JP2014062047A - Pyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound or a pharmaceutically acceptable salt thereof having antagonistic actions to a group II metabolism type glutamic acid (mGlu) receptor, and to provide a novel preventive or therapeutic agent for diseases such as mood disorder (depression disorder, bipolar disorder), anxiety disorder (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, stress disorder after trauma, specific phobia, acute stress disorder and the like), schizophrenia, Alzheimer disease, cognitive dysfunction, dementia, drug dependence, twitch, thrill, pain and sleep disorders.SOLUTION: There is provided a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof.

Description

  The present invention relates to a novel compound having an antagonistic action on a group II metabotropic glutamate (mGlu) receptor or a pharmaceutically acceptable salt thereof, and a mood disorder (depressive disorder, bipolar) containing them as an active ingredient Sexual disorder), anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive impairment The present invention relates to a preventive or therapeutic agent for diseases such as dementia, drug dependence, convulsions, tremors, pain, and sleep disorders.

Glutamic acid is known as one of the major excitatory neurotransmitters that regulate higher-order functions such as memory and learning in the mammalian central nervous system. The glutamate receptor is an ionotropic receptor (iGlu receptor) and a G-protein coupled receptor (GPCR), which is a metabotropic receptor (GPCR). ) Are divided into two categories. iGlu receptor is based on its agonist specificity, N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropion It is classified into three groups: acid (α-amino-3-hydroxy-5-methyl-4-isopropylpropionic acid (AMPA) receptor and kainate receptor. On the other hand, the mGlu receptor has eight subtypes (mGlu1 to 8), and group I (mGlu1, mGlu5), group II (mGlu2, mGlu3) and group III (mGlu4) depend on the coupled information transmission system and pharmacological properties. , MGlu6, mGlu7, mGlu8). Group II and Group III mGlu receptors are expressed primarily as autoreceptors or heteroreceptors at nerve endings, suppress adenylate cyclase through Gi proteins, and regulate specific K ⁺ or Ca ²⁺ channel activity. ing.

  In recent years, it has been reported that the concentration of glutamate in cerebrospinal fluid and plasma in patients with mental disorders such as mood disorders, anxiety disorders and schizophrenia has changed, suggesting abnormal glutamate neuronal function in mental disorders. Among glutamate receptors, group II mGlu receptor antagonists exhibit antidepressant and anti-anxiety effects in various animal models (Non-patent Document 1), so group II mGlu receptor antagonists are novel. The possibility of becoming an antidepressant and anxiolytic is suggested. Furthermore, the efficacy as a cognitive function enhancer (dementia, Alzheimer's disease) of a group II mGlu receptor antagonist is also suggested (nonpatent literature 2).

  Recently, compounds having group II mGlu receptor antagonistic activity have been reported in Patent Documents 1 to 5 and the like. However, these patent documents do not disclose or suggest any compound having a heteroaryl-pyrazole skeleton.

WO2008 / 128889 International Publication WO2008 / 119689 International Publication WO2007 / 039439 International Publication WO2006 / 084634 International Publication WO2001 / 029012 International Publication

Biochemical Pharmacology 2008 75 997-1006 Neuropharmacology 2004 46 907-917

  The object of the present invention is to find a novel compound that antagonizes the group II mGlu receptor, mood disorder (depressive disorder, bipolar disorder, etc.), anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, society) Anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremor, pain, and sleep disorders To provide a useful preventive or therapeutic agent.

The present inventors have found that a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof can solve the above-mentioned problems, and has completed the present invention.
That is, the present invention
(1) Formula [I]

[式［Ｉ］中、
Ｒ¹は、水素原子又はＣ_1-6アルキル基（ここで該Ｃ_1-6アルキル基は１から３個のハロゲン原子で置換されてもよい。）を示し、
Ｒ²は、水素原子又はＣ_1-6アルキル基（ここで該Ｃ_1-6アルキル基は１から３個のハロゲン原子で置換されてもよい。）を示し、
環Ａは、フェニル基又はヘテロアリール基を示し、
Ｒ³は、水素原子、ハロゲン原子又はＣ_1-6アルキル基（ここで該Ｃ_1-6アルキル基は１から３個のハロゲン原子で置換されてもよい。）を示し、
Ｒ⁴は、Ｃ_1-6アルキル基、Ｃ_1-6アルコキシ基（ここで該Ｃ_1-6アルキル基又はＣ_1-6アルコキシ基は、−ＣＯＮＲ^aＲ^b、−ＣＯＲ^c又はシアノ基で置換されている。）、−ＣＯＮＲ^aＲ^b、−Ｏ−ＣＯＮＲ^aＲ^b、−ＣＯＲ^c又はシアノ基を示し、
Ｒ^a及びＲ^bは、同一又は異なって、水素原子、Ｃ_1-6アルキル基、（ここで該Ｃ_1-6アルキル基はアミノ基、モノ−Ｃ_1-6アルキルアミノ基、ジ−Ｃ_1-6アルキルアミノ基及び水酸基からなる群より選択される１から２個の置換基で置換されてもよい。）又は４から６員の環状エーテル基を示すか、
又は、Ｒ^a及びＲ^bは、結合する窒素原子と共に一緒になって形成され、さらに窒素原子、酸素原子又は硫黄原子を１つ以上含んでもよい飽和又は不飽和の５又は６員環を形成してもよく、
Ｒ^cは、水酸基又はＣ_1-6アルコキシ基を示し、
Ｙ¹は、−(ＣＨ₂)_n−Ｏ−又は−(ＣＨ₂)_m−を示し、
ｎは、０から６の整数を示し、
ｍは、０から６の整数を示し、
Ｙ²は、アリール基又はヘテロアリール基｛ここで該アリール基又はヘテロアリール基は、Ｃ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_1-6アルコキシ基（ここで該Ｃ_1-6アルキル基、Ｃ_3-6シクロアルキル基又はＣ_1-6アルコキシ基は、１から３個のハロゲン原子で置換されてもよい。）、シアノ基及びハロゲン原子からなる群より選択される１から３個の置換基で置換されてもよい。｝を示し、
Ｙ³は、５員ヘテロアリーレンを示す］
で表される化合物又はその医薬上許容される塩、
（２）式［Ｉ］中、
環Ａが、フェニル基又は６員ヘテロアリール基である、（１）に記載の化合物又はその医薬上許容される塩、
（３）Ｙ¹が、−ＣＨ₂−Ｏ−であり、
Ｙ²が、フェニル基又はピリジル基｛ここで該フェニル基又はピリジル基は、Ｃ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_1-6アルコキシ基（ここで該Ｃ_1-6アルキル基、Ｃ_3-6シクロアルキル基又はＣ_1-6アルコキシ基は、１から３個のハロゲン原子で置換されてもよい。）、シアノ基及びハロゲン原子からなる群より選択される１から３個の置換基で置換されてもよい。｝である、（１）又は（２）に記載の化合物又はその医薬上許容される塩、
（４）（１）〜（３）のいずれかに記載の化合物又はその医薬上許容される塩を有効成分として含有する医薬、
（５）グループII代謝型グルタミン酸受容体拮抗物質である、（４）に記載の医薬、及び
（６）（１）〜（３）のいずれか１項に記載の化合物又はその医薬上許容される塩を有効成分とする、気分障害、不安障害、統合失調症、アルツハイマー病、認知機能障害、認知症、薬物依存、痙攣、振戦、疼痛、又は睡眠障害の予防又は治療剤である。

