WO2013062074A1 - Imidazolone derivative - Google Patents

Imidazolone derivative Download PDF

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Publication number
WO2013062074A1
WO2013062074A1 PCT/JP2012/077688 JP2012077688W WO2013062074A1 WO 2013062074 A1 WO2013062074 A1 WO 2013062074A1 JP 2012077688 W JP2012077688 W JP 2012077688W WO 2013062074 A1 WO2013062074 A1 WO 2013062074A1
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Prior art keywords
dihydro
imidazo
alkyl
imidazol
butyl
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PCT/JP2012/077688
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French (fr)
Japanese (ja)
Inventor
洋平 松田
信隆 服部
一成 坂上
英明 天田
洋樹 浦部
智子 民田
梨絵 下野
明登 安原
誠治 増田
一豪 小西
年男 中村
修資 山本
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大正製薬株式会社
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Publication of WO2013062074A1 publication Critical patent/WO2013062074A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/08—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
    • A61P25/24—Antidepressants
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel compound having a positive allosteric modulator action on metabotropic glutamate receptor subtype 2 (mGlu2 receptor) or a pharmaceutically acceptable salt thereof, and schizophrenia containing them as an active ingredient, Prevention or prevention of a disease selected from the group consisting of Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders
  • mGlu2 receptor metabotropic glutamate receptor subtype 2
  • the present invention relates to a therapeutic drug.
  • Glutamate receptors are broadly classified into ion channel glutamate receptors and metabotropic glutamate receptors (mGlu receptors) (Non-patent Documents 1 and 2). Among these, the mGlu receptor was identified as a GPCR-type glutamate receptor coupled to G protein, but receptor cDNAs were successively cloned in the early 1990s (Non-patent Documents 3 and 4). Currently, the existence of eight subtypes (mGlu1 to mGlu8) has been reported, and these are classified into three groups (group I: mGlu1, mGlu5; group II :) due to differences in receptor structure, pharmacological properties and signal transduction system.
  • group I mGlu1, mGlu5; group II :
  • mGlu2, mGlu3; Group III: mGlu4, mGlu6, mGlu7, mGlu8) (non-patent documents 5 to 7).
  • mGlu2 and mGlu3 receptors belonging to group II are coupled to Gi / Go proteins and suppress adenylate cyclase activity in an inhibitory manner, and activation of mGlu2 and mGlu3 receptors by agonists is forskolin. Stimulus-induced cAMP accumulation is suppressed (Non-Patent Documents 1, 8, and 9).
  • Non-Patent Documents 10 to 14 These sites are involved in brain functions such as emotion, cognition, motivation, and reward, suggesting an association with mGlu2 and mGlu3 receptor anxiety disorders, schizophrenia, depression, and drug dependence.
  • Non-patent Documents 20 to 22 From analysis using a receptor-deficient mouse, it is considered that the mGlu2 receptor is mainly involved in the antipsychotic-like action of the mGlu2 / 3 receptor agonist (Non-patent Documents 20 to 22). Furthermore, the existence of an active regulatory site (allosteric binding site) different from the binding site (orthosteric binding site) of glutamate, an endogenous ligand, was reported, and a selective mGlu2 receptor positive allosteric modulator (PAM) was created (non- Patent Documents 23 and 24).
  • PAM selective mGlu2 receptor positive allosteric modulator
  • Non-patent documents 25 to 32 show antipsychotic-like effects and cognitive dysfunction-improving effects in various animal models as well as mGlu2 / 3 receptors, suggesting the possibility as therapeutic drugs for schizophrenia ( Non-patent documents 25 to 32).
  • mGlu2 receptor PAM has been found to have anxiolytic effects on various animal models, it has also been suggested as a therapeutic agent for anxiety disorders (Non-Patent Documents 25, 28, 33 and 34).
  • Non-patent Documents 35 to 37 compounds having an mGlu2 receptor positive allosteric modulator activity have been reported.
  • these documents do not disclose or suggest any compounds having a pyrrolo-imidazolone skeleton or an imidazolimidazolone skeleton of the compound of the present invention.
  • the object of the present invention is to find a novel compound having a positive allosteric modulator action on the mGlu2 receptor, and to achieve schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (lack of attention) / Hyperactivity disorder), to provide drugs for the prevention or treatment of drug dependence, convulsions, tremors and sleep disorders.
  • R 1 is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl , C 1-6 alkyl, and C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: 3 may be substituted with three groups), or C 2-6 alkenyl;
  • R 2 represents a hydrogen atom or C 1-6 alkyl; Any one of R 3 and R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy), halo
  • Substituent group A ′ is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3 -8 cycloalkyl, C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl, and C 3-8 cycloalkyloxy are the same or different 1 to 3 selected from C 1-6 alkyl and a halogen atom) And optionally substituted with 1 to 5 groups selected from the group consisting of aryl, heteroaryl, aryloxy, and saturated heterocyclyl), C 1-6 alkoxy (including C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group of halogen atom and aryl.), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy C 3-8 cyclo
  • R 1 is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl , C 1-6 alkyl, and C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: May be substituted with three groups);
  • One of R 3 and R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl, and the other is aryl or heteroaryl (the aryl and heteroaryl Aryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A):
  • Substituent group A is a halogen atom
  • C 1-6 alkoxy the C 1-6 alkoxy is the same or different 1 to 3 groups selected from the group of halogen atoms and aryl
  • a C 3-8 cycloalkyl, a C 3-8 cycloalkyloxy the C 3-8 cycloalkyl and the C 3-8 cycloalkyloxy may be the same or different one to three).
  • R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl;
  • R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the substituent group A described in (2)) (1)
  • C 1-6 alkylsulfanyl is (1) to (4) imidazolone derivative of any one, or a pharmaceutically acceptable salt thereof, (6)
  • a pharmaceutical composition comprising the imidazolone derivative according to any one of (1) to (6) above or a pharmaceutically acceptable salt thereof as an active ingredient, (8)
  • a drug for the prevention or treatment of a disease selected from the group consisting of dysfunction,
  • novel imidazolone derivative of the present invention acts on the activity-regulating site of the mGlu2 receptor to enhance receptor stimulation by a physiological ligand (glutamic acid).
  • Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl refers to a linear or branched alkyl group having 1 to 6 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and the like.
  • Halo C 1-6 alkyl refers to an alkyl group in which 1 to 5 identical or different “halogen atoms” are substituted on the above “C 1-5 alkyl”, and includes monofluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2-fluoro-2-propyl, 1,1,1-trifluoromethyl-2-methyl-2-propyl, 4,4,4-trifluoro A group such as butyl may be mentioned.
  • C 3-8 cycloalkyl means a cyclic cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • C 2-6 alkenyl means a linear or branched alkenyl group having 2 to 6 carbon atoms, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 1-methyl- Examples include 2-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 4-pentenyl and the like.
  • C 1-6 alkoxy means a linear or branched alkoxy group having 1 to 6 carbon atoms, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy and the like.
  • C 3-8 cycloalkyloxy means a group in which the above “C 3-8 cycloalkyl” and an oxygen atom are bonded to each other. Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy And cyclooctyloxy group.
  • C 2-6 alkanoylamino means a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms in which amino is bonded, and acetylamino, propionylamino, butyrylamino, isobutyrylamino, Mention may be made of valerylamino, isovalerylamino, pivaloylamino groups.
  • Aryl means a monocyclic to bicyclic aromatic carbocyclic ring, and includes groups such as phenyl and naphthyl.
  • Heteroaryl means an aromatic group having 2 to 9 carbon atoms and having at least one heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Furyl, pyrrolyl , Thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, indolyl, benzofuranyl and the like.
  • Aryloxy means a group in which the above “aryl” is bonded to an oxygen atom, and examples thereof include groups such as phenoxy and naphthoxy.
