WO2012099200A1 - Pyrazole derivative - Google Patents

Pyrazole derivative Download PDF

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Publication number
WO2012099200A1
WO2012099200A1 PCT/JP2012/051070 JP2012051070W WO2012099200A1 WO 2012099200 A1 WO2012099200 A1 WO 2012099200A1 JP 2012051070 W JP2012051070 W JP 2012051070W WO 2012099200 A1 WO2012099200 A1 WO 2012099200A1
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Prior art keywords
group
methyl
pyrazol
oxadiazol
trifluoromethyl
Prior art date
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PCT/JP2012/051070
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French (fr)
Japanese (ja)
Inventor
誠治 増田
洋平 松田
一成 坂上
一豪 小西
洋樹 浦部
梨絵 下野
久美子 岡田
年男 中村
博 川元
幸祐 鹿沼
英明 天田
直樹 宮腰
修平 柏
彩 二村
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大正製薬株式会社
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Publication of WO2012099200A1 publication Critical patent/WO2012099200A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • Glutamate 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.
  • Glutamate receptors are ionotropic receptors (iGlu receptors) and G-protein coupled receptors (GPCRs), which are metabotropic receptors (metabolic glutamate receptors). ) are roughly divided.
  • iGlu receptor is based on its agonist specificity, N-methyl-D-aspartate (NMDA) receptor, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropion There are three types of receptors: acid ( ⁇ -amino-3-hydroxy-5-methyl-4-isopropylpropionic acid (AMPA)) receptors and kainate receptors.
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isopropylpropionic acid
  • 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 signal transduction system and pharmacological properties to be coupled. , 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.
  • Non-patent Document 1 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.
  • Group II mGlu receptor antagonists exhibit antidepressant and anxiolytic 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).
  • Patent Documents 1 to 5 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.
  • 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 includes a phenyl group, a heteroaryl group, an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group, a benzo [d] Represents an imidazol-2-one-5-yl group or a pyridonyl group; Ring A is an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group or a benzo [d] imidazol-2--
  • the octan-6-yl group may be substituted with 1 to 2 halogen atoms. May be substituted with 1 to 3 substituents selected from the group consisting of ⁇ , A C 1-6 alkanoyl group, an oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group, Alternatively, R a and R b are formed together with a nitrogen atom to be bonded, and are a saturated or unsaturated 4- to 6-membered ring (here, which may further contain one or more nitrogen atom, oxygen atom or sulfur atom (wherein The saturated or unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group.
  • R a1 and R b1 are formed together with a nitrogen atom to which they are bonded, and are a saturated or unsaturated 4- to 6-membered ring that may contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms, Or an unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group.
  • R c represents a C 1-6 alkyl group, a hydroxyl group or a C 1-6 alkoxy group
  • R d represents a hydrogen atom or a C 1-6 alkyl group
  • R e represents a C 1-6 alkoxy group, an amino group, a mono-C 1-6 alkylamino group or a di-C 1-6 alkylamino group
  • R f and R g are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group
  • Y 1 represents — (CH 2 ) n —O— or — (CH 2 ) m —
  • n represents an integer of 1 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
  • 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).
  • R a and R b are the same or different and are each a hydrogen atom, a C 1-6 alkyl group, 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.
  • 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.
  • 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 1 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 according to (1),
  • the present compound and pharmaceutically acceptable salts thereof have been found to have strong group II mGlu receptor antagonistic activity.
  • Halogen atom means 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, such as a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutyl group.
  • 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.
  • the “C 1-6 alkanoyl group” is a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, A valeryl group, a hexanoyl group, a pivaloyl group, etc. are 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 fused-ring 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-in
  • 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.
  • the “5-membered heteroaryl group” means a 5-membered aromatic heterocyclic group such as thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group.
  • C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • 5-membered heteroarylene means a divalent group formed by removing any one hydrogen atom from the above-mentioned “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 A piperazino group, a morpholino group, a thiomorpholino group, a 1,2,3,6-tetrahydropyridin-1-yl group, and the like.
  • “Saturated or unsaturated 4- to 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, an azetidino group, a pyrrolidino group And piperidino group, piperazino group, morpholino group, thiomorpholino group, 1,2,3,6-tetrahydropyridin-1-yl group and the like.
  • 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”.
  • R 1 is preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a C 1-6 alkyl group. Particularly preferred R 1 is a methyl group.
  • R 2 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.
  • R 3 is preferably 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), more preferably a hydrogen atom.
  • R 4 is a C 1-3 alkyl group, a C 1-3 alkoxy group (wherein the C 1-3 alkyl group or C 1-3 alkoxy group is substituted with —CONR a R b , or a hydroxyl group. ), —CONR a R b , —NR d COR e or —NR d SO 2 R e (wherein R a , R b , R c , R d and R e are as defined above).
  • Preferred Y 1 is —CH 2 —O—.
  • Y 2 is preferably 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 The alkyl group, C 3-6 cycloalkyl group or 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 May be substituted with one substituent.
  • Preferred Y 3 is any of the structures shown in formula [II]
  • R 1 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);
  • 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).
  • R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group (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 4-6 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.
  • 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 compound 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 their salts. 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.
  • an isotope eg, D, 3 H, 13 C, 14 C, 15 N, 31 P, 32 P, 35 S, 18 F, 125 I, etc.
  • the pharmaceutically acceptable salt means a pharmaceutically acceptable salt.
  • 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.
  • 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), lubricant (eg, magnesium stearate, calcium stearate, talc, colloidal silica), binder (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
  • preservatives for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • antioxidants for example, sulfites, Ascorbic acid and the like
  • colorants for example, sweeteners, adsorbents, wetting agents and the like
  • the compound [I] or 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
  • the compound [I] of the present invention or a pharmaceutically acceptable salt is appropriately selected depending on the administration subject, administration route, disease, patient age, weight and symptoms. For example, when treating an adult patient, the dose is 1 to 2000 mg / day, and this amount is administered once or divided into several times a day.
  • Group II mGlu receptor antagonist When Group II mGlu receptor antagonist is used as an active pharmaceutical ingredient, it is not intended for use only in humans, but in other animals other than humans (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.
  • “Inert solvent” means, for example, aromatic solvents such as benzene, toluene, xylene, pyridine; hydrocarbon solvents such as hexane, pentane, cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.
  • Halogenated hydrocarbon 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; sulfos such as dimethyl sulfoxide Sid solvents; acetonitrile, nitriles and water, such as propionitrile, and also these homogeneous and heterogeneous mixed solvents.
  • 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, Beauty hydroxide Alkali metal or alkaline earth metal hydroxides such as sodium carbonate; alkaline metal or alkaline earth metal carbonates such as sodium carbon
  • 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.
  • 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.
  • the compound [II] of the present invention is obtained by subjecting the compound (1) in which R 5 is a hydrogen atom to an amidation reaction known to those skilled in the art in an inert solvent, followed by the subsequent intramolecular cyclization reaction. ⁇ See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC. ⁇ .
  • 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.
  • 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)
  • the amidation reaction using the condensing agent additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.
  • 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.
  • 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) ⁇ .
  • R 5 is a hydrogen atom in an inert solvent
  • 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.
  • 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)
  • 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.
  • an activator such as tosyl chloride, thionyl chloride, phosphoryl chloride, Burgess Reagent ⁇ Methyl-N- (triethylammoniumsulfonyl) carbamate ⁇ can be used. ⁇ See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC. ⁇ .
  • compound (4) can be produced by the following method.
  • 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>.
  • R 6 is an amino-protecting group
  • 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. ⁇ .
  • compound (6) is produced 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.
  • Step 5 Compound (4) can be produced from compound (6) and compound (7) by the same method as in Step 2 in ⁇ Scheme 2>.
  • 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.
  • Step 6 Compound [I-IV] of the present invention can be produced from compound [I-III] of the present invention and compound (8) by the same method as in Step 2 in ⁇ Scheme 2>.
  • 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.
  • Step 7 The compound [IV] of the present invention is produced by a reductive amination reaction known to those skilled in the art of the compound (8) and the compound (9) in the presence of an acid and a reducing agent in an inert solvent. ⁇ Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC. ⁇ .
  • the compound (8) and the compound (9) 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.
  • the acid herein 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.
  • the reducing agent used in the reductive amination reaction is a reagent capable of reducing an imino group to convert it to an amino group.
  • sodium borohydride, sodium triacetoxyborohydride, cyanoborohydride Sodium, borane, borane-pyridine, borane-picoline and the like can be mentioned.
  • Step 8 Compound [I-VII] of the present invention can be produced by a hydration reaction known to those skilled in the art of Compound [I-VI] of the present invention ⁇ Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) See 1999 John Wiley & Sons, INC. ⁇ .
  • a compound in which compound (1) is represented by formula (1-1) or formula (1-2) can be produced by the following method.
  • R 10 , R 10 ′ and R 10 ′′ 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 represents a chlorine atom, bromine An atom, an iodine atom, or a fluorine atom is shown.
  • Step 9 Compound (1-1) can be produced by Mitsunobu reaction of compound (10) and compound (11) in an inert solvent.
  • the compound (10) and the compound (11) 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.
  • Step 10 Compound (1-2) is compound (10) and Compound (12) in an inert solvent in the presence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a palladium catalyst ligand.
  • a base in the presence or absence of a palladium catalyst
  • a palladium catalyst ligand in the presence or absence of a palladium catalyst ligand.
  • Examples of the base here include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hydride, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide.
  • Examples of the palladium catalyst include palladium acetate (II), 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), etc. It is done.
  • a compound in which compound (10) is represented by formula (10-1) can be produced by the following method.
  • Step 11 Compound (14) can be produced by reacting compound (13) with N, N-dimethylformamide or the like in the presence of a base in an inert solvent.
  • Compound (13) 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 12 Compound (10-1) can be produced by reacting compound (14) with a reducing agent in an inert solvent. ⁇ See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC. ⁇ .
  • the reducing agent is a reagent that can reduce a formyl group and convert it into a hydroxyl group.
  • a reagent that can reduce a formyl group and convert it into a hydroxyl group.
  • compound (2) can be produced by the following method.
  • Step 13 Compound (16) is appropriately combined with Compound (15) in an inert solvent in the presence or absence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a palladium catalyst ligand. It can be produced by reaction with a cyanating agent.
  • a cyanating agent As the compound (15), 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.
  • suitable cyanating agents include, for example, zinc cyanide, copper cyanide, potassium cyanide or sodium cyanide.
  • Step 14 Compound (2) can be produced by addition reaction of compound (16) with hydroxyamine or a salt thereof in an inert solvent in the presence or absence of a base.
  • compound (16) synthesized from the compound (15) 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.
  • compound (3) can be produced by the following method.
  • Step 15 Compound (3) can be produced from compound (17) and compound (5) by the same method as in Step 4 in ⁇ Scheme 3>.
  • the compound (17) and the compound (5) a commercially available compound, a known compound or a compound synthesized from a known compound by using various organic synthesis methods known to those skilled in the art can be used.
  • Biotage (registered trademark) SNAP cartridge KP-NH manufactured by Biotage was used for “NH silica gel cartridge” when purified using column chromatography, and Biotage was manufactured for “silica gel cartridge”.
  • Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil
  • Silica gel 60 N is silica gel 60 N manufactured by Kanto Chemical Co.
  • Chromatolex NH Chromatrex (registered trademark) NH manufactured by Fuji Silysia Chemical Ltd.
  • NMR nuclear magnetic resonance
  • Ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4-carboxylate Ethyl 5-formyl-1-methyl-1H-pyrazole-4-carboxylate Diisopropylamine (27 1.6 g) in tetrahydrofuran (400 mL) was added dropwise n-butyllithium (105 mL, 2.60 M hexane solution) under ice bath cooling, and the mixture was stirred for 1 hour.
  • 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 dropwise, and the mixture was stirred for 2 hr.
  • N, N-dimethylformamide (79.7 g) was added dropwise to the reaction solution at ⁇ 78 ° C., and the mixture was stirred for 1 hour, and then 2M aqueous hydrogen chloride solution was added.
  • the reaction mixture was acidified with 5M aqueous hydrogen chloride solution and extracted three times with ethyl acetate.
  • reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • HATU Tetramethyluronium hexafluorophosphoric acid
  • Example 2 Using the same method as in Example 1, the compounds of Examples 2 to 14 listed in Table 1-1 to Table 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-pyrazol-4- Yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 4 2- (3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] Oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide
  • Example 5 6- [5- (1-Methyl-5- ⁇ [4- (tri Fluor
  • Example 16 Using the same method as in Example 15, the compounds of Example 16 to Example 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-oxadiazol-3-yl] Benzoic acid
  • Example 17 3- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4-oxadiazol-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-pyrazol-4-yl) -1
  • Example 33 Using the same method 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 3- [5- (1-methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4-oxadiazol-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
  • Example 45 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-oxadiazol-2 -Yl] phenyl ⁇ acetamide
  • Example 46 4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,3,4-oxadiazol-2-yl ⁇ benzamide
  • Example 47 3- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl ) -1,3,4-oxadiazol-2-yl] benzamide
  • Example 48 4- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol
  • Example 20 Using the same procedure as in Example 50, ⁇ 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 ⁇ L, 2M tetrahydrofuran solution) gave the title compound (34 mg) as a colorless solid.
  • Example 53 3-Fluoro-4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1 , 2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 54 2- (2-Bromo-4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] Oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide
  • Example 55 N- (2-hydroxyethyl) -3- ⁇ 5- [1-methyl -5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 56 2
  • Example 50 Using the same method as in Example 50, the compounds of Examples 129 to 175 described in Table 6-1 to Table 6-8 were obtained.
  • N- (2,2-dimethoxyethyl) -3- (N′-hydroxycarbamimidoyl) benzamide (846 mg) obtained in Production Example 5 was added to the reaction solution, and the mixture was stirred at 120 ° C. for 10 hours.
  • the reaction mixture was allowed to cool to room temperature, ISOLUTE HM-N was added, and the mixture was concentrated under reduced pressure.
  • Example 177 and Example 178 were obtained using the same method as in Example 176.
  • Example 179 N- ⁇ 2-[(3S) -3-fluoropyrrolidin-1-yl] ethyl ⁇ -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridine-2 -Yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide N- (2,2-dimethoxyethyl) -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy obtained in Example 176-1) ⁇ Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide (52 mg) in tetrahydrofuran (1.0 mL) and p-toluenesulfonic acid monohydrate (8.4 mg) was added, and the mixture was stirred at room temperature for 19 hours.
  • Example 180 In the same manner as in Example 179, the compounds of Example 180 to Example 187 described in Table 7-1 to Table 7-2 were obtained.
  • Example 180 N- [2- (azetidin-1-yl) ethyl] -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 181 N- [2- (3,3-difluoroazetidin-1-yl) ethyl] -3- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇
  • Example 182 N- [2- (3-Fluoroazetidin-1-yl) ethyl] -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (triflu
  • Example 188 N-acetyl-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 2- (4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl obtained in Example 1 ] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide (100 mg), acetic anhydride (67 ⁇ L) and pyridine (2.0 mL) were stirred at 85 ° C.
  • Example 189 (4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2, 4-oxadiazol-3-yl ⁇ phenyl) acetonitrile 2- (4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl obtained in Example 1 ] To a solution of 1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide (100 mg) in pyridine (2.0 mL) under ice-cooling, phosphorus oxychloride (40 ⁇ L) was added at room temperature.
  • Example 190 2- [4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ -2-oxopyridin-1 (2H) -yl] acetamide 1) 4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl ⁇ pyridin-2 (1H) -one 1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H- obtained in Preparation Example 4 To a solution of pyrazole-4-carboxylic acid (100 mg) in N, N-dimethylformamide (2.0 mL) was added 1,1
  • N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboximidamide (62 mg) obtained in Production Example 5 was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and at 110 ° C. for 14 hours. did.
  • the reaction solution was allowed to cool to room temperature, water was added, and the precipitated crystals were collected by filtration. This afford the title compound recrystallized from ethyl acetate (74 mg) as a colorless solid.
  • Example 191 2- [5- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4 -Oxadiazol-3-yl ⁇ -2-oxopyridin-1 (2H) -yl] acetamide Using a method similar to that in Example 190, the title compound was obtained as a colorless solid.
  • Example 192 N- (3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ phenyl) sulfuric diamide 1) 3- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl ⁇ aniline 1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazole-4-carboxylic acid obtained in Production Example 4 To a solution of 800 mg) in N, N-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (517 mg) at room temperature and stirred for 30 minutes.
  • Triethylamine (319 ⁇ L) and 3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ aniline 159 mg was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 21 hours.
  • a saturated aqueous sodium hydrogen carbonate solution (1.6 mL) and water (1.6 mL) were added to the reaction solution, and the two layers were separated.
  • the organic layer was passed through a phase separator (manufactured by Biotage Corp.), water was removed, and the mixture was concentrated under reduced pressure. Chloroform was added to the residue, trifluoroacetic acid (3.2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and chloroform (6.4 mL), saturated aqueous sodium hydrogen carbonate solution (3.2 mL), water (6.4 mL) and methanol (3.2 mL) were added to the residue. After separating the two layers, the aqueous layer was extracted with a mixed solvent of chloroform (3.2 mL) -methanol (1.6 mL).
  • Test example 1 Preparation of crude membrane fraction of CHO cells stably expressing human metabotropic glutamate receptor (mGlu2)
  • CHO cells stably expressing human mGlu2 receptor were mixed with Dulbecco's modified Eagle medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 ⁇ g / mL streptomycin, 400 ⁇ g / mL Hygromycin B, 2 mM L-glutamine (for use) Added)] and cultured at 37 ° C. under 5% CO 2 .
  • Confluent cells were washed twice with PBS ( ⁇ ), detached with a cell scraper, and centrifuged at 4 ° C.
  • 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 resulting precipitate was washed twice by centrifugation and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at ⁇ 80 ° C.
  • 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 ⁇ L. 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] GTP ⁇ S 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] GTP ⁇ S 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] GTP ⁇ S binding amount was suppressed by 50% was calculated from the inhibition curve.
  • a compound having an IC 50 value of 0.1 ⁇ M or less is represented by A
  • a compound having 0.1 ⁇ M to 1 ⁇ M is represented by B
  • a compound having 1 ⁇ M to 10 ⁇ M is represented by C
  • a compound having 10 ⁇ M or more is represented by D.
  • IC 50 values are exemplified in Table 9.
  • the compound of the present invention has an antagonistic action on Group II mGlu receptor, and is a preventive and therapeutic agent for diseases related to Group II mGlu receptor, specifically mood disorders (depressive disorder, 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.
  • mood disorders depressive disorder, 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.

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

ピラゾール誘導体Pyrazole derivative
　本発明は、グループII代謝型グルタミン酸（ｍＧｌｕ）受容体に対して拮抗作用を有する新規な化合物又はその医薬上許容される塩、並びにそれらを有効成分として含有する気分障害（うつ病性障害、双極性障害等）、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、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、及び睡眠障害等の疾患の予防又は治療剤に関する。 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.
　グルタミン酸は哺乳類の中枢神経系において記憶・学習などの高次機能を調節する主要な興奮性神経伝達物質の１つとして知られている。グルタミン酸受容体は、イオンチャネル型受容体（ｉｏｎｏｔｒｏｐｉｃ　ｇｌｕｔａｍａｔｅ　ｒｅｃｅｐｔｏｒ：ｉＧｌｕ受容体）と、Ｇタンパク質共役型受容体（Ｇ－ｐｒｏｔｅｉｎ　ｃｏｕｐｌｅｄ　ｒｅｃｅｐｔｏｒ：ＧＰＣＲ）である代謝型受容体（ｍｅｔａｂｏｔｒｏｐｉｃ　ｇｌｕｔａｍａｔｅ　ｒｅｃｅｐｔｏｒ：ｍＧｌｕ受容体）の２つに大別される。ｉＧｌｕ受容体はそのアゴニスト特異性に基づいてＮ－メチル－Ｄ－アスパラギン酸（Ｎ－ｍｅｔｈｙｌ－Ｄ－ａｓｐａｒｔａｔｅ： ＮＭＤＡ）受容体、α－アミノ－３－ヒドロキシ－５－メチル－４－イソオキサゾールプロピオン酸（α－ａｍｉｎｏ－３－ｈｙｄｒｏｘｙ－５－ｍｅｔｈｙｌ－４－ｉｓｏｘａｚｏｌｅｐｒｏｐｉｏｎｉｃ　ａｃｉｄ：ＡＭＰＡ）受容体及びカイニン酸受容体の３つに分類される。一方、ｍＧｌｕ受容体は８つのサブタイプ（ｍＧｌｕ１～８）が存在し、共役する情報伝達系及び薬理学的特性によりグループＩ（ｍＧｌｕ１、ｍＧｌｕ５）、グループII（ｍＧｌｕ２、ｍＧｌｕ３）及びグループIII（ｍＧｌｕ４、ｍＧｌｕ６、ｍＧｌｕ７、ｍＧｌｕ８）に分類される。グループII及びグループIII　ｍＧｌｕ受容体は主に神経終末で自己受容体或いはヘテロ受容体として発現し、Ｇｉタンパク質を介してアデニル酸シクラーゼを抑制し、特定のＫ+あるいはＣａ2+チャネル活性を調節している。 Glutamate 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. Glutamate receptors are ionotropic receptors (iGlu receptors) and G-protein coupled receptors (GPCRs), which are metabotropic receptors (metabolic glutamate receptors). ) Are roughly divided. iGlu receptor is based on its agonist specificity, N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropion There are three types of receptors: acid (α-amino-3-hydroxy-5-methyl-4-isopropylpropionic acid (AMPA)) receptors and kainate receptors. 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 signal transduction system and pharmacological properties to be coupled. , 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.
　近年、気分障害、不安障害及び統合失調症等の精神疾患患者の脳脊髄液中及び血漿中グルタミン酸濃度が変化していることが報告され、精神疾患におけるグルタミン酸神経機能異常が示唆されている。グルタミン酸受容体の中でも、グループII　ｍＧｌｕ受容体の拮抗剤は、種々の動物モデルに於いて抗うつ作用・抗不安作用を示すことから（非特許文献１）、グループII　ｍＧｌｕ受容体拮抗剤は新規抗うつ薬・抗不安薬になる可能性が示唆されている。さらに、グループII　ｍＧｌｕ受容体拮抗剤の認知機能増強剤（認知症、アルツハイマー病）としての効能も示唆されている（非特許文献２）。 Recently, 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 the glutamate receptors, Group II mGlu receptor antagonists exhibit antidepressant and anxiolytic 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).
