-[5-( 5-{[(5-fluoropyridin-2-yl)oxy]methyl}-1-methyl-1Η-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl Phenyl}acetamide Example 101 2-(3-Chloro-5-{5-[1-methyl- 5-({[[4-(trifluoromethyl)pyridin-2-yl]oxyindole) Methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)acetamidine Example 1 02 3 -chloro-5- { 5-[ 1 -methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole -3-ylbenzimidamide Example 1〇3 2-(6-{5-[1-methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxyanthracene Methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}pyridin-3-yl)acetamide-106-201245187 Example 104 2-(2- Fluor-5-丨5-[1-methyl-5-(indolyl[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1 , 2,4-oxathiazol-3-yl}phenyl)acetamide Example 1 0 5 2 - ( 5 - { 5 -[ 1 -methyl-5 - ({[ 5 - (trifluoromethyl) Pyridin-2- Ethyloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadioxazol-3-yl}pyridin-2-yl)acetamide Example 1 06 2- ( 4- { 5-[ 1-Methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxyindolemethyl)-1H-pyrazole-4-indole-1,2 , 4_oxathiazol-3-yl}phenyl)ethanol Example 107 (4- { 5-[ 1-methyl-5-( { [ 5-(trifluoromethyl)pyridin-2-yl]) Oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxathiazol-3-yl}pyridin-2-yl)methanol Example 108 2-(3-{5- [1-Methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxa Azoxa-3-yl}phenyl)propan-2-ol Example 1〇9 2-(4-{5-[1-methyl- 5-({[[4-(trifluoromethyl)pyridine-2] -yloxy}carboindole-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)propan-2-ol-107-201245187 Example 1 10 ( 4· { 5-[ 1-methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1 , 2,4-oxathiazol-3-yl}phenyl)methanol Example 1 1 1 1-methyl-1-( 4- { 5-[ 1-methyl-5- ( { 〔 5-( Trifluoro Methyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindolephenyl)urea Example 1 12 1 - { 4-[ 5-( 5- { 〔(5-fluoropyridin-2-yl)oxy)methyl}-1-methyl-1H-pyrazol-4-yl)-1,2,4- Oxodioxazol-3-yl]phenyl guanidine urea Example 1 13 1- { 3-[ 5-( 5- { 〔( 5-fluoropyridin-2-yl)oxy)methyl} -1- -1-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl}urea Example 1 14 1-(3- { 5-[ 1-methyl-5 - ( { [(5-(Trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl} Phenyl)urea Example 1 15 1-(4-{ 5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H- Pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)urea-108- 201245187 Example 1 16 1- { 5-( 5- {[ (5 -fluoropyridin-2-yl)oxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl} -3 -methylurea Example 1 17 1- { 3-[ 5-( 5- { 〔( 5-fluoropyridin-2-yl)oxy)methyl}-1-methyl-11pyrazole 4-yl)-1,2,4-oxathiazol-3-yl]phenyl}-3-methylurea Example 118 1-methyl-3-(3-{5-[l-- 5-(5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3 -yl}phenyl)urea Example 119 1-Methyl-3-(4-{5-[l-methyl- 5-({[[4-(trifluoromethyl)pyridin-2-yl]oxy) }methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)urea Example 120 methyl { 4-[ 5- ( 5- { 〔 (5-fluoropyridin-2-yl)oxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazole-3-yl]phenyl} Carbamate Example 121 5- { 5-[ 1-methyl-5-( { 〔 5-(trifluoromethyl) pyridin-2-yl)oxy}methyl)-1H-pyrazole- 4-yl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-isoindol-1-one-109- 201245187 Example 122 6-{5-[ 1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiyl Zyrid-3-yl}-2,3-dihydro-1H-isoindole-1-one Example 1 23 5 - { 5-[ 1-methyl-5-( { [ 5-(trifluoromethyl) Pyridin-2-yloxy} -1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}-1,3-dihydro-2H-indol-2-one Example 124 5-{5 -[1-Methyl-5-(5-(3-trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxygen Heterodiazol-3-yl}-1,3-dihydro-2H-benzimidazol-2-one Example 125 1-(4- { 5-[ 1-methyl-5- ( { 〔 5-( Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)imidazolidin-2 - Ketone Example 126 1-(3-{ 5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole- 4-yl]-1,2,4-oxadiazole-3-ylindolephenyl)imidazolidine-2-one Example 127 1-(4-{5·[1-methyl- 5-({ [5-(Trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl) Pyrrrolidin-2-one Example 128 1-(3- { 5-[ 1-methyl-5-({ [ 5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H -Pyrazol-4-yl]-1,2,4-oxathiazol-3-yl}phenyl)pyrrolidin-2-one The same procedure as in Example 50 was used to obtain Table 6-1. The compound of Example 6-8 described in Embodiment Example 175 to 129. -110- 201245187 [Table 6-1] Example Structured Machine Data 129 7S MS (ESI/APCI Dual pos.) m/z: 541 [M+H] + RT=1.95 (Condition B) 130 r7\ 〇^ vL MS (ESI/APCI Dual pos.) m/z: 545 [M+H]+ RT=1.94 (Condition B) 131 Full \ MS (ESI pos.) m/z: 503 [U+H]+ RT= 0.894 (Condition A) 132 夕V 'S CH MS (ESI pos.) ra/z: 547 [M+H]+ RT=0.898 (Condition A) 133 MS (ESI pos.) m/z: 473 [M+ H]+. RT=0. 966 (Condition A) 134 A NH^ MS (ESI pos.) n/z: 572 [M+H] + ΪΤ=0. 649 (Condition A) -111 - 201245187 [Table 6 - 2] 135 % MS (ESI pos.) m/z: 516 [M+H]+ RT=0.857 (Condition A) 136 US (ESI pos.) m/z: 499 [M+H]+ RT=1.09 (Condition A) 137 MS (ESI pos.) m/z: 529 [M+H]+ RT=1.01 (Condition A) 138 A: MS (ESI pos.> m/z: 487 [M+H]+ RT =1.03 (Condition A) 139 A 卞Q MS (ESI pos.) n&gt;/z: 542 [M+H] + RT=0. 63 (Condition A) 140 0 ^ 〇τΓ ^Ν_〇JS (ESI pos .) m/z: 515 [M+H3+ ΐΤ=0. 94 (Condition A) -112 201245187 [Table 6 3] 141 夕气' &quot;Λ ir^\ MS (ESI pos.) m/z: 530 [ M+ H]+ RT=0.63 (Condition A) 142 ^ \ MS (ESI pos.) m/z: 556 [M+H] + RT=0. 92 (Condition A) 143 MS (ESI pos.) o/z: 515 [M+H]+ RT=1. 14 (Condition A) 144 -Λ J^iy 夕V, MS (ESI pos.) m/z: 517 [M+HJ + RT=0. 98 (Condition A) 145 rPv, £% 永α. iAS (ESI pos.) m/z-* 529 [Μ·^Η] + RT=0. 91 (Condition A) 146 Λ&gt; ^ \ CH MS (ESI pos.) m/ z: 529 [M+H]+ RT=0. 91 (Condition A) -113- 201245187 [Table 6 — 4] 147 Helium MS (ESI pos.) m/z: 542 [M+H]+ RT= 0 ( 88 ) ( ( ( ( ( /z: 517 [M+H]+ RT=0. 91 (Condition A) 150 ^ \ 0H MS (ESI pos.) m/z: 531 [M+H]+ RT=0. 94 (Condition A) 151 iJS (ESI pos.) m/z: 485 [M+H] + ΪΤ=1. 02 (Condition A) 152 Η Η US (ESI pos.) o/z: 501 [M+H]+ ΪΤ=0. 88 (Condition A) -114- 201245187 [Table 6 — 5] 153 MS (ESI pos.) ra/z: 530 [Μ+Η]+ RT= 0.96 (Condition A) 154 A Pv. MS (ESI pos.) n»/z: 544 [M+H] + RT= 0. 94 (Condition A) 155 { I. ^ &gt;T MS (ESI pos.) m/z: 516 [M+H] + RT= 0.90 (Condition A) 156 MS (ESI pos.) m/z: 542 [M+H] + RT= 0.92 ( Condition A) 157 ^ 0 US (ESI pos.) m/z; 528 [U+H]+ RT= 0.61 (Condition A) 158 7S ΝΗΌ〇MS (ESI pos·) m/z: 501 [M+H] + ΪΤ = 0.98 (Condition A) -115- 201245187 [Table 6-6] 159 Not 0 MS (ESI pos.) in/z: 515 [M+H] + RT= 1.01 (Condition A) 160 F-7V MS (ESI pos.) n/z: 515 [M+H] + RT= 0.91 (Condition A) 161 N, F-7V MS (ESI pos.) tn/z: 515 [M+H] + RT= 0.90 ( Condition A) 162 N, /V MS (ESI pos.) ra/z: 528 [M+H] + RT= 0. 87 (Condition A) 163 MS (ESI pos.) tn/z: 503 [M+H ] + RT= 1. 02 (Condition A) 164 N, ό 7S , MS (ESI pos.) tn/z: 516 [M+H] + RT= 0. 63 (Condition A) -116- 201245187 [Table 6 - 7] 165 /V MS (ESI pos.) m/z: 517 [M+H]+ RT= 0.98 (Condition A) 166 MS (ESI pos.) m/z: 503 [M+H]+ RT= 0.94 (Condition A) 167 Λ, Αν MS (ESI pos.) n/z: 503 [M+H]+ RT= 0.94 (Condition A) 168 MS (ESI pos.) m/z: 558 [M+H] + RT= 0.64 (Condition A) 169 MS (ESI pos.) m/z: 516 [M+H]+ ΪΤ= 0.87 (Condition A) 170 Let i&gt;i£: FF IS (ESI pos.) m/z: 533 [M+H] + RT= 0.92 (Condition A) -117- 201245187 [Table 6-8] 171 MS (ESI pos.) m/z: 513 [M+H]+ RT=1.09 (Condition A) 172 A 0 MS (ESI pos. m/z: 513 [M+H] + RT=}.08 (Condition A) 173 Λ〇MS (ESI pos.) ra/z: 499 [M+H]+ RT=1.08 (Condition A) 174 Α 〇MS (ESI pos.) m/z: 515 [M+H]+ RT=1.01 (Condition A) 175 MS (ESI/APCI Dual pos.) m/z: 475 [M+H]+ RT=1. 68 (Condition B) Example 129 2-(3-{5-[1-Methyl-5-(5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H- Pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)-N-(2,2,2-trifluoroethyl)acetamidine Example 130 2-( 3-{5-[1-Methyl- 5-({[[5-(trifluoromethyl-118-201245187))pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl] -1,2,4-oxathiazol-3-yl}phenyl)-N-[2-(propan-2-yloxy)ethyl]acetamide Example 131 N-(2-hydroxyethyl 2-(4-{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]) Methyl}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetamide Example 132 N-[2-(2-hydroxyethyl) Oxy)ethyl]-2-(4-{methyl_5_({[5.(trifluoromethyl)pyridine-2-yl)oxy}methyl)-1H-pyrazol-4-yl] -1,2,4-oxathiazol-3-yl}phenyl)acetamide Example 133N-Methyl-2-(4-{5·[1-methyl- 5-({[[- (trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)acetamide Example 134 2-(4-{5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4- -1,2,4-oxathiazol-3-yl}phenyl)-N-[2-(morpholin-4-yl)ethyl]acetamide Example 135 N2-[ (4- { 5-[ 1-Methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxyindolemethyl)-1H-pyrazol-4-yl]-1,2,4 -oxathiazol-3-ylindole phenyl)ethyl hydrazide]glycine decylamine-119-201245187 Example 136 (3-{5-[l-methyl- 5-({[]pyridinium- 2-yloxy]methyl}-1H-pyrazol-4-yl]oxadiazol-3-yl}phenyl)(pyrrolidin-1-yl)methanone