[In the formula [I],
R ¹ represents a hydrogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ² represents a hydrogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
Ring A represents a phenyl group or a heteroaryl group,
R ³ represents a hydrogen atom, a halogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ⁴ represents a C _1-6 alkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl group or C _1-6 alkoxy group is substituted with —CONR ^a R ^b , —COR ^c or a cyano group). -CONR ^a R ^b , -O-CONR ^a R ^b , -COR ^c or a cyano group,
R ^a and R ^b are the same or different, a hydrogen atom, C _1-6 alkyl, (wherein the C _1-6 alkyl group is an amino group, a mono -C _1-6 alkylamino group, di -C _{1 -6} may be substituted with 1 to 2 substituents selected from the group consisting of alkylamino groups and hydroxyl groups), or represents a 4- to 6-membered cyclic ether group,
Or, R ^a and R ^b are formed together with a nitrogen atom to be bonded to form a saturated or unsaturated 5- or 6-membered ring which may further contain one or more nitrogen atom, oxygen atom or sulfur atom. You can,
R ^c represents a hydroxyl group or a C _1-6 alkoxy group,
Y ¹ represents — (CH ₂ ) _n —O— or — (CH ₂ ) _m —,
n represents an integer of 0 to 6,
m represents an integer of 0 to 6,
Y ² represents an aryl group or heteroaryl group (wherein the aryl group or heteroaryl group is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group (wherein the C _{1- A 6} alkyl group, a C _3-6 cycloalkyl group or a C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 selected from the group consisting of a cyano group and a halogen atom It may be substituted with 3 substituents. },
Y ³ represents a 5-membered heteroarylene]
Or a pharmaceutically acceptable salt thereof,
(2) In the formula [I],
The compound or a pharmaceutically acceptable salt thereof according to (1), wherein ring A is a phenyl group or a 6-membered heteroaryl group,
(3) Y ¹ is —CH ₂ —O—,
Y ² is a phenyl group or a pyridyl group (wherein the phenyl group or pyridyl group is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl is Group, a C _3-6 cycloalkyl group or a C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 to 3 selected from the group consisting of a cyano group and a halogen atom It may be substituted with a substituent. }, The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof,
(4) A medicament comprising the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient,
(5) The pharmaceutical according to (4), which is a group II metabotropic glutamate receptor antagonist, and (6) the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof It is a prophylactic or therapeutic agent for mood disorders, anxiety disorders, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremors, pain, or sleep disorders containing salt as an active ingredient.

  It has been found that the compounds of the present invention and pharmaceutically acceptable salts thereof have a strong group II mGlu receptor antagonistic action.

  Hereinafter, the present invention will be described in more detail.

  Terms used in this specification will be described.

  The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, Examples include hexyl group, isopropyl group, isobutyl group, tert-butyl group, sec-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1,2-dimethylpropyl group and the like.

The “C _1-6 alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, or a pentyloxy group. Hexyloxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1,2-dimethylpropoxy group and the like.

The “mono-C _1-6 alkylamino group” is an amino group substituted with one C _1-6 alkyl group, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, Pentylamino group, hexylamino group, isopropylamino group, isobutylamino group, tert-butylamino group, sec-butylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, 1,2-dimethylpropyl An amino group etc. are mentioned.

The “di-C _1-6 alkylamino group” is an amino group substituted with two independent C _1-6 alkyl groups, for example, a dimethylamino group, a diethylamino group, a dipropylamino group, dibutyl Amino group, dipentylamino group, dihexylamino group, diisopropylamino group, diisobutylamino group, di-tert-butylamino group, di-sec-butylamino group, di-isopentylamino group, di-neopentylamino group, di- -Tert-pentylamino group, di-1,2-dimethylpropylamino group, ethylmethylamino group, isopropylmethylamino group, isobutylisopropylamino group and the like can be mentioned.

  The “aryl group” is a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms, such as a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a tetracenyl group. And pyrenyl group.

  `` Heteroaryl group '' means a monocyclic or condensed cyclic aromatic heterocyclic group, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, Pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, quinolyl group , Isoquinolyl group, naphthyridinyl group, quinazolinyl group, benzofuranyl group, benzothienyl group, indolyl group, benzoxazolyl group, benzisoxazolyl group, 1H-indazolyl group, 2H-indazolyl group, benzoimidazolyl group, benzooxadiazolyl group Group, benzothiadiazolyl group, Dorijiniru group, benzofurazanyl group, thienopyridyl group, pyrazolopyridyl group, imidazopyridyl group, imidazopyrazinyl group, pyrazolopyrimidinyl group, triazolopyrimidinyl group, thienothienyl group, imidazothiazolyl group, and the like.

  The “6-membered heteroaryl group” means a 6-membered aromatic heterocyclic group, and examples thereof include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group.

  “5-membered heteroaryl group” means a 5-membered aromatic heterocyclic group such as thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl Group, oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group and the like.

  “5-membered heteroarylene” means a divalent group formed by removing any one hydrogen atom from the “5-membered heteroaryl group”.

  “Saturated or unsaturated 5- or 6-membered ring which is formed together with the nitrogen atom to be bonded and may further contain one or more nitrogen atom, oxygen atom or sulfur atom” means, for example, pyrrolidino group, piperidino group , Piperazino group, morpholino group, thiomorpholino group, 1,2,3,6-tetrahydropyridin-1-yl group and the like.

  The “4- to 6-membered cyclic ether group” is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl group.

“C _1-6 alkylene” means a divalent group formed by removing any one hydrogen atom from the above “C _1-6 alkyl group”.

“C _1-6 oxyalkylene” means a divalent group formed by removing any one hydrogen atom from the “C _1-6 alkoxy group”.

Preferred forms of the compound of the present invention are as follows.
In the formula (I), R ¹ is preferably a hydrogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ² is a hydrogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
Ring A is a phenyl group or a 6-membered heteroaryl group,
R ³ is a hydrogen atom, a halogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ⁴ represents a C _1-6 alkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl group or C _1-6 alkoxy group is substituted with —CONR ^a R ^b , —COR ^c or a cyano group). -CONR ^a R ^b , -O-CONR ^a R ^b , -COR ^c or a cyano group,
R ^a and R ^b are the same or different, a hydrogen atom, C _1-6 alkyl, (wherein the C _1-6 alkyl group is an amino group, a mono -C _1-6 alkylamino group, di -C _{1 -6} may be substituted with 1 to 2 substituents selected from the group consisting of an alkylamino group and a hydroxyl group.) Or a 4 to 6 membered cyclic ether group,
Or, R ^a and R ^b are formed together with the nitrogen atom to which they are bonded to form a saturated or unsaturated 5- or 6-membered ring which may further contain one or more nitrogen, oxygen or sulfur atoms. You can,
R ^c is a hydroxyl group or a C _1-6 alkoxy group,
Y ¹ is —CH ₂ —O—,
Y ² is a phenyl group or a pyridyl group (wherein the phenyl group or pyridyl group is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl is Group, a C _3-6 cycloalkyl group or a C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 to 3 selected from the group consisting of a cyano group and a halogen atom It may be substituted with a substituent. },
Y ³ is a 5-membered heteroarylene.

The compounds of the present invention may have stereoisomers such as tautomers and geometric isomers, and optical isomers, and the present invention includes these isomers. Also included are various hydrates, solvates and polymorphic substances of the inventive compounds and salts thereof. Furthermore, the compound [I] of the present invention may be labeled with an isotope (eg, D, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²⁵ I, etc.). Good.

  In the present invention, the pharmaceutically acceptable salt means a pharmaceutically acceptable salt. For example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, malonic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methane Sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid (tosylic acid), lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, Salts with acids such as hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymer and carboxyvinyl polymer, lithium salt, sodium salt, Salts with inorganic bases such as potassium and calcium salts Salts with organic amines, as well as amino acids, such as morpholine and piperidine can be exemplified.

  The compound [I] or a pharmaceutically acceptable salt of the present invention can be formulated according to a method known per se as it is or together with a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials, such as excipients in solid formulations (eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silica Acid), lubricants (eg, magnesium stearate, calcium stearate, talc, colloidal silica), binders (eg, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl) Pyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), disintegrants (eg starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose Sodium, carboxymethyl starch sodium, low substituted hydroxypropyl cellulose, etc.) or solvents in liquid formulations (eg water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.), solubilizing agents (eg polyethylene glycol) , Propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, lauryl) Surfactants such as aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, or polyvinyl alcohol, polyvinyl (Hydrophilic polymers such as redone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (eg, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffers ( For example, phosphates, acetates, carbonates, citrates, etc.), soothing agents (eg, benzyl alcohol, etc.) and the like. In addition, preservatives (for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (for example, sulfites, Ascorbic acid and the like), colorants, sweeteners, adsorbents, wetting agents and the like can also be used.

  The compound [I] or a pharmaceutically acceptable salt of the present invention can be administered orally or parenterally (for example, intravenous, topical, rectal administration, etc.). The dosage form includes, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, powders, troches, capsules (including soft capsules), liquids, injections (for example, subcutaneous injections, intravenous injections) Injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments, creams, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.) ), Sustained-release agents (eg, sustained-release microcapsules, etc.), pellets, infusions, etc., all of which can be produced by conventional formulation techniques (eg, the method described in the 15th revised Japanese Pharmacopoeia, etc.). it can.

  The compound [I] or pharmaceutically acceptable salt of the present invention is appropriately selected depending on the administration subject, administration route, disease, patient age, body weight and symptoms. For example, when treating an adult patient, the dosage is 1 to 2000 mg per day, and this amount is administered once or divided into several times a day.