　最近、グループII　ｍＧｌｕ受容体拮抗作用を有する化合物が特許文献１～５等において報告されている。しかしながら、これらの特許文献にはヘテロアリール－ピラゾール骨格を有する化合物についてはなんら開示も示唆もない。 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国際公開公報WO2008 / 128889 International Publication ＷＯ２００８／１１９６８９国際公開公報WO2008 / 119689 International Publication ＷＯ２００７／０３９４３９国際公開公報WO2007 / 039439 International Publication ＷＯ２００６／０８４６３４国際公開公報WO2006 / 084634 International Publication ＷＯ２００１／０２９０１２国際公開公報WO2001 / 029012 International Publication
　本発明者らは、下記式［Ｉ］で表される化合物又はその医薬上許容される塩が上記課題を解決することを見出し、本発明を完結した。
すなわち、本発明は、
（１）式［Ｉ］ 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]
Figure JPOXMLDOC01-appb-C000003
 [式［Ｉ］中、
Ｒ1は、水素原子又はＣ1-6アルキル基（ここで該Ｃ1-6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Ｃ1-6アルキル基（ここで該Ｃ1-6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、ヘテロアリール基、インドリン－２－オン－５－イル基、イソインドリン－１－オン－５－イル基、イソインドリン－１－オン－６－イル基、ベンゾ[ｄ]イミダゾール－２－オン－５－イル基又はピリドニル基を示し、
環Ａがインドリン－２－オン－５－イル基、イソインドリン－１－オン－５－イル基、イソインドリン－１－オン－６－イル基又はベンゾ[ｄ]イミダゾール－２－オン－５－イル基のとき、
Ｒ3及びＲ4は、同一又は異なって、水素原子、ハロゲン原子又はＣ1-6アルキル基を示し、
環Ａがフェニル基、ヘテロアリール基又はピリドニル基のとき、
Ｒ3は、水素原子、ハロゲン原子、Ｃ1-6アルコキシ基又はＣ1-6アルキル基（ここで該Ｃ1-6アルコキシ基又はＣ1-6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、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基又はＣ1-6アルコキシ基は、－ＣＯＮＲaＲb、－ＣＯＲc、シアノ基又は水酸基で置換されている。）、－ＣＯＮＲaＲb、－Ｏ－ＣＯＮＲaＲb、－ＮＲa1Ｒb1、－ＣＯＲc、シアノ基、－ＮＲdＣＯＲe又は－ＮＲdＳＯ２Ｒeを示し、
Ｒa及びＲbは、同一又は異なって、水素原子、Ｃ1-6アルキル基
｛ここで該Ｃ1-6アルキル基は、
水酸基、
ハロゲン原子、
Ｃ1-6アルコキシ基
（ここで該Ｃ1-6アルコキシ基は、１から２個の水酸基で置換されてもよい。）、
－ＣＯＮＲfＲg、
アミノ基、
モノ－Ｃ1-6アルキルアミノ基、
ジ－Ｃ1-6アルキルアミノ基、
モルホリノ基、
ピペリジノ基、
ピロリジノ基、
アゼチジノ基、
１，３－ジオキソラン－２－イル基、
１，３－ジオキサン－２－イル基、
２－オキサ－６－アザスピロ[３.３]ヘプタン－６－イル基及び
５，７－ジオキサスピロ[２.５]オクタン－６－イル基
（ここで該モルホリノ基、ピペリジノ基、ピロリジノ基、アゼチジノ基、１，３－ジオキソラン－２－イル基、１，３－ジオキサン－２－イル基、２－オキサ－６－アザスピロ[３.３]ヘプタン－６－イル基及び５，７－ジオキサスピロ[２.５]オクタン－６－イル基
は１から２個のハロゲン原子で置換されてもよい。）
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。｝、
Ｃ1-6アルカノイル基、オキセタニル基、テトラヒドロフラニル基又はテトラヒドロピラニル基を示すか、
又は、Ｒa及びＲb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４から６員環（ここで該飽和又は不飽和の４から６員環は、Ｃ1-6アルキル基、オキソ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。）を形成してもよく、
Ｒa1及びＲb1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４から６員環（ここで該飽和又は不飽和の４から６員環は、Ｃ1-6アルキル基、オキソ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。）を形成し、
Ｒcは、Ｃ1-6アルキル基、水酸基又はＣ1-6アルコキシ基を示し、
Ｒdは、水素原子又はＣ1-6アルキル基を示し、
Ｒeは、Ｃ1-6アルコキシ基、アミノ基、モノ－Ｃ1-6アルキルアミノ基又はジ－Ｃ1-6アルキルアミノ基を示し、
Ｒf及びＲgは、同一又は異なって、水素原子又はＣ1-6アルキル基を示し、
Ｙ1は、－(ＣＨ2)n－Ｏ－又は－(ＣＨ2)ｍ－を示し、
ｎは、１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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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、
Figure JPOXMLDOC01-appb-C000003
 [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 includes a phenyl group, a heteroaryl group, an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group, a benzo [d] Represents an imidazol-2-one-5-yl group or a pyridonyl group;
Ring A is an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group or a benzo [d] imidazol-2-one-5 When Iru group,
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group,
When ring A is a phenyl group, heteroaryl group or pyridonyl group,
R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkoxy group or a C 1-6 alkyl group (wherein the C 1-6 alkoxy group or C 1-6 alkyl group is substituted with 1 to 3 halogen atoms) May be)
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 —CONR a R b , —COR c , a cyano group or a hydroxyl group) -CONR a R b , —O—CONR a R b , —NR a1 R b1 , —COR c , a cyano group, —NR d COR e or —NR d SO 2 R e ,
R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is
Hydroxyl group,
A halogen atom,
A C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with 1 to 2 hydroxyl groups),
-CONR f R g ,
An amino group,
Mono-C 1-6 alkylamino group,
Di-C 1-6 alkylamino group,
Morpholino groups,
Piperidino group,
Pyrrolidino group,
Azetidino group,
1,3-dioxolan-2-yl group,
1,3-dioxane-2-yl group,
2-oxa-6-azaspiro [3.3] heptan-6-yl group and 5,7-dioxaspiro [2.5] octane-6-yl group (wherein the morpholino group, piperidino group, pyrrolidino group, azetidino group 1,3-dioxolan-2-yl group, 1,3-dioxane-2-yl group, 2-oxa-6-azaspiro [3.3] heptan-6-yl group and 5,7-dioxaspiro [2. 5] The octan-6-yl group may be substituted with 1 to 2 halogen atoms.
May be substituted with 1 to 3 substituents selected from the group consisting of },
A C 1-6 alkanoyl group, an oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group,
Alternatively, R a and R b are formed together with a nitrogen atom to be bonded, and are a saturated or unsaturated 4- to 6-membered ring (here, which may further contain one or more nitrogen atom, oxygen atom or sulfur atom (wherein The saturated or unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group. Well,
R a1 and R b1 are formed together with a nitrogen atom to which they are bonded, and are a saturated or unsaturated 4- to 6-membered ring that may contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms, Or an unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group.
R c represents a C 1-6 alkyl group, a hydroxyl group or a C 1-6 alkoxy group,
R d represents a hydrogen atom or a C 1-6 alkyl group,
R e represents a C 1-6 alkoxy group, an amino group, a mono-C 1-6 alkylamino group or a di-C 1-6 alkylamino group,
R f and R g are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
Y 1 represents — (CH 2 ) n —O— or — (CH 2 ) m —,
n represents an integer of 1 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）[式［Ｉ］中、
Ｒ1は、水素原子又はＣ1-6アルキル基（ここで該Ｃ1-6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Ｃ1-6アルキル基（ここで該Ｃ1-6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Ｃ1-6アルキル基（ここで該Ｃ1-6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、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基又はＣ1-6アルコキシ基は、－ＣＯＮＲaＲb、－ＣＯＲc又はシアノ基で置換されている。）、－ＣＯＮＲaＲb、－Ｏ－ＣＯＮＲaＲb、－ＣＯＲc又はシアノ基を示し、
Ｒa及びＲbは、同一又は異なって、水素原子、Ｃ1-6アルキル基、（ここで該Ｃ1-6アルキル基はアミノ基、モノ－Ｃ1-6アルキルアミノ基、ジ－Ｃ1-6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。）、オキセタニル基、テトラヒドロフラニル基又はテトラヒドロピラニル基を示すか、
又は、Ｒa及びＲb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、
Ｒcは、水酸基又はＣ1-6アルコキシ基を示し、
Ｙ1は、－(ＣＨ2)n－Ｏ－又は－(ＣＨ2)ｍ－を示し、
ｎは、１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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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、（１）に記載の化合物又はその医薬上許容される塩、 (2) [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 and are each a hydrogen atom, a C 1-6 alkyl group, 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.), Represents an oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl 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 1 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 according to (1),
（３）環Ａが、フェニル基又は６員ヘテロアリール基である、（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）環Ａが、フェニル基又はピリジル基である、（３）に記載の化合物又はその医薬上許容される塩、
（５）Ｙ1が、－ＣＨ2－Ｏ－である、（１）～（４）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、
（６）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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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）～（５）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、
（７）Ｙ３が、式[II]に示す構造のいずれかである、（１）～（６）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、
Figure JPOXMLDOC01-appb-C000004
 （８）Ｒ3が、水素原子又はハロゲン原子である、（１）～（７）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、
（９）（１）～（８）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、
（１０）グループII代謝型グルタミン酸受容体拮抗物質である、（９）に記載の医薬、及び
（１１）（１）～（１０）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。 (3) The 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) The compound according to (3) or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a pyridyl group,
(5) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein Y 1 is —CH 2 —O—,
(6) 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 group, C 3-6 cycloalkyl group or 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 To 3 substituents. }, The compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof,
(7) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein Y 3 is any one of the structures shown in formula [II],
Figure JPOXMLDOC01-appb-C000004
 (8) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein R 3 is a hydrogen atom or a halogen atom,
(9) A medicament comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient,
(10) The pharmaceutical according to (9), which is a group II metabotropic glutamate receptor antagonist, and the compound according to any one of (11) (1) to (10) or a pharmaceutically acceptable salt thereof. It is a preventive or therapeutic agent for mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremor, pain, or sleep disorder as an active ingredient.
　本発明化合物及びその医薬上許容される塩は、強いグループII　ｍＧｌｕ受容体拮抗作用を有することを見出した。 The present compound and pharmaceutically acceptable salts thereof have been found to have strong group II mGlu receptor antagonistic activity.
　以下、更に詳細に本発明を説明する。 Hereinafter, the present invention will be described in more detail.
　本明細書で用いられている語句について説明する。 Explain the terms used in this specification.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　「Ｃ1-6アルキル基」とは、直鎖状又は分枝鎖状の炭素原子数１から６個のアルキル基であり、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、イソプロピル基、イソブチル基、ｔｅｒｔ－ブチル基、ｓｅｃ－ブチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ－ペンチル基、１，２－ジメチルプロピル基等が挙げられる。 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.
　「Ｃ1-6アルコキシ基」とは、直鎖状又は分枝鎖状の炭素原子数１から６個のアルコキシ基であり、例えば、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、イソプロポキシ基、イソブトキシ基、ｔｅｒｔ－ブトキシ基、ｓｅｃ－ブトキシ基、イソペンチルオキシ基、ネオペンチルオキシ基、ｔｅｒｔ－ペンチルオキシ基、１，２－ジメチルプロポキシ基等が挙げられる。 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.
　「モノ－Ｃ1-6アルキルアミノ基」とは、１個のＣ1-6アルキル基で置換されたアミノ基であり、例えば、メチルアミノ基、エチルアミノ基、プロピルアミノ基、ブチルアミノ基、ペンチルアミノ基、ヘキシルアミノ基、イソプロピルアミノ基、イソブチルアミノ基、ｔｅｒｔ－ブチルアミノ基、ｓｅｃ－ブチルアミノ基、イソペンチルアミノ基、ネオペンチルアミノ基、ｔｅｒｔ－ペンチルアミノ基、１，２－ジメチルプロピルアミノ基等が挙げられる。 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.
　「ジ－Ｃ1-6アルキルアミノ基」とは、それぞれ独立した２個のＣ1-6アルキル基で置換されたアミノ基であり、例えば、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジブチルアミノ基、ジペンチルアミノ基、ジヘキシルアミノ基、ジイソプロピルアミノ基、ジイソブチルアミノ基、ジ－ｔｅｒｔ－ブチルアミノ基、ジ－ｓｅｃ－ブチルアミノ基、ジ－イソペンチルアミノ基、ジ－ネオペンチルアミノ基、ジ－ｔｅｒｔ－ペンチルアミノ基、ジ－１，２－ジメチルプロピルアミノ基、エチルメチルアミノ基、イソプロピルメチルアミノ基、イソブチルイソプロピルアミノ基等が挙げられる。 The “di-C 1-6 alkylamino group” is an amino group substituted with two independent C 1-6 alkyl groups, such as a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutyl group. 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.
　「Ｃ1-6アルカノイル基」とは、直鎖状又は分枝鎖状の炭素原子数１から６個のアルカノイル基であり、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、ヘキサノイル基、ピバロイル基等が挙げられる。 The “C 1-6 alkanoyl group” is a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, A valeryl group, a hexanoyl group, a pivaloyl group, etc. are mentioned.
　「アリール基」とは、炭素原子数６から１８個で構成される単環から４環式の芳香族炭素環式基であり、例えば、フェニル基、ナフチル基、アントリル基、フェナントリル基、テトラセニル基、ピレニル基等が挙げられる。 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.
　「ヘテロアリール基」とは、単環式又は縮合環式芳香族複素環基を意味し、例えば、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、チエニル基、ピロリル基、チアゾリル基、イソチアゾリル基、ピラゾリル基、イミダゾリル基、フリル基、オキサゾリル基、イソオキサゾリル基、オキサジアゾリル基、１，３，４－チアジアゾリル基、１，２，３－トリアゾリル基、１，２，４－トリアゾリル基、テトラゾリル基、キノリル基、イソキノリル基、ナフチリジニル基、キナゾリニル基、ベンゾフラニル基、ベンゾチエニル基、インドリル基、ベンゾオキサゾリル基、ベンゾイソオキサゾリル基、１Ｈ－インダゾリル基、２Ｈ－インダゾリル基、ベンゾイミダゾリル基、ベンゾオキサジアゾリル基、ベンゾチアジアゾリル基、インドリジニル基、ベンゾフラザニル基、チエノピリジル基、ピラゾロピリジル基、イミダゾピリジル基、イミダゾピラジニル基、ピラゾロピリミジニル基、トリアゾロピリミジニル基、チエノチエニル基、イミダゾチアゾリル基等が挙げられる。 `` Heteroaryl group '' means a monocyclic or fused-ring 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, Ndorijiniru group, benzofurazanyl group, thienopyridyl group, pyrazolopyridyl group, imidazopyridyl group, imidazopyrazinyl group, pyrazolopyrimidinyl group, triazolopyrimidinyl group, thienothienyl group, imidazothiazolyl group, and the like.
　「６員ヘテロアリール基」とは、６員環式芳香族複素環基を意味し、例えば、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基等が挙げられる。 “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員ヘテロアリール基」とは、５員環式芳香族複素環基を意味し、例えば、チエニル基、ピロリル基、チアゾリル基、イソチアゾリル基、ピラゾリル基、イミダゾリル基、フリル基、オキサゾリル基、イソオキサゾリル基、オキサジアゾリル基、１，３，４－チアジアゾリル基、１，２，３－トリアゾリル基、１，２，４－トリアゾリル基、テトラゾリル基等が挙げられる。 The “5-membered heteroaryl group” means a 5-membered aromatic heterocyclic group such as thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group. Group, oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group and the like.
　「Ｃ3-6シクロアルキル基」とは、炭素原子数３から６個のシクロアルキル基を示し、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基を意味する。 The “C 3-6 cycloalkyl group” means a cycloalkyl group having 3 to 6 carbon atoms, and means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
　「５員ヘテロアリーレン」とは、前記の「５員のヘテロアリール基」から更に任意の１個の水素原子を除いてできる２価基を意味する。 “5-membered heteroarylene” means a divalent group formed by removing any one hydrogen atom from the above-mentioned “5-membered heteroaryl group”.
　「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」とは、例えば、ピロリジノ基、ピペリジノ基、ピペラジノ基、モルホリノ基、チオモルホリノ基、１，２，３，６－テトラヒドロピリジン－１－イル基、等が挙げられる。
　「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４から６員環」とは、例えば、アゼチジノ基、ピロリジノ基、ピペリジノ基、ピペラジノ基、モルホリノ基、チオモルホリノ基、１，２，３，６－テトラヒドロピリジン－１－イル基等が挙げられる。 “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 A piperazino group, a morpholino group, a thiomorpholino group, a 1,2,3,6-tetrahydropyridin-1-yl group, and the like.
“Saturated or unsaturated 4- to 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, an azetidino group, a pyrrolidino group And piperidino group, piperazino group, morpholino group, thiomorpholino group, 1,2,3,6-tetrahydropyridin-1-yl group and the like.
　「Ｃ1-6アルキレン」とは、前記の「Ｃ1-6アルキル基」から更に任意の１個の水素原子を除いてできる２価基を意味する。 “C 1-6 alkylene” means a divalent group formed by removing any one hydrogen atom from the above “C 1-6 alkyl group”.
　「Ｃ1-6オキシアルキレン」とは、前記の「Ｃ1-6アルコキシ基」から更に任意の１個の水素原子を除いてできる２価基を意味する。 “C 1-6 oxyalkylene” means a divalent group formed by removing any one hydrogen atom from the “C 1-6 alkoxy group”.
　本発明化合物の好ましい形態は以下の通りである。
式[Ｉ]において、
好ましいＲ1は、水素原子又はＣ1-6アルキル基であり、さらに好ましくはＣ1-6アルキル基である。特に好ましいＲ1は、メチル基である。
好ましいＲ2は、水素原子である。
好ましい環Ａは、フェニル基又は６員ヘテロアリール基であり、さらに好ましくはフェニル基又はピリジル基である。
好ましいＲ3は、水素原子、ハロゲン原子又はＣ1-6アルキル基（ここで該Ｃ1-6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。）であり、さらに好ましくは水素原子又はハロゲン原子である。
好ましいＲ4は、Ｃ1-3アルキル基、Ｃ1-3アルコキシ基（ここで該Ｃ1-3アルキル基又はＣ1-3アルコキシ基は、－ＣＯＮＲaＲb、又は水酸基で置換されている。）、－ＣＯＮＲaＲb、－ＮＲdＣＯＲe又は－ＮＲdＳＯ２Ｒeである（ここでＲa、Ｒb、Ｒc、Ｒd及びＲeは前記と同義である。）。
好ましいＹ1は、－ＣＨ2－Ｏ－である。
好ましいＹ2は、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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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。
好ましいＹ3は、式[II]に示す構造のいずれかである
Figure JPOXMLDOC01-appb-C000005
 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, more preferably a C 1-6 alkyl group. Particularly preferred R 1 is a methyl group.
Preferable R 2 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.
R 3 is preferably 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), more preferably a hydrogen atom. An atom or a halogen atom.
Preferred R 4 is a C 1-3 alkyl group, a C 1-3 alkoxy group (wherein the C 1-3 alkyl group or C 1-3 alkoxy group is substituted with —CONR a R b , or a hydroxyl group. ), —CONR a R b , —NR d COR e or —NR d SO 2 R e (wherein R a , R b , R c , R d and R e are as defined above).
Preferred Y 1 is —CH 2 —O—.
Y 2 is preferably 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 The alkyl group, C 3-6 cycloalkyl group or 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 May be substituted with one substituent. }.
Preferred Y 3 is any of the structures shown in formula [II]
Figure JPOXMLDOC01-appb-C000005
　式[Ｉ]における１つの好ましい形態は、
Ｒ1が、水素原子又はＣ1-6アルキル基（ここで該Ｃ1-6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。）であり、
Ｒ2が、水素原子又はＣ1-6アルキル基（ここで該Ｃ1-6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。）であり、
環Ａが、フェニル基又は６員ヘテロアリール基であり、
Ｒ3が、水素原子、ハロゲン原子又はＣ1-6アルキル基（ここで該Ｃ1-6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。）であり、
Ｒ4が、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基又はＣ1-6アルコキシ基は、－ＣＯＮＲaＲb、－ＣＯＲc又はシアノ基で置換されている。）、－ＣＯＮＲaＲb、－Ｏ－ＣＯＮＲaＲb、－ＣＯＲc又はシアノ基であり、
Ｒa及びＲbが、同一又は異なって、水素原子、Ｃ1-6アルキル基、（ここで該Ｃ1-6アルキル基はアミノ基、モノ－Ｃ1-6アルキルアミノ基、ジ－Ｃ1-6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４～６員の環状エーテル基であり、
又は、Ｒa及びＲbが、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、
Ｒcが、水酸基又はＣ1-6アルコキシ基であり、
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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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。｝であり、
Ｙ3が、５員ヘテロアリーレンである。 One preferred form in formula [I] is
R 1 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);
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 and each represents a hydrogen atom, a C 1-6 alkyl group (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 4-6 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.
　式[Ｉ]における、他の１つの好ましい形態は、下記式[III]で表される化合物である。
Figure JPOXMLDOC01-appb-C000006
 （式中、環Ａ、Ｒ3、Ｒ4及びＹ2は前記と同義である。） Another preferred form in the formula [I] is a compound represented by the following formula [III].
Figure JPOXMLDOC01-appb-C000006
 (In the formula, ring A, R 3 , R 4 and Y 2 are as defined above.)
　式[Ｉ]における、他の１つの好ましい形態は、下記式[IV]で表される化合物である。
Figure JPOXMLDOC01-appb-C000007
 （式中、環Ａ、Ｒ3、Ｒ4及びＹ2は前記と同義である。） Another preferred form in the formula [I] is a compound represented by the following formula [IV].
Figure JPOXMLDOC01-appb-C000007
 (In the formula, ring A, R 3 , R 4 and Y 2 are as defined above.)
　本発明化合物には互変異性体、幾何異性体等の立体異性体及び光学異性体が存在しうるが、本発明はそれらも包含する。また、発明化合物及びその塩の各種水和物、溶媒和物及び結晶多形の物質をも包含する。さらに、本発明化合物［Ｉ］は同位元素（例えば、Ｄ、3Ｈ、13Ｃ、14Ｃ、15Ｎ、31P、32P、35Ｓ、18Ｆ、125Ｉ等）で標識されていてもよい。 The compound 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 their salts. 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.
　本発明において、医薬上許容される塩とは、薬剤的に許容することのできる塩を意味する。それらは例えば、酢酸、プロピオン酸、酪酸、ギ酸、トリフルオロ酢酸、マレイン酸、酒石酸、クエン酸、ステアリン酸、コハク酸、エチルコハク酸、マロン酸、ラクトビオン酸、グルコン酸、グルコヘプトン酸、安息香酸、メタンスルホン酸、エタンスルホン酸、２－ヒドロキシエタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸（トシル酸）、ラウリル硫酸、リンゴ酸、アスパラギン酸、グルタミン酸、アジピン酸、システイン、Ｎ－アセチルシステイン、塩酸、臭化水素酸、リン酸、硫酸、ヨウ化水素酸、ニコチン酸、シュウ酸、ピクリン酸、チオシアン酸、ウンデカン酸、アクリル酸ポリマー及びカルボキシビニルポリマー等の酸との塩、リチウム塩、ナトリウム塩、カリウム塩及びカルシウム塩等の無機塩基との塩、モルホリン及びピペリジン等の有機アミン、並びにアミノ酸との塩を挙げることができる。 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.