  • Heteroaryloxy means a group in which an oxygen atom is bonded to the above “heteroaryl” and includes furyloxy, pyrrolyloxy, thienyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy And groups such as isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, quinolyloxy, indolyloxy, benzofuranyloxy and the like.
  • Saturated heterocyclyl means a saturated heterocyclic group having at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and having 2 to 9 carbon atoms.
  • Tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl And groups such as piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and the like.
  • the saturated or partially unsaturated heterocyclyl means a saturated or partially unsaturated heterocyclic group having at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and having 2 to 9 carbon atoms, Examples include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyridyl and the like.
  • C 1-6 alkylsulfanyl means a group in which the above “C 1-6 alkyl” and a sulfur atom are bonded to each other, and includes methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, Examples include groups such as isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, tert-pentylsulfanyl, n-hexylsulfanyl and the like.
  • C 1-6 alkylsulfonyl means a sulfonyl group substituted with the above “C 1-6 alkyl”, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutyl Examples include sulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl and the like.
  • Cyclic aminocarbonyl means a group in which a 4- to 8-membered cyclic amino and carbonyl are amide-bonded, and includes groups such as azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and the like. Can be mentioned.
  • C 1-6 alkoxycarbonyl means a group in which the above “C 1-6 alkoxy” is bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, Mention may be made of groups such as tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl and the like.
  • “Saturated heterocyclyloxy” means a group in which the above “saturated heterocyclyl” is bonded to an oxygen atom, and examples thereof include tetrahydrofuranyloxy, tetrahydropyranyloxy, and the like.
  • R 1 in the present invention is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, and the same or different 1 to 3 groups selected from the group consisting of C 1-6 alkoxy may be substituted. Or may be substituted with 1 to 3 different groups). More preferable R 1 is C 1-6 alkyl (wherein the C 1-6 alkyl is the same or different 1 to 3 selected from the group consisting of a halogen atom, C 3-8 cycloalkyl, and C 1-6 alkoxy). It may be substituted with a group of
  • R 2 in the present invention is a hydrogen atom or C 1-6 alkyl. More desirable R 2 is a hydrogen atom or methyl.
  • Preferred R 3 in the present invention is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl.
  • Preferred R 4 in the present invention is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A).
  • Substituent group A is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3-6 From 8 cycloalkyl, and C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and C 3-8 cycloalkyloxy may be substituted with the same or different 1 to 3 halogen atoms).
  • C 1-6 alkoxy which may be substituted with 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (wherein the C 1-6 alkoxy is the same or different 1 to 3 groups selected from the group of halogen atoms and aryl)
  • a C 3-8 cycloalkyl, a C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and the C 3-8 cycloalkyloxy may be the same or different one to three).
  • R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A1).
  • Substituent group A1 is a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, and C 3-8 cycloalkyl) Which may be substituted with 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (wherein the C 1-6 alkoxy is the same or different 1 to 3 selected from the group of halogen atoms and aryl) ), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, carbamoyl (wherein the carbamoyl is substituted with the same or different 1 or 2 C 1-6 alkyl).
  • Preferred X in the present invention is a nitrogen atom.
  • Examples of preferred compounds in the compounds of the present invention include 3- (biphenyl-4-yl) -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one, 6-butyl-3- [4- (pyridin-3-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one, 6-butyl-3- [4- (propan-2-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one, 6-butyl-3- (4-phenoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one, 6-butyl-3- [4- (propan-2-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-
  • “Pharmaceutically acceptable salt” refers to salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, formic acid, trifluoroacetic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, Maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid , Salts with organic acids such as galactaric acid, naphthalene-2-sulfonic acid, salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion,
  • the compound of the present invention may exist as various solvates. Moreover, it may be a hydrate from the viewpoint of applicability as a medicine.
  • the compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in arbitrary proportions, racemates, and the like.
  • the compound of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation.
  • a pharmaceutical preparation for example, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup And various oils such as methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil and soybean oil.
  • additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients, or diluents, and tablets are prepared by conventional formulation techniques.
  • the compound of the present invention can be orally or parenterally administered to an adult patient at a dose of 0.001 to 2000 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
  • the compounds of the present invention also include compounds in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
  • 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, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or
  • bases are appropriately selected according to various reaction conditions known to those skilled in the art.
  • the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and the like.
  • Lewis acids such as organic acids, zinc (II) chloride, aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • the compound of the present invention can be produced, for example, by the method shown below.
  • the compound of the present invention represented by the formula (II) can be produced by the method of the following scheme 1.
  • R 1 and R 2 are as defined above.
  • R 3 ′ represents aryl or heteroaryl.
  • M represents a metal atom or a metal atomic group used in the coupling reaction, and examples of the compound (4) include magnesium reactant, zinc reactant, boron reactant bound with boric acid or borate ester, tin reactant, and the like. Can be mentioned.
  • X 1 represents a leaving group such as chlorine atom, bromine atom, iodine atom, fluorine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.).
  • X 2 and X 3 are the same or different and represent a chlorine atom, a bromine atom or an iodine atom.
  • R 5 is a protecting group of a carboxy group such as methyl, ethyl, tert-butyl, benzyl, etc. ⁇ Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC. ) Reference ⁇ or a hydrogen atom.
  • Step 1 Compound (3) can be prepared by an amidation reaction known to those skilled in the art of Compound (1) and Compound (2) in an inert solvent ⁇ Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) See 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 means that when R 5 is a hydrogen atom, for example, O- (7-azabenzotriazol-1-yl) -N, N, N in an inert solvent in the presence or absence of a base.
  • HATU N'-tetramethyluronium hexafluorophosphoric acid
  • O- (benzotriazol-1-yl) -N N, N', N'-tetramethyluronium hexafluorophosphoric acid
  • HBTU N-tetramethyluronium hexafluorophosphoric acid
  • Condensing agents such as N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC ⁇ HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI) Condensation reaction using mixed acid anhydride using ethyl chloroformate, isobutyl chloroformate, trimethylacetyl chloride, etc.
  • DCC N′-dicyclohexylcarbodiimide
  • EDC ⁇ HCl
  • the amidation reaction means that when R 5 is a protecting group for a carboxy group, for example, in an inert solvent or without a solvent, in the presence or absence of a base or an acid, the compound (1) and the compound (2) It is a condensation reaction.
  • Step 2 Compound (5) is produced by a coupling reaction of Compound (3) and Compound (4) in an inert solvent, in the presence or absence of a base, using a palladium catalyst and optionally a ligand.
  • the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, ⁇ Comprehensive Organic Transformations Second Edition ⁇ ⁇ Comprehensive Organic Transformations Second Edition ⁇ 1999, John Willy and Sons (John Wiley & Sons, INC.) ⁇ Or the like, a method according to the method, or a combination thereof with a conventional method.
  • the palladium catalyst refers to, for example, palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium acetate (II), bis (triphenylphosphine) palladium chloride (II), (1,3- Bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenyl Phosphine palladium (0), [1,1′-bis (diphenylphosphino) ferroc
  • ligands include triphenylphosphine and 2,2-bis (diphenylphosphino).
  • 1,1-binaphthyl (BINAP) 2-(di -tert- butylphosphino) biphenyl, 9,9-dimethyl-4,5-bis (diphenylphosphino) can be exemplified xanthene (Xantphos) or the like.
  • Step 3 The compound (II) of the present invention can be produced by an alkylation reaction of the compound (5) and the compound (6) in the presence of a base in an inert solvent ⁇ Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) 1999, see John Wiley & Sons, INC. ⁇ .
  • the compound (5) and the compound (6) 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 present compound represented by the formula (I-II) can be produced by the method of Scheme 2 below.
  • Step 4 Compound (8) can be produced from Compound (7) and Compound (2) by the same method as in Step 1 in Scheme 1.