Example 1 3 7 2-(4-{ 5-[1-methyl-5-({I-based)pyridin-2-yl]oxyindolemethyl)-1 Η-pyrazole-4 -yl hetero Zyrid-3-yl}phenyl)-1-(morpholin-4-yl)ethanone Example 1 3 8 N,N-Dimethyl-2 - ( 4 - { 5 -[ 1 - [5-( Trifluoromethyl)pyridin-2-yloxy}methyl)yl-1,2,4-oxadiazol-3-yl}phenyl)acetamide Example 139 1-(4-A Piperazin-1-yl)-2-Pyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy 3 1H-pyrazol-4-yl]-1,2,4 Oxadioxazol-3-ylindole phenyl) Example 1 40 2-(4-{ 5-[1-methyl-5-({[yl)pyridin-2-yl]oxy}methyl) -1Η-pyrazol-4-yloxadiazol-3-yl}phenyl)-indole-(oxetan-3-yl) Example M1 Ν-[2-(dimethylamino)B [1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole- 3-yl}-(trifluoromethyl-1,2,4-oxa:5-(trifluoromethyl)-1,2,4-oxomethyl-5-({-1 Η-pyrazole- 4- 卜 { 5-[ 1 -曱i }methyl)-ethanone 5-(trifluoromethyl)-1,2,4-oxoacetamide-2-(4-(5-)oxyindole toluene base Acetyl -120-201245187