  When a Group II mGlu receptor antagonist is used as an active ingredient in a medicament, it is not intended for use only in humans, but in other non-human animals (cats, dogs, cows, chickens, fish, etc.) Can also be used.

  The compound of the present invention and a pharmaceutically acceptable salt thereof can be synthesized, for example, by the method shown below, but the production method of the compound of the present invention is not limited thereto.

  Examples of the “inert solvent” include aromatic solvents such as benzene, toluene, xylene and pyridine; hydrocarbon solvents such as hexane, pentane and cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like. Halogenated hydrocarbon solvents; ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; methanol, ethanol, isopropyl alcohol, tert- Alcohol solvents such as butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide De solvents; acetonitrile, nitriles and water, such as propionitrile, and also these homogeneous and heterogeneous mixed solvents. These inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.

  Examples of the “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or alkaline earth metal carbonate; Sodium hydrogen carbonate, potassium hydrogen carbonate or other alkali metal or alkaline earth Metal bicarbonate; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3 0.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; quaternary ammonium salts such as tetra-n-butylammonium fluoride and benzyltrimethylammonium hydroxide; pyridine, imidazole, 2,6 -Basic heterocyclic compounds such as lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.

  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. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.

[Production method 1]
The compound [I-I] of the present invention can be produced by the following method.

In the formula, rings A, R ¹ , R ² , R ³ , R ⁴ , Y ¹ and Y ² are as defined above. R ⁵ is a protecting group of a carboxy group such as a methyl group, an ethyl group, a tert-butyl group, or a benzyl group {Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons (John Wiley & Sons) Sons, INC.)} Or hydrogen atom.
Step 1: Compound [II] of the present invention is a condensation reaction known to those skilled in the art of Compound (1) and Compound (2) in which R ⁵ is a protecting group for a carboxy group in an inert solvent in the presence of a base. It can be produced by a subsequent intramolecular cyclization reaction {see Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}. Alternatively, the compound [II] of the present invention is obtained by subjecting the compound (1) in which R ⁵ is a hydrogen atom and an amidation reaction known to those skilled in the art to an intramolecular cyclization reaction in an inert solvent. {See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}. Here, as the compound (1) and the compound (2), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used. Here, the amidation reaction is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro in an inert solvent in the presence or absence of a base. Nium hexafluorophosphoric acid (HATU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide ( DCC), condensation reaction using a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI), chloroformic acid Condensation reaction via mixed acid anhydride using ethyl, isobutyl chloroformate or trimethylacetyl chloride, thionyl chloride, chloride A condensation reaction via an acid halide using oxalyl, 1-chloro-N, N, 2-trimethyl-1-propenylamine, and the like. Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.
Here, the intramolecular cyclization reaction is, for example, a cyclization reaction of an amide compound using an acid or a base as necessary under heating or non-heating conditions in an inert solvent.

[Production method 2]
The compound [I-II] of the present invention can be produced by the following method.

In the formula, ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Y ² are as defined above.
Step 2: Compound (4) can be produced by an amidation reaction known to those skilled in the art of compound (1) and compound (3) in which R ⁵ is a hydrogen atom in an inert solvent {Comprehensive Organic Transformations Second Edition (see John Wiley & Sons, INC., 1999)}. Here, as the compound (1) and the compound (3), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used. Here, the amidation reaction is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro in an inert solvent in the presence or absence of a base. Nium hexafluorophosphoric acid (HATU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide ( DCC), condensation reaction using a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI), chloroformic acid Condensation reaction via mixed acid anhydride using ethyl, isobutyl chloroformate or trimethylacetyl chloride, thionyl chloride, chloride A condensation reaction via an acid halide using oxalyl, 1-chloro-N, N, 2-trimethyl-1-propenylamine, and the like. Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.
Step 3: The compound [I-II] of the present invention can be produced by an intramolecular cyclization reaction of the compound (4) in an inert solvent. In this step, an activator such as tosyl chloride, thionyl chloride, phosphoryl chloride, Burgess Reagent {methyl carbamate-N- (triethylammoniumsulfonyl)} can be used as necessary. {See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC.}.

  For example, compound (4) can be produced by the following method.

In the formula, ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Y ² are as defined above. R ⁶ is an amino group such as methoxymethyl group, trimethylsilylethoxymethyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, acetyl group, benzyl group, trityl group, methanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, etc. Protective group {see Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, INC.} Or hydrogen atom.
Step 4: Compound (6) can be produced from Compound (1) and Compound (5) wherein R ⁵ is a hydrogen atom by the same method as in Step 2 in <Scheme 2>. Here, when R ⁶ is an amino-protecting group, the compound (6) can be prepared by various organic synthesis methods known to those skilled in the art for protecting group R ⁶ {Protective Groups in Organic Synthesis). 4th edition, see John Wiley & Sons, Inc.}. Alternatively, compound (6) is prepared by a condensation reaction known to those skilled in the art of compound (1) in which R ⁵ is a protecting group for a carboxy group and compound (5) in which R ⁶ is a hydrogen atom in an inert solvent. {Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC.}. Here, as the compound (1) and the compound (5), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.
Step 5: Compound (4) can be produced from compound (6) and compound (7) by the same method as in Step 2 in <Scheme 2>. Here, as the compound (7), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used.

[Production method 3]
The compound [I-IV] of the present invention can be produced by the following method.

In the formula, ring A, R ¹ , R ² , R ³ , R ^a , R ^b , Y ¹ , Y ² and Y ³ are as defined above. R ⁷ represents a bond, C _1-6 alkylene or C _1-6 oxyalkylene.
Step 6: The present compound [I-IV] can be produced from the present compound [I-III] and the compound (8) by the same method as in Step 2 in <Scheme 2>. Here, as the compound (8), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used.

[Production Method 4]
The compound [I-VI] of the present invention can be produced by the following method.

In the formula, ring A, R ¹ , R ² , R ³ , R ⁷ , R ^a , R ^b , Y ¹ , Y ² and Y ³ are as defined above.
Step 7: The compound [I-VI] of the present invention can be produced by a hydration reaction known to those skilled in the art of the compound [IV] of the present invention {Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) See 1999 John Wiley & Sons, INC.}.

  For example, a compound in which compound (1) is represented by formula (1-1) or formula (1-2) can be produced by the following method.

In the formula, n, R ¹ , R ² and R ⁵ are as defined above. R ⁸ , R ^{8 ′} and R ^{8 ″} are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl Group, a C _3-6 cycloalkyl group or a C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), A cyano group and a halogen atom, and X ¹ is a chlorine atom, bromine An atom, an iodine atom, or a fluorine atom is shown.
Step 8: Compound (1-1) can be produced by Mitsunobu reaction of compound (9) and compound (10) in an inert solvent. Here, as the compound (9) and the compound (10), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used. Mitsunobu reaction is, for example, a method using an organic phosphorus compound such as triphenylphosphine or tributylphosphine and an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditertbutyl azodicarboxylate, or cyanomethyltributylphosphorane. (See Chem. Rev. 2009. 109, 2551-2651).
Step 9: Compound (1-2) is produced by reacting Compound (9) and Compound (11) in an inert solvent in the presence of a base and in the presence or absence of a palladium catalyst and a palladium catalyst ligand. {Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC.}. Examples of the palladium catalyst include palladium (II) acetate, dichlorobistriphenylphosphine palladium (II), dichlorobisacetonitrile palladium (II), tetrakistriphenylphosphine palladium (0), and the like. Examples of the ligand include rac-2- (di-t-butylphosphino) -1,1′-binaphthyl, triphenylphosphine, tributylphosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl. (BINAP), 2- (di-tert-butylphosphino) biphenyl, 1,1′-bis (diphenylphosphino) ferrocene (dppf), 1,3-bis (diphenylphosphino) propane (dppp) and the like It is done.

  For example, a compound in which compound (9) is represented by formula (9-1) can be produced by the following method.

In the formula, R ¹ , R ² and R ⁵ are as defined above.
Step 10: Compound (13) can be produced by reacting compound (12) with N, N′-dimethylformamide or the like in the presence of a base in an inert solvent. Compound (12) may be a commercially available compound, a known compound, or a compound synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art.
Step 11: Compound (9-1) can be produced by reacting compound (13) with a reducing agent in an inert solvent. {See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC.}. Here, the reducing agent is a reagent that can reduce a formyl group and convert it into a hydroxyl group. For example, lithium borohydride, sodium borohydride, calcium borohydride, zinc borohydride, lithium aluminum hydride , Sodium aluminum hydride, diisobutylaluminum hydride and the like.