  • the compound (7) and the compound (2) 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 5 Compound (9) is reacted with a halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, etc. in an inert solvent in the presence or absence of an acid. Can be manufactured.
  • compound (9) can be produced by reacting compound (8) with a halogenating agent such as iodine monochloride, iodine or bromine in an inert solvent in the presence or absence of a base.
  • 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 (10) can be produced from compound (9) and compound (4) by the same method as in Step 2 in Scheme 1.
  • the compound (9) and the compound (4) 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 Compound (I-II) of the present invention can be produced from compound (10) and compound (6) by the same method as in step 3 in scheme 1.
  • the compound (10) and the compound (6) 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 compound of the present invention represented by the formula (I-II) can also be produced by the method of Scheme 3 below.
  • Step 8 Compound (11) can be produced from compound (8) and compound (6) by the same method as in Step 3 in Scheme 1.
  • the compound (8) and the compound (6) 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 9 Compound (12) can be produced from compound (11) by the same method as in Step 5 in Scheme 2.
  • the compound (11) 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.
  • Step 10 Compound (I-II) of the present invention can be produced from compound (12) and compound (4) by the same method as in step 2 in scheme 1.
  • the compound (12) and the compound (4) 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 compound of the present invention represented by the formula (I-III) can be produced by the method of Scheme 4 below.
  • R 1 , R 2 , R 5 , M, X 1 , X 2 and X 3 are as defined above.
  • R 4 ′ represents aryl or heteroaryl.
  • Examples of the compound (14) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, a tin reactant, and the like.
  • Step 11 Compound (15) can be produced from compound (13) and compound (14) by the same method as in Step 2 in Scheme 1.
  • the compound (13) and the compound (14) 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 12 Compound (16) can be produced from compound (15) and compound (2) by the same method as in Step 1 in Scheme 1.
  • the compound (15) and the compound (2) 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 13 Compound (I-II) of the present invention can be produced from compound (16) and compound (6) by the same method as in Step 3 in Scheme 1.
  • the compound (16) and the compound (6) 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 compound of the present invention represented by the formula (I-IV) can be produced by the method of Scheme 5 below.
  • Step 14 Compound (18) can be produced from compound (17) and compound (2) by the same method as in Step 1 in Scheme 1.
  • the compound (17) and the compound (2) 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 15 Compound (19) can be produced from compound (18) and compound (6) by the same method as in Step 3 in Scheme 1.
  • Step 16 Compound (20) can be produced from compound (19) by the same method as in Step 5 in Scheme 2.
  • Step 17 Compound (I-IV) of the present invention can be produced from compound (20) and compound (14) by the same method as in step 2 in scheme 1.
  • the compound (20) and the compound (14) 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 compound of the present invention represented by the formula (IV) and the formula (I-VI) can be produced by the method of the following scheme 6.
  • R 1 , R 2 , R 4 ′, M, X 2 and X 3 are as defined above.
  • R 3 ′′ represents C 1-6 alkyl, C 2-6 alkenyl, aryl, heteroaryl.
  • Examples of the compound (22) include a magnesium reactant, a zinc reactant, a boron reactant bound with boric acid or a borate ester. And tin reactants.
  • Step 18 Compound (21) can be produced from compound (11) by the same method as in Step 5 in Scheme 2.
  • the compound (11) 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.
  • Step 19 Compound (IV) of the present invention can be produced from compound (21) and compound (14) by the same method as in Step 2 in Scheme 1.
  • the compound (21) and the compound (14) 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 20 Compound (I-VI) of the present invention can be produced from compound (IV) of the present invention and compound (22) by the same method as in Step 2 in Scheme 1.
  • the compound (22) 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 compound of the present invention represented by the formula (I-VII) can be produced by the method of Scheme 7 below.
  • Step 21 The compound (I-VII) of the present invention can be produced by reacting the compound (18) with the compound (23) in an inert solvent in the presence or absence of an acid.
  • the compound (18) and the compound (23) 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 compound of the present invention represented by the formula (I-IX) can be produced by the method of Scheme 8 below.
  • R 1 , R 2 , M and X 2 are as defined above.
  • R 3 ′ ′′ represents C 1-6 alkyl (wherein the C 1-6 alkyl may be substituted with 1 hydroxy), haloC 1-6 alkyl, or C 2-6 alkenyl; 7 represents aryl, heteroaryl, or heterocyclyl.
  • Examples of the compound (25) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, a tin reactant, and the like.
  • X 5 represents a leaving group such as organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.).
  • Step 22 Compound (I-IX) of the present invention can be produced from compound (24) or compound (I-VIII) of the present invention and compound (25) by the same method as in step 2 in scheme 1.
  • the compound (24) and the compound (25) 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 compound of the present invention represented by the formula (I-IX) can be produced by the method of Scheme 9 below.
  • Step 23 Compound (I-IX) of the present invention can be produced from compound (26) and compound (27) by the same method as in Step 2 in Scheme 1.
  • the compound (26) and the compound (27) 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 compound of the present invention represented by the formula (I-XI) can be produced by the method of Scheme 10 below.
  • R 1 , R 2 , R 3 ′ ′′ and X 1 are as defined above.
  • R 8 represents C 1-6 alkyl, C 3-8 cycloalkyl, heteroaryl, heterocyclyl, and n represents an integer of 0-6.
  • Step 24 The compound (IX) of the present invention can be produced by the reaction of the compound (IX) of the present invention and the compound (27) in the presence of a base in an inert solvent ⁇ Comprehensive Organic Transformations Second edition (Comprehensive Organic Transformations Second Edition) 1999, see John Wiley & Sons, INC. ⁇ .
  • the compound (27) 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 compound of the present invention represented by the formula (I-XIII) can be produced by the method of Scheme 11 below.
  • Step 25 The compound (I-XIII) of the present invention is reacted with the compound (I-XII) of the present invention and the compound (28) in an inert solvent using a copper catalyst and, if necessary, a ligand in the presence of a base.
  • a copper catalyst and, if necessary, a ligand in the presence of a base.
  • the compound (28) 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 copper catalyst is, for example, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I) tristriphenylphosphine complex, copper trifluoromethanesulfonate.
  • copper (0) copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I) tristriphenylphosphine complex, copper trifluoromethanesulfonate.
  • copper (I) A benzene complex etc. are mentioned.
  • the ligand is a ligand known to those skilled in the art in a coupling reaction using a copper catalyst, such as N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, 2-aminopyridine, 1,10- Examples include phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, picolinic acid and the like (Synlett, 15, 2428-2439, 2003).
  • the compound (I-XIII) of the present invention can be produced by reacting the compound (I-XII) of the present invention with a compound (28) in the presence of a base in an inert solvent.
  • R 3 or R 4 in the formula is a C 2-6 alkenyl group, or the substituent of R 3 or R 4 is a 3,4-dihydro-2H-pyranyl group, etc.
  • a reduced form of the compound (I) of the present invention is produced by a catalytic reduction reaction of the compound (I) of the present invention in an inert solvent in the presence of a transition metal catalyst, in a hydrogen atmosphere, at normal pressure or under pressure.
  • a transition metal catalyst used in the reduction reaction include palladium carbon, palladium hydroxide, palladium black, palladium-fibroin, platinum (IV) oxide, Raney nickel, and the like.
  • R 3 or R 4 is a halogen atom in the formula, or when the substituent of R 3 or R 4 is a halogen atom, the same compounds of the present invention by a method (I)
  • the reductant of can be produced.
  • the reduced form of the compound (I) of the present invention is also encompassed in the compound of the present invention.
  • the compound of the present invention represented by the formula (I-XIV) can be produced by the method of Scheme 12 below.
  • R 1 , R 2 and R 3 ′ ′′ have the same meanings as described above.
  • R 9 represents C 1-6 alkyl, C 3-8 cycloalkyl, or saturated heterocyclyl.