　本発明化合物［Ｉ］又は医薬上許容される塩は、そのまま或いは医薬上許容される担体とともに、自体公知の手段に従って製剤化することができる。医薬上許容される担体としては、製剤素材として慣用の各種有機或いは無機担体物質、例えば、固形製剤における賦形剤（例えば、乳糖、白糖、Ｄ－マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等）、滑沢剤（例えば、ステアリング酸マグネシウム、ステアリング酸カルシウム、タルク、コロイドシリカ等）、結合剤（例えば、結晶セルロース、白糖、Ｄ－マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等）、崩壊剤（例えば、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース等）、又は液状製剤における溶剤（例えば、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油等）、溶解補助剤（例えば、ポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等）、懸濁化剤（例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤、若しくは例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等）、等張化剤（例えば、ブドウ糖、Ｄ－ソルビトール、塩化ナトリウム、グリセリン、Ｄ－マンニトール等）、緩衝剤（例えば、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等）、無痛化剤（例えば、ベンジルアルコール等）等が挙げられる。また、製剤化の際に、必要に応じて、防腐剤（例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等）、抗酸化剤（例えば、亜硫酸塩、アスコルビン酸等）、着色剤、甘味剤、吸着剤、湿潤剤等を用いることもできる。 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), lubricant (eg, magnesium stearate, calcium stearate, talc, colloidal silica), binder (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.), buffering agents ( 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.
　本発明化合物［Ｉ］又は医薬上許容される塩は、経口的又は非経口的（例えば、静脈、局所、直腸投与等）に投与することができる。その投与剤型は、例えば、錠剤（糖衣錠、フィルムコーティング錠を含む）、散剤、顆粒剤、粉剤、トローチ剤、カプセル剤（ソフトカプセルを含む）、液剤、注射剤（例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤等）、外用剤（例えば、経鼻投与製剤、経皮製剤、軟膏剤、クリーム剤等）、坐剤（例えば、直腸坐剤、膣坐剤等）、徐放剤（例えば、徐放性マイクロカプセル等）、ペレット、点滴剤等であり、いずれも慣用の製剤技術（例えば、第１５改正日本薬局方に記載する方法等）によって製造することができる。 The compound [I] or 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.
　本発明化合物［Ｉ］又は医薬上許容される塩は、投与対象、投与経路、疾患、患者の年齢、体重及び症状によって適宜選択される。例えば、成人患者を治療する場合、その投与量は１日１～２０００ ｍｇであり、この量を１日１回又は数回に分けて投与する。 The compound [I] of the present invention or a pharmaceutically acceptable salt is appropriately selected depending on the administration subject, administration route, disease, patient age, weight and symptoms. For example, when treating an adult patient, the dose is 1 to 2000 mg / day, and this amount is administered once or divided into several times a day.
　グループII　ｍＧｌｕ受容体拮抗物質を医薬の活性成分として使用する場合、それはヒトだけに使用することを意図するのではなく、ヒト以外のその他の動物（ネコ、イヌ、ウシ、ニワトリ、魚等）にも使用することが可能である。 When Group II mGlu receptor antagonist is used as an active pharmaceutical ingredient, it is not intended for use only in humans, but in other animals other than humans (cats, dogs, cows, chickens, fish, etc.) Can also be used.
　本発明化合物及びその医薬上許容される塩は、例えば、以下に示す方法によって合成することができるが、本発明の化合物の製造方法はこれらに限定されるものではない。 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.
　「不活性溶媒」とは例えば、ベンゼン、トルエン、キシレン、ピリジン等の芳香族系溶媒；ヘキサン、ペンタン、シクロヘキサン等の炭化水素系溶媒；ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒；テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン等のエーテル系溶媒；酢酸エチル、ギ酸エチル等のエステル系溶媒；メタノール、エタノール、イソプロピルアルコール、ｔｅｒｔ－ブチルアルコール、エチレングリコール等のアルコール系溶媒；アセトン、メチルエチルケトン等のケトン系溶媒；Ｎ、Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、Ｎ、Ｎ－ジメチルアセトアミド等のアミド系溶媒；ジメチルスルホキシド等のスルホキシド系溶媒；アセトニトリル、プロピオニトリル等のニトリル系溶媒及び水であり、並びにこれらの均一系及び不均一系混合溶媒等である。これらの不活性溶媒は当業者に公知である種々の反応条件に応じて適宜選択される。 “Inert solvent” means, for example, aromatic solvents such as benzene, toluene, xylene, pyridine; hydrocarbon solvents such as hexane, pentane, cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc. 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; sulfos such as dimethyl sulfoxide Sid 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.
　「塩基」とは例えば、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム等のアルカリ金属又はアルカリ土類金属の水素化物；リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等のアルカリ金属又はアルカリ土類金属のアミド；ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシド等のアルカリ金属又はアルカリ土類金属の低級アルコキシド；ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウム等のアルキルリチウム；水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウム等のアルカリ金属又はアルカリ土類金属の水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸セシウム等のアルカリ金属又はアルカリ土類金属の炭酸塩；炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属又はアルカリ土類金属の炭酸水素塩；トリエチルアミン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジメチルアニリン等のアミン；フッ化テトラ-n-ブチルアンモニウム、ベンジルトリメチルアンモニウムヒドロキシド等の４級アンモニウム塩；ピリジン、イミダゾール、２，６－ルチジン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノン－５－エン（ＤＢＮ）等の塩基性複素環化合物等である。これらの塩基は当業者に公知である種々の反応条件に応じて適宜選択される。 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, Bali hydroxide Alkali metal or alkaline earth metal hydroxides such as sodium carbonate; alkaline metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metals or alkaline earth such as sodium hydrogen carbonate and potassium hydrogen carbonate Metal carbonates; amines such as triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, N, N-dimethylaniline; quaternary ammonium such as tetra-n-butylammonium fluoride and benzyltrimethylammonium hydroxide Salt; pyridine, imidazole, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene And basic heterocyclic compounds such as (DBN). These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
　「酸」とは例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の無機酸及びｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、蟻酸、酢酸等の有機酸である。これらの酸は当業者に公知である種々の反応条件に応じて適宜選択される。 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.
〔製造法１〕
　本発明化合物［Ｉ－Ｉ］は以下の方法にて製造することができる。 [Production method 1]
The compound [II] of the present invention can be produced by the following method.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　式中、環Ａ、Ｒ1、Ｒ2、Ｒ３、Ｒ４、Ｙ1及びＹ2は前記と同義である。Ｒ５は、メチル基、エチル基、ｔｅｒｔ－ブチル基、ベンジル基等のカルボキシ基の保護基｛プロテクティブ　グループズ　イン　オーガニック　シンセシス（Protective Groups in Organic Synthesis）第４版、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝又は水素原子を示す。
　工程１：本発明化合物［Ｉ－Ｉ］は不活性溶媒中、塩基存在下、Ｒ５がカルボキシ基の保護基である化合物（１）と化合物（２）の当業者に公知である縮合反応、続く分子内環化反応により製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。或いは、本発明化合物［Ｉ－Ｉ］は不活性溶媒中、Ｒ５が水素原子である化合物（１）と化合物（２）の当業者に公知であるアミド化反応後、続く分子内環化反応により製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。ここで化合物（１）及び化合物（２）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここでアミド化反応とは、例えば、不活性溶媒中、塩基存在下又は非存在下、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸（ＨＡＴＵ）、Ｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸（ＨＢＴＵ）、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）、ジフェニルホスホリルアジド（ＤＰＰＡ）又はカルボニルジイミダゾール（ＣＤＩ）等の縮合剤を用いた縮合反応、クロロギ酸エチル、クロロギ酸イソブチル又はトリメチルアセチルクロリド等を用いた混合酸無水物経由の縮合反応、塩化チオニル、塩化オキサリル、１－クロロ－Ｎ，Ｎ，２－トリメチル－１－プロペニルアミン等を用いた酸ハロゲン化物経由の縮合反応等である。またここで、縮合剤を用いたアミド化反応の際、必要に応じて１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、ヒドロキシスクシンイミド（ＨＯＳｕ）等の添加剤を使用することができる。
　ここで分子内環化反応とは、例えば、不活性溶媒中、加熱または非加熱条件下、必要に応じて酸又は塩基を用いたアミド化合物の環化反応である。 In the formula, ring 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 to an amidation reaction known to those skilled in the art in an inert solvent, followed by the subsequent intramolecular cyclization reaction. {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), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), and other condensation reactions, chloroformate 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.
〔製造法２〕
　本発明化合物［Ｉ－ＩＩ］は以下の方法にて製造することができる。 [Production method 2]
The compound [I-II] of the present invention can be produced by the following method.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　式中、環Ａ、Ｒ1、Ｒ2、Ｒ３、Ｒ４、Ｒ５、Ｙ1及びＹ2は前記と同義である。
　工程２：化合物（４）は不活性溶媒中、Ｒ５が水素原子である化合物（１）と化合物（３）の当業者に公知であるアミド化反応により製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。ここで化合物（１）及び化合物（３）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここでアミド化反応とは、例えば、不活性溶媒中、塩基存在下又は非存在下、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸（ＨＡＴＵ）、Ｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸（ＨＢＴＵ）、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）、ジフェニルホスホリルアジド（ＤＰＰＡ）又はカルボニルジイミダゾール（ＣＤＩ）等の縮合剤を用いた縮合反応、クロロギ酸エチル、クロロギ酸イソブチル又はトリメチルアセチルクロリド等を用いた混合酸無水物経由の縮合反応、塩化チオニル、塩化オキサリル、１－クロロ－Ｎ，Ｎ，２－トリメチル－１－プロペニルアミン等を用いた酸ハロゲン化物経由の縮合反応等である。またここで、縮合剤を用いたアミド化反応の際、必要に応じて１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、ヒドロキシスクシンイミド（ＨＯＳｕ）等の添加剤を使用することができる。
　工程３：本発明化合物［Ｉ－ＩＩ］は不活性溶媒中、化合物（４）の分子内環化反応により製造することができる。本工程において必要に応じて、例えば、塩化トシル、塩化チオニル、塩化ホスホリル、バージェス試薬（Ｂｕｒｇｅｓｓ　Ｒｅａｇｅｎｔ）｛カルバミン酸メチル-N-(トリエチルアンモニウムスルホニル）｝等の活性化剤を使用することができる。｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。 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), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), and other condensation reactions, chloroformate 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, for example, an activator such as tosyl chloride, thionyl chloride, phosphoryl chloride, Burgess Reagent {Methyl-N- (triethylammoniumsulfonyl) carbamate} can be used. {See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC.}.
　また例えば、化合物（４）は以下の方法にて製造することができる。 For example, compound (4) can be produced by the following method.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　式中、環Ａ、Ｒ1、Ｒ2、Ｒ３、Ｒ４、Ｒ５、Ｙ1及びＹ2は前記と同義である。Ｒ６ はメトキシメチル基、トリメチルシリルエトキシメチル基、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、アセチル基、ベンジル基、トリチル基、メタンスルホニル基、ベンゼンスルホニル基、ｐ－トルエンスルホニル基等のアミノ基の保護基｛プロテクティブ　グループズ　イン　オーガニック　シンセシス（Protective Groups in Organic Synthesis）第４版、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝又は水素原子を示す。
　工程４：化合物（６）は＜スキーム２＞中の工程２と同様の手法により、Ｒ５が水素原子である化合物（１）と化合物（５）から製造することができる。ここでＲ６がアミノ基の保護基である場合は、化合物（６）は保護基Ｒ６を当業者に公知である種々の有機合成手法｛プロテクティブ　グループズ　イン　オーガニック　シンセシス（Protective Groups in Organic Synthesis）第４版、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝を用いて除去することにより製造することができる。または化合物（６）は不活性溶媒中、Ｒ５がカルボキシ基の保護基である化合物（１）とＲ６が水素原子である化合物（５）の当業者に公知である縮合反応により製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。ここで化合物（１）及び化合物（５）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。
工程５：化合物（４）は＜スキーム２＞中の工程２と同様の手法により、化合物（６）と化合物（７）から製造することができる。ここで化合物（７）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。 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, 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 produced 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.
〔製造法３〕
　本発明化合物［Ｉ－ＩＶ］は以下の方法にて製造することができる。 [Production method 3]
The compound [I-IV] of the present invention can be produced by the following method.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　式中、環Ａ、Ｒ1、Ｒ2、Ｒ３、Ｒa、Ｒb、Ｙ1、Ｙ２及びＹ３は前記と同義である。Ｒ７ は結合手、Ｃ1-6アルキレン又はＣ1-6オキシアルキレンを示す。
　工程６：本発明化合物［Ｉ－ＩＶ］は＜スキーム２＞中の工程２と同様の手法により、本発明化合物［Ｉ－ＩＩＩ］と化合物（８）から製造することができる。ここで化合物（８）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。 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: Compound [I-IV] of the present invention can be produced from compound [I-III] of the present invention and 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.
〔製造法４〕
　本発明化合物［Ｉ－Ｖ］は以下の方法にて製造することができる。 [Production Method 4]
The compound [IV] of the present invention can be produced by the following method.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　式中、環Ａ、Ｒ1、Ｒ2、Ｒ3、Ｒ７、Ｒa、Ｒb、Ｙ1、Ｙ２及びＹ３は前記と同義である。Ｒ8はＣ1-6アルキレン、Ｒ9はＣ1-6アルキル基を示す。
　工程７：本発明化合物［Ｉ－Ｖ］は、不活性溶媒中、酸及び還元剤存在下、化合物（８）と化合物（９）の当業者に公知である還元的アミノ化反応により製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。ここで化合物（８）及び化合物（９）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで酸とは、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の無機酸及びｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、蟻酸、酢酸等の有機酸が挙げられる。また、還元的アミノ化反応で用いる還元剤とは、イミノ基を還元してアミノ基に変換することができる試薬であり、例えば、水素化ホウ素ナトリウム、水素化ホウ素トリアセトキシナトリウム、水素化ホウ素シアノナトリウム、ボラン、ボラン－ピリジン、ボラン－ピコリン等が挙げられる。 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. R 8 represents C 1-6 alkylene, and R 9 represents a C 1-6 alkyl group.
Step 7: The compound [IV] of the present invention is produced by a reductive amination reaction known to those skilled in the art of the compound (8) and the compound (9) in the presence of an acid and a reducing agent in an inert solvent. {Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC.}. Here, as the compound (8) and the compound (9), 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. Examples of the acid herein 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. . The reducing agent used in the reductive amination reaction is a reagent capable of reducing an imino group to convert it to an amino group. For example, sodium borohydride, sodium triacetoxyborohydride, cyanoborohydride Sodium, borane, borane-pyridine, borane-picoline and the like can be mentioned.
〔製造法５〕
　本発明化合物［Ｉ－ＶＩＩ］は以下の方法にて製造することができる。 [Production Method 5]
The compound [I-VII] of the present invention can be produced by the following method.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　式中、環Ａ、Ｒ1、Ｒ2、Ｒ３、Ｒ７、Ｒa、Ｒb、Ｙ1、Ｙ２及びＹ３は前記と同義である。
　工程８：本発明化合物［Ｉ－ＶＩＩ］は、本発明化合物［Ｉ－ＶＩ］の当業者に公知である水和反応により製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。 In the formula, rings 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 8: Compound [I-VII] of the present invention can be produced by a hydration reaction known to those skilled in the art of Compound [I-VI] of the present invention {Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) See 1999 John Wiley & Sons, INC.}.
　例えば、化合物（１）が式（１－１）又は式（１－２）で表される化合物は以下の方法にて製造することができる。 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.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　式中、ｎ、Ｒ1、Ｒ2、Ｒ5及びＹ2は前記と同義である。Ｒ10、Ｒ10’及びＲ10’’ は同一又は異なって、水素原子、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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を示し、Ｘ1は、塩素原子、臭素原子、ヨウ素原子、フッ素原子を示す。
　工程９：化合物（１－１）は不活性溶媒中、化合物（１０）と化合物（１１）の光延反応により製造することができる。ここで化合物（１０）及び化合物（１１）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。光延反応とは、例えば、トリフェニルホスフィン、トリブチルホスフィン等の有機リン化合物とアゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル、アゾジカルボン酸ジｔｅｒｔブチル等のアゾ化合物を用いる方法、或いはシアノメチルトリブチルホスホラン等のリンイリド試薬を用いる方法が挙げられる（Ｃｈｅｍ．　Ｒｅｖ．　２００９．　１０９，２５５１－２６５１参照）。
　工程１０：化合物（１－２）は不活性溶媒中、塩基存在下、パラジウム触媒存在下又は非存在下、パラジウム触媒配位子の存在下又は非存在下、化合物（１０）と化合物（１２）を反応させることにより製造することができる｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。ここで化合物（１０）及び化合物（１２）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで塩基とは例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、水素化リチウム、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシド、ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等が挙げられる。パラジウム触媒とは例えば、酢酸パラジウム（II）、ジクロロビストリフェニルホスフィンパラジウム（II）、ジクロロビスアセトニトリルパラジウム（II）、テトラキストリフェニルホスフィンパラジウム（０）等が挙げられる。配位子とは例えばrac-2-(ジ-ｔ-ブチルホスフィノ)-1,1'-ビナフチル、トリフェニルホスフィン、トリブチルホスフィン、２，２－ビス（ジフェニルホスフィノ）－１，１－ビナフチル（ＢＩＮＡＰ）、２－（ジ－ｔｅｒｔ－ブチルホスフィノ）ビフェニル、1,1'-ビス(ジフェニルホスフィノ)フェロセン（ｄｐｐｆ）、１，３－ビス（ジフェニルホスフィノ）プロパン（ｄｐｐｐ）等が挙げられる。 In the formula, n, R 1 , R 2 , R 5 and Y 2 are as defined above. R 10 , R 10 ′ and R 10 ″ 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 represents a chlorine atom, bromine An atom, an iodine atom, or a fluorine atom is shown.
Step 9: Compound (1-1) can be produced by Mitsunobu reaction of compound (10) and compound (11) in an inert solvent. Here, as the compound (10) and the compound (11), 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 10: Compound (1-2) is compound (10) and Compound (12) in an inert solvent in the presence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a palladium catalyst ligand. {See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}. Here, as the compound (10) and the compound (12), 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. Examples of the base here include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hydride, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide. Sodium methoxide, sodium ethoxide, potassium tert-butoxide, butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Examples of the palladium catalyst include palladium acetate (II), 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), etc. It is done.
　例えば、化合物（１０）が式（１０－１）で表される化合物は以下の方法にて製造することができる。 For example, a compound in which compound (10) is represented by formula (10-1) can be produced by the following method.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　式中、Ｒ1、Ｒ2及びＲ５は前記と同義である。
　工程１１：化合物（１４）は不活性溶媒中、塩基存在下、化合物（１３）をＮ，Ｎ－ジメチルホルムアミド等と反応させることにより製造することができる。化合物（１３）は市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。
　工程１２：化合物（１０－１）は不活性溶媒中、化合物（１４）に対し、還元剤を反応させることにより製造することができる。｛コンプリヘンシブ　オーガニック　トランスフォーメーションズ　セカンド　エディション　（Comprehensive Organic Transformations Second Edition）　１９９９年、ジョン　ウィリー　アンド　サンズ（John Wiley & Sons, INC.）参照｝。ここで還元剤とは、ホルミル基を還元して水酸基に変換することができる試薬であり、例えば、水素化ホウ素リチウム、水素化ホウ素ナトリウム、水素化ホウ素カルシウム、水素化ホウ素亜鉛、水素化アルミニウムリチウム、水素化アルミニウムナトリウム、水素化ジイソブチルアルミニウム等が挙げられる。 In the formula, R 1 , R 2 and R 5 are as defined above.
Step 11: Compound (14) can be produced by reacting compound (13) with N, N-dimethylformamide or the like in the presence of a base in an inert solvent. Compound (13) 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 12: Compound (10-1) can be produced by reacting compound (14) 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.
　例えば、化合物（２）は、以下の方法にて製造することができる。 For example, compound (2) can be produced by the following method.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　式中、環Ａ、Ｘ１、Ｒ３及びＲ４は前記と同義である。
　工程１３：化合物（１６）は不活性溶媒中、塩基存在下又は非存在下、パラジウム触媒存在下又は非存在下、パラジウム触媒配位子の存在下又は非存在下、化合物（１５）と適当なシアノ化剤との反応により製造することができる。化合物（１５）は市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで、適当なシアノ化剤とは、例えば、シアン化亜鉛、シアン化銅、シアン化カリウム又はシアン化ナトリウムなどが挙げられる。
　工程１４：化合物（２）は不活性溶媒中、塩基存在下又は非存在下、化合物（１６）とヒドロキシアミン又はその塩の付加反応により製造することができる。化合物（１６）は化合物（１５）から合成する他に、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。 In the formula, rings A, X 1 , R 3 and R 4 are as defined above.
Step 13: Compound (16) is appropriately combined with Compound (15) in an inert solvent in the presence or absence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a palladium catalyst ligand. It can be produced by reaction with a cyanating agent. As the compound (15), 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. Here, suitable cyanating agents include, for example, zinc cyanide, copper cyanide, potassium cyanide or sodium cyanide.
Step 14: Compound (2) can be produced by addition reaction of compound (16) with hydroxyamine or a salt thereof in an inert solvent in the presence or absence of a base. In addition to the compound (16) synthesized from the compound (15), 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.
　例えば、化合物（３）は、以下の方法にて製造することができる。 For example, compound (3) can be produced by the following method.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　式中、環Ａ、Ｒ３、Ｒ４、Ｒ５及びＲ６は前記と同義である。
　工程１５：化合物（３）は＜スキーム３＞中の工程４と同様の手法により、化合物（１７）と化合物（５）から製造することができる。ここで化合物（１７）及び化合物（５）は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。 In the formula, rings A, R 3 , R 4 , R 5 and R 6 are as defined above.
Step 15: Compound (3) can be produced from compound (17) and compound (5) by the same method as in Step 4 in <Scheme 3>. Here, as the compound (17) and the compound (5), a commercially available compound, a known compound or a compound synthesized from a known compound by using various organic synthesis methods known to those skilled in the art can be used.
　次に、製造例、実施例及び試験例により本発明をさらに詳細に説明するが、本発明はこれらの製造例、実施例及び試験例に限定されるものではなく、また、本発明の範囲を逸脱しない範囲で変化させてもよい。 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.
　製造例及び実施例中で、カラムクロマトグラフィーを使用して精製した際の「ＮＨシリカゲルカートリッジ」にはバイオタージ社製Ｂｉｏｔａｇｅ（登録商標）ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－ＮＨ、「シリカゲルカートリッジ」にはバイオタージ社製Ｂｉｏｔａｇｅ（登録商標）ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－Ｓｉｌ及びＨＰ－Ｓｉｌ、「シリカゲル 60 N」には関東化学社製シリカゲル 60 N、「クロマトレックスNH」には富士シリシア化学社製クロマトレックス（登録商標）NHをそれぞれ市販されているものを使用した。逆相カラムクロマトグラフィーを使用して精製した際の「ＣＡＰＣＥＬＬ　ＰＡＫ」には資生堂社製のＣＡＰＣＥＬＬ　ＰＡＫ（登録商標）Ｃ１８　ＴＹＰＥ　ＭＧIIを使用した。ＴＬＣを使用して精製した際のＴＬＣ（シリカゲルプレート）にはＳｉｌｉｃａ　ｇｅｌ　６０Ｆ２５４（メルク）、ＴＬＣ（ＮＨシリカゲルプレート）にはＴＬＣプレートＮＨ（Ｆｕｊｉ　Ｓｉｌｙｓｉａ）を使用した。 In the production examples and examples, Biotage (registered trademark) SNAP cartridge KP-NH manufactured by Biotage was used for “NH silica gel cartridge” when purified using column chromatography, and Biotage was manufactured for “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., and "Chromatolex NH" is Chromatrex (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).