Example 142 1-Methyl-4-[(4-{5-[1.methyl-5-(5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H -pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)ethinyl]piperazin-2-one Example 143 N-tert-butyl-2- ( 4- { 5-[ 1-Methyl-5-( {[ 5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2 , 4-oxathiazol-3-yl}phenyl)acetamide Example 144 N-(2-methoxyethyl)-2-(4-{5-[1-methyl- 5-( {[5-(Trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl Ethylamine Example 145 1-[(3S)-3-Hydroxypyrrolidin-1-yl]-2-(4-{5·[1_methyl_5_( { [5-(trifluoromethyl)) Pyridin-2-yloxy}methyl)-1 Η-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)ethanone Example 1 4 6 1 - [( 3 R ) - 3 -Hydroxypyrrolidin-1 -yl]-2 -( 4 - { 5-[ 1-methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl] Oxy}methyl}-1Η-pyrazol-4-yl]-1,2,4-oxathiazol-3-yl}phenyl)ethanone-121 - 201245187 Example 1 47 4-[(4- { 5-[ 1-Methyl-5-(methyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4oxathiazol-3-yl} Phenyl)ethinylpiperazin-2-one Example 148 N-[(2S)-2-hydroxypropyl]-: 1-methyl-5-({[5-(trifluoromethyl)pyridine) 2-yl])-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}benzene 3 Example 149 N-[(2R)-2-hydroxypropyl] 1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl])-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl Toluene Benzene | Example 150 N-(2-Hydroxy-2-methylpropyl)-2-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy 1H-pyrazole 4-yl]-1,2,4-oxadiazol-3-yl}phenyl) Example 151 trimethyleneimine-1-yl (3 · { 5 ·[ {[ 5-(trifluoromethyl) Pyridin-2-yloxy]methyl 4-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanone Example 152 (3-hydroxytrimethyleneimine- 1-yl)methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxy 1H-pyrazol-4-yl]-1,2,4-oxadiazole-3- Base phenyl) { 〔 5-(trifluoro-yl)-1,2,4- I-(4-{ 5-{oxy}methylS)acetamide &gt;-(4- { 5-(oxy}methyl I )acetamide (4-(5-(1-yl}methyl)-acetamidomethyl-5-()-1 Η-pyridyl Oxazole-(3-(5-(1-yl}methyl)-methanone-122- 201245187 Example 153 N-[2-(Dimethylamino)-2-oxoethyl]-3-{ 5-[1-Methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4- Oxadioxazol-3-yl}benzamide 154 N-[2-(Dimethylamino)-2-oxoethyl]-cardiomethyl-3- { 5-[1-A -5-5· ( { 〔 5-(dimethyl)D-dext-2-yloxy)methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole -3-yl} benzalkonium amide Example 155 N-[2-(methylamino)-2-sideoxyethyl]-3- { 5-[1_methyl_5_( { [5·( Trifluoromethyl)pyridine-2-yloxyoxymethyl)-1H-pyrazole-4-yl]-1,2,4-oxadiazol-3-yl}benzamide 156 1-Methyl-4-(3-{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazole- 4-yl]-1,2,4-oxadiazole-3-yl}benzylidene)piperazin-2-one Example 1 5 7 (4-Methylpiperazine-1-yl) (3 - { 5 -[ 1 -methyl-5-({[5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole -3-yl}phenyl)methanone Example 158 3-{5-[1-methyl- 5-({[[3-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)- 1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}-N-(oxetan-3-yl)benzamide-123- 201245187 Example 159 (3-{5-[1-Methyl-5-(5-(trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]-1, 2,4-oxadiazol-3-yl}phenyl)(morpholin-4-yl)methanone Example 160 [(3S)-3-hydroxypyrrolidin-1-yl](3- { 5- [ 1-Methyl-5-( { 〔5-(trifluoromethyl)pyridine-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxa Azoxa-3-yl}phenyl)methanone Example 161 [(3R)-3-Hydroxypyrrolidin-1-yl](3- { 5-[ 1-methyl-5·( { 〔5-( Example of trifluoromethyl)pyridin-2-yloxy}methyl)-1Η-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanone 162 4-(3·{5-[1-methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxyindolemethyl)-1H-pyrazole- 4-yl]-1,2,4-oxadiazole-3-yl}benzylidene)piperazin-2-one Example 163&gt; 4-(2-methoxyethyl)-3-{ 5-[1-Methyl-5-({ 〔 5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4- Oxodiazol-3-yl}benzamide 164 N-[2-(Dimethylamino)ethyl]-3-{5-[l-methyl- 5-({[[ 5- (trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzamide-124 - 201245187 Example 165((2-hydroxy-2-methylpropyl)-3-{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy) Methyl}methyl)- 1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindole benzamide 166N-[(2R)-2-hydroxypropyl] -3-{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1, 2,4-oxathiazol-3-yl}benzamide 167N-[(2S)-2-hydroxypropyl]-3-{5-[l-methyl-5- ( { 〔 5 -(Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiin-3-yl}benzamide example 168 3-{5-[1-Methyl-5-({[[3-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1, 2,4-oxathiazol-3-yl}-N-[2-(morpholin-4-yl)ethyl]benzimidamide Example 169 N-(2-Amino-2-oxo-oxygen B -) N-methyl-3-{ 5-[1-methyl- 5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxyindolemethyl)-111-pyrazole 4-yl]-1,2,4-oxadiazole-3-yl}benzimidamide Example 170 N-(1,3-dihydroxy-2-methylpropan-2-yl)-3 - { 5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2, 4-oxathiazol-3-yl}benzamide-9-201245187 Example 171 2-(3- { 5-[ 1-methyl-5-( { [ 5-(trifluoromethyl)pyridine) -2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)-1-(pyrrolidin-1-yl) Ethyl Ketone Example 172 2-(4-(5-[1-Methyl-5-(5-(3-trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole 4-yl]-1,2,4-oxadiazole-3-ylindolephenyl)-1-(pyrrolidin-1-yl)ethanone Example 173 (4- { 5-[ 1-基-5- ( { 〔 5-(three Methyl)pyridin-2-yloxycarbonylmethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}phenyl)(pyrrolidin-1- Methyl ketone K Example 174 (4- { 5-[ 1-methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole 4-yl]-1,2,4-oxadiazole-3-yl}phenyl)(morpholin-4-yl)methanone Example 175 2-(3-chloro-4-{5-[ 5-( { 〔5-(Difluoromethyl)pyridin-2-yl]oxyindolemethyl)-1-methyl-1H-pyrazol-4-yl]-1,2,4-oxadi Zyrid-3-yl}phenyl)acetamidine Example 176 N-(1,3-Dioxalin-2-ylmethyl)-3- { 5-[ 1-methyl-5-( { 〔 5-(Trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindole benzamide -126- 201245187 【化2 5】