  • Step 26 The compound (I-XIV) of the present invention can be produced by Mitsunobu reaction of the compound (IX ′) of the present invention and the compound (29) in an inert solvent.
  • the compound (29) 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).
  • the compound of the present invention represented by the formula (I-XV) can be produced by the method of Scheme 13 below.
  • Step 27 The compound of the present invention (I-XV) can be produced from the compound of the present invention (IX ′) and the compound (30) by the same method as in Step 25 in Scheme 11.
  • the compound (30) 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 compound shown by Formula (18) can be manufactured by the method of the following scheme 14.
  • R 1, R 3 and X 1 are as defined above.
  • R 11 is an imidazole ring such as an acetyl group, a methanesulfonyl group, a p-methoxyphenylsulfonyl group, a p-toluenesulfonyl group, a benzyloxycarbonyl group, a t-butyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group, or a trityl group.
  • the protecting group for the nitrogen atom see Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.) Is shown.
  • Step 28 Compound (33) can be produced by reacting compound (31) with compound (32) in the presence of a base in an inert solvent. ⁇ See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC. ⁇ Where compound (31) and compound (32) are commercially available compounds A commercially available compound or a compound synthesized from a known compound can be used using known compounds or various organic synthesis methods known to those skilled in the art.
  • Step 29 Compound (18) in an inert solvent, various organic synthesis ⁇ Protective Groups's Inn Organic Synthesis protecting group R 11 of the compound (33) are known to those skilled in the art (Protective Groups in Organic Synthesis) 4 Plate, see John Wiley & Sons, Inc. ⁇ .
  • 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.
  • the “NH silica gel cartridge” when purified by column chromatography is Biotage (registered trademark) SNAPPartridge KP-NH manufactured by Biotage, and the “silica gel cartridge” is manufactured by Biotage.
  • Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil, Grace's Liberalis (registered trademark) Silica, and "ISOLUTE (registered trademark) HM-N” include Biotage's ISOLUTE (registered trademark) HM-N. Each commercially available product was used.
  • SunFire (registered trademark)” when purified using reverse-phase column chromatography SunFire (registered trademark) prep C18 OBD (registered trademark) 5.0 ⁇ m, ⁇ 30 ⁇ 50 mm manufactured by Waters was used.
  • chloroiodomethane 100 g was added dropwise to the reaction suspension, followed by stirring at room temperature for 18 hours.
  • Water 51 mL was added dropwise to the reaction suspension at room temperature, stirred for 30 minutes, and concentrated under reduced pressure.
  • Chloroform 1.0 L was added to the residue and stirred at room temperature for 1 hour.
  • the insoluble material was filtered off through Celite (registered trademark) and washed with chloroform.
  • the filtrate was concentrated under reduced pressure, and the resulting residue was diluted with methanol (600 mL) and then washed three times with hexane (400 mL). The methanol layer was concentrated under reduced pressure.
  • N-bromosuccinimide (18.6 g) was added with cooling in an ice bath, and the mixture was stirred for 30 minutes and then stirred at room temperature for 18 hours.
  • a 15% aqueous sodium thiosulfate solution (280 mL) was added dropwise to the reaction solution while cooling in an ice bath, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform.
  • n-butyl isocyanate (69.1 mL) was added dropwise at ⁇ 40 ° C., followed by stirring at room temperature for 2.5 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution while cooling in an ice bath, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • N-butyl-4- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide (94 mg) obtained in Production Example 1 in N, N-dimethylformamide (1.0 mL) at room temperature.
  • 60% sodium hydride 38 mg was added and stirred for 1 hour.
  • Chloroiodomethane 107 mg was added to the reaction solution at room temperature, and the mixture was stirred for 2 hours.
  • N-butyl-5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide (119 mg) obtained in Production Example 4 was added to an N, N-dimethylformamide (1.0 mL) solution in an ice bath. Under cooling, 60% sodium hydride (48 mg) was added and stirred for 30 minutes, and then stirred at room temperature for 15 minutes. Under ice bath cooling, chloroiodomethane (85 mg) was added to the reaction solution, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 7 2-Butyl-5- (4-methoxyphenyl) -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
  • Example 8 2-Butyl-5- [4 -(Trifluoromethoxy) phenyl] -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
  • Example 9 5- (4-tert-Butylphenyl) -2- (3- Methylbutyl) -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
  • Example 10 5- (4-tert-butylphenyl) -2- (cyclopropylmethyl) -2,3 -Dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
  • Table 1 The structural formulas and instrument data of the compounds of Examples 7 to 10 are shown in Table 1.
  • Example 12 6-Butyl-3- (4-tert-butylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 13 3- (Biphenyl-4 -Yl) -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 14 3- (Biphenyl-3-yl) -6-butyl-5,6 -Dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 15 6-Butyl-3- [3- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1 , 5-a] imidazol-7-one
  • Example 16 6-Butyl-3- [4- (trifluoromethyl) phenyl] -5,6-dihydro-7H-imidazo [1 , 5-a] imidazol
  • Example 57 6-Butyl-3- (3-chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 58 6-Butyl-3- (2- Chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 59 6-Butyl-3- (2,4-dichlorophenyl) -5,6-dihydro-7H- Imidazo [1,5-a] imidazol-7-one
  • Example 60 6-Butyl-3- (3,4-dichlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On
  • Example 61 6-Butyl-3- [4- (2-methylpropoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On
  • Example 65 6-butyl-3- (6-phenoxypyridin-3-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • the compound (12 mg) was obtained as a colorless solid.
  • Example 54 6-butyl-3- (4-chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7- obtained in Example 54 was used.
  • the title compound (80 mg) was obtained as a colorless solid from ON (100 mg) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (87 mg).