　製造例及び実施例中記載の各機器データは以下の測定機器で測定した。
　マイクロウェーブ反応装置：Ｉｎｉｔｉａｔｏｒ（Ｂｉｏｔａｇｅ　ＡＢ）
　ＬＣＭＳスペクトル：島津ＬＣＭＳ－ＩＴ－ＴＯＦ、島津ＬＣＭＳ－２０１０ＥＶ、ｍｉｃｒｏｍａｓｓ　Ｐｌａｔｆｏｒｍ　ＬＣ、ｍｉｃｒｏｍａｓｓ　ＧＣＴ、Ａｇｉｌｅｎｔ　６１５０、Ａｇｉｌｅｎｔ　１２９０Ｉｎｆｉｎｉｔｙ及びＡｇｉｌｅｎｔ１１００
　ＮＭＲスペクトル：［1Ｈ-ＮＭＲ］６００ＭＨｚ：ＪＮＭ－ＥＣＡ６００（日本電子）、５００ＭＨｚ：ＪＮＭ－ＥＣＡ５００（日本電子）、３００ＭＨｚ：ＵＮＩＴＹＮＯＶＡ３００（Varian Inc.）、２００ＭＨｚ：ＧＥＭＩＮＩ２０００／２００（Ｖａｒｉａｎ　Ｉｎｃ．）
　製造例及び実施例中の化合物名はＡＣＤ／Ｎａｍｅ　（ＡＣＤ／Ｌａｂｓ　１２．０，　Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．）により命名した。 Each instrument data described in the production examples and examples was measured with the following measuring instruments.
Microwave reactor: Initiator (Biotage AB)
LCMS spectrum: Shimadzu LCMS-IT-TOF, Shimadzu LCMS-2010EV, micromass platform LC, micromass GCT, Agilent 6150, Agilent 1290 Infinity and Agilent 1100
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.).
　製造例及び実施例中のＬＣＭＳのＲＴ（保持時間）は以下に示す何れかの条件で測定した値を用いた。
Ｃｏｎｄｉｔｉｏｎ　Ａ
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ　１２９０Ｉｎｆｉｎｉｔｙ及びＡｇｉｌｅｎｔ　６１５０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８，１．７μｍ，φ２．１ｘ５０ｍｍ
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝８０／２０）、１．２－１．４分（Ａ液／Ｂ液＝１／９９）
流速：０．８ｍＬ／ｍｉｎ、検出法：２５４ｎｍ
Ｃｏｎｄｉｔｉｏｎ　Ｂ
測定機械：Ｓｈｉｍａｄｚｕ社　ＬＣＭＳ－２０１０ＥＶ
カラム：Ｓｈｉｍｐａｃｋ　ＸＲ－ＯＤＳ，２．２μｍ，φ２．０ｘ３０ｍｍ
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝９０／１０）、３分（Ａ液／Ｂ液＝０／１００）
流速：０．６ｍＬ／ｍｉｎ、検出法：２５４ｎｍ
Ｃｏｎｄｉｔｉｏｎ　Ｃ
測定機器：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ　１１００及びｍｉｃｒｏｍａｓｓ社　Ｐｌａｔｆｏｒｍ　ＬＣ
カラム：Ｗａｔｅｒｓ社　ＳｕｎＦｉｒｅ　Ｃ１８，２．５μｍ，φ４．６ｘ５０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝９０／１０）、０．５分（Ａ液／Ｂ液＝９０／１０）、５．５分（Ａ液／Ｂ液＝２０／８０）、６．０分（Ａ液／Ｂ液＝１／９９）、６．３分（Ａ液／Ｂ液＝１／９９）
流速：１ｍＬ／ｍｉｎ、検出法：２５４ｎｍ For the RT (retention time) of LCMS in the production examples and examples, values measured under any of the following conditions were used.
Condition A
Measuring machine: Agilent Agilent 1290 Infinity and Agilent 6150
Column: Waters Acquity CSH C18, 1.7 μm, φ2.1 × 50 mm
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 80/20), 1.2-1.4 minutes (A solution / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: 254 nm
Condition B
Measuring machine: Shimadzu LCMS-2010EV
Column: Shimpack XR-ODS, 2.2 μm, φ2.0 × 30 mm
Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 3 minutes (A solution / B solution = 0 / 100)
Flow rate: 0.6 mL / min, detection method: 254 nm
Condition C
Measuring instrument: Agilent Agilent 1100 and micromass Platform LC
Column: Waters SunFire C18, 2.5 μm, φ4.6 × 50 mm
Solvent: A liquid; 0.1% trifluoroacetic acid-containing water, B liquid; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 0 minutes (A liquid / B liquid = 90/10), 0.5 minutes (A liquid / B liquid = 90/10), 5.5 minutes (A liquid / B liquid = 20/80), 6.0 minutes (A liquid / B liquid = 1/99), 6.3 minutes (A liquid / B Liquid = 1/99)
Flow rate: 1 mL / min, detection method: 254 nm
　製造例及び実施例中で使用した核磁気共鳴（ＮＭＲ）スペクトルに於ける略語を以下に示す。
s：シングレット（ｓｉｎｇｌｅｔ）、ｄ：ダブレット（ｄｏｕｂｌｅｔ）、t：トリプレット（ｔｒｉｐｌｅｔ）、q：カルテット（ｑｕａｒｔｅｔ）、d d：ダブルダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）、d t：ダブルトリプレット（ｄｏｕｂｌｅ　ｔｒｉｐｌｅｔ）、d q：ダブルカルテット（ｄｏｕｂｌｅ　ｑｕａｒｔｅｔ）、d d d：ダブルダブルダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）、ｍ：マルチプレット（ｍｕｌｔｉｐｌｅｔ）、ｂｒ：ブロード（ｂｒｏａｄ）、Ｊ：カップリング定数、Ｈｚ：ヘルツ、DMSO-d6：重水素化ジメチルスルホキシド 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 (Double quartz), ddd: double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, DMSO-d 6 : deuterated dimethyl Sulfoxide
製造例１　エチル 5-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-4-カルボキシラート
１）エチル 5-ホルミル-1-メチル-1H-ピラゾール-4-カルボキシラート
　窒素雰囲気下、ジイソプロピルアミン（２７．６　ｇ）のテトラヒドロフラン（４００　ｍＬ）溶液に、氷浴冷却下にてｎ－ブチルリチウム（１０５　ｍＬ、２．６０Ｍ　ヘキサン溶液）を滴下し、１時間撹拌した。反応液を－７８　℃に冷却後、エチル 1-メチル-1H-ピラゾール-4-カルボキシラート（２０．０　ｇ）のテトラヒドロフラン（１００　ｍＬ）溶液を滴下し、２時間撹拌した。反応液に－７８　℃にてＮ，Ｎ－ジメチルホルムアミド（７９．７　ｇ）を滴下し１時間撹拌した後、２Ｍ　塩化水素水溶液を加えた。反応液を５Ｍ　塩化水素水溶液にて酸性とした後、酢酸エチルにて３回抽出した。合わせた有機層を水にて２回洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９０:１０～５０:５０）にて精製し、表題化合物（１７．０　ｇ）を淡黄色固体として得た。
２）エチル 5-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-4-カルボキシラート
　氷浴冷却下、エチル 5-ホルミル-1-メチル-1H-ピラゾール-4-カルボキシラート（２３．０　ｇ）のメタノール（３００　ｍＬ）溶液に、水素化ホウ素ナトリウム（５．２５　ｇ）を加え、１時間撹拌した。反応液に塩化アンモニウム水溶液を加え、水にて希釈した後、酢酸エチルにて３回抽出した。合わせた有機層を水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下濃縮して表題化合物（２２．８　ｇ）を淡黄色固体として得た。
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 1 Ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4-carboxylate 1) Ethyl 5-formyl-1-methyl-1H-pyrazole-4-carboxylate Diisopropylamine (27 1.6 g) in tetrahydrofuran (400 mL) was added dropwise n-butyllithium (105 mL, 2.60 M hexane solution) under ice bath cooling, and the mixture was stirred for 1 hour. 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 dropwise, and the mixture was stirred for 2 hr. N, N-dimethylformamide (79.7 g) was added dropwise to the reaction solution at −78 ° C., and the mixture was stirred for 1 hour, and then 2M aqueous hydrogen chloride solution was added. 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 obtain 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)
製造例２　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
　エチル 5-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-4-カルボキシラート（５．００　ｇ）、4-ヒドロキシベンゾトリフルオリド（６．６０　ｇ）及びトリフェニルホスフィン（９．６１　ｇ）のテトラヒドロフラン（２５０　ｍＬ）溶液に、室温にてアゾジカルボン酸ジイソプロピル（７．６０　ｍＬ）を滴下し、３時間撹拌した。溶媒を減圧下留去した後、酢酸エチルにて希釈し、食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥した後、減圧下濃縮した。残渣をカラムクロマトグラフィー｛（ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝９０：１０～７５：２５）及び（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０）｝にて精製し、表題化合物（７．３６　ｇ）を無色固体として得た。
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 [M-H]- Production Example 2 Ethyl 1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4-carboxylate ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4- A solution of carboxylate (5.00 g), 4-hydroxybenzotrifluoride (6.60 g) and triphenylphosphine (9.61 g) in tetrahydrofuran (250 mL) at room temperature with diisopropyl azodicarboxylate (7. 60 mL) was added dropwise and 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]-
　同様にして以下の化合物を合成した。
エチル 5-[(4-フルオロフェノキシ)メチル]-1-メチル-1H-ピラゾール-4-カルボキシラート
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)
エチル 5-[(3,4-ジフルオロフェノキシ)メチル]-1-メチル-1H-ピラゾール-4-カルボキシラート
MS (ESI/APCI Dual pos.) m/z: 297 [M+H]+
エチル 5-{[(6-フルオロピリジン-3-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート
MS (ESI/APCI Dual pos.) m/z: 280 [M+H]+ 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)
Ethyl 5-[(3,4-difluorophenoxy) methyl] -1-methyl-1H-pyrazole-4-carboxylate
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] +
製造例３　エチル 5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート
　窒素雰囲気下、エチル 5-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-4-カルボキシラート（３００　ｍｇ）、2-クロロ-5-フルオロピリジン（３２２　ｍｇ）、酢酸パラジウム（II）（３７　ｍｇ）、炭酸セシウム　（７９７　ｍｇ）、rac-2-(ジ-ｔ-ブチルホスフィノ)-1,1'-ビナフチル（６５　ｍｇ）及び１，４－ジオキサン（１６　ｍＬ）の混合物を１００　℃にて１時間攪拌した。反応液を酢酸エチルにて希釈し、セライト濾過後、濾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、ヘキサン：酢酸エチル＝９０：１０～５０:５０）にて精製し、表題化合物（１４９　ｍｇ）を無色固体として得た。
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]+ 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] +
　同様にして以下の化合物を合成した。
エチル 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-カルボキシラート
MS (ESI pos.) m/z: 330 [M+H]+
エチル 1-メチル-5-({[4-(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-カルボキシラート
MS (ESI/APCI Dual pos.) m/z: 330 [M+H]+
エチル 1-メチル-5-{[(5-メチルピリジン-2-イル)オキシ]メチル}-1H-ピラゾール-4-カルボキシラート
MS (ESI/APCI Dual pos.) m/z: 276  [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] +
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] +
製造例４　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
　エチル 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-カルボキシラート（２４９　ｍｇ）、２Ｍ　水酸化ナトリウム水溶液（１．１３　ｍＬ）、テトラヒドロフラン（４．０　ｍＬ）及びメタノール（２．０　ｍＬ）の混合物を１時間加熱還流した。クエン酸水溶液にて約ｐH６に調整した後、クロロホルムにて３回抽出した。合わせた有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムにて乾燥した後、減圧下濃縮して表題化合物（１８８　ｍｇ）を無色固体として得た。
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 [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. The pH was adjusted to about pH 6 with an aqueous citric acid solution, followed by extraction with chloroform three times. 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]-
　同様にして以下の化合物を合成した。
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
MS (ESI pos.) m/z: 301 [M+H]+
5-[(4-フルオロフェノキシ)メチル]-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI pos.) m/z: 251 [M+H]+
5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI pos.) m/z: 252 [M+H]+
5-[(3,4-ジフルオロフェノキシ)メチル]-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI/APCI Dual pos.) m/z: 269 [M+H]+
1-メチル-5-({[4-(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
MS (ESI/APCI Dual pos.) m/z: 302 [M+H]+
5-{[(5-クロロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI/APCI Dual pos.) m/z: 290 [M+Na]+
5-{[(6-メトキシピリジン-3-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI/APCI Dual neg.) m/z: 262  [M-H]-
5-({[5-(ジフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI/APCI Dual neg.) m/z: 282  [M-H]-
1-メチル-5-{[(5-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
1H NMR (600 MHz, DMSO-d6) δ ppm 2.19 - 2.25 (m, 3 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) 7.81 (s, 1 H) 8.02 (dd, J=1.65, 0.83 Hz, 1 H) 12.42 - 12.57 (m, 1 H)
5-{[(5-シクロプロピルピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボン酸
MS (ESI/APCI Dual pos.) m/z: 274  [M+H]+ 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] +
5-[(3,4-Difluorophenoxy) 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] +
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: 262 [MH]-
5-({[5- (Difluoromethyl) pyridin-2-yl] oxy} methyl) -1-methyl-1H-pyrazole-4-carboxylic acid
MS (ESI / APCI Dual neg.) M / z: 282 [MH]-
1-methyl-5-{[(5-methylpyridin-2-yl) oxy] methyl} -1H-pyrazole-4-carboxylic acid
1H NMR (600 MHz, DMSO-d6) δ ppm 2.19-2.25 (m, 3 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) 7.81 (s, 1 H) 8.02 (dd, J = 1.65, 0.83 Hz, 1 H) 12.42-12.57 (m, 1 H)
5-{[(5-Cyclopropylpyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylic acid
MS (ESI / APCI Dual pos.) M / z: 274 [M + H] +
製造例５　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
１）2-(4-シアノフェニル)アセトアミド
　窒素雰囲気下、(4-シアノフェニル)酢酸（５００　ｍｇ）のクロロホルム（６．０　ｍＬ）溶液に、氷浴冷却下、塩化オキサリル（６２０　ｍｇ）及びＮ，Ｎ－ジメチルホルムアミド（１滴）を加えた後、室温にて１時間攪拌した。　反応液を減圧下濃縮した。残渣のテトラヒドロフラン（７．０　ｍＬ）懸濁液に氷浴冷却下、２８％アンモニア水（３.００　ｍＬ）を加えた後、室温にて１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下濃縮した。得られた固体をジイソプロピルエーテルにて洗浄し、表題化合物（３５０　ｍｇ）を淡黄色固体として得た。
２）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
　2-(4-シアノフェニル)アセトアミド（３５０　ｍｇ）、５０％ヒドロキシアミン水溶液（１６０　μL）及びエタノール（１．５　ｍＬ）の混合物を１２時間加熱還流した。反応液を減圧下濃縮して表題化合物（４００　ｍｇ）を無色固体として得た。
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) Production Example 5 2- [4- (N′-Hydroxycarbamimidoyl) phenyl] acetamide 1) 2- (4-Cyanophenyl) acetamide In a nitrogen atmosphere, (4-cyanophenyl) acetic acid (500 mg) in chloroform ( To the 6.0 mL solution, oxalyl chloride (620 mg) and N, N-dimethylformamide (1 drop) were added while cooling in an ice bath, and the mixture was stirred 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) with cooling in an ice bath, and the mixture was stirred at room temperature for 1 hr. The reaction mixture saturated aqueous solution of sodium hydrogen carbonate was added, followed by extraction 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 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 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)
　同様にして以下の化合物を合成した。
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
MS (ESI pos.) m/z : 194 [M+H]+
4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
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'-ヒドロキシカルバムイミドイル)ベンズアミド
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'-ヒドロキシカルバムイミドイル)-3-メチルベンズアミド
MS (ESI pos.) m/z: 194 [M+H]+
4-フルオロ-3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS　(ESI pos.) m/z: 198 [M+H]+
N-[2-(ジメチルアミノ)エチル]-3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド　
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'-ヒドロキシカルバムイミドイル)フェノキシ]アセトアミド
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'-ヒドロキシカルバムイミドイル)-N-(オキセタン-3-イル)ベンズアミド
MS (ESI pos.) m/z: 236 [M+H]+
6-(N'-ヒドロキシカルバムイミドイル)ピリジン-3-カルボキサミド
MS (ESI/APCI Dual pos.) m/z: 181 [M+H]+
N-[2-(ジメチルアミノ)エチル]-4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
1H NMR (200 MHz, DMSO-d6) δ ppm 2.12 (s, 9 H) 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-フルオロ-4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 198 [M+H]+
3-(N'-ヒドロキシカルバムイミドイル)-4-メチルベンズアミド
MS (ESI/APCI Dual pos.) m/z: 194 [M+H]+
4-(N'-ヒドロキシカルバムイミドイル)-N-メチルベンズアミド
MS (ESI/APCI Dual pos.) m/z: 194 [M+H]+
4-(N'-ヒドロキシカルバムイミドイル)安息香酸
1H NMR (200 MHz, DMSO-d6) δ ppm 5.67 - 8.25 (m, 7 H)
3-(N'-ヒドロキシカルバムイミドイル)安息香酸
1H NMR (200 MHz, DMSO-d6) δ ppm 5.65 - 8.32 (m, 7 H)
[4-(N'-ヒドロキシカルバムイミドイル)フェニル]酢酸
[3-(N'-ヒドロキシカルバムイミドイル)フェニル]酢酸
6-(N'-ヒドロキシカルバムイミドイル)ピリジン-2-カルボキサミド
1H NMR (200 MHz, DMSO-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 (br. s., 1 H) 9.93 (s, 1 H)
4-(N'-ヒドロキシカルバムイミドイル)フェニル カルバマート
1H NMR (200 MHz, DMSO-d6) δ ppm 5.56 - 9.69 (m, 9 H)
3-(N'-ヒドロキシカルバムイミドイル)-N-メチルベンズアミド
2-[3-(N'-ヒドロキシカルバムイミドイル)フェノキシ]アセトアミド
1H 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-(N'-ヒドロキシカルバムイミドイル)-N-(2-ヒドロキシエチル)ベンズアミド
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-ブチル 3-(N'-ヒドロキシカルバムイミドイル)ベンゾエ－ト
1H NMR (200 MHz, DMSO-d6) δ ppm 1.56 (s, 9 H) 5.72 - 9.84 (m, 7 H)
5-(N'-ヒドロキシカルバムイミドイル)ピリジン-3-カルボキサミド
MS (ESI/APCI Dual pos.) m/z: 181 [M+H]+
2-[2-ブロモ-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
1H 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-フルオロ-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
1H NMR (200 MHz, DMSO-d6) δ ppm 3.33 (s, 2 H) 6.73 - 8.20 (m, 8 H)
2-フルオロ-4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 198 [M+H]+
2-[3-フルオロ-5-(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
MS (ESI/APCI Dual pos.) m/z: 234 [M+Na]+
2-[3-フルオロ-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
MS (ESI/APCI Dual pos.) m/z: 212 [M+H]+
5-(N'-ヒドロキシカルバムイミドイル)ピリジン-2-カルボキサミド
MS (ESI/APCI Dual pos.) m/z: 181 [M+H]+
2-[2-フルオロ-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
MS (ESI/APCI Dual pos.) m/z: 212 [M+H]+
2-[2-フルオロ-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
MS (ESI/APCI Dual pos.) m/z: 212 [M+H]+
2-[2-クロロ-5-(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
MS (ESI/APCI Dual pos.) m/z: 228 [M+H]+
5-(N'-ヒドロキシカルバムイミドイル)-2-メチルベンズアミド
MS (ESI/APCI Dual pos.) m/z: 194 [M+H]+
2-[5-(N'-ヒドロキシカルバムイミドイル)-2-メチルフェニル]アセトアミド
MS (ESI/APCI Dual pos.) m/z: 208 [M+H]
2-クロロ-4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 214 [M+H]+
3-クロロ-4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 214 [M+H]+
4-(N'-ヒドロキシカルバムイミドイル)-2-メチルベンズアミド
MS (ESI/APCI Dual pos.) m/z: 194 [M+H]+
2-[2-クロロ-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
MS (ESI/APCI Dual pos.) m/z: 228 [M+H]+
2-[4-(N'-ヒドロキシカルバムイミドイル)-2-メチルフェニル]アセトアミド
MS (ESI/APCI Dual pos.) m/z: 208 [M+H]+
2-[4-(N'-ヒドロキシカルバムイミドイル)-3-メチルフェニル]アセトアミド
MS (ESI/APCI Dual pos.) m/z: 208 [M+H]+
N'-ヒドロキシ-3-[(3-オキソピペラジン-1-イル)カルボニル]ベンゼンカルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 263 [M+H]+
2-フルオロ-3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 198 [M+H]+
3-[3-(N'-ヒドロキシカルバムイミドイル)フェニル]プロパンアミド
1H NMR (200 MHz, DMSO-d6) δ ppm 2.68 - 2.91 (m, 3 H) 3.33 (br. s., 1 H) 5.75 (s, 2 H) 6.76 (br. s., 1 H) 7.10 - 7.62 (m, 5 H) 9.57 (s, 1 H)
2-[4-(N'-ヒドロキシカルバムイミドイル)フェニル]-2-メチルプロパンアミド
1H NMR (200 MHz, DMSO-d6) δ ppm 1.43 (s, 6 H) 5.76 (s, 2 H) 6.90 (s, 2 H) 7.32 (d, J=8.4 Hz, 2 H) 7.61 (d, J=8.4 Hz, 2 H) 9.57 (s, 1 H)
3-アセチル-N'-ヒドロキシベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 2.51 (dt, J=3.7, 1.9 Hz, 3 H) 5.68 (s, 2 H) 6.69 (s, 2 H) 6.92 (d, J=5.0 Hz, 1 H) 8.20 (d, J=5.4 Hz, 1 H) 10.14 (s, 1 H)
2-フルオロ-5-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 198 [M+H]+
3-フルオロ-5-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI pos.) m/z: 198 [M+H]+
4-(N'-ヒドロキシカルバムイミドイル)-3-メトキシベンズアミド
MS (ESI pos.) m/z: 210 [M+H]+
5-(N'-ヒドロキシカルバムイミドイル)-2-メトキシベンズアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 5.77 (s, 2 H) 7.12 (d, J=9.1 Hz, 1 H) 7.49 - 7.58 (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'-ヒドロキシカルバムイミドイル)-4-メトキシベンズアミド
1H NMR (600 MHz, DMSO-d6) δ 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'-ヒドロキシカルバムイミドイル)-2-メトキシベンズアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 4.05 (s, 2 H) 5.91 - 5.97 (m, 1 H) 7.06 - 8.29 (m, 7 H) 8.63 - 8.72 (m, 1 H)
N-(2-アミノ-2-オキソエチル)-3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
1H NMR (600 MHz, DMSO-d6) δ 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) 8.18 (t, J=1.7 Hz, 1 H) 8.65 (t, J=5.8 Hz, 1 H) 9.70 (s, 1 H)
N-(2-アミノ-2-オキソエチル)-4-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
1H 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-クロロ-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
2-[3-クロロ-5-(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