  For example, compound (2) can be produced by the following method.

In the formula, rings A, R ³ and R ⁴ are as defined above.
Step 12: Compound (2) can be produced by addition reaction of compound (14) with hydroxyamine or a salt thereof in an inert solvent in the presence or absence of a base. Compound (14) may be a commercially available compound, a known compound, or a compound synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art.

  For example, compound (3) can be produced by the following method.

In the formula, rings A, R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above.
Step 13: Compound (3) can be produced from compound (15) and compound (5) by the same method as in Step 4 in <Scheme 3>. Here, as the compound (15) and the compound (5), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.

  Next, the present invention will be described in more detail with reference to production examples, examples and test examples. However, the present invention is not limited to these production examples, examples and test examples, and the scope of the present invention is not limited thereto. You may change in the range which does not deviate.

  In the production examples and examples, “NH silica gel cartridge” when purified using column chromatography is Biotage (registered trademark) SNAP cartridge KP-NH manufactured by Biotage, and Biotage is manufactured by “Silica gel cartridge”. Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil, “silica gel 60 N” is silica gel 60 N manufactured by Kanto Chemical Co., Ltd., and “Chromatolex NH” is chromatolex (registered trademark) NH manufactured by Fuji Silysia Chemical Ltd. A commercially available product was used. CAPCELL PAK (registered trademark) C18 TYPE MGII manufactured by Shiseido Co., Ltd. was used for “CAPCELL PAK” when purified using reverse phase column chromatography. Silica gel 60F254 (Merck) was used for TLC (silica gel plate) when purified using TLC, and TLC plate NH (Fuji Silysia) was used for TLC (NH silica gel plate).

Each instrument data described in the production examples and examples was measured with the following measuring instruments.
Microwave reactor: Initiator (Biotage AB)
MS spectrum: Shimadzu LCMS-2010EV, micromass platform LC or micromass GCT
NMR spectrum: [ ¹ H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL), 300 MHz: UNITYNOVA300 (Varian Inc.), 200 MHz: GEMINI 2000/200 (Varian Inc.)
The compound name in a manufacture example and an Example was named by ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).

Abbreviations in the nuclear magnetic resonance (NMR) spectra used in the production examples and examples are shown below.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, dq: double triplet, dq: double triplet, dq: double triplet, dq: double triplet, dq: double triplet, dq: double triplet, dq: double triplet (double quartet), ddd: double double doublet (double double doublet), m: multiplet (multiplet), br: broad (broad), J: coupling constant, Hz: hertz, DMSO-d _6: deuterated dimethyl Sulfoxide

Production Example 1 Ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4-carboxylate 1) Ethyl 5-formyl-1-methyl-1H-pyrazole-4-carboxylate
Under a nitrogen atmosphere, n-butyllithium (105 mL, 2.60 M hexane solution) was added dropwise to a solution of diisopropylamine (27.6 g) in tetrahydrofuran (400 mL) under ice bath cooling, and the mixture was stirred for 1 hour. The reaction solution was cooled to −78 ° C., a solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (20.0 g) in tetrahydrofuran (100 mL) was added dropwise, and the mixture was stirred for 2 hours. N, N′-dimethylformamide (79.7 g) was added dropwise to the reaction solution at −78 ° C. and stirred for 1 hour, followed by addition of 2M aqueous hydrogen chloride solution. The reaction mixture was acidified with 5M aqueous hydrogen chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-50: 50) to give the title compound (17.0 g) as a pale yellow solid.
2) Ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4-carboxylate Ethyl 5-formyl-1-methyl-1H-pyrazole-4-carboxylate (23.0 g) under ice bath cooling Sodium borohydride (5.25 g) was added to a methanol (300 mL) solution and stirred for 1 hour. An aqueous ammonium chloride solution was added to the reaction solution, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (22.8 g) as a pale yellow solid.
1H NMR (200 MHz, DMSO-d6) δ ppm 1.27 (t, J = 7.03 Hz, 3 H) 3.87 (s, 3 H) 4.21 (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} -1H-pyrazole-4-carboxylate
Of ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4-carboxylate (5.00 g), 4-hydroxybenzotrifluoride (6.60 g) and triphenylphosphine (9.61 g) Diisopropyl azodicarboxylate (7.60 mL) was added dropwise to a tetrahydrofuran (250 mL) solution at room temperature, and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure, diluted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography {(NH silica gel cartridge, hexane: ethyl acetate = 90: 10 to 75:25) and (silica gel cartridge, hexane: ethyl acetate = 80: 20)} to give the title compound (7.36 g) was obtained as a colorless solid.
1H NMR (200 MHz, CHLOROFORM-d) δppm 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 [MH]-

The following compounds were synthesized in the same manner.
Ethyl 5-[(4-fluorophenoxy) methyl] -1-methyl-1H-pyrazole-4-carboxylate
1H NMR (600 MHz, CHLOROFORM-d) δppm 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)

Production Example 3 Ethyl 5-{[(5-fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylate Ethyl 5- (hydroxymethyl) -1-methyl under nitrogen atmosphere -1H-pyrazole-4-carboxylate (300 mg), 2-chloro-5-fluoropyridine (322 mg), palladium (II) acetate (37 mg), cesium carbonate (797 mg), rac-2- (di A mixture of -t-butylphosphino) -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, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-50: 50) to give the title compound (149 mg) as a colorless solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.26-1.38 (m, 3 H) 3.95 (s, 3 H) 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 = 9.12, 7.58, 3.08 Hz, 1 H) 7.90 (s, 1 H) 8.01 (d, J = 3.08 Hz, 1 H); MS (ESI pos.) m / z: 280 [M + H] +

The following compounds were 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: 330 [M + H] +

Production Example 4 Ethyl 1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carboxylate 1-methyl-5-({[5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carboxylate (249 mg), 2M aqueous sodium hydroxide (1.13 mL), tetrahydrofuran (4.0 mL) and methanol (2.0 mL) was heated to reflux for 1 hour. After adjusting to about pH 6 with an aqueous citric acid solution, the mixture was extracted three times with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (188 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.97 (s, 3 H) 5.74 (s, 2 H) 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 neg.) M / z: 300 [MH]-

The following compounds were 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: 251 [M + H] +
5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylic acid
MS (ESI pos.) M / z: 252 [M + H] +

Production Example 5 2- [4- (N′-Hydroxycarbamimidoyl) phenyl] acetamide
1) 2- (4-Cyanophenyl) acetamide Under a nitrogen atmosphere, a solution of (4-cyanophenyl) acetic acid (500 mg) in chloroform (6.0 mL) was cooled to an oxalyl chloride (620 mg) and N under cooling in an ice bath. , N′-dimethylformamide (1 drop) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. To a suspension of the residue in tetrahydrofuran (7.0 mL) was added 28% aqueous ammonia (3.00 mL) under ice bath cooling, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether to give the title compound (350 mg) as a pale yellow solid.
2) 2- [4- (N'-Hydroxycarbamimidoyl) phenyl] acetamide
A mixture of 2- (4-cyanophenyl) acetamide (350 mg), 50% aqueous hydroxyamine solution (160 μL) and ethanol (1.5 mL) was heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (400 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δppm 5.72 (s, 2 H) 6.85 (br. S., 1 H) 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- (N'-Hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI pos.) M / z: 194 [M + H] +
4- (N'-hydroxycarbamimidoyl) benzamide
1H NMR (200 MHz, DMSO-d6) δppm 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- (N'-Hydroxycarbamimidoyl) benzamide
1H NMR (200 MHz, DMSO-d6) δ ppm 5.85 (s, 2 H) 7.26-7.52 (m, 2 H) 7.72-7.89 (m, 2 H) 7.96 (br. S., 1 H) 8.15 (s , 1 H) 9.68 (s, 1 H)
4- (N'-hydroxycarbamimidoyl) -3-methylbenzamide
MS (ESI pos.) M / z: 194 [M + H] +
4-Fluoro-3- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI pos.) M / z: 198 [M + H] +
N- [2- (Dimethylamino) ethyl] -3- (N'-hydroxycarbamimidoyl) benzamide
1H NMR (200 MHz, DMSO-d6) δ ppm 2.18 (s, 6 H) 2.40 (t, J = 6.81 Hz, 2 H) 3.32-3.43 (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'-Hydroxycarbamimidoyl) phenoxy] acetamide
1H NMR (600 MHz, DMSO-d6) δ ppm 4.40 (s, 2 H) 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'-Hydroxycarbamimidoyl) -N- (oxetan-3-yl) benzamide
MS (ESI pos.) M / z: 236 [M + H] +