  • Example 70 6-Butyl-3- [6- (cyclopentyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 71 6-Butyl-3- [4- (cyclopentyloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 72 6- Butyl-2-methyl-3- [4- (3,3,3-trifluoropropoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 73 3- [4- (tert-Butoxymethyl) phenyl] -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 80 6-Butyl-3- [6- (cyclopentyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 81 6-Butyl-3- [4- (cyclopentyloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 82 6- Butyl-2-methyl-3- [4- (3,3,3-trifluoropropoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 83 3- [4- (tert-Butoxymethyl) phenyl] -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 83 3- [4- (tert-Butoxymethyl)
  • Example 86 6- (2-methoxyethyl) -2-methyl-3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -One and 6- (2-methoxyethyl) -3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 87 6-Butyl-2-methyl-3- (4-propoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 88 6-Butyl- 3- (4-propoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 89 6-Butyl-3- [4- (2-fluoroethoxy) phenyl ] -2-Methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 90 6-Butyl-3- [4- (2-fluoroethoxy) phenyl] -5 , 6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 91 3- [4- (Cyclopropyloxy) phen
  • Example 98 6-Butyl-2-methyl-3- [4- (2,2,2-trifluoroethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -ON
  • Example 99 6-Butyl-2-methyl-3- [4- (3,3,3-trifluoropropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole -7-one
  • Example 100 6-Butyl-3- [4- (2-fluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Imidazol-7-one
  • Example 101 6-Butyl-3- [6- (cyclobutyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Imidazol-7-one
  • Example 101 6-Buty
  • Example 102 6-Butyl-3- [4- (1,1-difluoroethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 103 6-Butyl-3- [4- (cyclopropylcarbonyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 104 2 -[4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) phenyl] -2-methylpropanenitrile
  • Example 105 6-butyl-3- ⁇ 4- [cyclopropyl (difluoro) methyl] phenyl ⁇ -2-methyl-5,6-
  • Example 150 6- (cyclobutylmethyl) -3- ⁇ 4- [cyclopropyl (difluoro) methyl] phenyl ⁇ -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole- 7-one hydrochloride
  • Example 151 1 3- ⁇ 4- [cyclopropyl (difluoro) methyl] phenyl ⁇ -2-methyl-6- (prop-2-en-1-yl) -5,6-dihydro-7H-imidazo [1, 5-a] imidazol-7-one hydrochloride
  • Example 152 3- ⁇ 4- [cyclopropyl (difluoro) methyl] phenyl ⁇ -6- (cyclopropylmethyl) -2-methyl-5,6-dihydro-7H -Imidazo [1,5-a] imidazol-7-one hydrochloride
  • Example 153 6-Butyl-3- [4- (1,1-difluoro-2,2-dimethylpropyl) phenyl] -2-methyl- 5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride
  • Example 154 6-Butyl-3- [4- (1,1-difluoro-2,2-
  • Example 161 6- (cyclopropylmethyl) -3- ⁇ 4- [difluoro (phenyl) methyl] phenyl ⁇ -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On hydrochloride and 6- (cyclopropylmethyl) -3- ⁇ 4- [difluoro (phenyl) methyl] phenyl ⁇ -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloric acid salt
  • Example 162 6- (cyclopropylmethyl) -3- [4- (1,1-difluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5- a] imidazol-7-one
  • Example 164 6-Butyl-3- (2-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 165 6- (Cyclopropylmethyl) -3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 166 6- (Cyclobutylmethyl) -3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 167 6- (2,2-dimethylpropyl) -3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Table 167 6- (2,2-dimethylpropyl) -3
  • Example 169 6-butyl-3- [4- (cyclopentyloxy) -2-fluorophenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 170 6-Butyl-3- [4- (cyclopentyloxy) -3-fluorophenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • 171 6-Butyl-3- [2-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole -7-one hydrochloride
  • Example 172 6- (cyclopropylmethyl) -3- [3-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl] -2-methyl-5,6-
  • Example 180 6-butyl-3- [3-fluoro-4- (pyridin-4-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -One dihydrochloride
  • Example 181 6-Butyl-2-methyl-3- [3-methyl-4- (pyridazin-4-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5- a] Imidazol-7-one hydrochloride
  • Example 182 6- (Cyclobutylmethyl) -3- [3-fluoro-4- (pyridin-2-yloxy) phenyl] -2-methyl-5,6-dihydro- 7H-imidazo [1,5-a] imidazol-7-one
  • Example 185 6-butyl-3- [3-fluoro-4- (pyrazin-2-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -ONE Hydrochloride
  • Example 186 6- (Cyclopropylmethyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1 , 5-a] imidazol-7-one hydrochloride
  • Example 187 6- (Cyclobutylmethyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6 -Dihydro-7H-imidazo [1,5-a] imidazol-7-one
  • Example 188 6- (2,2-Dimethylpropyl) -3- [3-fluoro-4- (pyrida
  • Example 1 [ 35 S] GTP ⁇ S binding test (1) (Preparation of crude membrane fraction of CHO cells stably expressing rat metabotropic glutamate receptor (mGlu2)) Rat-type mGlu2 stably expressing CHO cells were mixed with Dulbecco's modified Eagle's medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 ⁇ g / mL streptomycin, 1 mM sodium Pyruba. te, 1 mM succinic acid, 2 mM L-glutamine (added when used)], and cultured at 37 ° C.
  • mGlu2 rat metabotropic glutamate receptor
  • reaction solution was suction filtered onto a GF / C filter, and the GF / C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a scintillation cocktail was added to the filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.
  • the amount of [ 35 S] GTP ⁇ S binding obtained in the absence of glutamic acid is defined as the nonspecific binding amount
  • the difference from the amount of [ 35 S] GTP ⁇ S binding obtained in the presence of glutamic acid is defined as the specific binding amount. did. From the difference between 3 ⁇ M glutamic acid and the specific binding amount in the presence of each compound at various concentrations, the EC 50 value of each compound was calculated by a regression curve using a nonlinear least square method.
  • Confluent cells were washed twice with PBS ( ⁇ ), detached with a cell scraper, and centrifuged at 4 ° C. and 1,000 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 homogenizer, and centrifuged again at 4 ° C., 48,000 ⁇ g for 20 minutes, thereby again. Got sunk. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction.
  • the obtained crude membrane fraction was stored at ⁇ 80 ° C.
  • the reaction solution was suction filtered onto a GF / C filter, and the GF / C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a scintillation cocktail was added to the filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.
  • the amount of [ 35 S] GTP ⁇ S binding obtained in the absence of glutamic acid is defined as the nonspecific binding amount
  • the difference from the amount of [ 35 S] GTP ⁇ S binding obtained in the presence of glutamic acid is defined as the specific binding amount. did. From the difference between 1 ⁇ M glutamic acid and the specific binding amount in the presence of each compound at various concentrations, the EC 50 value of each compound was calculated by a regression curve using a nonlinear least square method.

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Abstract

A novel imidazolone derivative represented by general formula (I) and having the action of a positive allosteric modulator with respect to the metabotropic glutamate receptor subtype 2 (mGlu2 receptor), or a pharmaceutically acceptable salt of said imidazolone derivative, is useful as a pharmaceutical product for the prophylaxis or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders, depression, AD/HD (attention-deficit/hyperactivity disorder), drug dependence, convulsion, tremor, and sleep disorder.

Description

イミダゾロン誘導体Imidazolone derivatives
　本発明は、代謝型グルタミン酸受容体サブタイプ２（ｍＧｌｕ２受容体）に対してポジティブアロステリックモジュレーター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統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、ＡＤ／ＨＤ（注意欠如/多動性障害）、薬物依存、痙攣、振戦及び睡眠障害からなる群から選択される疾患の予防又は治療用医薬に関する。 The present invention relates to a novel compound having a positive allosteric modulator action on metabotropic glutamate receptor subtype 2 (mGlu2 receptor) or a pharmaceutically acceptable salt thereof, and schizophrenia containing them as an active ingredient, Prevention or prevention of a disease selected from the group consisting of Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders The present invention relates to a therapeutic drug.
　グルタミン酸受容体は、イオンチャネル型グルタミン酸受容体及び代謝型グルタミン酸受容体（ｍＧｌｕ受容体）に大きく分類される（非特許文献１、２）。このうちｍＧｌｕ受容体はＧタンパク質と共役するＧＰＣＲ型グルタミン酸受容体として同定されたが、１９９０年代初めに相次いで受容体ｃＤＮＡがクローニングされた（非特許文献３、４）。現在、８つのサブタイプ（ｍＧｌｕ１～ｍＧｌｕ８）の存在が報告されており、これらは受容体構造、薬理学的特性及び情報伝達系の違いにより３つのグループ（グループＩ：ｍＧｌｕ１、ｍＧｌｕ５；グループＩＩ：ｍＧｌｕ２、ｍＧｌｕ３；グループＩＩＩ：ｍＧｌｕ４、ｍＧｌｕ６、ｍＧｌｕ７、ｍＧｌｕ８）に分類される（非特許文献５～７）。これらの中で、グループＩＩに属するｍＧｌｕ２及びｍＧｌｕ３受容体は、Ｇｉ／Ｇｏタンパク質と共役し、アデニル酸シクラーゼ活性を抑制的に調節しており、アゴニストによるｍＧｌｕ２及びｍＧｌｕ３受容体の活性化はフォルスコリン刺激誘発ｃＡＭＰ蓄積を抑制する（非特許文献１、８、９）。中枢神経系において、ｍＧｌｕ２及びｍＧｌｕ３受容体は、大脳皮質、嗅球、線条体、側坐核、視床、海馬、扁桃体などに多くの発現が認められている（非特許文献１０～１４）。これらの部位は情動・認知・意欲・報酬といった脳機能に関与していることから、ｍＧｌｕ２及びｍＧｌｕ３受容体の不安障害、統合失調症、うつ病、薬物依存症といった精神疾患との関連性が示唆されている（非特許文献１５～１９）。 Glutamate receptors are broadly classified into ion channel glutamate receptors and metabotropic glutamate receptors (mGlu receptors) (Non-patent Documents 1 and 2). Among these, the mGlu receptor was identified as a GPCR-type glutamate receptor coupled to G protein, but receptor cDNAs were successively cloned in the early 1990s (Non-patent Documents 3 and 4). Currently, the existence of eight subtypes (mGlu1 to mGlu8) has been reported, and these are classified into three groups (group I: mGlu1, mGlu5; group II :) due to differences in receptor structure, pharmacological properties and signal transduction system. mGlu2, mGlu3; Group III: mGlu4, mGlu6, mGlu7, mGlu8) (non-patent documents 5 to 7). Among these, mGlu2 and mGlu3 receptors belonging to group II are coupled to Gi / Go proteins and suppress adenylate cyclase activity in an inhibitory manner, and activation of mGlu2 and mGlu3 receptors by agonists is forskolin. Stimulus-induced cAMP accumulation is suppressed (Non-Patent Documents 1, 8, and 9). In the central nervous system, many expressions of mGlu2 and mGlu3 receptors have been observed in the cerebral cortex, olfactory bulb, striatum, nucleus accumbens, thalamus, hippocampus, amygdala, etc. (Non-Patent Documents 10 to 14). These sites are involved in brain functions such as emotion, cognition, motivation, and reward, suggesting an association with mGlu2 and mGlu3 receptor anxiety disorders, schizophrenia, depression, and drug dependence (Non-Patent Documents 15 to 19).