1) N-( 2,2 -methoxyethyl)-3- { 5-[ i-methyl·5_ ( { 〔5-(difluoromethyl)D to steep-2 -yl)oxy} Methyl) _ih - 卩 ratio π sits - 4 yl -1,2,4-oxadiazole-3-yl}benzamide The 1-methyl hydrazine obtained in Production Example 4 [5_(three Fluoromethyl)D-di-2-yloxy}methyl)-iH-shame-4. Capric acid (969 mg) of N,N-dimethylacetamide (5·0 mL) solution 1,1'-carbonyldiimidazole (626 mg) was added at room temperature and stirred for 1 hour. N-(2,2-dimethoxyethyl)-3-(N,-diamidyl)benzamide (846 mg) obtained in Production Example 5 was added to the reaction solution at 120 °. C was stirred for 10 hours. The reaction solution was allowed to cool to room temperature, then added &lt;RTI ID=0.0&gt;&gt; The residue was purified by column chromatography (cerium dioxide gel, chloroform:methanol = &lt; The solid obtained was washed with diethyl ether to give the title compound (1.00 g) as a colorless solid. MS ( ESI/APCI Dual pos.) m/z : 53 3 ( M + H ) + 2) N-( 1,3-dioxan-2-ylmethyl)-3- { 5-[ 1- Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)dH-pyrazol-4-yl]-1,2,4-oxadiazole-3 -yl}benzamide to N-(2,2-dimethoxyethyl)-3-{5·[1-methyl- 5-({-127- 201245187 [5-(trifluoromethyl) a solution of pyridin-2-yl]oxy}methyl)indole_4·yl]-1,2,4-oxadiazol-3-yl}benzamide (30 mg) in toluene (3.0 mL) Among them, p-toluenesulfonic acid monohydrate (9.7 mg) and ethanol-1,2-diol (16 μM) were added, and the mixture was stirred at 60 ° C for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was subjected to reverse phase column chromatography (CAPCELL PAK MG II, water containing 0.1% trifluoroacetic acid: hydrazine containing 1% triacetic acid = 90:10~ 10: 90) Refining to give the title compound (m. 1H NMR (600 MHz, DMS0-d6) δ ppm 3.40 ( dd, J-5.6, 4.75 Hz, 2 H) 3.75 - 3.81 (m, 2 H) 3.88 - 3.92 ( m,2 H) 4_01 ( s,3 H ) 4.96 ( t, J = 4.5 Hz, 1 H) 5.93 ( s, 2 H) 7.07 ( d, J-8.7 Hz, lh) 7.59 ( t, J = 7.6 Hz, 1 H) 7.98 - 8.05 ( m, 2 H) 8.09 ( dd, J = 8 7,2 48 Hz, 1 H) 8 24 (s, 1 H) 8.46 ( d, J = 3.3 Hz, 1 H) 8.65 ( d, J = 2.5 Hz, 1 H) 8.84 (t, J = 5.8 Hz, 1 H); MS (ESI pos.) m/z: 531 [M + H]+ The same procedure as in Example 1 76 was used to obtain Example i 77 and Example 178. Compound. Example 177 N-(1,3-Diyl-5-({[ 5-(trifluoromethyl 1H-pyrazol-4-yl)-I,2,4-oxaoxan-2-yl) ))-3- { 5-[ 1 -methyl)pyridin-2-yl]oxy}methyl)-oxadiazol-3-yl}benzamide-128- 201245187 [Chem. 2 6]

MS (ESI pos.) m/z: 545 [ M + H] + RT = 1.07 (Cons. A) Example 178 N-(5,7-dioxaspiro[2.5]oct-6-ylmethyl)- 3-{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2 , 4-oxadiazole-3-yl}benzimidamide [Chemical 2 7]

MS ( ESI pos. ) m/z: 57 1 [M + H] + RT = 1.10 (Cons. A) Example 179 N-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl }-3-{5-[l-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1 , 2,4-oxathiazol-3-yl}benzamide-129- 201245187 [Chem. 2 8

3-{5-[l-methyl- 5-({[5-(trimethylmethyl) guanidine-2-yl)oxy}methyl)-111-pyrazol-4-yl]-1, P-toluenesulfonic acid monohydrate (8.4 mg) was added to a solution of 2,4-oxadiazole-3-yl}benzamide (52 mg) in tetrahydrofuran (i_〇mL), and stirred at room temperature. 19 hours. P-toluenesulfonic acid monohydrate (8.4 mg) was added, and the mixture was stirred at 50 ° C for 5 hours. After the reaction solution was allowed to cool to room temperature, (3S) -3 -fluoropyrrolidine (25 mg), triethylamine (41 μ! 〇 and sodium hydride triethoxy hydride (62 mg) were added to the reaction solution. The mixture was stirred at room temperature for 10 minutes. After concentration under reduced pressure, the residue was subjected to reversed phase column chromatography (0:??£1^?81&lt;:1^〇11, containing 〇.1°/ Water of trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid = 90: 1 〇~1 〇: 90) Purified to give the title compound (1 7 mg) as a colorless solid. 1 NMR (600 MHz, DMSO-d6) &lt;5 ppm 1.77 - 1.93 ( m, 1 H) 2.03 - 2.19 (m, 1 H) 2.32 - 2.41 (m, 1 H) 2.57 -2.72 (m, 3 H) 2.79 - 2.91 (m, 2 H) 3.38 - 3.45 (m, 2 H) 4.05 ( s, 3 H) 5.05 - 5.34 (m, 1 H) 5.97(s, 2 H) 7.11 ( d, J = 8.7 Hz, 1 H) 7.63 ( t, J = 7.8 Hz, 1 H) 8.01 -8.07 ( m, 2 H) 8.12 ( dd, J = 8.7, 2.48 Hz, 1 H) 8.27 ( s, 1 H) 8.48 (s, 1 H) 8.64 - 8.73 (m, 2 H MS ( ESI pos. -130 - 201245187 ) m / z : 56 0 [ M + H] + The same procedure as in Example 179 was used to obtain the examples 1 to 80 in Tables 7-1 to 7-2. To the compound of Example 1 87. [Table 7 - 1] Implementation Structured Machine Data 180 US (ESI pos·) d/z: 528 [&amp;ΗΗ]+ RT=0.64 (Condition A) 181 MS (ESI pos.) m/z- 564 [U+H]+ RT=0 74 (Condition A) 182 MS (ESI pos.) m/z- 546 [M+H,) + RT=0.64 (Condition A) 183 long &gt; US (ESI pos.) m/z: 487 [U+ H]+ RT=0.94 (Condition A) 184 US (ESI pos.) m/z: 560 [M+H]+ RT=0.66 (Condition A) 185 MS (ESI pos.) m/z: 570 [H+ H]+ RT=0.63 (Condition A) -131 - 201245187 [Table 7 - 2] 186 〇TV&gt; MS (ESI pos·) m/z: 574 [M+H]+ RT=0.67 (Condition A) 187 MS (ESI pos.) o/z: 592 [U^H]+ RT=0.70 (Condition A) Example 180 N-[2-(trimethyleneimine-1-yl)ethyl]-3-{ 5- [l-Methyl-5-( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxa Azoxa-3-yl}benzamide 181 N-[2-(3,3-Difluorotrimethyleneimine-1-yl)ethyl]_3-{5-[1-methyl- 5 -( { 〔5-(Trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-ylindole Benzamide Example 182 N-[2-(3-Fluorotrimethyleneimine-1- Ethyl]-3-{5-[1-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4- -1,2,4-oxadiazol-3-yl}benzamide 183 N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-3- {5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}-132- 201245187 methyl)-1H-pyrazol-4-yl]-1 , 2,4-oxathiazol-3-yl}benzamide 184 N- { 2-[( 3R) -3-fluoropyrrolidin-1-yl]ethyl}-3-{5- [1-Methyl-5·( { 〔5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1Η-pyrazol-4-yl]-1,2,4-oxa Oxazol-3-ylindolecarboxamide Example 1 8 5 3 - { 5-[ 1-methyl-5-( { 〔 5-(trifluoromethyl)pyridin-2-yl)oxy} -1Η-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}-indole-[2-(2-oxa-6-azaspiro[3.3]heptane- 6-yl)ethyl]benzamide 186&gt;4-[2-(4-Fluoropiperidin-1-yl)ethyl]-3-{5-[1-methyl- 5-({ [5-(Trifluoromethyl)pyridin-2-yl]oxy}methyl)-11^pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}benzimidazole Amine Example 18 7N-[2-(4,4-Difluoropiperidin-1-yl)ethyl]-3-{ 5_[丨-methyl_5-( { 〔5-(trifluoromethyl)pyridine-2-蕋]oxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}benzamide 188N-ethenyl- 2-(4 -{5-[l-methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl]-1,2, 4-oxathiazol-3-yl}phenyl)acetamide-133- 201245187 [Chem. 2 9]