3-クロロ-5-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
2-[6-(N'-ヒドロキシカルバムイミドイル)ピリジン-3-イル]アセトアミド
MS (ESI/APCI Dual pos.) m/z: 195 [M+H]+
2-[2-フルオロ-5-(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
MS (ESI/APCI Dual pos.) m/z: 212 [M+H]+
2-[5-(N'-ヒドロキシカルバムイミドイル)ピリジン-2-イル]アセトアミド
MS (ESI/APCI Dual pos.) m/z: 195 [M+H]+
N'-ヒドロキシ-4-(2-ヒドロキシエチル)ベンゼンカルボキシミドアミド
1H NMR (200 MHz, CHLOROFORM-d) δ 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)
N'-ヒドロキシ-2-(ヒドロキシメチル)ピリジン-4-カルボキシミドアミド
N'-ヒドロキシ-3-(2-ヒドロキシプロパン-2-イル)ベンゼンカルボキシミドアミド
1H NMR (200 MHz, DMSO-d6) δ ppm 1.42 (s, 6 H) 3.32 (s, 1 H) 5.01 (s, 1 H) 5.76 (s, 1 H) 7.19 - 7.37 (m, 1 H) 7.41 - 7.56 (m, 2 H) 7.76 (t, J=1.5 Hz, 1 H) 9.55 (s, 1 H)
N'-ヒドロキシ-4-(2-ヒドロキシプロパン-2-イル)ベンゼンカルボキシミドアミド
1H NMR (200 MHz, DMSO-d6) δ ppm 1.42 (s, 6 H) 3.33 (s, 1 H) 5.02 (s, 1 H) 5.74 (s, 1 H) 7.32 - 7.49 (m, 2 H) 7.52 - 7.66 (m, 2 H) 9.54 (s, 1 H)
N'-ヒドロキシ-4-(ヒドロキシメチル)ベンゼンカルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 167 [M+H]+
4-[カルバモイル(メチル)アミノ]-N'-ヒドロキシベンゼンカルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 209 [M+H]+
4-(カルバモイルアミノ)-N'-ヒドロキシベンゼンカルボキシミドアミド
1H NMR (200 MHz, DMSO-d6) δ ppm 5.67 (s, 2 H) 5.87 (s, 2 H) 7.26 - 7.62 (m, 4 H) 8.60 (s, 1 H) 9.42 (s, 1 H)
3-(カルバモイルアミノ)-N'-ヒドロキシベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 3.08 (d, J=5.4 Hz, 1 H) 5.59 (s, 2 H) 5.74 (s, 1 H) 7.01 - 7.17 (m, 2 H) 7.31 - 7.40 (m, 1 H) 7.57 (t, J=1.9 Hz, 1 H) 8.45 (s, 1 H) 9.47 (s, 1 H)
N'-ヒドロキシ-4-[(メチルカルバモイル)アミノ]ベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 2.64 (d, J=4.5 Hz, 3 H) 5.66 (s, 2 H) 6.03 (d, J=4.5 Hz, 1 H) 7.37 (d, J=8.7 Hz, 2 H) 7.47 - 7.55 (m, 2 H) 8.58 (s, 1 H) 9.41 (s, 1 H)
N'-ヒドロキシ-3-[(メチルカルバモイル)アミノ]ベンゼンカルボキシミドアミド
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) 7.05 - 7.28 (m, 2 H) 7.47 (dt, J=7.5, 2.0 Hz, 1 H) 7.56 - 7.68 (m, 1 H) 8.52 (s, 1 H) 9.55 (s, 1 H)
メチル [4-(N'-ヒドロキシカルバムイミドイル)フェニル]カルバマート
N'-ヒドロキシ-1-オキソ-2,3-ジヒドロ-1H-イソインドール-5-カルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 192 [M+H]+
N'-ヒドロキシ-3-オキソ-2,3-ジヒドロ-1H-イソインドール-5-カルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 192 [M+H]+
N'-ヒドロキシ-2-オキソ-2,3-ジヒドロ-1H-インドール-5-カルボキシミドアミド
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)
N'-ヒドロキシ-2-オキソ-2,3-ジヒドロ-1H-ベンゾイミダゾール-5-カルボキシミドアミド
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) 10.69 (br. s., 2 H)
N'-ヒドロキシ-4-(2-オキソイミダゾリジン-1-イル)ベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 3.37 - 3.50 (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)
N'-ヒドロキシ-3-(2-オキソイミダゾリジン-1-イル)ベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 3.36 - 3.45 (m, 2 H) 3.81 - 3.92 (m, 2 H) 5.76 (s, 2 H) 6.96 (s, 1 H) 7.24 - 7.32 (m, 2 H) 7.63 - 7.78 (m, 2 H) 9.60 (s, 1 H)
N'-ヒドロキシ-4-(2-オキソピロリジン-1-イル)ベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ 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) 7.56 - 7.76 (m, 4 H) 9.56 (s, 1 H)
N'-ヒドロキシ-3-(2-オキソピロリジン-1-イル)ベンゼンカルボキシミドアミド
1H NMR (600 MHz, DMSO-d6) δ ppm 2.03 - 2.12 (m, 2 H) 2.46 - 2.55 (m, 2 H) 3.80 - 3.90 (m, 2 H) 5.81 (s, 2 H) 7.32 - 8.04 (m, 4 H) 9.65 (s, 1 H)
N-(2,2-ジメトキシエチル)-3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド
MS (ESI/APCI Dual pos.) m/z: 268 [M+H]+
N'-ヒドロキシ-2-オキソ-1,2-ジヒドロピリジン-4-カルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 154 [M+H]+
N'-ヒドロキシ-6-オキソ-1,6-ジヒドロピリジン-3-カルボキシミドアミド
MS (ESI/APCI Dual pos.) m/z: 154 [M+H]+
3-アミノ-N'-ヒドロキシベンゼンカルボキシミドアミド 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] +
6- (N'-Hydroxycarbamimidoyl) pyridine-3-carboxamide
MS (ESI / APCI Dual pos.) M / z: 181 [M + H] +
N- [2- (Dimethylamino) ethyl] -4- (N'-hydroxycarbamimidoyl) benzamide
1H NMR (200 MHz, DMSO-d6) δ ppm 2.12 (s, 9 H) 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- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 198 [M + H] +
3- (N'-hydroxycarbamimidoyl) -4-methylbenzamide
MS (ESI / APCI Dual pos.) M / z: 194 [M + H] +
4- (N'-hydroxycarbamimidoyl) -N-methylbenzamide
MS (ESI / APCI Dual pos.) M / z: 194 [M + H] +
4- (N'-hydroxycarbamimidoyl) benzoic acid
1H NMR (200 MHz, DMSO-d6) δ ppm 5.67-8.25 (m, 7 H)
3- (N'-Hydroxycarbamimidoyl) benzoic acid
1H NMR (200 MHz, DMSO-d6) δ ppm 5.65-8.32 (m, 7 H)
[4- (N'-Hydroxycarbamimidoyl) phenyl] acetic acid
[3- (N'-Hydroxycarbamimidoyl) phenyl] acetic acid
6- (N'-hydroxycarbamimidoyl) pyridine-2-carboxamide
1H NMR (200 MHz, DMSO-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 (br. S., 1 H) 9.93 (s, 1 H)
4- (N'-hydroxycarbamimidoyl) phenyl carbamate
1H NMR (200 MHz, DMSO-d6) δ ppm 5.56-9.69 (m, 9 H)
3- (N'-Hydroxycarbamimidoyl) -N-methylbenzamide
2- [3- (N'-Hydroxycarbamimidoyl) phenoxy] acetamide
1H 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- (N'-hydroxycarbamimidoyl) -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- (N'-hydroxycarbamimidoyl) benzoate
1H NMR (200 MHz, DMSO-d6) δ ppm 1.56 (s, 9 H) 5.72-9.84 (m, 7 H)
5- (N'-Hydroxycarbamimidoyl) pyridine-3-carboxamide
MS (ESI / APCI Dual pos.) M / z: 181 [M + H] +
2- [2-Bromo-4- (N'-hydroxycarbamimidoyl) phenyl] acetamide
1H 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- (N'-hydroxycarbamimidoyl) phenyl] acetamide
1H NMR (200 MHz, DMSO-d6) δ ppm 3.33 (s, 2 H) 6.73-8.20 (m, 8 H)
2-Fluoro-4- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 198 [M + H] +
2- [3-Fluoro-5- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 234 [M + Na] +
2- [3-Fluoro-4- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 212 [M + H] +
5- (N'-hydroxycarbamimidoyl) pyridine-2-carboxamide
MS (ESI / APCI Dual pos.) M / z: 181 [M + H] +
2- [2-Fluoro-3- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 212 [M + H] +
2- [2-Fluoro-4- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 212 [M + H] +
2- [2-Chloro-5- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 228 [M + H] +
5- (N'-hydroxycarbamimidoyl) -2-methylbenzamide
MS (ESI / APCI Dual pos.) M / z: 194 [M + H] +
2- [5- (N'-Hydroxycarbamimidoyl) -2-methylphenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 208 [M + H]
2-Chloro-4- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 214 [M + H] +
3-Chloro-4- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 214 [M + H] +
4- (N'-hydroxycarbamimidoyl) -2-methylbenzamide
MS (ESI / APCI Dual pos.) M / z: 194 [M + H] +
2- [2-Chloro-4- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 228 [M + H] +
2- [4- (N'-Hydroxycarbamimidoyl) -2-methylphenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 208 [M + H] +
2- [4- (N'-Hydroxycarbamimidoyl) -3-methylphenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 208 [M + H] +
N'-hydroxy-3-[(3-oxopiperazin-1-yl) carbonyl] benzenecarboximidamide
MS (ESI / APCI Dual pos.) M / z: 263 [M + H] +
2-Fluoro-3- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 198 [M + H] +
3- [3- (N'-Hydroxycarbamimidoyl) phenyl] propanamide
1H NMR (200 MHz, DMSO-d6) δ ppm 2.68-2.91 (m, 3 H) 3.33 (br. S., 1 H) 5.75 (s, 2 H) 6.76 (br. S., 1 H) 7.10- 7.62 (m, 5 H) 9.57 (s, 1 H)
2- [4- (N'-Hydroxycarbamimidoyl) phenyl] -2-methylpropanamide
1H NMR (200 MHz, DMSO-d6) δ ppm 1.43 (s, 6 H) 5.76 (s, 2 H) 6.90 (s, 2 H) 7.32 (d, J = 8.4 Hz, 2 H) 7.61 (d, J = 8.4 Hz, 2 H) 9.57 (s, 1 H)
3-acetyl-N'-hydroxybenzenecarboximidoamide
1H NMR (600 MHz, DMSO-d6) δ ppm 2.51 (dt, J = 3.7, 1.9 Hz, 3 H) 5.68 (s, 2 H) 6.69 (s, 2 H) 6.92 (d, J = 5.0 Hz, 1 H) 8.20 (d, J = 5.4 Hz, 1 H) 10.14 (s, 1 H)
2-Fluoro-5- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 198 [M + H] +
3-Fluoro-5- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI pos.) M / z: 198 [M + H] +
4- (N'-hydroxycarbamimidoyl) -3-methoxybenzamide
MS (ESI pos.) M / z: 210 [M + H] +
5- (N'-hydroxycarbamimidoyl) -2-methoxybenzamide
1H NMR (600 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 5.77 (s, 2 H) 7.12 (d, J = 9.1 Hz, 1 H) 7.49-7.58 (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'-hydroxycarbamimidoyl) -4-methoxybenzamide
1H NMR (600 MHz, DMSO-d6) δ 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'-hydroxycarbamimidoyl) -2-methoxybenzamide
1H NMR (600 MHz, DMSO-d6) δ ppm 4.05 (s, 2 H) 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- (N'-hydroxycarbamimidoyl) benzamide
1H NMR (600 MHz, DMSO-d6) δ 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) 8.18 (t, J = 1.7 Hz, 1 H) 8.65 (t, J = 5.8 Hz, 1 H) 9.70 (s, 1 H)
N- (2-amino-2-oxoethyl) -4- (N'-hydroxycarbamimidoyl) benzamide
1H 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- (N'-hydroxycarbamimidoyl) phenyl] acetamide
2- [3-Chloro-5- (N'-hydroxycarbamimidoyl) phenyl] acetamide
3-Chloro-5- (N'-hydroxycarbamimidoyl) benzamide
2- [6- (N'-Hydroxycarbamimidoyl) pyridin-3-yl] acetamide
MS (ESI / APCI Dual pos.) M / z: 195 [M + H] +
2- [2-Fluoro-5- (N'-hydroxycarbamimidoyl) phenyl] acetamide
MS (ESI / APCI Dual pos.) M / z: 212 [M + H] +
2- [5- (N'-Hydroxycarbamimidoyl) pyridin-2-yl] acetamide
MS (ESI / APCI Dual pos.) M / z: 195 [M + H] +
N'-hydroxy-4- (2-hydroxyethyl) benzenecarboximidamide
1H NMR (200 MHz, CHLOROFORM-d) δ 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)
N'-hydroxy-2- (hydroxymethyl) pyridine-4-carboximidamide
N'-hydroxy-3- (2-hydroxypropan-2-yl) benzenecarboximidamide
1H NMR (200 MHz, DMSO-d6) δ ppm 1.42 (s, 6 H) 3.32 (s, 1 H) 5.01 (s, 1 H) 5.76 (s, 1 H) 7.19-7.37 (m, 1 H) 7.41 -7.56 (m, 2 H) 7.76 (t, J = 1.5 Hz, 1 H) 9.55 (s, 1 H)
N'-hydroxy-4- (2-hydroxypropan-2-yl) benzenecarboximidamide
1H NMR (200 MHz, DMSO-d6) δ ppm 1.42 (s, 6 H) 3.33 (s, 1 H) 5.02 (s, 1 H) 5.74 (s, 1 H) 7.32-7.49 (m, 2 H) 7.52 -7.66 (m, 2 H) 9.54 (s, 1 H)
N'-hydroxy-4- (hydroxymethyl) benzenecarboximidamide
MS (ESI / APCI Dual pos.) M / z: 167 [M + H] +
4- [Carbamoyl (methyl) amino] -N'-hydroxybenzenecarboximidamide
MS (ESI / APCI Dual pos.) M / z: 209 [M + H] +
4- (Carbamoylamino) -N'-hydroxybenzenecarboximidamide
1H NMR (200 MHz, DMSO-d6) δ ppm 5.67 (s, 2 H) 5.87 (s, 2 H) 7.26-7.62 (m, 4 H) 8.60 (s, 1 H) 9.42 (s, 1 H)
3- (Carbamoylamino) -N'-hydroxybenzenecarboximidamide
1H NMR (600 MHz, DMSO-d6) δ ppm 3.08 (d, J = 5.4 Hz, 1 H) 5.59 (s, 2 H) 5.74 (s, 1 H) 7.01-7.17 (m, 2 H) 7.31-7.40 (m, 1 H) 7.57 (t, J = 1.9 Hz, 1 H) 8.45 (s, 1 H) 9.47 (s, 1 H)
N'-hydroxy-4-[(methylcarbamoyl) amino] benzenecarboximidamide
1H NMR (600 MHz, DMSO-d6) δ ppm 2.64 (d, J = 4.5 Hz, 3 H) 5.66 (s, 2 H) 6.03 (d, J = 4.5 Hz, 1 H) 7.37 (d, J = 8.7 Hz, 2 H) 7.47-7.55 (m, 2 H) 8.58 (s, 1 H) 9.41 (s, 1 H)
N'-hydroxy-3-[(methylcarbamoyl) amino] benzenecarboximidamide
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) 7.05-7.28 (m, 2 H) 7.47 (dt, J = 7.5, 2.0 Hz, 1 H) 7.56-7.68 (m, 1 H) 8.52 (s, 1 H) 9.55 (s, 1 H)
Methyl [4- (N'-hydroxycarbamimidoyl) phenyl] carbamate
N'-hydroxy-1-oxo-2,3-dihydro-1H-isoindole-5-carboximidamide
MS (ESI / APCI Dual pos.) M / z: 192 [M + H] +
N'-hydroxy-3-oxo-2,3-dihydro-1H-isoindole-5-carboximidamide
MS (ESI / APCI Dual pos.) M / z: 192 [M + H] +
N'-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carboximidamide
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)
N'-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboximidamide
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) 10.69 (br s., 2 H)
N'-hydroxy-4- (2-oxoimidazolidin-1-yl) benzenecarboximidamide
1H NMR (600 MHz, DMSO-d6) δ ppm 3.37-3.50 (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)
N'-hydroxy-3- (2-oxoimidazolidin-1-yl) benzenecarboximidamide
1H NMR (600 MHz, DMSO-d6) δ ppm 3.36-3.45 (m, 2 H) 3.81-3.92 (m, 2 H) 5.76 (s, 2 H) 6.96 (s, 1 H) 7.24-7.32 (m, 2 H) 7.63-7.78 (m, 2 H) 9.60 (s, 1 H)
N'-hydroxy-4- (2-oxopyrrolidin-1-yl) benzenecarboximidamide
1H NMR (600 MHz, DMSO-d6) δ 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) 7.56-7.76 (m, 4 H) 9.56 (s, 1 H)
N'-hydroxy-3- (2-oxopyrrolidin-1-yl) benzenecarboximidamide
1H NMR (600 MHz, DMSO-d6) δ ppm 2.03-2.12 (m, 2 H) 2.46-2.55 (m, 2 H) 3.80-3.90 (m, 2 H) 5.81 (s, 2 H) 7.32-8.04 ( m, 4 H) 9.65 (s, 1 H)
N- (2,2-dimethoxyethyl) -3- (N'-hydroxycarbamimidoyl) benzamide
MS (ESI / APCI Dual pos.) M / z: 268 [M + H] +
N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboximidamide
MS (ESI / APCI Dual pos.) M / z: 154 [M + H] +
N'-hydroxy-6-oxo-1,6-dihydropyridine-3-carboximidamide
MS (ESI / APCI Dual pos.) M / z: 154 [M + H] +
3-Amino-N'-hydroxybenzenecarboximidamide
製造例６　4-(シアノメチル)ベンゾヒドラジド
　メチル 4-(シアノメチル)ベンゾアート（１．００　ｇ）、ヒドラジン一水和物（２．８６　ｇ）及びメタノール（２０　ｍＬ）の混合物を２時間加熱還流した。反応液を氷浴冷却下にて１５分間攪拌した後、生じた固体をろ取し、メタノールにて洗浄して表題化合物（５２７　ｍｇ）を淡茶色固体として得た。
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 [M-H]-   Production Example 6 4- (Cyanomethyl) benzohydrazide Methyl A mixture of 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]-
　同様にして以下の化合物を合成した。
3-(シアノメチル)ベンゾヒドラジド
MS (ESI neg.) m/z: 174 [M-H]-
4-シアノベンゾヒドラジド
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-シアノベンゾヒドラジド
MS (ESI neg.) m/z: 160 [M-H]- 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]-
製造例７　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
　窒素雰囲気下、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（２６　ｍｇ）のテトラヒドロフラン（０．４０　ｍＬ）溶液に、室温にて4-(シアノメチル)ベンゾヒドラジド（２３　ｍｇ）、ジイソプロピルエチルアミン（３１　μＬ）及びＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸（ＨＡＴＵ）（４９　ｍｇ）を加えて１４時間撹拌した。反応液に水を加え、クロロホルム/メタノール（５/１）にて抽出した。有機層を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）にて精製して、表題化合物（３６　ｍｇ）を無色固体として得た。
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]+ 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 give 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] +
　同様にして以下の化合物を合成した。
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
MS　(ESI neg.) m/z : 457 [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]-
製造例８　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
１）tert-ブチル 2-[(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)カルボニル]ヒドラジンカルボキシラート
　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（５００　ｍｇ）のクロロホルム（５．０　ｍＬ）溶液に、氷浴冷却下、塩化オキサリル（２５４　ｍｇ）及びＮ，Ｎ－ジメチルホルムアミド（１滴）を加えた後、室温にて１時間攪拌した。　反応液を減圧下濃縮した。残渣のテトラヒドロフラン（５．０　ｍＬ）懸濁液に氷浴冷却下、ピリジン（２６０　ｍｇ）及びtert-ブチル ヒドラジンカルボキシラート（２６４　ｍｇ）を加えた後、室温にて１時間攪拌した。反応液を減圧下濃縮した後、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～クロロホルム：メタノール＝９０：１０）にて精製して、表題化合物（７３０　ｍｇ）を無色固体として得た。
２）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-カルボヒドラジド 塩酸塩
　tert-ブチル 2-[(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)カルボニル]ヒドラジンカルボキシラート（６９０　ｍｇ）、クロロホルム（７．０　ｍＬ）及び塩化水素溶液（１．２５　ｍＬ、４Ｍ　ジオキサン溶液）の混合物を室温にて２０時間攪拌した。反応液を減圧下濃縮した後、酢酸エチルにて洗浄して、表題化合物（５５０　ｍｇ）を無色固体として得た。
３）2-[4-({2-[(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)カルボニル]ヒドラジニル}カルボニル)フェニル]アセトアミド
　4-(2-アミノ-2-オキソエチル)安息香酸（１８８　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．０　ｍＬ）溶液に、室温にて１，１’－カルボニルジイミダゾール（１９３　ｍｇ）を加えた後、４０　℃にて１時間攪拌した。反応液に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-カルボヒドラジド 塩酸塩（３００　ｍｇ）を加え、４０　℃にて５時間攪拌した。反応液に水を加え、クロロホルムにて抽出した。有機層を減圧下濃縮した後、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～クロロホルム：メタノール＝９０：１０）にて精製して、表題化合物（１８０　ｍｇ）を無色固体として得た。
４）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
　窒素雰囲気下、2-[4-({2-[(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)カルボニル]ヒドラジニル}カルボニル)フェニル]アセトアミド（１８０　ｍｇ）、テトラヒドロフラン（３．８　ｍＬ）及びＢｕｒｇｅｓｓ試薬（４５１　ｍｇ）の混合物を７０　℃にて２時間撹拌した。反応液を減圧下濃縮した後、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～クロロホルム：メタノール＝９５：５）にて精製して、表題化合物（１２０　ｍｇ）を無色固体として得た。
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]+ 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) was cooled with an ice bath. Oxalyl chloride (254 mg) and N, N-dimethylformamide (1 drop) were added, and the mixture was stirred at room temperature for 1 hr. 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 that, 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 Under nitrogen atmosphere 2- [4-({2-[(1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole-4- Yl) carbonyl] hydrazinyl} carbonyl) phenyl] acetamide (180 mg), tetrahydrofuran (3.8 mL) and Burgess reagent (451 mg) were 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] +
製造例９　エチル 5-({[5-(ジフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1-メチル-1H-ピラゾール-4-カルボキシラート
　製造例１で得られたエチル 5-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-4-カルボキシラート（１．６９　ｇ）及び2-クロロ-5-(ジフルオロメチル)ピリジン（１．３２　ｇ）のＮ，Ｎ－ジメチルホルムアミド（２０　ｍＬ）溶液に、氷浴冷却下、水素化ナトリウム（６０％、３８７　ｍｇを少しずつ加えた後、同温にて１０分間、室温にて１８時間攪拌した。　反応液に水（１００　ｍＬ）を加え、析出した結晶をろ取し、表題化合物（１．９９　ｇ）を無色固体として得た。
MS (ESI/APCI Dual pos.) m/z: 312 [M+H]+ Production Example 9 Ethyl 5-({[5- (Difluoromethyl) pyridin-2-yl] oxy} methyl) -1-methyl-1H-pyrazole-4-carboxylate Ethyl 5- (hydroxy) obtained in Production Example 1 Methyl) -1-methyl-1H-pyrazole-4-carboxylate (1.69 g) and 2-chloro-5- (difluoromethyl) pyridine (1.32 g) in N, N-dimethylformamide (20 mL) To the solution, sodium hydride (60%, 387 mg) was added little by little with cooling in an ice bath, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 18 hours. The precipitated crystals were collected by filtration to give the title compound (1.99 g) as a colorless solid.