　受容体欠損マウスを用いた解析から、ｍＧｌｕ２／３受容体アゴニストの抗精神病様作用には主にｍＧｌｕ２受容体が関与していると考えられている（非特許文献２０～２２）。さらに内因性リガンドであるグルタミン酸の結合部位（オルソステリック結合部位）とは異なる活性調節部位（アロステリック結合部位）の存在が報告され、選択的ｍＧｌｕ２受容体ポジティブアロステリックモジュレーター（ＰＡＭ）が創出された（非特許文献２３、２４）。これら選択的ｍＧｌｕ２受容体ＰＡＭはｍＧｌｕ２／３受容体と同様に各種動物モデルにおいて抗精神病様作用や認知機能障害改善作用を示すことから、統合失調症治療薬としての可能性が示唆されている（非特許文献２５～３２）。また、ｍＧｌｕ２受容体ＰＡＭは各種動物モデルに対する抗不安作用が認められていることから、不安障害治療薬としての可能性も示唆されている（非特許文献２５、２８、３３、３４）。 From analysis using a receptor-deficient mouse, it is considered that the mGlu2 receptor is mainly involved in the antipsychotic-like action of the mGlu2 / 3 receptor agonist (Non-patent Documents 20 to 22). Furthermore, the existence of an active regulatory site (allosteric binding site) different from the binding site (orthosteric binding site) of glutamate, an endogenous ligand, was reported, and a selective mGlu2 receptor positive allosteric modulator (PAM) was created (non- Patent Documents 23 and 24). These selective mGlu2 receptor PAMs show antipsychotic-like effects and cognitive dysfunction-improving effects in various animal models as well as mGlu2 / 3 receptors, suggesting the possibility as therapeutic drugs for schizophrenia ( Non-patent documents 25 to 32). In addition, since mGlu2 receptor PAM has been found to have anxiolytic effects on various animal models, it has also been suggested as a therapeutic agent for anxiety disorders (Non-Patent Documents 25, 28, 33 and 34).
　最近、ｍＧｌｕ２受容体ポジティブアロステリックモジュレーター作用を有する化合物が報告されている（非特許文献３５～３７）。しかし、これらの文献には本発明化合物のピロロイミダゾロン骨格やイミダゾイミダゾロン骨格をもつ化合物についてはなんら開示も示唆もない。 Recently, compounds having an mGlu2 receptor positive allosteric modulator activity have been reported (Non-patent Documents 35 to 37). However, these documents do not disclose or suggest any compounds having a pyrrolo-imidazolone skeleton or an imidazolimidazolone skeleton of the compound of the present invention.
　本発明の目的は、ｍＧｌｕ２受容体に対してポジティブアロステリックモジュレーター作用を有する新規な化合物を見出し、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、ＡＤ／ＨＤ（注意欠如/多動性障害）、薬物依存、痙攣、振戦及び睡眠障害等の予防又は治療用医薬を提供することにある。 The object of the present invention is to find a novel compound having a positive allosteric modulator action on the mGlu2 receptor, and to achieve schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (lack of attention) / Hyperactivity disorder), to provide drugs for the prevention or treatment of drug dependence, convulsions, tremors and sleep disorders.
　本発明者らは、鋭意検討した結果、ｍＧｌｕ２受容体ポジティブアロステリックモジュレーター作用を有する新規イミダゾロン誘導体を見出し、本発明を完成した。
すなわち本発明は、
（１）式（Ｉ）
Figure JPOXMLDOC01-appb-C000002
 ［式（Ｉ）中、
Ｒ1は、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、Ｃ3-8シクロアルキル、Ｃ1-6アルコキシ、及びフェニル（該フェニルはハロゲン原子、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、及びＣ1-6アルコキシからなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）からなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、又はＣ2-6アルケニルを示し；
Ｒ2は、水素原子、又はＣ1-6アルキルを示し；
Ｒ3及びＲ4は、いずれか一方が水素原子、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは１個のヒドロキシで置換されてもよい。）、ハロＣ1-6アルキル、又はＣ2-6アルケニルを示し、他方がアリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａ’より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）を示し；
置換基群Ａ’はハロゲン原子、シアノ、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、ヒドロキシ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシはＣ1-6アルキル及びハロゲン原子より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、及び飽和のヘテロシクリルからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）、アミノ、カルバモイル（該アミノ及びカルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルキルスルファニル、Ｃ1-6アルキルスルホニル、環状アミノカルボニル、Ｃ2-6アルケニル、Ｃ1-6アルコキシカルボニル、及び飽和のヘテロシクリルオキシを示し；
Ｘは窒素原子又は式ＣＨを示す。]
で表されるイミダゾロン誘導体、又はその医薬上許容される塩、
（２）上記式（Ｉ）において、
Ｒ1が、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、Ｃ3-8シクロアルキル、Ｃ1-6アルコキシ、及びフェニル（該フェニルはハロゲン原子、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、及びＣ1-6アルコキシからなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）からなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
Ｒ3及びＲ4が、いずれか一方が水素原子、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、又はＣ2-6アルケニルであり、他方がアリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａより選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
置換基群Ａがハロゲン原子、シアノ、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、ヒドロキシ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）からなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）、アミノ、カルバモイル（該アミノ及びカルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルキルスルファニル、及びＣ1-6アルキルスルホニルである（１）に記載のイミダゾロン誘導体、又はその医薬上許容される塩、
（３）上記式（Ｉ）において、
Ｒ3が、水素原子、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、又はＣ2-6アルケニルであり；
Ｒ4が、アリール又はヘテロアリール（該アリール及びヘテロアリールは（２）記載の置換基群Ａより選ばれる同一の又は異なる１～３個の基で置換されてもよい。）である（１）又は（２）に記載のイミダゾロン誘導体、又はその医薬上許容される塩、
（４）上記式（Ｉ）において、
Ｒ4が、アリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａ１より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
置換基群Ａ１がハロゲン原子、シアノ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、アリール、及びヘテロアリールからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ、カルバモイル（該カルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、及びＣ1-6アルキルスルファニルである（１）～（３）いずれか一つに記載のイミダゾロン誘導体、又はその医薬上許容される塩、
（５）上記式（Ｉ）において、
Ｒ4が、アリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａ２より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
置換基群Ａ２がハロゲン原子、シアノ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、及びＣ3-8シクロアルキルからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ、カルバモイル（該カルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、及びＣ1-6アルキルスルファニルである（１）～（４）いずれか一つに記載のイミダゾロン誘導体、又はその医薬上許容される塩、
（６）上記式（Ｉ）において、
Ｘが窒素原子である（１）～（５）いずれか一つに記載のイミダゾロン誘導体、又はその医薬上許容される塩、
（７）上記（１）～（６）のいずれか一つに記載のイミダゾロン誘導体、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組成物、
（８）上記（１）～（６）のいずれか一つに記載のイミダゾロン誘導体、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ことを特徴とする、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、ＡＤ／ＨＤ（注意欠如/多動性障害）、薬物依存、痙攣、振戦及び睡眠障害からなる群から選択される疾患の予防又は治療用医薬、
である。 As a result of intensive studies, the present inventors have found a novel imidazolone derivative having an mGlu2 receptor positive allosteric modulator action and completed the present invention.