2·(4 _ { 5 _[ 1 -methyl _ 5 _(丨[5 _ (trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyridyl obtained in Example 1. a mixture of oxazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetamide (1 〇〇 mg), anhydrous acetic acid (67 μί) and pyridine (2. 〇mL) Stir at 85 °C overnight. After the reaction mixture was allowed to cool to room temperature, water was added and ethyl acetate was evaporated. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (CAPCELL PAK MG II, water containing 0.1% trifluoroacetic acid: acetonitrile containing 0.1% trifluoroacetic acid = 90:10 to 10:90) to give the title compound (32 mg) ) a yellow solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 2.08 ( s, 3 Η ) 3.77 ( s, 2 Η) 3.95 ( s, 3 Η) 5.84 ( s, 2 Η) 7.01 ( d, J = 8.7 Hz, 1 H) 7.31 ( d, J = 8.3 Hz, 2 H) 7.76 ( d, J = 7.8 Hz, 2 H) 8.03 ( dd, J = 8.7, 2.5 Hz, 1 H) 8.15 ( s, 1 H) 8.59 ( s , 1 H ) 10.76 ( s, 1 H ) ; MS ( ESI/APCI Dual pos.) m/z: 501 [ M + H ) + Example 189 ( 4- { 5-[ 1-methyl-5- ( {[ 5-(Trifluoromethyl)pyridin-2-yl]oxyindolemethyl)-1H-pyrazol-4-yl]-1,2,4-oxa-134- 201245187 Diazole-3- Base}phenyl)acetonitrile [chemical 3 0]

2-(4-{5-[1-methyl-5-({(trifluoromethyl)pyridin-2-yl)oxyindolemethyl)-1H-pyrazole-4- obtained in Example 1 5 1,2,4-oxadiazol-3-yl}phenyl)acetamidamine (100 mg) in a solution of 2.0 mL of pyridine, oxyphosphonium chloride (40 pL) was added to the solution under ice bath. 3 hours. The reaction solution was poured into ice-water, and the precipitate was separated by filtration. The obtained solid was washed with water, isopropyl ether and hexane to afford compound (98 mg) as a yellow solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 4.01 ( s, ) 4.06 - 4.19 ( m, 2 H) 5.91 ( s, 2 H) 7.07 ( d, J = 8.' 1 H) 7.47 ( d, J = 8.3 Hz, 2 H) 7.82 - 7.99 ( m, 2 H) (dd, J; 8.7, 2.5 Hz, 1 H ) 8.22 ( s,1 H ) 8.66 ( s,1 ;MS ( ESI/APCI Dual pos. m/z: 441 [M+H]+ Example 190 2-[4-{5-[1-methyl-5-({[5-(triyl)pyridin-2-yl)oxy} Base)-1 Η-pyrazole-4-yl]-1,2oxadiazol-3-yl}-2-oxopyridine-1 (2H)-yl]acetamide [5-I)-pyridine ( , in the solid title 3 Η, Hz, 8.09 Η) Fluorine 4-Oxo-135- 201245187 [Chem. 3 1]

1) 4-{5-[1-Methyl-5-({[5-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazole-4-yl]-1 , 2,4-oxathiazol-3-yl}pyridine-2(1H)-one ι_methyl_5_( { 〔5-(trifluoromethyl)pyridine-2 obtained in Production Example 4. -1 -1'- in a solution of N,N-dimethylformamide (2.0 mL) in a solution of 1-methyl-pyrazole-4-carboxylic acid (100 mg) Carbonyldiimidazole (65 mg) was stirred for 1 hour. N'-hydroxy-2-oxo-oxo-1,2-dihydropyridine-4-formamidine (62 mg) obtained in Production Example 5 was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and stirred at U0 ° C. 14 hours. The reaction solution was allowed to cool to room temperature, and after adding water, the precipitated crystals were collected by filtration. This was recrystallized from ethyl acetate to give the title compound (m. 1H NMR (600 MHz, DMSO-d6) &lt;5 ppm 4.04 ( s, 3 Η ) 5.92 ( s, 2 Η) 6.61 ( d, J = 6.6 Hz, 1 H) 6.87 ( d, J = 1.2 Hz, 1 H) 7.11 ( d, J = 8.7 Hz, 1 H) 7.54 ( d, J = 7.0 Hz, 1 H ) 8.13 ( dd, J = 8.9, 2.7 Hz, 1 H) 8.26 ( s, 1 H) 8.67 ( s , 1 H) MS ( ESI/APCI Dual pos.) m/z : 419 [ M + H]+ -136- 201245187 2) 2-[4- {5-[1-methyl- 5-( { 〔5_ (trifluoromethyl)pyridin-2-yloxy}methyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazole-3-yl}-2-oxopyridine -1 ( 2H)-yl]acetamidine .4 - { 5 -[ 1 -methyl-5 · ( { 〔 5 _ (trifluoromethyl)pyridine · 2 yl ) oxy} methyl)-iH -pyrazol-4-yl]-12,4-oxadiazole-3-yl}pyridine·2(1Η)-one (47 mg), 2-bromoacetamide (20 mg) and potassium carbonate (26 mg) A solution of N,N-dimethylformamide (!·〇mL) was stirred at room temperature for 18 hours and at 60 ° C for 4 hours. The reaction solution was diluted with ethyl acetate (70 mL) and washed with water (20 mL), brine (20 mL) and brine (30 mL). ISOLUTE HM-N was added to the organic layer and concentrated under reduced pressure. The residue was purified by column chromatography (cerium dioxide gel, hexane: ethyl acetate = 60: 40 to 0: 100 to chloroform: methanol = 95: 5 to 90: 10). The obtained solid was washed with ethyl acetate-hexane toield 1H NMR (600 MHz, DMSO-d6) &lt;5 ppm 4.04 ( s, 3 Η ) 4.56 ( s, 2 Η) 5.92 ( s, 2 Η) 6.68 ( dd, J = 7.0, 1.7 Hz, 1 H) 6.91 ( d, J = 1.7 Hz, 1 H) 7.11 ( d, J = 8.7 Hz, 1 H) 7.22 (brs, 1 H ) 7.65 ( brs, 1 H ) 7.76 ( d, J = 7.0 Hz, 1 H ) 8.12 (dd, J = 8.7, 2.5 Hz, 1 H) 8.26 ( s, 1 H ) 8.66 ( s, 1 H ) MS ( ESI/APCI Dual pos. ) m/z : 476 [ M + H]+ Example 191 2-[ 5- { 5-[ 1-Methyl-5-( { [ 5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl]· 1,2,4·oxy-137- 201245187 heterodiazole·3-yl}-2-oxopyridine-丨(2H)-yl]acetamide