Production Example 6 4- (Cyanomethyl) benzohydrazide
A mixture of methyl 4- (cyanomethyl) benzoate (1.00 g), hydrazine monohydrate (2.86 g) and methanol (20 mL) was heated to reflux for 2 hours. The reaction mixture was stirred for 15 minutes under ice bath cooling, and the resulting solid was collected by filtration and washed with methanol to give the title compound (527 mg) as a pale brown solid.
1H NMR (200 MHz, DMSO-d6) δ ppm 4.11 (s, 2 H) 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 neg.) M / z: 174 [MH]-

The following compounds were synthesized in the same manner.
3- (Cyanomethyl) benzohydrazide
MS (ESI neg.) M / z: 174 [MH]-
4-cyanobenzohydrazide
1H NMR (600 MHz, DMSO-d6) δ ppm 4.56 (br. S., 2 H) 7.87-7.95 (m, 4 H) 10.00 (br. S., 1 H)
3-Cyanobenzohydrazide
MS (ESI neg.) M / z: 160 [MH]-

Production Example 7 N ′-[4- (Cyanomethyl) benzoyl] -1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carbohydrazide Under a nitrogen atmosphere, 1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carboxylic acid (26 mg) in tetrahydrofuran (0.40 mL) ) Solution of 4- (cyanomethyl) benzohydrazide (23 mg), diisopropylethylamine (31 μL) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′- at room temperature. Tetramethyluronium hexafluorophosphoric acid (HATU) (49 mg) was added and stirred for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (5/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 97: 3) to obtain the title compound (36 mg) as a colorless solid.
1H NMR (600 MHz, METHANOL-d3) δ ppm 3.98 (s, 3 H) 3.99 (s, 2 H) 5.83 (s, 2 H) 6.99 (d, J = 9.08 Hz, 1 H) 7.49 (d, J = 8.26 Hz, 2 H) 7.90-7.97 (m, 4 H) 8.53 (s, 1 H); MS (ESI pos.) M / z: 459 [M + H] +

The following compounds were synthesized in the same manner.
N '-[3- (cyanomethyl) benzoyl] -1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carbohydrazide
MS (ESI neg.) M / z: 457 [MH]-

Production Example 8 Methyl ({4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4-oxadiazole -2-yl] phenyl} acetyl) carbamate 1) tert-butyl 2-[(1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) carbonyl] hydrazine Carboxylate
1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4-carboxylic acid (500 mg) in chloroform (5.0 mL) in an ice bath cooled with oxalyl chloride (254 mg) and N, N′-dimethylformamide (1 drop) were added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. To a suspension of the residue in tetrahydrofuran (5.0 mL), pyridine (260 mg) and tert-butyl hydrazinecarboxylate (264 mg) were added while cooling in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform to chloroform: methanol = 90: 10) to give the title compound (730 mg) as a colorless solid.
2) 1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4-carbohydrazide hydrochloride
tert-butyl 2-[(1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) carbonyl] hydrazinecarboxylate (690 mg), chloroform (7.0 mL) and hydrogen chloride solution (1.25 mL, 4M dioxane solution) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and washed with ethyl acetate to give the title compound (550 mg) as a colorless solid.
3) 2- [4-({2-[(1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) carbonyl] hydrazinyl} carbonyl) phenyl] acetamide
To a solution of 4- (2-amino-2-oxoethyl) benzoic acid (188 mg) in N, N′-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (193 mg) at room temperature. After the addition, the mixture was stirred at 40 ° C. for 1 hour. 1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4-carbohydrazide hydrochloride (300 mg) was added to the reaction solution, and the mixture was stirred at 40 ° C. for 5 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform to chloroform: methanol = 90: 10) to give the title compound (180 mg) as a colorless solid.
4) Methyl ({4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4-oxadiazole- 2-yl] phenyl} acetyl) carbamate
2- [4-({2-[(1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) carbonyl] hydrazinyl} carbonyl) phenyl under nitrogen atmosphere A mixture of acetamide (180 mg), tetrahydrofuran (3.8 mL) and Burgess reagent (451 mg) was stirred at 70 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform to chloroform: methanol = 95: 5) to give the title compound (120 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δppm 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] +

Example 1 2- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} phenyl) acetamide

窒素雰囲気下、製造例４で得られた1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-カルボン酸（１００ ｍｇ）のＮ，Ｎ’−ジメチルホルムアミド（２．０ ｍＬ）溶液に室温にて１，１’−カルボニルジイミダゾール（１０８ ｍｇ）を加え３時間撹拌した。反応液に製造例５で得られた2-[4-(N'-ヒドロキシカルバムイミドイル)フェニル]アセトアミド（１２８ ｍｇ）を加え、８０ ℃にて２時間撹拌した後、酢酸（２．０ ｍＬ）を加え８０ ℃にて１２時間撹拌した。反応液を減圧下濃縮し、水を加えた後、クロロホルム/メタノール（９/１）にて３回抽出した。合わせた有機層を水にて洗浄した後、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝９０：１０）にて精製した。得られた固体をクロロホルム、水及びヘキサンにて洗浄して表題化合物（４９ ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δppm 3.38 (s, 2 H) 3.96 (s, 3 H) 5.85 (s, 2 H) 6.85 (br. s., 1 H) 7.02 (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) (ESI pos.) m/z : 459 [M+H]+ ; MS (ESI pos.) m/z : 459 [M+H]+

1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carboxylic acid (100 mg) obtained in Production Example 4 under nitrogen atmosphere 1,1′-carbonyldiimidazole (108 mg) was added to a solution of N, N′-dimethylformamide (2.0 mL) at room temperature and stirred for 3 hours. To the reaction solution was added 2- [4- (N′-hydroxycarbamimidoyl) phenyl] acetamide (128 mg) obtained in Production Example 5, and the mixture was stirred at 80 ° C. for 2 hours. mL) was added and stirred at 80 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted 3 times with chloroform / methanol (9/1). The combined organic layers were washed with water and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 90: 10). The obtained solid was washed with chloroform, water and hexane to give the title compound (49 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δppm 3.38 (s, 2 H) 3.96 (s, 3 H) 5.85 (s, 2 H) 6.85 (br. S., 1 H) 7.02 (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) (ESI pos.) M / z: 459 [M + H] +; MS (ESI pos.) M / z: 459 [M + H] +

  In the same manner as in Example 1, the compounds of Examples 2 to 14 described in Tables 1-1 to 1-3 were obtained.

Example 2 4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4 -Oxadiazol-3-yl} benzamide Example 3 3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole- 4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 4 2- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine- 2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 5 6- [5- (1-Methyl-5- {[4- (Trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] pyridine-3-carboxamide Example 6 N- [2- (Dimethylamino) ethyl] -4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadi Azol-3- L] benzamide Example 7 3-Methyl-4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4 -Oxadiazol-3-yl] benzamide Example 8 3-Fluoro-4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl ) -1,2,4-oxadiazol-3-yl] benzamide Example 9 4-Fluoro-3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl}- 1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 10 4-Methyl-3- [5- (1-methyl-5-{[4- (trifluoro Methyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 11 N-methyl-4- {5- [1-methyl-5- ({[5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} Zuamide 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 Example 13 3-Methyl-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] Oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 14 4-Fluoro-3- {5- [1-methyl-5-({ [5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide

Example 15 2- {3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazole -3-yl] phenyl} acetamide

製造例４で得られた1-メチル-5-{[4-(トリフルオロメチル)フェノキシ]メチル}-1H-ピラゾール-4-カルボン酸（１５０ ｍｇ）、製造例５で得られた2-[3-(N'-ヒドロキシカルバムイミドイル)フェニル]アセトアミド（１２５ ｍｇ）、１，１’−カルボニルジイミダゾール（１０５ ｍｇ）及びＮ，Ｎ’−ジメチルホルムアミド（１．０ ｍＬ）の混合物を、マイクロウェーブ照射下１５０ ℃にて３０分間撹拌した。反応液を減圧下濃縮した後、残渣を逆相カラムクロマトグラフィー（ＣＡＰＣＥＬＬ ＰＡＫ ＭＧ II、０．１％トリフルオロ酢酸/水：アセトニトリル＝９０：１０〜１０：９０）にて精製して、表題化合物（４４ ｍｇ）を無色固体として得た。
1H NMR (500 MHz, DMSO-d6) δ ppm 3.43 (s, 2 H) 3.99 (s, 3 H) 5.72 (s, 2 H) 6.90 (br. s., 1 H) 7.30 (d, J=8.79 Hz, 2 H) 7.41 - 7.45 (m, 2 H) 7.52 (br. s., 1 H) 7.69 (d, J=8.79 Hz, 2 H) 7.76 - 7.80 (m, 1 H) 7.90 (s, 1 H) 8.24 (s, 1 H) ; MS (ESI pos.) m/z : 458 [M+H]+