That is, the present invention
(1) Formula (I)
Figure JPOXMLDOC01-appb-C000002
 [In the formula (I),
R 1 is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl , C 1-6 alkyl, and C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: 3 may be substituted with three groups), or C 2-6 alkenyl;
R 2 represents a hydrogen atom or C 1-6 alkyl;
Any one of R 3 and R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy), halo C 1-6 alkyl, Or C 2-6 alkenyl, the other being aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A ′). Show;
Substituent group A ′ is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3 -8 cycloalkyl, C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl, and C 3-8 cycloalkyloxy are the same or different 1 to 3 selected from C 1-6 alkyl and a halogen atom) And optionally substituted with 1 to 5 groups selected from the group consisting of aryl, heteroaryl, aryloxy, and saturated heterocyclyl), C 1-6 alkoxy (including C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group of halogen atom and aryl.), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy C 3-8 cycloalkyl Alkyl and C 3-8 cycloalkyloxy optionally substituted by the same or different 1 to 3 halogen atoms.), Amino, carbamoyl (said amino and carbamoyl same or different one or two C 1 -6 alkyl may be substituted.), Aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be the same or different 1 or 2 C 1-6 alkyl may be substituted.), C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, cyclic aminocarbonyl, C 2-6 alkenyl, C 1-6 alkoxycarbonyl, and saturated heterocyclyloxy Indicates;
X represents a nitrogen atom or the formula CH. ]
An imidazolone derivative represented by: or a pharmaceutically acceptable salt thereof,
(2) In the above formula (I),
R 1 is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl , C 1-6 alkyl, and C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: May be substituted with three groups);
One of R 3 and R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl, and the other is aryl or heteroaryl (the aryl and heteroaryl Aryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A):
Substituent group A is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3-6 From 8 cycloalkyl, and C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and C 3-8 cycloalkyloxy may be substituted with the same or different 1 to 3 halogen atoms). 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (the C 1-6 alkoxy is the same or different 1 to 3 groups selected from the group of halogen atoms and aryl) A C 3-8 cycloalkyl, a C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and the C 3-8 cycloalkyloxy may be the same or different one to three). May be substituted with a halogen atom of ), Amino, carbamoyl (said amino and carbamoyl optionally substituted by the same or different one or two C 1-6 alkyl.), Aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated Saturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be substituted with the same or different 1 or 2 C 1-6 alkyl), C 1-6 alkylsulfanyl, and C 1-6 alkylsulfonyl The imidazolone derivative according to (1), or a pharmaceutically acceptable salt thereof,
(3) In the above formula (I),
R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl;
R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the substituent group A described in (2)) (1) Or the imidazolone derivative according to (2), or a pharmaceutically acceptable salt thereof,
(4) In the above formula (I),
R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A1);
Substituent group A1 is a halogen atom, cyano, C 1-6 alkyl (wherein C 1-6 alkyl is a halogen atom, cyano, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3-8 cycloalkyl, Optionally substituted with 1 to 5 groups selected from the group consisting of aryl and heteroaryl.), C 1-6 alkoxy (the C 1-6 alkoxy is the same selected from the group of halogen atoms and aryl) Or may be substituted with 1 to 3 different groups), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, carbamoyl (wherein the carbamoyl is the same or different 1 or 2 C 1-6 May be substituted with alkyl), aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be the same or different) That one or two in the C 1-6 alkyl may be substituted.), And a C 1-6 alkylsulfanyl (1) to (3) imidazolone derivative of any one, or their pharmaceutically Acceptable salts,
(5) In the above formula (I),
R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A2);
Substituent group A2 is a halogen atom, cyano, C 1-6 alkyl (wherein C 1-6 alkyl is a halogen atom, cyano, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, and C 3-8 cycloalkyl) Which may be substituted with 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (wherein the C 1-6 alkoxy is the same or different 1 to 3 selected from the group of halogen atoms and aryl) ), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, carbamoyl (wherein the carbamoyl is substituted with the same or different 1 or 2 C 1-6 alkyl). or.), aryl, heteroaryl, aryloxy, heteroaryloxy, heterocyclyl, saturated or partially unsaturated heterocyclyl (saturated and partially unsaturated identical or different one or two C 1-6 alkyl Substituted.), And C 1-6 alkylsulfanyl is (1) to (4) imidazolone derivative of any one, or a pharmaceutically acceptable salt thereof,
(6) In the above formula (I),
(1) to (5) the imidazolone derivative according to any one of (1) to (5), or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom;
(7) A pharmaceutical composition comprising the imidazolone derivative according to any one of (1) to (6) above or a pharmaceutically acceptable salt thereof as an active ingredient,
(8) A schizophrenia, Alzheimer's disease, cognition, characterized by containing the imidazolone derivative according to any one of (1) to (6) above or a pharmaceutically acceptable salt thereof as an active ingredient. A drug for the prevention or treatment of a disease selected from the group consisting of dysfunction, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders,
It is.
　本発明の新規イミダゾロン誘導体は、ｍＧｌｕ２受容体の活性調節部位に作用して、生理的リガンド（グルタミン酸）による受容体刺激を増強させることが明らかになった。 It has been clarified that the novel imidazolone derivative of the present invention acts on the activity-regulating site of the mGlu2 receptor to enhance receptor stimulation by a physiological ligand (glutamic acid).
　本明細書で使用される用語は、以下の意味を有する。 The terms used in this specification have the following meanings.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、又はヨウ素原子を示す。 “Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
　「Ｃ1-6アルキル」とは、直鎖状、又は分枝鎖状の炭素原子数１～６のアルキル基を示し、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、ｎ－ヘキシル等の基を挙げることができる。 “C 1-6 alkyl” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and the like.
　「ハロＣ1-6アルキル」とは、前記の「Ｃ1-5アルキル」に１～５個の同一又は異なる前記の「ハロゲン原子」が置換したアルキル基を示し、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、２－フルオロエチル、１，１－ジフルオロエチル、２－フルオロ－２－プロピル、１，１，１－トリフルオロメチル－２－メチル－２－プロピル、４，４，４－トリフルオロブチル等の基を挙げることができる。 “Halo C 1-6 alkyl” refers to an alkyl group in which 1 to 5 identical or different “halogen atoms” are substituted on the above “C 1-5 alkyl”, and includes monofluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2-fluoro-2-propyl, 1,1,1-trifluoromethyl-2-methyl-2-propyl, 4,4,4-trifluoro A group such as butyl may be mentioned.