The title compound was obtained as a colorless solid. 1H NMR (600 MHz, DMSO-d6) &lt;5 ppm 4.02 ( s, 3 Η ) 4.65 ( s, 2 Η) 5.92 ( s, 2 Η) 6.52 ( d, J = 9.5 Hz, 1 H) 7.11 (d , J = 8.7 Hz, 1 H) 7.25 ( brs, 1 H) 7.70 ( brs, 1 H ) 7.85 ( dd, J = 9.5, 2.9 Hz, 1 H) 8.13 ( dd, J = 8.7, 2.5 Hz, 1 H 8.20 ( s, 1 H) 8.39 ( d, J = 2.5 Hz, 1 H) 8.65 ( s, 1 H ) MS ( ESI/APCI Dual p〇s. ) m/z : 476 [ M + H]+ 贲Example 192N-(3-{5-[l-methyl-5-({[[3-(trifluoromethyl)pyridin-2-yl)oxy}methyl)-1H-pyrazol-4-yl) ]-1,2,4-oxadiazole-3-yl}phenyl)sulfonamide-138- 201245187 [Chem. 3 3]

i) 3_ { 5-[ 1-methyl-5. ( ί [ 5-(trifluoromethyl)pyridyl)oxy}methyl)-1H-pyridin-4-yl]·1,2,4 1-oxa·5-( { 〔5-(difluoro)pyridin-2-yl)oxy}methyl)·1Η_pyrazole-4· obtained in Production Example 4 Carboxylic acid (800 Ν, Ν-dimethylformamide (3.0 mL) in solution 'at room temperature 1,1'-cutting dim ton (517 mg) 'stirring for 30 minutes. Addition to reaction 5 3-Amino-indole-hydroxybenzhydrazide (480), stirred at room temperature for 1 hour, stirred at 110 ° C for 16 hours. Concentrated against reduced pressure, the residue was applied to a column The residue was purified by chromatography (EtOAc EtOAc:EtOAc:EtOAc:

1H NMR ( 600 MHz, CHLOROFORM-d ) δ ppm (br. s., 2 H) 4.05 ( s, 3 H ) 5.95 ( s, 2 H ) 6.81 J = 8.1, 1.4 Hz, 1 H) 6.88 (d, J-8.7 Hz, 1 H) 7.22 -(m, 1 H) 7.41 ( s, 1 H) 7.46 ( d, J = 7.4 Hz, 1 H) 7 dd, J = 8.7, 2.48 Hz, 1 H) 8.14 ( s, 1 H) 8.48 ( s, 1 H pyridine-2--3-ylmethyl mg ) added to the solution of mg) 匣, body by mg) 3.78 (dd, 7.26 • 82 ( -139- 201245187 2 ) N-(3-{ 5-[1·methyl-5-({[pyridin-2-yl]oxy}methyl)-1H-pyrazol-4-yl-3-yl}phenyl)sulfonate Amine in t-butanol (181 μιη) of chloroform (3.2 times, add chlorosulfonamide isocyanate (166 μί) minutes. Triethylamine (319 μΙΟ and 3-{5 5-(trifluoromethyl) Pyridin-2-yloxy}methyl]-1,2,4-oxadiazol-3-yl}aniline (159 m reaction solution, stirred at room temperature for 2 hr. (5 mL) and water (1.6 mL) The layer was concentrated under reduced pressure by a phase separator (manufactured by Biotage), and chloroform was added to the residue, and the mixture was stirred at room temperature for 1.5 hr. Add chloroform (6.4 mL), liquid (3.2 mL), water 6.4 mL) and methanol (after the layer, the aqueous layer was extracted with chloroform (3.2 mL)-methanol (the solvent was extracted. After the organic layers were combined, the organic layer was concentrated and concentrated under reduced pressure. , chloroform: methanol = 100: 〇 ~ 90: 10) refined (99 mg) of a colorless solid. 1H NMR (600 MHz, DMS0-d6) δ ) 5.93 ( s, 2 Η ) 7. 10 - 7.13 ( m, 1 Η ) 7.37 - 7.44 ( m, 2 Η) 7.48 - 7.51 ( m, m, 1 Η ) 8. 1 1 - 8.1 4 ( m, 1 Η ) 8.23 ( s: 5-(trifluoromethyl)pyr] 1,2,4-oxadiazole-mL) solution, ice bath, stirring at the same temperature 10 -[1-methyl-5-({[yl)-1H-pyrazol-4-yl) Saturated carbonic acid was added to the addition liquid under ice bath, and two layers were separated. After removing water, the mixture was added to trifluoroethylene under a reduced pressure. The reaction solution was dissolved in saturated aqueous sodium hydrogencarbonate (3.2 mL) under reduced pressure. Separation of 2 1 · 6 m L of the mixed-dissolver, removal of the water method (cerium oxide gel, the title compound ppm 4.04 ( s, 3 Η 7. 15 ( br. s, 2 Η ) 1 Η ) 7.83 - 7.8 5 ( ,1 Η ) 8.67 ( br. s, -140- 201245187 1 Η) 9.75 ( br. s, 1 Η) ; MS ( ESI/APCI Dual neg.) m/z : 494 [ MH ] - Test Example 1 (Preparation of the crude membrane fraction of CHO cells stably expressing the human type metabotropic glutamate receptor (mGU2)) Dulbecco's Modified Eagle Medium containing 10% dialyzed fetal bovine serum [1% proline] 50 units/mL penicillin, 50 μg/mL streptomycin, 400 pg/mL Hygromycin B, 2 mM L-glutamine (added) were used to culture CHO cells stably expressing human type mGlu2 receptor at 37 ° C under 5% CO 2 . The cells in the confluent state were washed twice with PB S (-), and then exfoliated with a cell scraper, and centrifuged at 1 OOO rpm for 5 minutes to recover the cells at 4 ° C. The resulting precipitate was treated with 20 mM HEPES buffer. (ΡΗ7·4) Suspended, the suspension was homogenized by a Teflon (registered trademark) homogenizer, and centrifuged at 4 ° C, 48,000 x g. After separating for 20 minutes, the precipitate was again obtained. Further, the obtained precipitate was washed twice by centrifugation, and then homogenized by the above buffer to obtain a crude membrane portion. The obtained crude membrane portion was stored at -80 °. C. ([35S]GTPr S binding assay) The above-mentioned prepared frozen membrane fraction was melted during use to bind the assay buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl 2 ' 8.4 μΜ GDP &gt; 10 μg /m L s ap ο nin, 0 · 1 % BSA ) Dilution -141 - 201245187. The example compound was added to the membrane portion of membrane protein 1C^g/assay, and cultured at 30 ° C for 20 minutes. Thereafter, added The glutamic acid (final concentration 20 μΜ) and [35S]GTPr S (final concentration 〇.15ηΜ) were cultured at 30 ° C for 1 hour. After the incubation, the above reaction solution was pre-impregnated with 20 mM HEPES buffer (pH 7. 4) The Whatman GF/C filter was suction-filtered, and the above filter was washed 3 times with ice-cold 20 mM HEPES buffer (pH 7.4) 300 μί. A scintillation cocktail was added to the obtained filter, and the membrane-bound radioactivity was measured by a liquid flash counter. The [35s]gtp r s binding amount in the case where the above reaction was carried out in the absence of glutamic acid was used as non-specific binding, and specific binding was carried out in comparison with the amount of [35S]GTP rs bound in the presence of glutamic acid. The competitive inhibition curve (i n h i b i t i ο n c u r V e ) was obtained by non-linear analysis from the specific binding inhibition ratios of the various concentrations of the compounds of the respective examples. The concentration of the compound of each example (IC5Q値) in which the specific [35S]GTP r S binding amount was inhibited by 50% was calculated from the competition inhibition curve. Among the compounds of the present invention, IC5 will be used. The compound below g is AμΜ, and the compound of Ο.ΙμΜ~ΙμΜ is denoted as B, the compound of 1 μΜ~10 μΜ is denoted by C, and the compound of ΙΟμΜ or more is denoted by 〇, and is shown in Table 8. Further, IC5G oxime of several compounds of the present invention is shown in Table 9. -142- 201245187