1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4-carboxylic acid (150 mg) obtained in Production Example 4 and 2- [ A mixture of 3- (N′-hydroxycarbamimidoyl) phenyl] acetamide (125 mg), 1,1′-carbonyldiimidazole (105 mg) and N, N′-dimethylformamide (1.0 mL) was The mixture was stirred at 150 ° C. for 30 minutes under microwave irradiation. After the reaction solution was concentrated under reduced pressure, the residue was purified by reverse phase column chromatography (CAPCELL PAK MG II, 0.1% trifluoroacetic acid / water: acetonitrile = 90: 10 to 10:90) to give the title compound. (44 mg) was obtained as a colorless solid.
1H NMR (500 MHz, DMSO-d6) δ ppm 3.43 (s, 2 H) 3.99 (s, 3 H) 5.72 (s, 2 H) 6.90 (br. S., 1 H) 7.30 (d, J = 8.79 Hz, 2 H) 7.41-7.45 (m, 2 H) 7.52 (br. S., 1 H) 7.69 (d, J = 8.79 Hz, 2 H) 7.76-7.80 (m, 1 H) 7.90 (s, 1 H) 8.24 (s, 1 H); MS (ESI pos.) M / z: 458 [M + H] +

  In the same manner as in Example 15, the compounds of Examples 16 to 31 described in Tables 2-1 to 2-3 were obtained.

Example 16 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazole-3- Yl] benzoic acid Example 17 3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadi Azol-3-yl] benzoic acid Example 18 2- {4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1 , 2,4-oxadiazol-3-yl] phenyl} acetamide Example 19 {4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole- 4-yl) -1,2,4-oxadiazol-3-yl] phenyl} acetic acid Example 20 {3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl } -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} acetic acid Example 21 6- [5- (1-Methyl-5-{[4- (trifluoro) Methyl) fe Xyl] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] pyridine-2-carboxamide Example 22 2- [3- (5- {5-[(4 -Fluorophenoxy) methyl] -1-methyl-1H-pyrazol-4-yl} -1,2,4-oxadiazol-3-yl) phenyl] acetamide Example 23 2- [4- (5- {5 -[(4-Fluorophenoxy) methyl] -1-methyl-1H-pyrazol-4-yl} -1,2,4-oxadiazol-3-yl) phenyl] acetamide Example 24 2- {3- [ 5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl } Acetamide Example 25 2- {4- [5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2, 4-oxadiazol-3-yl] phenyl} acetamide Example 26 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole -4-yl) -1,2,4-oxadiazol-3-yl] phenyl carbamate Example 27 N- [2- (dimethylamino) ethyl] -3- [5- (1-methyl-5- { [4- (Trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 28 N-methyl-3- {5- [ 1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} Benzamide Example 29 2- {3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadi Azol-3-yl] phenoxy} acetamide Example 30 N- (2-hydroxyethyl) -3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole -4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 31 3- [5- (1-methyl-5-{[4- (trifluoromethyl) ) Phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] -N- (oxetan-3-yl) benzamide

Example 32 3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazole-3- Il] benzamide

製造例２で得られたエチル 1-メチル-5-{[4-(トリフルオロメチル)フェノキシ]メチル}-1H-ピラゾール-4-カルボキシラート（１００ ｍｇ）及び製造例５で得られた3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド（６６ ｍｇ）のエタノール（１.５ ｍＬ）懸濁液にナトリウムメトキシド（１３４ μL、２８％メタノール溶液）を加え、マイクロウェーブ照射下１５０ ℃にて３０分間撹拌した。反応液を減圧下濃縮した。残渣を逆相カラムクロマトグラフィー（ＣＡＰＣＥＬＬ ＰＡＫ ＭＧ II、０．１％トリフルオロ酢酸/水：アセトニトリル＝９０：１０〜１０：９０）にて精製して、表題化合物（２.１ ｍｇ）を淡黄色固体として得た。
1H NMR (600 MHz, DMSO-d6) δppm 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]+

Ethyl 1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4-carboxylate (100 mg) obtained in Production Example 2 and 3-methyl obtained in Production Example 5 Sodium methoxide (134 μL, 28% methanol solution) was added to an ethanol (1.5 mL) suspension of (N′-hydroxycarbamimidoyl) benzamide (66 mg) at 150 ° C. under microwave irradiation. Stir for 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CAPCELL PAK MG II, 0.1% trifluoroacetic acid / water: acetonitrile = 90: 10 to 10:90) to give the title compound (2.1 mg) as pale yellow Obtained as a solid.
1H NMR (600 MHz, DMSO-d6) δppm 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] +

  In the same manner as in Example 32, the compounds of Example 33 to Example 41 described in Table 3-1 to Table 3-2 were obtained.

Example 33 tert-butyl 4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazole -3-yl] benzoate Example 34 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4 -Oxadiazol-3-yl] benzamide Example 35 3- [5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 36 4- [5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H- Pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 37 4- (5- {5-[(4-fluorophenoxy) methyl] -1-methyl-1H-pyrazole -4-yl} -1,2,4-oxadiazol-3-yl) benzamide Example 38 3- (5- {5-[(4-fluorophenoxy) methyl] -1-methyl-1H-pi Zol-4-yl} -1,2,4-oxadiazol-3-yl) benzamide Example 39 5- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] pyridine-3-carboxamide Example 40 N-methyl-3- [5- (1-methyl-5-{[ 4- (Trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 41 N-methyl-4- [5- (1 -Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide

Example 42 (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,3, 4-oxadiazol-2-yl} phenyl) acetonitrile

窒素雰囲気下、製造例７で得られたN'-[4-(シアノメチル)ベンゾイル]-1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-カルボヒドラジド（３５ ｍｇ）のテトラヒドロフラン（０．７６ ｍＬ）懸濁液に室温にてＢｕｒｇｅｓｓ試薬（５５ ｍｇ）を加え、５０ ℃にて１時間撹拌した。反応液を減圧下濃縮した。残渣をカラムクロマトグラフィー｛（シリカゲルカートリッジ、クロロホルム：メタノール＝９９：１〜９７：３）及び（ＮＨシリカゲルカートリッジ、クロロホルム）｝にて精製して、表題化合物（２１ ｍｇ）を無色アモルファスとして得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 3.83 (s, 2 H) 4.06 (s, 3 H) 5.92 (s, 2 H) 6.86 (d, J=8.67 Hz, 1 H) 7.48 (d, J=8.67 Hz, 2 H) 7.80 (dd, J=8.67, 2.06 Hz, 1 H) 8.05 (s, 1 H) 8.07 (d, J=8.67 Hz, 2 H) 8.42 - 8.47 (m, 1 H); MS (ESI pos.) m/z : 441 [M+H]+

N ′-[4- (cyanomethyl) benzoyl] -1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl)-obtained in Production Example 7 under a nitrogen atmosphere Burgess reagent (55 mg) was added to a suspension of 1H-pyrazole-4-carbohydrazide (35 mg) in tetrahydrofuran (0.76 mL) at room temperature, and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography {(silica gel cartridge, chloroform: methanol = 99: 1 to 97: 3) and (NH silica gel cartridge, chloroform)} to obtain the title compound (21 mg) as a colorless amorphous.
1H NMR (600 MHz, CHLOROFORM-d) δppm 3.83 (s, 2 H) 4.06 (s, 3 H) 5.92 (s, 2 H) 6.86 (d, J = 8.67 Hz, 1 H) 7.48 (d, J = 8.67 Hz, 2 H) 7.80 (dd, J = 8.67, 2.06 Hz, 1 H) 8.05 (s, 1 H) 8.07 (d, J = 8.67 Hz, 2 H) 8.42-8.47 (m, 1 H); MS (ESI pos.) M / z: 441 [M + H] +

Example 43 2- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 3,4-oxadiazol-2-yl} phenyl) acetamide