MS (ESI / APCI Dual pos.) M / z: 312 [M + H] +
　同様にして以下の化合物を合成した。
エチル 5-{[(5-クロロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート
エチル 5-{[(5-ヨードピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート
MS (ESI/APCI Dual pos.) m/z: 388  [M+H]+   The following compounds were synthesized in the same manner.
Ethyl 5-{[(5-chloropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylate ethyl 5-{[(5-iodopyridin-2-yl) oxy] methyl } -1-Methyl-1H-pyrazole-4-carboxylate
MS (ESI / APCI Dual pos.) M / z: 388 [M + H] +
製造例１０　メチル 5-{[(6-メトキシピリジン-3-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート Production Example 10 Methyl 5-{[(6-methoxypyridin-3-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylate
　製造例２で得られたエチル 5-{[(6-フルオロピリジン-3-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート（２６６　ｍｇ）、ナトリウムメトキシド（２８％/メタノール、５５０　μＬ）及びメタノール（２．０　ｍＬ）の混合物を、マイクロウェーブ照射下１５０　℃にて１時間撹拌した。反応液を減圧下濃縮した後、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＝９５：５～９０：１０）にて精製し、表題化合物（１５０　ｍｇ）を無色固体として得た。
MS (ESI/APCI Dual pos.) m/z: 278 [M+H]+ Ethyl 5-{[(6-fluoropyridin-3-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylate (266 mg) obtained in Preparation Example 2, sodium methoxide (28% / Methanol, 550 μL) and methanol (2.0 mL) were stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 95: 5 to 90:10) to give the title compound (150 mg) as a colorless solid.
MS (ESI / APCI Dual pos.) M / z: 278 [M + H] +
製造例１１　エチル 5-{[(5-シクロプロピルピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート
　製造例９で得られたエチル 5-{[(5-ヨードピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾール-4-カルボキシラート（２．００　ｇ）、シクロプロピルジンク(II) ブロミド（０．５Ｍ/テトラヒドロフラン，１５．５　ｍＬ）、テトラキストリフェニルホスフィンパラジウム（４９７　ｍｇ）及びテトラヒドロフラン（２０　ｍＬ）の混合物を、窒素雰囲気下、６０　℃にて１時間攪拌した。反応液に水を加え、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、ヘキサン：酢酸エチル＝９０：１０～５０:５０）にて精製し、表題化合物（５１０　ｍｇ）を黄色固体として得た。
MS (ESI/APCI Dual pos.) m/z: 302  [M+H]+ Production Example 11 Ethyl 5-{[(5-Cyclopropylpyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylate Ethyl 5-{[(5 -Iodopyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazole-4-carboxylate (2.00 g), cyclopropylzinc (II) bromide (0.5M / tetrahydrofuran, 15.5 mL) ), Tetrakistriphenylphosphine palladium (497 mg) and tetrahydrofuran (20 mL) were stirred at 60 ° C. for 1 hour under a nitrogen atmosphere. Water was added to the reaction solution, and the reaction solution 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 (510 mg) as a yellow solid.
MS (ESI / APCI Dual pos.) M / z: 302 [M + H] +
実施例１　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド 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
Figure JPOXMLDOC01-appb-C000018
 　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); MS　(ESI pos.) m/z : 459 [M+H]+
Figure JPOXMLDOC01-appb-C000018
 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 the mixture was 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); MS (ESI pos.) M / z: 459 [M + H] +
　実施例１と同様の手法を用いて、表１－１から表１－３に記載した実施例２から実施例１４の化合物を得た。 Using the same method as in Example 1, the compounds of Examples 2 to 14 listed in Table 1-1 to Table 1-3 were obtained.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
実施例２　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例３　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例４　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例５　6-[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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ピリジン-3-カルボキサミド
実施例６　N-[2-(ジメチルアミノ)エチル]-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例７　3-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例８　3-フルオロ-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例９　4-フルオロ-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例１０　4-メチル-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例１１　N-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１２　4-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１３　3-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１４　4-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド 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-pyrazol-4- Yl] -1,2,4-oxadiazol-3-yl} benzamide Example 4 2- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] Oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 5 6- [5- (1-Methyl-5-{[4- (tri Fluoromethyl) 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-oxadiazol-3-yl] 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- (trifluoromethyl) phenoxy] methyl} -1H-pyrazole -4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 11 N-methyl-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine- 2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide 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-pyrazole- 4-yl] -1,2,4-oxadiazol-3-yl} benzamide
実施例１５　2-{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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド Example 15 2- {3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3 -Il] phenyl} acetamide
Figure JPOXMLDOC01-appb-C000022
 　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％トリフルオロ酢酸含有水：０．１％トリフルオロ酢酸含有アセトニトリル＝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]+
Figure JPOXMLDOC01-appb-C000022
 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) The mixture was stirred at 150 ° C. for 30 minutes under wave irradiation. After the reaction solution was concentrated under reduced pressure, the residue was subjected to 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 (44 mg) 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] +
　実施例１５と同様の手法を用いて、表２－１から表２－３に記載した実施例１６から実施例３１の化合物を得た。 Using the same method as in Example 15, the compounds of Example 16 to Example 31 described in Tables 2-1 to 2-3 were obtained.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
実施例１６　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]安息香酸
実施例１７　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]安息香酸
実施例１８　2-{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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例１９　{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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}酢酸
実施例２０　{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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}酢酸
実施例２１　6-[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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ピリジン-2-カルボキサミド
実施例２２　2-[3-(5-{5-[(4-フルオロフェノキシ)メチル]-1-メチル-1H-ピラゾル-4-イル}-1,2,4-オキサジアゾル-3-イル)フェニル]アセトアミド
実施例２３　2-[4-(5-{5-[(4-フルオロフェノキシ)メチル]-1-メチル-1H-ピラゾル-4-イル}-1,2,4-オキサジアゾル-3-イル)フェニル]アセトアミド
実施例２４　2-{3-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例２５　2-{4-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例２６　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル カルバマート
実施例２７　N-[2-(ジメチルアミノ)エチル]-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例２８　N-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例２９　2-{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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェノキシ}アセトアミド
実施例３０　N-(2-ヒドロキシエチル)-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例３１　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]-N-(オキセタン-3-イル)ベンズアミド Example 16 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] Benzoic acid Example 17 3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-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-pyrazol-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- (trifluoromethyl) phenoxy] methyl} -1H-pyra Le-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-fluoropyridine- 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-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl Rubamate 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- (tri Fluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenoxy} acetamide Example 30 N- (2-hydroxyethyl) -3- [5- ( 1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-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- (Oxetane-3-yl) benzamide
実施例３２　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド Example 32 3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] 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％トリフルオロ酢酸含有水：０．１％トリフルオロ酢酸含有アセトニトリル＝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, water containing 0.1% trifluoroacetic acid: acetonitrile containing 0.1% trifluoroacetic acid = 90: 10 to 10:90) to give the title compound ( 2.1 mg) was obtained as a pale yellow 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] +
　実施例３２と同様の手法を用いて、表３－１から表３－２に記載した実施例３３から実施例４１の化合物を得た。 Using the same method as in Example 32, the compounds of Example 33 to Example 41 described in Table 3-1 to Table 3-2 were obtained.
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
実施例３３　tert-ブチル 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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンゾアート
実施例３４　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例３５　3-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例３６　4-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例３７　4-(5-{5-[(4-フルオロフェノキシ)メチル]-1-メチル-1H-ピラゾル-4-イル}-1,2,4-オキサジアゾル-3-イル)ベンズアミド
実施例３８　3-(5-{5-[(4-フルオロフェノキシ)メチル]-1-メチル-1H-ピラゾル-4-イル}-1,2,4-オキサジアゾル-3-イル)ベンズアミド
実施例３９　5-[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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ピリジン-3-カルボキサミド
実施例４０　N-メチル-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例４１　N-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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド Example 33 tert-butyl 3- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-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-pyrazol-4-yl} -1, 2,4-oxadiazol-3-yl) benzamide Example 38 3- (5- {5-[(4-fluorophenoxy) methyl] -1-methyl-1H-pyrazol-4-yl} -1,2,4 -Oki Sadiazol-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
実施例４２　(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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-2-イル}フェニル)アセトニトリル 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
Figure JPOXMLDOC01-appb-C000029
 　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]+ 
Figure JPOXMLDOC01-appb-C000029
 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] +
実施例４３　2-(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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-2-イル}フェニル)アセトアミド 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
Figure JPOXMLDOC01-appb-C000030
 　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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-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]+ 
Figure JPOXMLDOC01-appb-C000030
 (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 palladium chloride ( 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. A 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, insoluble material was 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] +
実施例４４　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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-2-イル}フェニル)アセトアミド 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
Figure JPOXMLDOC01-appb-C000031
 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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-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。得られた固体を逆相カラムクロマトグラフィー（ＣＡＰＣＥＬＬ　ＰＡＫ　ＭＧ　II、０．１％トリフルオロ酢酸含有水：０．１％トリフルオロ酢酸含有アセトニトリル＝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]+
Figure JPOXMLDOC01-appb-C000031
 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 In the same manner as in Example 42, N ′-[3- (cyanomethyl) benzoyl] -1-methyl-5-({[5 The title compound (225 mg) was obtained as a colorless solid from-(trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carbohydrazide (367 mg).
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-oxadiazol-2-yl} phenyl) acetonitrile (119 mg) in N, N-dimethylformamide (3.0 mL) at room temperature with 35% hydrogen peroxide (261) μL) was added and stirred for 1 hour, followed by stirring at 40 ° C. for 4 hours and at room temperature for 12 hours. 35% hydrogen peroxide (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, water containing 0.1% trifluoroacetic acid: acetonitrile containing 0.1% trifluoroacetic acid = 90: 10 to 10:90), The title compound (56 mg) was obtained as a colorless 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] +
　実施例４４と同様の手法を用いて、表４に記載した実施例４５から実施例４９の化合物を得た。 Using the same method as in Example 44, the compounds of Example 45 to Example 49 listed in Table 4 were obtained.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
実施例４５　2-{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-ピラゾル-4-イル)-1,3,4-オキサジアゾル-2-イル]フェニル}アセトアミド
実施例４６　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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-2-イル}ベンズアミド
実施例４７　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-ピラゾル-4-イル)-1,3,4-オキサジアゾル-2-イル]ベンズアミド
実施例４８　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-ピラゾル-4-イル)-1,3,4-オキサジアゾル-2-イル]ベンズアミド
実施例４９　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-ピラゾル-4-イル]-1,3,4-オキサジアゾル-2-イル}ベンズアミド Example 45 2- {3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4-oxadiazol-2 -Yl] phenyl} acetamide Example 46 4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,3,4-oxadiazol-2-yl} benzamide Example 47 3- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-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) pyridin-2-yl] oxy} methyl ) -1H-pyrazol-4-yl] -1,3,4-oxadiazol-2-yl} benzamide
実施例５０　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]-N-(オキセタン-3-イル)ベンズアミド Example 50 4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] -N- (Oxetane-3-yl) benzamide
Figure JPOXMLDOC01-appb-C000033
 　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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-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]+
Figure JPOXMLDOC01-appb-C000033
 4- [5- (1-Methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol- obtained in Example 16 3-Iyl] benzoic acid (22 mg) in tetrahydrofuran (2.0 mL) at room temperature with diisopropylethylamine (17 μL), uronium hexafluorophosphate 2- (1H-7-azabenzotriazol-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] +
実施例５１　N-メチル-2-{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-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド 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
Figure JPOXMLDOC01-appb-C000034
 　実施例５０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]-
Figure JPOXMLDOC01-appb-C000034
 Using the same procedure as in Example 50, {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]-
実施例５２　2-{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-ピラゾル-4-イル)-1,3,4-オキサジアゾル-2-イル]フェニル}アセトアミド Example 52 2- {4- [5- (1-methyl-5-{[4- (trifluoromethyl) phenoxy] methyl} -1H-pyrazol-4-yl) -1,3,4-oxadiazol-2 -Il] phenyl} acetamide
Figure JPOXMLDOC01-appb-C000035
 　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-ピラゾル-4-イル)-1,3,4-オキサジアゾル-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]+
Figure JPOXMLDOC01-appb-C000035
 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] +
　実施例１と同様の手法を用いて、表５－１から表５－１３に記載した実施例５３から実施例１２８の化合物を得た。
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
 In the same manner as in Example 1, the compounds of Example 53 to Example 128 described in Tables 5-1 to 5-13 were obtained.
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
実施例５３　3-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例５４　2-(2-ブロモ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例５５　N-(2-ヒドロキシエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例５６　2-(4-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例５７　2-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例５８　2-(3-フルオロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例５９　2-(4-{5-[1-メチル-5-({[4-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例６０　2-(3-{5-[1-メチル-5-({[4-(トリフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1H-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例６１　2-[4-(5-{5-[(3,4-ジフルオロフェノキシ)メチル]-1-メチル-1H-ピラゾル-4-イル}-1,2,4-オキサジアゾル-3-イル)フェニル]アセトアミド
実施例６２　2-[3-(5-{5-[(3,4-ジフルオロフェノキシ)メチル]-1-メチル-1H-ピラゾル-4-イル}-1,2,4-オキサジアゾル-3-イル)フェニル]アセトアミド
実施例６３　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェノキシ)アセトアミド
実施例６４　2-(3-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例６５　5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ピリジン-2-カルボキサミド
実施例６６　2-(2-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例６７　2-(2-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例６８　2-{3-[5-(5-{[(5-クロロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]-5-フルオロフェニル}アセトアミド
実施例６９　2-(2-クロロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例７０　2-メチル-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例７１　2-(2-メチル-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例７２　2-{4-[5-(5-{[(6-メトキシピリジン-3-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例７３　2-クロロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例７４　3-クロロ-4-[5-(5-{[(5-クロロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンズアミド
実施例７５　3-クロロ-4-{5-[5-({[5-(ジフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1-メチル-1H-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例７６　2-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例７７　2-(2-クロロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例７８　2-(2-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例７９　2-(3-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例８０　4-{3-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンゾイル}ピペラジン-2-オン
実施例８１　4-{3-[5-(5-{[(5-クロロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]ベンゾイル}ピペラジン-2-オン
実施例８２　4-(3-{5-[5-({[5-(ジフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1-メチル-1H-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンゾイル)ピペラジン-2-オン
実施例８３　2-フルオロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例８４　3-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)プロパンアミド
実施例８５　2-メチル-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)プロパンアミド
実施例８６　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)エタノン
実施例８７　2-フルオロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例８８　2-(4-{5-[5-({[5-(ジフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1-メチル-1H-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例８９　2-{4-[5-(1-メチル-5-{[(5-メチルピリジン-2-イル)オキシ]メチル}-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例９０　3-フルオロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９１　3-メトキシ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９２　2-メトキシ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９３　4-メトキシ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９４　2-{4-[5-(5-{[(5-シクロプロピルピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例９５　2-メトキシ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９６　N-(2-アミノ-2-オキソエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９７　N-(2-アミノ-2-オキソエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９８　3-クロロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例９９　2-(3-クロロ-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１００　2-{3-クロロ-4-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}アセトアミド
実施例１０１　2-(3-クロロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１０２　3-クロロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１０３　2-(6-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ピリジン-3-イル)アセトアミド
実施例１０４　2-(2-フルオロ-5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１０５　2-(5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ピリジン-2-イル)アセトアミド
実施例１０６　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)エタノール
実施例１０７　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ピリジン-2-イル)メタノール
実施例１０８　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)プロパン-2-オール
実施例１０９　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)プロパン-2-オール
実施例１１０　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)メタノール
実施例１１１　1-メチル-1-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ウレア
実施例１１２　1-{4-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}ウレア
実施例１１３　1-{3-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}ウレア
実施例１１４　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ウレア
実施例１１５　1-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ウレア
実施例１１６　1-{4-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}-3-メチルウレア
実施例１１７　1-{3-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}-3-メチルウレア
実施例１１８　1-メチル-3-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ウレア
実施例１１９　1-メチル-3-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ウレア
実施例１２０　メチル {4-[5-(5-{[(5-フルオロピリジン-2-イル)オキシ]メチル}-1-メチル-1H-ピラゾル-4-イル)-1,2,4-オキサジアゾル-3-イル]フェニル}カルバマート
実施例１２１　5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-2,3-ジヒドロ-1H-イソインドル-1-オン
実施例１２２　6-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-2,3-ジヒドロ-1H-イソインドル-1-オン
実施例１２３　5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-1,3-ジヒドロ-2H-インドル-2-オン
実施例１２４　5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-1,3-ジヒドロ-2H-ベンゾイミダゾル-2-オン
実施例１２５　1-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)イミダゾリジン-2-オン
実施例１２６　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)イミダゾリジン-2-オン
実施例１２７　1-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ピロリジン-2-オン
実施例１２８　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)ピロリジン-2-オン Example 53 3-Fluoro-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1 , 2,4-oxadiazol-3-yl} benzamide Example 54 2- (2-Bromo-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] Oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 55 N- (2-hydroxyethyl) -3- {5- [1-methyl -5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 56 2 -(4-Fluoro-3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} phenyl) acetamide Example 57 2-Fluoro-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} Tyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 58 2- (3-Fluoro-5- {5- [1-methyl-5-({[ 5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 59 2- (4- {5- [1-Methyl-5-({[4- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3- Yl} phenyl) acetamide Example 60 2- (3- {5- [1-Methyl-5-({[4- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4- Yl] -1,2,4-oxadiazol-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 Example 62 2- [3- (5- {5-[(3,4-difluorophenoxy) methyl] -1- Mechi -1H-pyrazol-4-yl} -1,2,4-oxadiazol-3-yl) phenyl] acetamide Example 63 2- (3- {5- [1-methyl-5-({[5- (tri Fluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenoxy) acetamide Example 64 2- (3-Fluoro-4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} 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-oxadiazol-3-yl} pyridine-2-carboxamide Example 66 2- (2-Fluoro-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 67 2- (2-fur Rho-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl} phenyl) acetamide Example 68 2- {3- [5- (5-{[(5-chloropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4- Yl) -1,2,4-oxadiazol-3-yl] -5-fluorophenyl} acetamide Example 69 2- (2-Chloro-5- {5- [1-methyl-5-({[5- ( Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 70 2-methyl-5- {5 -[1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} Benzamide Example 71 2- (2-Methyl-5- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4- Yl] -1,2,4-oxa Azol-3-yl} phenyl) acetamide Example 72 2- {4- [5- (5-{[(6-methoxypyridin-3-yl) oxy] methyl} -1-methyl-1H-pyrazol-4- Yl) -1,2,4-oxadiazol-3-yl] phenyl} acetamide Example 73 2-Chloro-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine-2 -Yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 74 3-Chloro-4- [5- (5-{[(5- Chloropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzamide Example 75 3-chloro-4- {5- [5-({[5- (Difluoromethyl) pyridin-2-yl] oxy} methyl) -1-methyl-1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 76 2-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 77 2- (2-Chloro-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl)- 1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 78 2- (2-methyl-4- {5- [1-methyl-5-({[5 -(Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 79 2- (3-Methyl -4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol -3-yl} phenyl) acetamide Example 80 4- {3- [5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl ) -1,2,4-oxadiazol-3-yl] benzoyl} piperazin-2-one Example 81 4- {3- [5- (5-{[(5-chloropyridin-2-yl) oxy] methyl } -1- Methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] benzoyl} 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-oxadiazol-3-yl} benzoyl) piperazin-2-one Example 83 2 -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 84 3- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole -4-yl] -1,2,4-oxadiazol-3-yl} phenyl) propanamide Example 85 2-methyl-2- (4- {5- [1-methyl-5-({[5- ( Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) propanamide Example 86 1- (3- {5 - [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-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-oxadiazol-3-yl} benzamide Example 88 2- (4- {5- [5-({[5- (Difluoromethyl) pyridin-2-yl] oxy} methyl) -1- Methyl-1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 89 2- {4- [5- (1-methyl-5-{[(5-methyl Pyridin-2-yl) oxy] methyl} -1H-pyrazol-4-yl) -1,2,4-oxadiazol-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- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} benzamide Example 92 2-Methoxy-5- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 93 4-Methoxy-3- {5- [1-methyl-5-({[5- (trifluoro Methyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 94 2- {4- [5- (5- { [(5-Cyclopropylpyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} acetamide Example 95 2- Methoxy-3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadia Ru-3-yl} benzamide 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-oxadiazol-3-yl} benzamide Example 97 N- (2-amino-2-oxoethyl) -4- {5- [1- Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 98 3-chloro-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2, 4-oxadiazol-3-yl} benzamide Example 99 2- (3-Chloro-4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl ) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 100 2- {3-Chloro-4- [5- (5-{[(5-fluoro Pyridine-2-y L) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} acetamide Example 101 2- (3-Chloro-5- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl ) Acetamide Example 102 3-Chloro-5- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 103 2- (6- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} pyridin-3-yl) acetamide Example 104 2- (2-Fluoro-5- {5- [1-methyl) -5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) a Cetamide Example 105 2- (5- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1 , 2,4-oxadiazol-3-yl} pyridin-2-yl) acetamide Example 106 2- (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2- Yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-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-oxadiazol-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- Oxadiazol-3-yl} phenyl) propan-2-ol Example 109 2- (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl ) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) propan-2-ol Example 110 (4- {5- [1-methyl-5-({[5 -(Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) methanol Example 111 1-methyl-1- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol -3-yl} phenyl) urea Example 112 1- {4- [5- (5-{[(5-fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl ) -1,2,4-oxadiazol-3-yl] phenyl} urea Example 113 1- {3- [5- (5-{[(5-fluoropyridin-2-yl) oxy] methyl} -1- Methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} urea Example 114 1- (3- {5- [1-methyl-5-({[5- ( Trifluoromethyl) pyridin-2-yl] Xyl} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) urea Example 115 1- (4- {5- [1-methyl-5-({[ 5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) urea Example 116 1- {4- [5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} -3-Methylurea Example 117 1- {3- [5- (5-{[(5-Fluoropyridin-2-yl) oxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1, 2,4-oxadiazol-3-yl] phenyl} -3-methylurea Example 118 1-methyl-3- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine- 2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) urea Example 119 1-methyl-3- (4- {5- [1 -Methyl-5-({[5- (trifluoro Methyl) 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-oxadiazol-3-yl] phenyl} carbamate Example 121 5- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3- Yl} -2,3-dihydro-1H-isoindol-1-one Example 122 6- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl ) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} -2,3-dihydro-1H-isoindol-1-one Example 123 5- {5- [1-Methyl- 5-({[5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro -2H-I Dol-2-one Example 124 5- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl]- 1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one Example 125 1- (4- {5- [1-methyl-5-({[5 -(Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) imidazolidin-2-one Example 126 1 -(3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl} phenyl) imidazolidin-2-one Example 127 1- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) pyrrolidin-2-one Example 128 1- (3- {5- [1-Methyl-5- ( {[5- (trifluoromethyl) pi 2-yl] oxy} methyl)-1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) pyrrolidin-2-one
　実施例５０と同様の手法を用いて、表６－１から表６－８に記載した実施例１２９から実施例１７５の化合物を得た。
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
 Using the same method as in Example 50, the compounds of Examples 129 to 175 described in Table 6-1 to Table 6-8 were obtained.