[Table 8] Example Ι〇50 Implementation of Ι〇5〇 Example 1C50 1 A 51 A 101 A 2 A 52 c 102 A 3 A 53 A 103 C 4 A 54 A 104 A 5 B 55 A 105 B 6 A 56 A 106 B 7 A 57 A 107 A 8 A 58 A 108 A 9 A 59 B 109 B 10 A 60 B 110 B 11 A 61 B 111 A 12 A 62 B 112 A 13 A 63 A 113 B 14 A 64 A 114 A 15 A 65 A 115 A 16 A 66 A 116 B 17 A 67 A 117 B 18 A 68 A 118 B 19 B 69 A 119 A 20 A 70 A 120 B 21 B 71 A 121 B 22 B 72 C 122 B 23 B 73 A 123 A 24 B 74 A 124 B 25 B 75 A 125 B 26 A 76 A 126 B 27 A 77 A 127 c 28 A 78 A 128 A 29 A 79 A 129 A 30 A 80 B 130 B 31 A 81 A 131 A 32 A 82 A 132 B 33 D 83 A 133 A 34 A 84 A 134 B 35 B 85 A 135 A 36 B 86 C 136 A 37 B 87 A 137 A 38 B 88 A 138 A 39 A 89 B 139 B 40 A 90 A 140 A 41 A 91 A 141 A 42 C 92 B 142 B 43 B 93 B 143 A 44 B 94 B 144 A 45 B 95 B 145 A 46 B 96 A 146 A 47 B 97 A 147 B 48 B 98 A 148 A 49 B 99 A 149 A 50 A 100 B 150 A

Example ic5〇151 A 152 A 153 B 154 B 155 A 156 A 157 A 158 A 159 B 160 A 161 A 162 A 163 A 164 A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 A 173 A 174 B 175 A 176 A 177 A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189 B 190 B 191 B 192 A -143- 201245187 [Table 9] Example No. IC5 〇(nM) Example 1 17.6 Example 2 13.4 Example 7 4.12 Example 13 2.70 Example 14 23.3 Example 15 12.6 Example 20 59.7 Example 27 5.95 Example 29 40.2 Example 30 19.1 Example 31 36.4 Example 32 11.1 Example 41 20.2 [Industrial Applicability] The compound of the present invention has an antagonistic action on the type II mGlu receptor, and can be used as a prophylactic and therapeutic agent for a type II mGlu receptor-related disease, specifically, Available as mood disorders (depression, bipolar disorder, etc.), anxiety disorders (general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific fear, acute stress disorder, etc.), schizophrenia , Alzheimer's disease, cognitive impairment, dementia, drug dependence, climbing spasm, tremor, pain, sleep disorders and the prevention or therapeutic drug -144-

Claims (1)