実施例４２で得られた(4-{5-[1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-イル]-1,3,4-オキサジアゾール-2-イル}フェニル)アセトニトリル（３０ ｍｇ）のテトラヒドロフラン/水（０．６８ ｍＬ、３/１）懸濁液に、室温にてアセトアミド（１８ ｍｇ）及び塩化パラジウム(II)（１．２ ｍｇ）を加え、１２時間撹拌した。反応液に室温にて塩化パラジウム(II)（１２ ｍｇ）を加え、２．５日間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム/メタノール/テトラヒドロフランにて２回抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下濃縮した。残渣をクロロホルム/メタノール/テトラヒドロフランにて希釈し、不溶物をろ別した後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝９９：１〜９６：４）及びＴＬＣ（シリカゲルプレート、クロロホルム：メタノール＝１０：１）にて精製して、表題化合物（３．１ ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 3.44 (s, 2 H) 4.00 (s, 3 H) 5.86 (s, 2 H) 6.91 (br. s., 1 H) 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.) m/z : 459 [M+H]+

(4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl]-obtained in Example 42 1,3,4-oxadiazol-2-yl} phenyl) acetonitrile (30 mg) in tetrahydrofuran / water (0.68 mL, 3/1) suspension at room temperature with acetamide (18 mg) and chloride Palladium (II) (1.2 mg) was added and stirred for 12 hours. To the reaction solution was added palladium (II) chloride (12 mg) at room temperature, and the mixture was stirred for 2.5 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform / methanol / tetrahydrofuran. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with chloroform / methanol / tetrahydrofuran, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 96: 4) and TLC (silica gel plate, chloroform: methanol = 10: 1) to give the title compound (3.1 mg). Obtained as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 3.44 (s, 2 H) 4.00 (s, 3 H) 5.86 (s, 2 H) 6.91 (br. S., 1 H) 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.) M / z: 459 [M + H] +

Example 44 2- (3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 3,4-oxadiazol-2-yl} phenyl) acetamide

１）(3-{5-[1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-イル]-1,3,4-オキサジアゾール-2-イル}フェニル)アセトニトリル
実施例４２と同様の手法を用いて、製造例７で得られたN'-[3-(シアノメチル)ベンゾイル]-1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-カルボヒドラジド（３６７ｍｇ）より、表題化合物（２２５ ｍｇ）を無色固体として得た。
MS (ESI neg.) m/z : 439 [M-H]-
２）2-(3-{5-[1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-イル]-1,3,4-オキサジアゾール-2-イル}フェニル)アセトアミド
(3-{5-[1-メチル-5-({[5-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾール-4-イル]-1,3,4-オキサジアゾール-2-イル}フェニル)アセトニトリル（１１９ ｍｇ）のＮ，Ｎ’−ジメチルホルムアミド（３．０ ｍＬ）溶液に室温にて３５％過酸化水素水（２６１ μL）を加え１時間撹拌した後、４０ ℃にて４時間、室温にて１２時間攪拌した。反応液に室温にて３５％過酸化水素水（２６１ μL）を加えた後、６０ ℃にて２時間攪拌した。反応液に水及び１０％チオ硫酸ナトリウム水溶液を加え、生じた固体をろ取した。得られた個体を逆相カラムクロマトグラフィー（ＣＡＰＣＥＬＬ ＰＡＫ ＭＧ II、０．１％トリフルオロ酢酸/水：アセトニトリル＝９０：１０〜１０：９０）にて精製して、表題化合物（５６ ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δppm 3.44 (s, 2 H) 4.00 (s, 3 H) 5.86 (s, 2 H) 6.91 (br. s., 1 H) 7.07 (d, J=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, J=8.67, 2.48 Hz, 1 H) 8.13 (s, 1 H) 8.63 (d, J=2.48 Hz, 1 H) ; MS (ESI pos.) m/z : 459 [M+H]+

1) (3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,3,4 -Oxadiazol-2-yl} phenyl) acetonitrile
Using the same method as in Example 42, N ′-[3- (cyanomethyl) benzoyl] -1-methyl-5-({[5- (trifluoromethyl) pyridine-2- [Il] oxy} methyl) -1H-pyrazole-4-carbohydrazide (367 mg) gave the title compound (225 mg) as a colorless solid.
MS (ESI neg.) M / z: 439 [MH]-
2) 2- (3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,3 , 4-Oxadiazol-2-yl} phenyl) acetamide
(3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,3,4-oxa To a solution of diazol-2-yl} phenyl) acetonitrile (119 mg) in N, N′-dimethylformamide (3.0 mL) was added 35% aqueous hydrogen peroxide (261 μL) at room temperature and stirred for 1 hour. The mixture was stirred at 40 ° C. for 4 hours and at room temperature for 12 hours. 35% hydrogen peroxide solution (261 μL) was added to the reaction solution at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. Water and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the resulting solid was collected by filtration. The obtained solid was purified by reverse phase column chromatography (CAPCELL PAK MG II, 0.1% trifluoroacetic acid / water: acetonitrile = 90: 10 to 10:90) to give the title compound (56 mg) as colorless Obtained as a solid.
1H NMR (600 MHz, DMSO-d6) δppm 3.44 (s, 2 H) 4.00 (s, 3 H) 5.86 (s, 2 H) 6.91 (br. S., 1 H) 7.07 (d, J = 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, J = 8.67, 2.48 Hz, 1 H) 8.13 (s, 1 H) 8.63 (d, J = 2.48 Hz, 1 H); MS (ESI pos.) M / z: 459 [M + H] +

  Using the same method as in Example 44, the compounds of Example 45 to Example 49 listed in Table 4 were obtained.

Example 45 2- {3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4-oxadiazole -2-yl] phenyl} acetamide Example 46 4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4- Yl] -1,3,4-oxadiazol-2-yl} benzamide Example 47 3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole -4-yl) -1,3,4-oxadiazol-2-yl] benzamide Example 48 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl}- 1H-pyrazol-4-yl) -1,3,4-oxadiazol-2-yl] benzamide Example 49 3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine -2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,3,4-oxadiazol-2-yl} benzamide

Example 50 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazole-3- Il] -N- (Oxetane-3-yl) benzamide

実施例１６で得られた4-[5-(1-メチル-5-{[4-(トリフルオロメチル)フェノキシ]メチル}-1H-ピラゾール-4-イル)-1,2,4-オキサジアゾール-3-イル]安息香酸（２２ ｍｇ）のテトラヒドロフラン（２．０ ｍＬ）溶液に、室温にてジイソプロピルエチルアミン（１７ μL）ヘキサフルオロリン酸ウロニウム ２−（１Ｈ−７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルメタンアミニウム（ＨＡＴＵ）（２８ ｍｇ）及びオキセタン-3-イルアミン塩酸塩（８．１ ｍｇ）を加え、４時間撹拌した。反応液に水を加えた後、クロロホルム/メタノール（９/１）にて３回抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液にて洗浄し、無水硫酸マグネシウムにて乾燥した後、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝９０：１０）にて精製して、表題化合物（２４ ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.57 (t, J=6.61 Hz, 2 H) 4.75 (t, J=7.02 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]+

4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadidioxide obtained in Example 16 [Azol-3-yl] benzoic acid (22 mg) in tetrahydrofuran (2.0 mL) at room temperature with diisopropylethylamine (17 μL) uronium hexafluorophosphate 2- (1H-7-azabenzotriazole-1- Yl) -1,1,3,3-tetramethylmethanaminium (HATU) (28 mg) and oxetan-3-ylamine hydrochloride (8.1 mg) were added and stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform / methanol (9/1). The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 90: 10) to give the title compound (24 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 4.57 (t, J = 6.61 Hz, 2 H) 4.75 (t, J = 7.02 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- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4 -Oxadiazol-3-yl] phenyl} acetamide

実施例５１と同様の手法を用いて、実施例２０で得られた{3-[5-(1-メチル-5-{[4-(トリフルオロメチル)フェノキシ]メチル}-1H-ピラゾール-4-イル)-1,2,4-オキサジアゾール-3-イル]フェニル}酢酸（４３ｍｇ）及びメチルアミン（７０ μＬ、２Ｍ テトラヒドロフラン溶液）より、表題化合物（３４ ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δppm 2.53 (d, J=4.54 Hz, 3 H) 3.45 (s, 2 H) 3.99 (s, 3H) 5.72 (s, 2 H) 7.30 (d, J=8.67 Hz, 2 H) 7.39 - 7.44 (m, 2 H) 7.69 (d, J=8.67 Hz, 2 H) 7.75 - 7.79 (m, 1 H) 7.89 (s, 1 H) 7.98 (d, J=4.54 Hz, 1 H) 8.23 (s, 1 H); MS (ESI neg.) m/z : 470 [M-H]-