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
実施例１２９　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-N-(2,2,2-トリフルオロエチル)アセトアミド
実施例１３０　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-N-[2-(プロパン-2-イルオキシ)エチル]アセトアミド
実施例１３１　N-(2-ヒドロキシエチル)-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１３２　N-[2-(2-ヒドロキシエトキシ)エチル]-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１３３　N-メチル-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１３４　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-N-[2-(モルホリン-4-イル)エチル]アセトアミド
実施例１３５　N2-[(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセチル]グリシンアミド
実施例１３６　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)(ピロリジン-1-イル)メタノン
実施例１３７　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-1-(モルホリン-4-イル)エタノン
実施例１３８　N,N-ジメチル-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１３９　1-(4-メチルピペラジン-1-イル)-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)エタノン
実施例１４０　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-N-(オキセタン-3-イル)アセトアミド
実施例１４１　N-[2-(ジメチルアミノ)エチル]-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１４２　1-メチル-4-[(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセチル]ピペラジン-2-オン
実施例１４３　N-tert-ブチル-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１４４　N-(2-メトキシエチル)-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１４５　1-[(3S)-3-ヒドロキシピロリジン-1-イル]-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)エタノン
実施例１４６　1-[(3R)-3-ヒドロキシピロリジン-1-イル]-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)エタノン
実施例１４７　4-[(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセチル]ピペラジン-2-オン
実施例１４８　N-[(2S)-2-ヒドロキシプロピル]-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１４９　N-[(2R)-2-ヒドロキシプロピル]-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１５０　N-(2-ヒドロキシ-2-メチルプロピル)-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
実施例１５１　アゼチジン-1-イル(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)メタノン
実施例１５２　(3-ヒドロキシアゼチジン-1-イル)(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)メタノン
実施例１５３　N-[2-(ジメチルアミノ)-2-オキソエチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１５４　N-[2-(ジメチルアミノ)-2-オキソエチル]-N-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１５５　N-[2-(メチルアミノ)-2-オキソエチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１５６　1-メチル-4-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンゾイル)ピペラジン-2-オン
実施例１５７　(4-メチルピペラジン-1-イル)(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)メタノン
実施例１５８　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-N-(オキセタン-3-イル)ベンズアミド
実施例１５９　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)(モルホリン-4-イル)メタノン
実施例１６０　[(3S)-3-ヒドロキシピロリジン-1-イル](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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)メタノン
実施例１６１　[(3R)-3-ヒドロキシピロリジン-1-イル](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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)メタノン
実施例１６２　4-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンゾイル)ピペラジン-2-オン
実施例１６３　N-(2-メトキシエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１６４　N-[2-(ジメチルアミノ)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１６５　N-(2-ヒドロキシ-2-メチルプロピル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１６６　N-[(2R)-2-ヒドロキシプロピル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１６７　N-[(2S)-2-ヒドロキシプロピル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１６８　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-N-[2-(モルホリン-4-イル)エチル]ベンズアミド
実施例１６９　N-(2-アミノ-2-オキソエチル)-N-メチル-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１７０　N-(1,3-ジヒドロキシ-2-メチルプロパン-2-イル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１７１　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-1-(ピロリジン-1-イル)エタノン
実施例１７２　2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)-1-(ピロリジン-1-イル)エタノン
実施例１７３　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)(ピロリジン-1-イル)メタノン
実施例１７４　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)(モルホリン-4-イル)メタノン
実施例１７５　2-(3-クロロ-4-{5-[5-({[5-(ジフルオロメチル)ピリジン-2-イル]オキシ}メチル)-1-メチル-1H-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド Example 129 2- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} phenyl) -N- (2,2,2-trifluoroethyl) acetamide Example 130 2- (3- {5- [1-methyl-5-({[5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) -N- [2- (propan-2- Iloxy) ethyl] acetamide Example 131 N- (2-hydroxyethyl) -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 Example 132 N- [2- (2-hydroxyethoxy) ethyl] -2- (4- { 5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl } Phenyl) Cetamide Example 133 N-methyl-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 Example 134 2- (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine-2- Yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) -N- [2- (morpholin-4-yl) ethyl] acetamide Example 135 N 2 -[(4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2, 4-oxadiazol-3-yl} phenyl) acetyl] glycinamide Example 136 (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) (pyrrolidin-1-yl) methanone Example 137 2- (4- {5- [1-methyl- 5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) -1- ( Morpholin-4-yl) ethanone Example 138 N, N-dimethyl-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 Example 139 1- (4-Methylpiperazin-1-yl) -2- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl ) Ethanone Example 140 2- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl]- 1,2,4-oxadiazol-3-yl} phenyl) -N- (oxetan-3-yl) acetamide Example 141 N- [2- (dimethylamino) ethyl] -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 Example 142 1-Methyl-4- [(4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl} phenyl) acetyl] piperazin-2-one Example 143 N-tert-butyl-2- (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine] -2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 144 N- (2-methoxyethyl) -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 Example 145 1-[(3S) -3-Hydroxypyrrolidin-1-yl] -2- (4- {5- [1-methyl-5-({[5- (trifluoro Methyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) ethanone Example 146 1-[(3R) -3-hydroxy Pyrrolidin-1-yl] -2- (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl ] -1,2,4-oxadiazol-3-yl} phenyl) ethanone Example 147 4-[(4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine-2- Yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetyl] piperazin-2-one Example 148 N-[(2S) -2-hydroxy Propyl] -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 Example 149 N-[(2R) -2-hydroxypropyl] -2- (4- {5- [1-methyl-5-({[5- ( (Trifluoromethyl) Lysin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) acetamide Example 150 N- (2-hydroxy-2-methylpropyl) -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 Example 151 Azetidin-1-yl (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) methanone Example 152 (3-hydroxyazetidin-1-yl) (3- {5- [1- Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) methanone Example 153 N- [2- (dimethylamino) -2-oxoethyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pi Gin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 154 N- [2- (dimethylamino) -2-oxoethyl] -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 155 N- [2- (Methylamino) -2-oxoethyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) Pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 156 1-methyl-4- (3- {5- [1 -Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzoyl) piperazine -2-one Example 157 (4-methylpiperazin-1-yl) (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy } Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) methanone Example 158 3- {5- [1-methyl-5-({[5- (tri Fluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} -N- (oxetan-3-yl) benzamide Example 159 3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -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) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) methanone Example 161 [(3R) -3-hydroxy Pyrrolidin-1-yl] (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl ] -1,2,4-oxadiazol-3-yl} phenyl) methanone Example 162 4- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] ] Oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzoyl) piperazin-2-one Example 163 N- (2-methoxyethyl) -3- {5 -[1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} Benzamide Example 164 N- [2- (Dimethylamino) ethyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H -Pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 165 N- (2-hydroxy-2-methylpropyl) -3- {5- [1-methyl-5- ( {[5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Examples 66 N-[(2R) -2-hydroxypropyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole -4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 167 N-[(2S) -2-hydroxypropyl] -3- {5- [1-methyl-5-({[ 5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 168 3- {5- [1 -Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} -N- [2- (Morpholin-4-yl) ethyl] benzamide Example 169 N- (2-amino-2-oxoethyl) -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 170 N- (1,3-Dihydroxy-2 -Mechi Rupropan-2-yl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1 , 2,4-oxadiazol-3-yl} benzamide Example 171 2- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) -1- (pyrrolidin-1-yl) ethanone Example 172 2- (4- {5- [1-methyl -5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) -1- (Pyrrolidin-1-yl) ethanone Example 173 (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4 -Yl] -1,2,4-oxadiazol-3-yl} phenyl) (pyrrolidin-1-yl) methanone Example 174 (4- {5- [1-methyl-5-({[5- (trifluoro Methyl) pyridine-2-y ] Oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl) (morpholin-4-yl) methanone Example 175 2- (3-Chloro-4- { 5- [5-({[5- (Difluoromethyl) pyridin-2-yl] oxy} methyl) -1-methyl-1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} Phenyl) acetamide
実施例１７６　N-(1,3-ジオキソラン-2-イルメチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
Figure JPOXMLDOC01-appb-C000057
 １）N-(2,2-ジメトキシエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
　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-ピラゾル-4-カルボン酸（９６９　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５．０　ｍＬ）溶液に、室温にて１，１’－カルボニルジイミダゾール（６２６　ｍｇ）を加え１時間撹拌した。反応液に製造例５で得られたN-(2,2-ジメトキシエチル)-3-(N'-ヒドロキシカルバムイミドイル)ベンズアミド（８４６　ｍｇ）を加え、１２０　℃にて１０時間撹拌した。反応液を室温まで放冷し、ＩＳＯＬＵＴＥ　ＨＭ－Ｎを加え、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。得られた固体をジエチルエーテルにて洗浄して、表題化合物（１．００　ｇ）を無色固体として得た。
MS (ESI/APCI Dual pos.) m/z: 533 [M+H]+
２）N-(1,3-ジオキソラン-2-イルメチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
N-(2,2-ジメトキシエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド（３０　ｍｇ）のトルエン（３．０　ｍＬ）溶液に、ｐ－トルエンスルホン酸　１水和物（９．７　ｍｇ）及びエタン－１，２－ジオール（１６　μＬ）を加え、６０　℃にて２時間攪拌した。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％トリフルオロ酢酸含有水：０．１％トリフルオロ酢酸含有アセトニトリル＝９０：１０～１０：９０）にて精製して、表題化合物（１８　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-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, 1 H) 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]+ Example 176 N- (1,3-dioxolan-2-ylmethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl)- 1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide
Figure JPOXMLDOC01-appb-C000057
 1) N- (2,2-dimethoxyethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole- 4-yl] -1,2,4-oxadiazol-3-yl} benzamide 1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl obtained in Preparation Example 4 ) -1H-pyrazole-4-carboxylic acid (969 mg) in N, N-dimethylformamide (5.0 mL) was added 1,1′-carbonyldiimidazole (626 mg) at room temperature and stirred for 1 hour. did. N- (2,2-dimethoxyethyl) -3- (N′-hydroxycarbamimidoyl) benzamide (846 mg) obtained in Production Example 5 was added to the reaction solution, and the mixture was stirred at 120 ° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, ISOLUTE HM-N was added, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 90: 10). The obtained solid was washed with diethyl ether to give the title compound (1.00 g) as a colorless solid.
MS (ESI / APCI Dual pos.) M / z: 533 [M + H] +
2) N- (1,3-Dioxolan-2-ylmethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H -Pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide
N- (2,2-dimethoxyethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4- Yl] -1,2,4-oxadiazol-3-yl} benzamide (30 mg) in toluene (3.0 mL) was added p-toluenesulfonic acid monohydrate (9.7 mg) and ethane-1 , 2-diol (16 μL) was added and stirred at 60 ° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to 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 (18 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-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, 1 H) 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] +
　実施例１７６と同様の手法を用いて、実施例１７７及び実施例１７８の化合物を得た。 Example 177 and Example 178 were obtained using the same method as in Example 176.
実施例１７７　N-(1,3-ジオキサン-2-イルメチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
Figure JPOXMLDOC01-appb-C000058
 MS (ESI pos.) m/z: 545 [M+H]+
RT=1.07 (Condition A) Example 177 N- (1,3-dioxan-2-ylmethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl)- 1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide
Figure JPOXMLDOC01-appb-C000058
 MS (ESI pos.) M / z: 545 [M + H] +
RT = 1.07 (Condition A)
実施例１７８　N-(5,7-ジオキサスピロ[2.5]オクト-6-イルメチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
Figure JPOXMLDOC01-appb-C000059
 MS (ESI pos.) m/z: 571 [M+H]+
RT=1.10 (Condition A) Example 178 N- (5,7-dioxaspiro [2.5] oct-6-ylmethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy } Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide
Figure JPOXMLDOC01-appb-C000059
 MS (ESI pos.) M / z: 571 [M + H] +
RT = 1.10 (Condition A)
実施例１７９　N-{2-[(3S)-3-フルオロピロリジン-1-イル]エチル}-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
Figure JPOXMLDOC01-appb-C000060
 　実施例１７６－１）で得られたN-(2,2-ジメトキシエチル)-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド（５２　ｍｇ）のテトラヒドロフラン（１．０　ｍＬ）溶液に、ｐ－トルエンスルホン酸　１水和物（８．４　ｍｇ）を加え、室温にて１９時間攪拌した。ｐ－トルエンスルホン酸　１水和物（８．４　ｍｇ）を追加し、５０　℃にて５時間攪拌した。反応液を室温まで放冷後、(3S)-3-フルオロピロリジン（２５　ｍｇ）、トリエチルアミン（４１　μＬ）及び水素化ホウ素トリアセトキシナトリウム（６２　ｍｇ）を反応液に加え、室温にて１０分間攪拌した。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％トリフルオロ酢酸含有水：０．１％トリフルオロ酢酸含有アセトニトリル＝９０：１０～１０：９０）にて精製して、表題化合物（１７　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ 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.) m/z: 560 [M+H]+ Example 179 N- {2-[(3S) -3-fluoropyrrolidin-1-yl] ethyl} -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine-2 -Yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide
Figure JPOXMLDOC01-appb-C000060
 N- (2,2-dimethoxyethyl) -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy obtained in Example 176-1) } Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide (52 mg) in tetrahydrofuran (1.0 mL) and p-toluenesulfonic acid monohydrate (8.4 mg) was added, and the mixture was stirred at room temperature for 19 hours. p-Toluenesulfonic acid monohydrate (8.4 mg) was added, and the mixture was stirred at 50 ° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, (3S) -3-fluoropyrrolidine (25 mg), triethylamine (41 μL) and sodium triacetoxyborohydride (62 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. did. After concentration under reduced pressure, 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). The title compound (17 mg) was obtained as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ 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.) M / z: 560 [M + H] +
　実施例１７９と同様の手法を用いて、表７－１から表７－２に記載した実施例１８０から実施例１８７の化合物を得た。
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
 In the same manner as in Example 179, the compounds of Example 180 to Example 187 described in Table 7-1 to Table 7-2 were obtained.
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
実施例１８０　N-[2-(アゼチジン-1-イル)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１８１　N-[2-(3,3-ジフルオロアゼチジン-1-イル)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１８２　N-[2-(3-フルオロアゼチジン-1-イル)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１８３　N-[2-(3,3-ジフルオロピロリジン-1-イル)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１８４　N-{2-[(3R)-3-フルオロピロリジン-1-イル]エチル}-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１８５　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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-N-[2-(2-オキサ-6-アザスピロ[3.3]ヘプト-6-イル)エチル]ベンズアミド
実施例１８６　N-[2-(4-フルオロピペリジン-1-イル)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド
実施例１８７　N-[2-(4,4-ジフルオロピペリジン-1-イル)エチル]-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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ベンズアミド Example 180 N- [2- (azetidin-1-yl) ethyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 181 N- [2- (3,3-difluoroazetidin-1-yl) ethyl] -3- { 5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl } Benzamide Example 182 N- [2- (3-Fluoroazetidin-1-yl) ethyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine-2- Yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 183 N- [2- (3,3-difluoropyrrolidin-1-yl) ethyl ] -3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl} benz Example 184 N- {2-[(3R) -3-fluoropyrrolidin-1-yl] ethyl} -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridine- 2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 185 3- {5- [1-methyl-5-({[5 -(Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} -N- [2- (2-oxa-6 -Azaspiro [3.3] hept-6-yl) ethyl] benzamide Example 186 N- [2- (4-fluoropiperidin-1-yl) ethyl] -3- {5- [1-methyl-5-({[ 5- (Trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl} benzamide Example 187 N- [2- (4 , 4-Difluoropiperidin-1-yl) ethyl] -3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol- 4-yl] -1,2,4-o Sajiazoru-3-yl} benzamide
実施例１８８　N-アセチル-2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド
Figure JPOXMLDOC01-appb-C000063
 　実施例１で得られた2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド（１００　ｍｇ）、無水酢酸（６７　μＬ）及びピリジン（２.０　ｍＬ）の混合物を、８５　℃にて終夜攪拌した。反応液を室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、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％トリフルオロ酢酸含有水：０．１％トリフルオロ酢酸含有アセトニトリル＝９０：１０～１０：９０）にて精製して、表題化合物（３２　ｍｇ）を黄色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 2.08 (s, 3 H) 3.77 (s, 2 H) 3.95 (s, 3 H) 5.84 (s, 2 H) 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 188 N-acetyl-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
Figure JPOXMLDOC01-appb-C000063
 2- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl obtained in Example 1 ] -1,2,4-oxadiazol-3-yl} phenyl) acetamide (100 mg), acetic anhydride (67 μL) and pyridine (2.0 mL) were stirred at 85 ° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 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) was obtained as a yellow solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 2.08 (s, 3 H) 3.77 (s, 2 H) 3.95 (s, 3 H) 5.84 (s, 2 H) 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] +
実施例１８９　(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトニトリル
Figure JPOXMLDOC01-appb-C000064
 　実施例１で得られた2-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)アセトアミド（１００　ｍｇ）のピリジン（２．０　ｍＬ）溶液に、氷冷下、オキシ塩化リン（４０　μＬ）を加え、室温にて３時間攪拌した。反応液を氷－水に注ぎ、析出した固体をろ取した。得られた固体を水、イソプロピルエーテル及びヘキサンで洗浄し、表題化合物（９８　ｍｇ）を黄色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 4.01 (s, 3 H) 4.06 - 4.19 (m, 2 H) 5.91 (s, 2 H) 7.07 (d, J=8.7 Hz, 1 H) 7.47 (d, J=8.3 Hz, 2 H) 7.82 - 7.99 (m, 2 H) 8.09 (dd, J=8.7, 2.5 Hz, 1 H) 8.22 (s, 1 H) 8.66 (s, 1 H) ; MS (ESI/APCI Dual pos.) m/z: 441 [M+H]+ Example 189 (4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2, 4-oxadiazol-3-yl} phenyl) acetonitrile
Figure JPOXMLDOC01-appb-C000064
 2- (4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl obtained in Example 1 ] To a solution of 1,2,4-oxadiazol-3-yl} phenyl) acetamide (100 mg) in pyridine (2.0 mL) under ice-cooling, phosphorus oxychloride (40 μL) was added at room temperature. Stir for hours. The reaction solution was poured into ice-water, and the precipitated solid was collected by filtration. The obtained solid was washed with water, isopropyl ether and hexane to give the title compound (98 mg) as a yellow solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 4.01 (s, 3 H) 4.06-4.19 (m, 2 H) 5.91 (s, 2 H) 7.07 (d, J = 8.7 Hz, 1 H) 7.47 (d , J = 8.3 Hz, 2 H) 7.82-7.99 (m, 2 H) 8.09 (dd, J = 8.7, 2.5 Hz, 1 H) 8.22 (s, 1 H) 8.66 (s, 1 H); MS (ESI / APCI Dual pos.) M / z: 441 [M + H] +
実施例１９０　2-[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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-2-オキソピリジン-1(2H)-イル]アセトアミド
Figure JPOXMLDOC01-appb-C000065
 １）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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ピリジン-2(1H)-オン
　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（６５　ｍｇ）を加え１時間撹拌した。反応液に製造例５で得られたN'-ヒドロキシ-2-オキソ-1,2-ジヒドロピリジン-4-カルボキシミドアミド（６２　ｍｇ）を加え、室温にて３０分間、１１０　℃にて１４時間撹拌した。反応液を室温まで放冷し、水を加えた後、析出した結晶をろ取した。これを酢酸エチルにて再結晶して表題化合物（７４　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δppm 4.04 (s, 3 H) 5.92 (s, 2 H) 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]+
２）2-[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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-2-オキソピリジン-1(2H)-イル]アセトアミド
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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}ピリジン-2(1H)-オン（４７　ｍｇ）、２－ブロモアセトアミド（２０　ｍｇ）及び炭酸カリウム（２６ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０　ｍＬ）溶液を室温にて１８時間、６０　℃にて４時間攪拌した。反応液を酢酸エチル（７０　ｍＬ）で希釈し、水（２０　ｍＬ）－飽和食塩水（２０　ｍＬ）、飽和食塩水（３０　ｍＬ）で順次洗浄した。有機層にＩＳＯＬＵＴＥ　ＨＭ－Ｎを加え、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、ヘキサン：酢酸エチル＝６０：４０～０：１００～クロロホルム：メタノール＝９５：５～９０：１０）にて精製した。得られた固体を酢酸エチル－ヘキサンにて洗浄して、表題化合物（４２　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 4.04 (s, 3 H) 4.56 (s, 2 H) 5.92 (s, 2 H) 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 190 2- [4- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} -2-oxopyridin-1 (2H) -yl] acetamide