201245187 VII. Patent application scope: 1. A compound represented by formula [I] or a pharmaceutically acceptable salt thereof; - R 2 R1 [In the formula [I], R1 represents a hydrogen atom or a Ci_6 alkyl group (wherein the Ci-6 alkyl group may be substituted by 1 to 3 halogen atoms), and R2 represents a hydrogen atom or an alkyl group (here) The (^_6 alkyl group may be substituted by 1 to 3 halogen atoms), and the ring A represents a phenyl group, a heteroaryl group, a porphyrin-2-one-5-yl group, an isoindolin-1-one-5- Base, iso- D-indol-1-one-6-yl, benzo[d] miso-2-y-5-yl or pyridinyl, ring A is porphyrin-2-one-5-yl When isoindolin-1-one-5-yl, isoindolin-1-one-6-yl or benzo[d]imidazol-2-one-5-yl, R3 and R4 are the same or phase When a hetero atom represents a hydrogen atom, a halogen atom or a Cu alkyl group, and when ring A is a phenyl group, a heteroaryl group or a pyridone group, R3 represents a hydrogen atom, a _ atom, a Ci-6 alkoxy group or a C|_6 yard group ( Here, the C!-6 alkoxy group or Cu alkyl group may be substituted by 1 to 3 halogen atoms), and R4 represents a C 6 alkyl group, a Ci. 6 alkoxy group (here the C!·6 alkyl group or -145- 201245187 Cu alkoxy is via -CONRaRb, -CORe, cyano or hydroxy substituted), CONRaRb, -0-C0NRaRb, -NRalRbl, -CORc, cyano, NRdCORe or -NRdS02Re, Ra and Rb phase Or dissimilarly represent a hydrogen atom, a hospital base {here, the Ci-6 courtyard group may be via a hydroxyl group, a halogen atom, a CI.6 alkoxy group (wherein the C|-6-yard oxy group may be substituted with 1 to 2 hydroxy groups) ), -CONRfR6 'Amino, mono-C 1.6. Amine, bis-C. 6 alkylamino, morpholinyl, piperidino, pyrrolidino, aza Azetidino, 1,3-dioxan-2-yl, 1,3 -dioxan-2-yl, 2-oxa-6-azaspiro[3.3]heptane-6 - and 5,7-dioxaspiro[2.5]octane-6-yl (here the morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, 1,3-dioxole Alkan-2-yl, 1,3-dioxan-2-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl and 5,7-dioxaspiro[2.5]octyl The alkyl-6 group may be substituted by 1 to 146 to 201245187 to 2 halogen atoms) 1 to 3 substituents selected from the group consisting of}, C!-6 alkanoyl, oxetane, Tetrahydrofuranmethyl or tetrahydropyranyl, or &amp; 3 and 1^ may form together with the bonded nitrogen atom to form a further a saturated or unsaturated 4 to 6 membered ring of a nitrogen atom, an oxygen atom or a sulfur atom (wherein a saturated or unsaturated 4 to 6 membered ring may be formed by a C1-6 alkyl group, a pendant oxy group, and a hydroxyl group). One or two substituents selected in the group are substituted.) Ral and Rbl are formed together with the bonded nitrogen atom, and further forms a saturated & amp which may contain more than one nitrogen atom, oxygen atom or sulfur atom. Or an unsaturated 4- to 6-membered ring (here the saturated or unsaturated 4 to 6 gastric ring, $1 to 2 can be selected from the group consisting of C.6 alkyl, pendant oxy and hydroxy) Substituent substituted), Re represents Ci.6 alkyl, hydroxy or Cu alkoxy, Rd represents a hydrogen atom or a Cu alkyl group, Re represents c丨·6 alkoxy 'amine group, mono-c丨_6 alkylamine Or a di-C丨.6 alkylamino group, Rf and Rg are the same or different meaning hydrogen atom or alkyl group, Y1 represents -(ch2) no- or -(ch2) m-, η represents an integer of 1 to 6 m represents an integer from 0 to 6, and Y2 represents an aryl or heteroaryl group (wherein the aryl or heteroaryl group may be via an alkyl group, a C3-6 cycloalkyl group, a Cm alkoxy group (here the Ci. 6 Alkyl, -147- 201245187 C3.6 naphthenic Or Ci-6 alkoxy group may be substituted with 1 to 3 halogen atoms), a cyano group and a halogen atom selected the group consisting from 1 to 3 substituents}, Y3 represents an arylene group having 5] heteroaryl. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein in the formula [I], R1 represents a hydrogen atom or a C!-6 alkyl group (wherein the C, .6 alkyl group may pass through 1 Up to 3 halogen atoms are substituted), R2 represents a hydrogen atom or a Ci-6 alkyl group (wherein the C!-6 alkyl group may be substituted by 1 to 3 halogen atoms), ring A represents a phenyl group or a heteroaryl group, and R3 represents a hydrogen atom, a halogen atom or a Ci.6 courtyard group (wherein the Ci-6 alkyl group may be substituted by 1 to 3 halogen atoms), and R4 represents a Cu alkyl group and a Cu alkoxy group (here, the q.6 alkyl group) Or a Ci.6 alkoxy group is substituted by -CONRaRb, -COV or an aryl group), _CONRaRb, -0-C0NRaRb, -CORc or a cyano group, and Ra and Rb are the same or different, each represents a hydrogen atom, a CU6 alkyl group, (wherein the Ci.6 alkyl group may be substituted by one to two substituents selected from the group consisting of an amine group, a mono-C].6 alkylamino group, a di-C|.6 alkylamino group and a hydroxyl group) An oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group, or Ra and Rb may be formed together with the bonded nitrogen atom, and further formed may contain one or more nitrogen atoms, oxygen atoms or Saturation or not of sulfur atoms Saturated 5 or 6 membered ring, Re represents hydroxy or Ci.6 alkoxy, -148- 201245187 丫1 indicates -(〇1^2) nO- or -(CH2) m·, n represents 1 to 6 An integer, m represents an integer from 0 to 6, and Y2 represents an aryl or heteroaryl group. Here, the aryl or heteroaryl group may be via a Cu alkyl group, a Cm cycloalkyl group, a Cl 6 alkoxy group (here the Ci 6 institute) a group, a C3·6 cycloalkyl group or a Cu alkoxy group may be substituted by 1 to 3 halogen atoms), a cyano group and a halogen atom selected from the group consisting of 1 to 3 substituents} &gt; Y3 represents 5 members Heteroaryl. 3. A compound according to claim 1 or 2, wherein the ring A is a phenyl group or a 6 membered heteroaryl group, or a pharmaceutically acceptable salt thereof. 4. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridyl. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y1 is -CH2-0-. The compound of any one of claims 1 to 5, wherein the Y2 is a phenyl group or a pyridyl group, wherein the phenyl group or the phenyl group is via a Cl-6 alkyl group, or a pharmaceutically acceptable salt thereof. , C3.6 cycloalkyl, Cl_6 alkoxy (here the G.6 alkyl, (: 3-6 cycloalkyl or Cl-6 alkoxy may be substituted by i to 3 _ Mil), cyano and halogen atom And a pharmaceutically acceptable salt thereof, wherein Y3 is represented by formula [II], wherein one or three substituents are selected in the group consisting of: The structure of the test ~ test -149- 201245187 [chemical 2] 8. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R3 is a hydrogen atom or a halogen atom. A medicine comprising the compound of any one of the above-mentioned claims, or a pharmaceutically acceptable salt thereof, as an active ingredient. 10. A pharmaceutical of the ninth aspect of the patent application, which is a metabolite type glutamate receptor antagonist. 11. A preventive or therapeutic agent for mood disorders, anxiety disorders, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremors, pain, or sleep disorders, such as applying The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof is used as an active ingredient. -150- 201245187 IV. Designation of representative drawings: (1) The representative representative of the case is: No (2) The symbol of the symbol of the representative figure is simple: No. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. :式[I] 4-