Using the same procedure as in Example 51, the {3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4 obtained in Example 20 was used. -Il) -1,2,4-oxadiazol-3-yl] phenyl} acetic acid (43 mg) and methylamine (70 μL, 2M tetrahydrofuran solution) gave the title compound (34 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δppm 2.53 (d, J = 4.54 Hz, 3 H) 3.45 (s, 2 H) 3.99 (s, 3H) 5.72 (s, 2 H) 7.30 (d, J = 8.67 Hz, 2 H) 7.39-7.44 (m, 2 H) 7.69 (d, J = 8.67 Hz, 2 H) 7.75-7.79 (m, 1 H) 7.89 (s, 1 H) 7.98 (d, J = 4.54 Hz , 1 H) 8.23 (s, 1 H); MS (ESI neg.) M / z: 470 [MH]-

Example 52 2- {4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4-oxadiazole -2-yl] phenyl} acetamide

製造例８で得られたメチル ({4-[5-(1-メチル-5-{[4-(トリフルオロメチル)フェノキシ]メチル}-1H-ピラゾール-4-イル)-1,3,4-オキサジアゾール-2-イル]フェニル}アセチル)カルバマート（１１０ ｍｇ）、エタノール（２．２ ｍＬ）及び３Ｍ 水酸化ナトリウム水溶液（０．２１ ｍＬ）の混合物を室温にて２０時間攪拌した。反応液を１Ｍ 塩化水素水溶液にて酸性とした後、クロロホルムにて抽出した。有機層を減圧下濃縮した後、カラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム〜クロロホルム：メタノール＝９０：１０）及びＴＬＣ（シリカゲルプレート、クロロホルム：メタノール＝９：１）にて精製して、表題化合物（２２ ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 3.96 (s, 3 H) 4.35 (s, 2 H) 5.59 (s, 2 H) 7.24 (s, 2 H) 7.34 (br. s., 1 H) 7.39 (s, 2 H) 7.69 (s, 2 H) 7.83 (s, 2 H) 7.93 (br. s., 1 H) 8.00 (s, 1 H); MS (ESI pos.) m/z: 458 [M+H]+

Methyl ({4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4 obtained in Production Example 8 A mixture of -oxadiazol-2-yl] phenyl} acetyl) carbamate (110 mg), ethanol (2.2 mL) and 3M aqueous sodium hydroxide (0.21 mL) was stirred at room temperature for 20 hours. The reaction solution was acidified with 1M aqueous hydrogen chloride solution and extracted with chloroform. The organic layer was concentrated under reduced pressure, and purified by column chromatography (silica gel cartridge, chloroform to chloroform: methanol = 90: 10) and TLC (silica gel plate, chloroform: methanol = 9: 1) to give the title compound (22 mg) was obtained as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 3.96 (s, 3 H) 4.35 (s, 2 H) 5.59 (s, 2 H) 7.24 (s, 2 H) 7.34 (br. S., 1 H) 7.39 (s, 2 H) 7.69 (s, 2 H) 7.83 (s, 2 H) 7.93 (br. S., 1 H) 8.00 (s, 1 H); MS (ESI pos.) M / z: 458 [M + H] +

Test example 1
(Preparation of crude membrane fraction of CHO cells stably expressing human metabotropic glutamate receptor (mGlu2))
Human-type mGlu2 receptor stably expressing CHO cells were obtained by using 10% dialyzed fetal bovine serum-containing Dulbecco's modified Eagle medium [1% proline, 50 units / mL penicillin, 50 μg / mL streptomycin, 400 μg / mL Hygromycin B, 2 mM L-glutamine (for use) Added)] and cultured at 37 ° C. under 5% CO ₂ . The confluent cells were washed twice with PBS (−), detached with a cell scraper, and centrifuged at 4 ° C., 1000 rpm for 5 minutes to collect the cells. The obtained precipitate was suspended in 20 mM HEPES buffer (pH 7.4), the suspension was homogenized with a Teflon (registered trademark) homogenizer, and then centrifuged at 4 ° C., 48,000 × g for 20 minutes. By getting sunk again. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at −80 ° C.

([ ³⁵ S] GTPγS binding test)
The frozen membrane fraction prepared above was thawed before use, and a binding test buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , 8.4 μM GDP, 10 μg / mL saponin, 0.1% BSA) Diluted with Example compounds were added to the membrane fraction of membrane protein 10 μg / assay and incubated at 30 ° C. for 20 minutes. Then, glutamic acid (final concentration 20 μM) and [ ³⁵ S] GTPγS (final concentration 0.15 nM) were added, and incubation was performed at 30 ° C. for 1 hour. After the incubation, the reaction solution was suction filtered onto a Whatman GF / C filter pre-soaked in 20 mM HEPES buffer (pH 7.4), and the filter was ice-cooled 20 mM HEPES buffer (pH 7.4). Washed 3 times with 300 μL. A scintillation cocktail was added to the obtained filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.
The amount of [ ³⁵ S] GTPγS binding when the above reaction was performed in the absence of glutamic acid was defined as non-specific binding, and the difference from the amount of [ ³⁵ S] GTPγS binding obtained in the presence of glutamic acid was defined as specific binding. Inhibition curves were obtained from the specific binding inhibition rates at various concentrations of each Example compound using nonlinear analysis. The concentration (IC ₅₀ value) of each Example compound at which the specific [ ³⁵ S] GTPγS binding amount was suppressed by 50% was calculated from the inhibition curve.
As a result of the above test, the IC ₅₀ value of the compound of the present invention was 10 μM or less. The IC ₅₀ values of the compounds of the present invention are exemplified in Table 5.

  The compound of the present invention has an antagonistic action on a group II mGlu receptor, and is a prophylactic and therapeutic agent for diseases related to the group II mGlu receptor, specifically, mood disorders (depressive disorders, bipolar) Disorders), anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive impairment, It can be used as a preventive or therapeutic agent for dementia, drug dependence, convulsions, tremors, pain, sleep disorders and the like.

Claims (6)

Formula [I]

[In the formula [I],
R ¹ represents a hydrogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ² represents a hydrogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
Ring A represents a phenyl group or a heteroaryl group,
R ³ represents a hydrogen atom, a halogen atom or a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ⁴ represents a C _1-6 alkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl group or C _1-6 alkoxy group is substituted with —CONR ^a R ^b , —COR ^c or a cyano group). -CONR ^a R ^b , -O-CONR ^a R ^b , -COR ^c or a cyano group,
R ^a and R ^b are the same or different, a hydrogen atom, C _1-6 alkyl, (wherein the C _1-6 alkyl group is an amino group, a mono -C _1-6 alkylamino group, di -C _{1 -6} may be substituted with 1 to 2 substituents selected from the group consisting of alkylamino groups and hydroxyl groups), or represents a 4- to 6-membered cyclic ether group,
Or, R ^a and R ^b are formed together with a nitrogen atom to be bonded to form a saturated or unsaturated 5- or 6-membered ring which may further contain one or more nitrogen atom, oxygen atom or sulfur atom. You can,
R ^c represents a hydroxyl group or a C _1-6 alkoxy group,
Y ¹ represents — (CH ₂ ) _n —O— or — (CH ₂ ) _m —,
n represents an integer of 0 to 6,
m represents an integer of 0 to 6,
Y ² represents an aryl group or heteroaryl group (wherein the aryl group or heteroaryl group is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group (wherein the C _{1- A 6} alkyl group, a C _3-6 cycloalkyl group or a C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 selected from the group consisting of a cyano group and a halogen atom It may be substituted with 3 substituents. },
Y ³ represents a 5-membered heteroarylene]
Or a pharmaceutically acceptable salt thereof. In the formula [I],
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a 6-membered heteroaryl group. Y ¹ is —CH ₂ —O—,
Y ² is a phenyl group or a pyridyl group (wherein the phenyl group or pyridyl group is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group (wherein the C _1-6 alkyl is Group, a C _3-6 cycloalkyl group or a C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 to 3 selected from the group consisting of a cyano group and a halogen atom It may be substituted with a substituent. } Or a pharmaceutically acceptable salt thereof according to claim 1 or 2. The pharmaceutical which contains the compound or its pharmaceutically acceptable salt of any one of Claims 1-3 as an active ingredient. The medicament according to claim 4, which is a group II metabotropic glutamate receptor antagonist. Mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, comprising as an active ingredient the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. , Preventive or therapeutic agent for convulsions, tremors, pain, or sleep disorders.