Figure JPOXMLDOC01-appb-C000065
 1) 4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl} pyridin-2 (1H) -one 1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H- obtained in Preparation Example 4 To a solution of pyrazole-4-carboxylic acid (100 mg) in N, N-dimethylformamide (2.0 mL) was added 1,1′-carbonyldiimidazole (65 mg) at room temperature and stirred for 1 hour. N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboximidamide (62 mg) obtained in Production Example 5 was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and at 110 ° C. for 14 hours. did. The reaction solution was allowed to cool to room temperature, water was added, and the precipitated crystals were collected by filtration. This afford the title compound recrystallized from ethyl acetate (74 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δppm 4.04 (s, 3 H) 5.92 (s, 2 H) 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 m / z (ESI / APCI Dual pos.): 419 [M + H] +
2) 2- [4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2 , 4-Oxadiazol-3-yl} -2-oxopyridin-1 (2H) -yl] acetamide
4- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol- A solution of 3-yl} pyridin-2 (1H) -one (47 mg), 2-bromoacetamide (20 mg) and potassium carbonate (26 mg) in N, N-dimethylformamide (1.0 mL) at room temperature for 18 The mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (70 mL), and washed successively with water (20 mL) -saturated brine (20 mL) and saturated brine (30 mL). Added ISOLUTE HM-N in the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, 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 to give the title compound (42 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 4.04 (s, 3 H) 4.56 (s, 2 H) 5.92 (s, 2 H) 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 m / z (ESI / APCI Dual pos.): 476 [M + H] +
実施例１９１
2-[5-{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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}-2-オキソピリジン-1(2H)-イル]アセトアミド
Figure JPOXMLDOC01-appb-C000066
 　実施例１９０と同様の手法を用いて、表題化合物を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 4.02 (s, 3 H) 4.65 (s, 2 H) 5.92 (s, 2 H) 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 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 -Oxadiazol-3-yl} -2-oxopyridin-1 (2H) -yl] acetamide
Figure JPOXMLDOC01-appb-C000066
 Using a method similar to that in Example 190, the title compound was obtained as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 4.02 (s, 3 H) 4.65 (s, 2 H) 5.92 (s, 2 H) 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 m / z (ESI / APCI Dual pos.): 476 [M + H] +
実施例１９２　N-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)スルフリック ジアミド
Figure JPOXMLDOC01-appb-C000067
 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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}アニリン
　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（８００　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．０　ｍＬ）溶液に室温にて１，１’－カルボニルジイミダゾール（５１７　ｍｇ）を加え３０分間撹拌した。反応液に製造例５で得られた3-アミノ-N'-ヒドロキシベンゼンカルボキシミドアミド（４８０　ｍｇ）を加え、室温にて１時間、１１０　℃にて１６時間撹拌した。反応液を減圧下濃縮し、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、ヘキサン：酢酸エチル＝８８：１２～５０：５０）にて精製した。得られた固体をテトラヒドロフラン－イソプロピルエーテルより再結晶し、表題化合物（４６４　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.78 (br. s., 2 H) 4.05 (s, 3 H) 5.95 (s, 2 H) 6.81 (dd, J=8.1, 1.4 Hz, 1 H) 6.88 (d, J=8.7 Hz, 1 H) 7.22 - 7.26 (m, 1 H) 7.41 (s, 1 H) 7.46 (d, J=7.4 Hz, 1 H) 7.82 (dd, J=8.7, 2.48 Hz, 1 H) 8.14 (s, 1 H) 8.48 (s, 1 H)
２）N-(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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}フェニル)スルフリック ジアミド
　ｔ－ブタノール（１８１　μＬ）のクロロホルム（３．２　ｍＬ）溶液に、氷冷下、スルフリソシアナチドイル クロリド（１６６　μＬ）を加え、同温にて１０分間攪拌した。トリエチルアミン（３１９　μＬ）及び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-ピラゾル-4-イル]-1,2,4-オキサジアゾル-3-イル}アニリン（１５９　ｍｇ）を、氷冷下、反応液に加え、室温にて２１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液（１．６　ｍＬ）及び水（１．６　ｍＬ）を加え、２層を分離した。有機層をフェーズセパレーター（バイオタージ社製）に通し、水分を除去後、減圧下濃縮した。残渣にクロロホルムを加え、氷冷下、トリフルオロ酢酸（３．２　ｍＬ）を加え、室温にて１．５時間攪拌した。反応液を減圧下濃縮し、残渣にクロロホルム（６．４　ｍＬ）、飽和炭酸水素ナトリウム水溶液（３．２　ｍＬ）、水（６．４　ｍＬ）及びメタノール（３．２　ｍＬ）を加えた。２層を分離後、水層をクロロホルム（３．２　ｍＬ）－メタノール（１．６　ｍＬ）の混合溶媒で抽出した。一緒にした有機層をフェーズセパレーターに通し、水分を除去後、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＝１００：０～９０：１０）にて精製し、表題化合物（９９　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 4.04 (s, 3 H) 5.93 (s, 2 H) 7.10 - 7.13 (m, 1 H) 7.15 (br. s, 2 H) 7.37 - 7.44 (m, 2 H) 7.48 - 7.51 (m, 1 H) 7.83 - 7.85 (m, 1 H) 8.11 - 8.14 (m, 1 H) 8.23 (s, 1 H) 8.67 (br. s, 1 H) 9.75 (br. s, 1 H); MS (ESI/APCI Dual neg.) m/z: 494 [M-H]- Example 192 N- (3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} phenyl) sulfuric diamide
Figure JPOXMLDOC01-appb-C000067
 1) 3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl} aniline 1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazole-4-carboxylic acid obtained in Production Example 4 To a solution of 800 mg) in N, N-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (517 mg) at room temperature and stirred for 30 minutes. To the reaction solution, 3-amino-N′-hydroxybenzenecarboxymidoamide (480 mg) obtained in Production Example 5 was added, and the mixture was stirred at room temperature for 1 hour and at 110 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 88: 12 to 50:50). The obtained solid was recrystallized from tetrahydrofuran-isopropyl ether to give the title compound (464 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.78 (br. S., 2 H) 4.05 (s, 3 H) 5.95 (s, 2 H) 6.81 (dd, J = 8.1, 1.4 Hz, 1 H) 6.88 (d, J = 8.7 Hz, 1 H) 7.22-7.26 (m, 1 H) 7.41 (s, 1 H) 7.46 (d, J = 7.4 Hz, 1 H) 7.82 (dd, J = 8.7, 2.48 Hz , 1 H) 8.14 (s, 1 H) 8.48 (s, 1 H)
2) N- (3- {5- [1-Methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1,2 , 4-Oxadiazol-3-yl} phenyl) sulfuric diamide t-butanol (181 μL) in chloroform (3.2 mL) was added with sulfrocyanocyanidyl chloride (166 μL) under ice cooling, and the same temperature. at the mixture was stirred for 10 minutes. Triethylamine (319 μL) and 3- {5- [1-methyl-5-({[5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl} aniline (159 mg) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 21 hours. A saturated aqueous sodium hydrogen carbonate solution (1.6 mL) and water (1.6 mL) were added to the reaction solution, and the two layers were separated. The organic layer was passed through a phase separator (manufactured by Biotage Corp.), water was removed, and the mixture was concentrated under reduced pressure. Chloroform was added to the residue, trifluoroacetic acid (3.2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and chloroform (6.4 mL), saturated aqueous sodium hydrogen carbonate solution (3.2 mL), water (6.4 mL) and methanol (3.2 mL) were added to the residue. After separating the two layers, the aqueous layer was extracted with a mixed solvent of chloroform (3.2 mL) -methanol (1.6 mL). The combined organic layers were passed through a phase separator to remove moisture, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 90:10) to give the title compound (99 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 4.04 (s, 3 H) 5.93 (s, 2 H) 7.10-7.13 (m, 1 H) 7.15 (br. S, 2 H) 7.37-7.44 (m, 2 H) 7.48-7.51 (m, 1 H) 7.83-7.85 (m, 1 H) 8.11-8.14 (m, 1 H) 8.23 (s, 1 H) 8.67 (br. S, 1 H) 9.75 (br. s, 1 H); MS (ESI / APCI Dual neg.) m / z: 494 [MH]-
試験例１
(ヒト型代謝型グルタミン酸受容体（ｍＧｌｕ２）安定発現ＣＨＯ細胞の粗膜画分調製)
　ヒト型ｍＧｌｕ２受容体安定発現ＣＨＯ細胞を、１０％透析牛胎児血清含有ダルベッコ改変イーグル培地［１％　ｐｒｏｌｉｎｅ、５０ｕｎｉｔｓ／ｍＬ　ｐｅｎｉｃｉｌｌｉｎ、５０μｇ／ｍＬ　ｓｔｒｅｐｔｏｍｙｃｉｎ、４００μｇ／ｍＬ　Ｈｙｇｒｏｍｙｃｉｎ　Ｂ、２ｍＭ Ｌ－ｇｌｕｔａｍｉｎｅ（用時添加）］を用いて、３７℃、５％ＣＯ2下で培養した。コンフルエント状態の細胞をＰＢＳ（－）で２回洗浄した後、セルスクレ－パ－で剥離し、４℃、１０００ｒｐｍ、５分間遠心分離を行って細胞を回収した。得られた沈さを、２０ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）に懸濁し、当該懸濁液をテフロン（登録商標）ホモジナイザ－でホモジナイズした後、４℃、４８，０００×ｇ、２０分間遠心分離することにより、再び沈さを得た。さらに得られた沈さを２回遠心洗浄した後に、上記緩衝液でホモジナイズすることにより粗膜画分を得た。得られた粗膜画分は、－８０℃で保存した。 Test example 1
(Preparation of crude membrane fraction of CHO cells stably expressing human metabotropic glutamate receptor (mGlu2))
CHO cells stably expressing human mGlu2 receptor were mixed with Dulbecco's modified Eagle medium containing 10% dialyzed fetal bovine serum [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 . Confluent cells were washed twice with PBS (−), detached with a cell scraper, and centrifuged at 4 ° C. and 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 resulting precipitate was washed twice by centrifugation and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at −80 ° C.
（[35Ｓ]ＧＴＰγＳ結合試験）
　上記で調製した凍結膜画分を用時融解して、結合試験用緩衝液（終濃度；２０ｍＭ　ＨＥＰＥＳ、１００ｍＭ　ＮａＣｌ、１０ｍＭ　ＭｇＣｌ2、８．４μＭ　ＧＤＰ、１０μｇ／ｍＬ　ｓａｐｏｎｉｎ、０．１％　ＢＳＡ）にて希釈した。膜タンパク質１０μｇ／ａｓｓａｙの膜画分に実施例化合物を添加して、３０℃で２０分間インキュベ－ションを行った。その後、グルタミン酸（終濃度２０μＭ）と[35Ｓ]ＧＴＰγＳ（終濃度０．１５ｎＭ）を添加して、３０℃で１時間インキュベ－ションを行った。インキュベ－ションの後、上記反応液を２０ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）に予め浸したＷｈａｔｍａｎ　ＧＦ／Ｃフィルタ－上に吸引濾過し、上記フィルタ－を氷冷２０ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）３００μＬで３回洗浄した。得られたフィルタ－にシンチレーションカクテルを添加して、液体シンチレーションカウンターで膜結合放射活性を測定した。
　グルタミン酸非存在下で上記反応を行った場合における[35Ｓ]ＧＴＰγＳ結合量を非特異的結合とし、グルタミン酸存在下で得られた[35Ｓ]ＧＴＰγＳ結合量との差を特異的結合とした。各実施例化合物の様々な濃度における特異的結合阻害率より、非線形解析を用いて阻害曲線を得た。特異的[35Ｓ]ＧＴＰγＳ結合量が５０％抑制される各実施例化合物の濃度（ＩＣ50値）を阻害曲線より算出した。
　本発明化合物中、ＩＣ50値が０．１μＭ以下の化合物をＡ、０．１μＭ～１μＭの化合物をＢ、１μＭ～１０μＭの化合物をＣ、１０μＭ以上の化合物をＤと表記し、表８に示す。更に本発明化合物の幾つかについて、ＩＣ50値を表９に例示する。 ([ 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 a membrane fraction of membrane protein 10 μg / assay and incubated at 30 ° C. for 20 minutes. Thereafter, glutamic acid (final concentration 20 μM) and [ 35 S] GTPγS (final concentration 0.15 nM) were added, followed by incubation 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.
Among the compounds of the present invention, a compound having an IC 50 value of 0.1 μM or less is represented by A, a compound having 0.1 μM to 1 μM is represented by B, a compound having 1 μM to 10 μM is represented by C, and a compound having 10 μM or more is represented by D. . Further, for some of the compounds of the present invention, IC 50 values are exemplified in Table 9.
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
　本発明化合物は、グループII　ｍＧｌｕ受容体に対して拮抗作用を有し、グループII　ｍＧｌｕ受容体に関連する疾患の予防薬及び治療薬、具体的には、気分障害（うつ病性障害、双極性障害等）、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、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、及び睡眠障害等の予防薬又は治療薬として利用できる。 The compound of the present invention has an antagonistic action on Group II mGlu receptor, and is a preventive and therapeutic agent for diseases related to Group II mGlu receptor, specifically mood disorders (depressive disorder, 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 (11)

  1. 　式［Ｉ］
    Figure JPOXMLDOC01-appb-C000001
     [式［Ｉ］中、
    Ｒ1は、水素原子又はＣ1-6アルキル基（ここで該Ｃ1-6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Ｃ1-6アルキル基（ここで該Ｃ1-6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、ヘテロアリール基、インドリン－２－オン－５－イル基、イソインドリン－１－オン－５－イル基、イソインドリン－１－オン－６－イル基、ベンゾ[ｄ]イミダゾール－２－オン－５－イル基又はピリドニル基を示し、
    環Ａがインドリン－２－オン－５－イル基、イソインドリン－１－オン－５－イル基、イソインドリン－１－オン－６－イル基又はベンゾ[ｄ]イミダゾール－２－オン－５－イル基のとき、
    Ｒ3及びＲ4は、同一又は異なって、水素原子、ハロゲン原子又はＣ1-6アルキル基を示し、
    環Ａがフェニル基、ヘテロアリール基又はピリドニル基のとき、
    Ｒ3は、水素原子、ハロゲン原子、Ｃ1-6アルコキシ基又はＣ1-6アルキル基（ここで該Ｃ1-6アルコキシ基又はＣ1-6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、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基又はＣ1-6アルコキシ基は、－ＣＯＮＲaＲb、－ＣＯＲc、シアノ基又は水酸基で置換されている。）、－ＣＯＮＲaＲb、－Ｏ－ＣＯＮＲaＲb、－ＮＲa1Ｒb1、－ＣＯＲc、シアノ基、－ＮＲdＣＯＲe又は－ＮＲdＳＯ２Ｒeを示し、
    Ｒa及びＲbは、同一又は異なって、水素原子、Ｃ1-6アルキル基
    ｛ここで該Ｃ1-6アルキル基は、
    水酸基、
    ハロゲン原子、
    Ｃ1-6アルコキシ基
    （ここで該Ｃ1-6アルコキシ基は、１から２個の水酸基で置換されてもよい。）、
    －ＣＯＮＲfＲg、
    アミノ基、
    モノ－Ｃ1-6アルキルアミノ基、
    ジ－Ｃ1-6アルキルアミノ基、
    モルホリノ基、
    ピペリジノ基、
    ピロリジノ基、
    アゼチジノ基、
    １，３－ジオキソラン－２－イル基、
    １，３－ジオキサン－２－イル基、
    ２－オキサ－６－アザスピロ[３.３]ヘプタン－６－イル基及び
    ５，７－ジオキサスピロ[２.５]オクタン－６－イル基
    （ここで該モルホリノ基、ピペリジノ基、ピロリジノ基、アゼチジノ基、１，３－ジオキソラン－２－イル基、１，３－ジオキサン－２－イル基、２－オキサ－６－アザスピロ[３.３]ヘプタン－６－イル基及び５，７－ジオキサスピロ[２.５]オクタン－６－イル基
    は１から２個のハロゲン原子で置換されてもよい。）
    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。｝、
    Ｃ1-6アルカノイル基、オキセタニル基、テトラヒドロフラニル基又はテトラヒドロピラニル基を示すか、
    又は、Ｒa及びＲb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４から６員環（ここで該飽和又は不飽和の４から６員環は、Ｃ1-6アルキル基、オキソ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。）を形成してもよく、
    Ｒa1及びＲb1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４から６員環（ここで該飽和又は不飽和の４から６員環は、Ｃ1-6アルキル基、オキソ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。）を形成し、
    Ｒcは、Ｃ1-6アルキル基、水酸基又はＣ1-6アルコキシ基を示し、
    Ｒdは、水素原子又はＣ1-6アルキル基を示し、
    Ｒeは、Ｃ1-6アルコキシ基、アミノ基、モノ－Ｃ1-6アルキルアミノ基又はジ－Ｃ1-6アルキルアミノ基を示し、
    Ｒf及びＲgは、同一又は異なって、水素原子又はＣ1-6アルキル基を示し、
    Ｙ1は、－(ＣＨ2)n－Ｏ－又は－(ＣＨ2)ｍ－を示し、
    ｎは、１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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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。     Formula [I]
    Figure JPOXMLDOC01-appb-C000001
     [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 includes a phenyl group, a heteroaryl group, an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group, a benzo [d] Represents an imidazol-2-one-5-yl group or a pyridonyl group;
    Ring A is an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group or a benzo [d] imidazol-2-one-5 when yl group,
    R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group,
    When ring A is a phenyl group, heteroaryl group or pyridonyl group,
    R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkoxy group or a C 1-6 alkyl group (wherein the C 1-6 alkoxy group or C 1-6 alkyl group is substituted with 1 to 3 halogen atoms) May be)
    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 —CONR a R b , —COR c , a cyano group or a hydroxyl group) -CONR a R b , —O—CONR a R b , —NR a1 R b1 , —COR c , a cyano group, —NR d COR e or —NR d SO 2 R e ,
    R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is
    A hydroxyl group,
    A halogen atom,
    A C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with 1 to 2 hydroxyl groups),
    -CONR f R g ,
    An amino group,
    Mono-C 1-6 alkylamino group,
    Di-C 1-6 alkylamino group,
    Morpholino group,
    Piperidino group,
    Pyrrolidino group,
    Azetidino group,
    1,3-dioxolan-2-yl group,
    1,3-dioxane-2-yl group,
    2-oxa-6-azaspiro [3.3] heptan-6-yl group and 5,7-dioxaspiro [2.5] octan-6-yl group (wherein the morpholino group, piperidino group, pyrrolidino group, azetidino group 1,3-dioxolan-2-yl group, 1,3-dioxane-2-yl group, 2-oxa-6-azaspiro [3.3] heptan-6-yl group and 5,7-dioxaspiro [2. 5] The octan-6-yl group may be substituted with 1 to 2 halogen atoms.
    May be substituted with 1 to 3 substituents selected from the group consisting of },
    A C 1-6 alkanoyl group, an oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group,
    Alternatively, R a and R b are formed together with a nitrogen atom to be bonded, and are a saturated or unsaturated 4- to 6-membered ring (here, which may further contain one or more nitrogen atom, oxygen atom or sulfur atom (wherein The saturated or unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group. Well,
    R a1 and R b1 are formed together with a nitrogen atom to which they are bonded, and are a saturated or unsaturated 4- to 6-membered ring that may contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms, Or an unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group.
    R c represents a C 1-6 alkyl group, a hydroxyl group or a C 1-6 alkoxy group,
    R d represents a hydrogen atom or a C 1-6 alkyl group,
    R e represents a C 1-6 alkoxy group, an amino group, a mono-C 1-6 alkylamino group or a di-C 1-6 alkylamino group,
    R f and R g are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
    Y 1 represents — (CH 2 ) n —O— or — (CH 2 ) m —,
    n represents an integer of 1 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. 　式［Ｉ］中、
    Ｒ1は、水素原子又はＣ1-6アルキル基（ここで該Ｃ1-6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Ｃ1-6アルキル基（ここで該Ｃ1-6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Ｃ1-6アルキル基（ここで該Ｃ1-6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、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基又はＣ1-6アルコキシ基は、－ＣＯＮＲaＲb、－ＣＯＲc又はシアノ基で置換されている。）、－ＣＯＮＲaＲb、－Ｏ－ＣＯＮＲaＲb、－ＣＯＲc又はシアノ基を示し、
    Ｒa及びＲbは、同一又は異なって、水素原子、Ｃ1-6アルキル基、（ここで該Ｃ1-6アルキル基はアミノ基、モノ－Ｃ1-6アルキルアミノ基、ジ－Ｃ1-6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。）、オキセタニル基、テトラヒドロフラニル基又はテトラヒドロピラニル基を示すか、
    又は、Ｒa及びＲb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、
    Ｒcは、水酸基又はＣ1-6アルコキシ基を示し、
    Ｙ1は、－(ＣＨ2)n－Ｏ－又は－(ＣＨ2)ｍ－を示し、
    ｎは、１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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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、
    請求項１に記載の化合物又はその医薬上許容される塩。     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 and are each a hydrogen atom, a C 1-6 alkyl group, 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.), Represents an oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group,
    Alternatively, R a and R b are formed together with the 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 1 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,
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. 　環Ａが、フェニル基又は６員ヘテロアリール基である、請求項１又は２に記載の化合物又はその医薬上許容される塩。 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a 6-membered heteroaryl group.
  4. 　環Ａが、フェニル基又はピリジル基である、請求項３に記載の化合物又はその医薬上許容される塩。 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a pyridyl group.
  5. 　Ｙ1が、－ＣＨ2－Ｏ－である、請求項１～４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。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Y 1 is -CH 2 -O-.
  6. 　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、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ1-6アルコキシ基（ここで該Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基又はＣ1-6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、請求項１～５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。 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 any one of claims 1 to 5.
  7. 　Ｙ３が、式[II]に示す構造のいずれかである、請求項１～６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。
    Figure JPOXMLDOC01-appb-C000002
         The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Y 3 is any one of the structures represented by formula [II].
    Figure JPOXMLDOC01-appb-C000002
  8. 　Ｒ3が、水素原子又はハロゲン原子である、請求項１～７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。 R 3 is a hydrogen atom or a halogen atom, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
  9. 　請求項１～８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して含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient.
  10. 　グループII代謝型グルタミン酸受容体拮抗物質である、請求項９に記載の医薬。 The medicament according to claim 9, which is a group II metabotropic glutamate receptor antagonist.
  11. 　請求項１～１０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。 A mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient , Preventive or therapeutic agent for convulsions, tremors, pain, or sleep disorders.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111796A1 (en) * 2012-01-25 2013-08-01 大正製薬株式会社 N-substituted pyrazole derivative
EP3000814A1 (en) 2014-09-26 2016-03-30 Domain Therapeutics Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors
WO2016141258A1 (en) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Sterol regulatory element-binding proteins (srebps) inhibitors
US10183015B2 (en) 2015-03-04 2019-01-22 Medivation Technologies Llc Heterocyclic compounds and methods of use

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040110A1 (en) * 2003-10-08 2005-05-06 Eli Lilly And Company Pyrrole and pyrazole derivatives as potentiators of glutamate receptors
WO2007039439A1 (en) * 2005-09-27 2007-04-12 F.Hoffmann-La Roche Ag Oxadiazolyl pyrazolo-pyrimidines as mglur2 antagonists
WO2007110337A1 (en) * 2006-03-29 2007-10-04 F. Hoffmann-La Roche Ag Pyridine and pyrimidine derivatives as mglur2 antagonists
WO2008119689A1 (en) * 2007-04-02 2008-10-09 F. Hoffmann-La Roche Ag Pyridine and pyrimidine derivatives as mglur2 antagonists
WO2009078432A1 (en) * 2007-12-18 2009-06-25 Taisho Pharmaceutical Co., Ltd. 1-alkyl-4-amino-1h-pyrazole-3-carboxamide compound
WO2010142628A1 (en) * 2009-06-08 2010-12-16 Merck Serono S.A. Pyrazole oxadiazole derivatives as s1p1 agonists
WO2012020820A1 (en) * 2010-08-11 2012-02-16 大正製薬株式会社 Heteroaryl-pyrazole derivative

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040110A1 (en) * 2003-10-08 2005-05-06 Eli Lilly And Company Pyrrole and pyrazole derivatives as potentiators of glutamate receptors
WO2007039439A1 (en) * 2005-09-27 2007-04-12 F.Hoffmann-La Roche Ag Oxadiazolyl pyrazolo-pyrimidines as mglur2 antagonists
WO2007110337A1 (en) * 2006-03-29 2007-10-04 F. Hoffmann-La Roche Ag Pyridine and pyrimidine derivatives as mglur2 antagonists
WO2008119689A1 (en) * 2007-04-02 2008-10-09 F. Hoffmann-La Roche Ag Pyridine and pyrimidine derivatives as mglur2 antagonists
WO2009078432A1 (en) * 2007-12-18 2009-06-25 Taisho Pharmaceutical Co., Ltd. 1-alkyl-4-amino-1h-pyrazole-3-carboxamide compound
WO2010142628A1 (en) * 2009-06-08 2010-12-16 Merck Serono S.A. Pyrazole oxadiazole derivatives as s1p1 agonists
WO2012020820A1 (en) * 2010-08-11 2012-02-16 大正製薬株式会社 Heteroaryl-pyrazole derivative

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111796A1 (en) * 2012-01-25 2013-08-01 大正製薬株式会社 N-substituted pyrazole derivative
EP3000814A1 (en) 2014-09-26 2016-03-30 Domain Therapeutics Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors
WO2016141258A1 (en) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Sterol regulatory element-binding proteins (srebps) inhibitors
US10183015B2 (en) 2015-03-04 2019-01-22 Medivation Technologies Llc Heterocyclic compounds and methods of use
US10189826B2 (en) 2015-03-04 2019-01-29 Medivation Technologies Llc Heterocyclic compounds and methods of use

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