　「Ｃ3-8シクロアルキル」とは、環状の炭素原子数３～８のシクロアルキル基を意味し、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロへプチル、シクロオクチル基を挙げることができる。 “C 3-8 cycloalkyl” means a cyclic cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
　「Ｃ2-6アルケニル」とは、直鎖状又は分岐鎖状の炭素原子数２～６のアルケニル基を意味し、ビニル、アリル、１－プロペニル、イソプロペニル、１－ブテニル、１－メチル－２－プロペニル、１－エチル－１－エテニル、２－メチル－２－プロペニル、３－メチル－２－ブテニル、４－ペンテニル等の基を挙げることができる。 “C 2-6 alkenyl” means a linear or branched alkenyl group having 2 to 6 carbon atoms, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 1-methyl- Examples include 2-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 4-pentenyl and the like.
　「Ｃ1-6アルコキシ」とは、直鎖状又は分岐鎖状の炭素原子数１～６のアルコキシ基を意味し、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ｔｅｒｔ－ペンチルオキシ、ｎ－ヘキシルオキシ等の基を挙げることができる。 “C 1-6 alkoxy” means a linear or branched alkoxy group having 1 to 6 carbon atoms, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy and the like.
　「Ｃ3-8シクロアルキルオキシ」とは、前記の「Ｃ3-8シクロアルキル」と酸素原子が結合した基を意味し、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロへプチルオキシ、シクロオクチルオキシ基を挙げることができる。 “C 3-8 cycloalkyloxy” means a group in which the above “C 3-8 cycloalkyl” and an oxygen atom are bonded to each other. Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy And cyclooctyloxy group.
　「Ｃ2-6アルカノイルアミノ」とは、直鎖状又は分岐鎖状の炭素原子数２～６のアルカノイルにアミノが結合した基を意味し、アセチルアミノ、プロピオニルアミノ、ブチリルアミノ、イソブチリルアミノ、バレリルアミノ、イソバレリルアミノ、ピバロイルアミノ基を挙げることができる。 “C 2-6 alkanoylamino” means a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms in which amino is bonded, and acetylamino, propionylamino, butyrylamino, isobutyrylamino, Mention may be made of valerylamino, isovalerylamino, pivaloylamino groups.
　「アリール」とは、単環から２環式の芳香族炭素環を意味し、フェニル、ナフチル等の基を挙げることができる。 “Aryl” means a monocyclic to bicyclic aromatic carbocyclic ring, and includes groups such as phenyl and naphthyl.
　「ヘテロアリール」とは、酸素原子、窒素原子及び硫黄原子から選ばれる少なくとも1個のヘテロ原子を有し、１ないし２環からなる炭素数２～９の芳香族基を意味し、フリル、ピロリル、チエニル、ピラゾリル、イミダゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、キノリル、インドリル、ベンゾフラニル等の基を挙げることができる。 “Heteroaryl” means an aromatic group having 2 to 9 carbon atoms and having at least one heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Furyl, pyrrolyl , Thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, indolyl, benzofuranyl and the like.
　「アリールオキシ」とは、前記の「アリール」と酸素原子が結合した基を意味し、フェノキシ、ナフトキシ等の基を挙げることができる。 “Aryloxy” means a group in which the above “aryl” is bonded to an oxygen atom, and examples thereof include groups such as phenoxy and naphthoxy.
　「ヘテロアリールオキシ」とは、前記の「ヘテロアリール」と酸素原子が結合した基を意味し、フリルオキシ、ピロリルオキシ、チエニルオキシ、ピラゾリルオキシ、イミダゾリルオキシ、オキサゾリルオキシ、イソオキサゾリルオキシ、チアゾリルオキシ、イソチアゾリルオキシ、ピリジルオキシ、ピリダジニルオキシ、ピリミジニルオキシ、ピラジニルオキシ、キノリルオキシ、インドリルオキシ、ベンゾフラニルオキシ等の基を挙げることができる。 “Heteroaryloxy” means a group in which an oxygen atom is bonded to the above “heteroaryl” and includes furyloxy, pyrrolyloxy, thienyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy And groups such as isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, quinolyloxy, indolyloxy, benzofuranyloxy and the like.
　飽和のヘテロシクリルとは、酸素原子、窒素原子及び硫黄原子から選ばれる少なくとも1個のヘテロ原子を有し、炭素数２～９の飽和の複素環基を意味し、テトラヒドロフラニル、テトラヒドロピラニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、チオモルホリニル等の基を挙げることができる。 Saturated heterocyclyl means a saturated heterocyclic group having at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and having 2 to 9 carbon atoms. Tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl And groups such as piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and the like.
　飽和又は部分不飽和のヘテロシクリルとは、酸素原子、窒素原子及び硫黄原子から選ばれる少なくとも1個のヘテロ原子を有し、炭素数２～９の飽和又は部分不飽和の複素環基を意味し、テトラヒドロフラニル、テトラヒドロピラニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、チオモルホリニル、ジヒドロピラニル、テトラヒドロピリジル等の基を挙げることができる。 The saturated or partially unsaturated heterocyclyl means a saturated or partially unsaturated heterocyclic group having at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and having 2 to 9 carbon atoms, Examples include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyridyl and the like.
　「Ｃ1-6アルキルスルファニル」とは、前記の「Ｃ1-6アルキル」と硫黄原子が結合した基を意味し、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル、ｎ－ブチルスルファニル、イソブチルスルファニル、ｓｅｃ－ブチルスルファニル、ｔｅｒｔ－ブチルスルファニル、ｎ－ペンチルスルファニル、イソペンチルスルファニル、ネオペンチルスルファニル、ｔｅｒｔ－ペンチルスルファニル、ｎ－ヘキシルスルファニル等の基を挙げることができる。 “C 1-6 alkylsulfanyl” means a group in which the above “C 1-6 alkyl” and a sulfur atom are bonded to each other, and includes methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, Examples include groups such as isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, tert-pentylsulfanyl, n-hexylsulfanyl and the like.
　「Ｃ1-6アルキルスルホニル」とは、前記の「Ｃ1-6アルキル」で置換されたスルホニル基を意味し、メチルスルホニル、エチルスルホニル、ｎ－プロピルスルホニル、イソプロピルスルホニル、ｎ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル、ｔｅｒｔ－ブチルスルホニル、ｎ－ペンチルスルホニル、イソペンチルスルホニル、ネオペンチルスルホニル、ｔｅｒｔ－ペンチルスルホニル、ｎ－ヘキシルスルホニル等の基を挙げることができる。 “C 1-6 alkylsulfonyl” means a sulfonyl group substituted with the above “C 1-6 alkyl”, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutyl Examples include sulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl and the like.
　「環状アミノカルボニル」とは、４～８員環の環状アミノとカルボニルがアミド結合した基を意味し、アゼチジニルカルボニル、ピロリジニルカルボニル、ピペリジニルカルボニル、モルホリニルカルボニル等の基を挙げることができる。 “Cyclic aminocarbonyl” means a group in which a 4- to 8-membered cyclic amino and carbonyl are amide-bonded, and includes groups such as azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and the like. Can be mentioned.
　「Ｃ1-6アルコキシカルボニル」とは、前記の「Ｃ1-6アルコキシ」とカルボニルが結合した基を意味し、メトキシカルボニル、エトキシカルボニル、ｎ－プロポキシカルボニル、イソプロポキシカルボニル、ｎ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ｎ－ペンチルオキシカルボニル、ｎ－ヘキシルオキシカルボニル等の基を挙げることができる。 “C 1-6 alkoxycarbonyl” means a group in which the above “C 1-6 alkoxy” is bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, Mention may be made of groups such as tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl and the like.
　「飽和のヘテロシクリルオキシ」とは、前記の「飽和のヘテロシクリル」と酸素原子が結合した基を意味し、テトラヒドロフラニルオキシ、テトラヒドロピラニルオキシ等の基を挙げることができる。 “Saturated heterocyclyloxy” means a group in which the above “saturated heterocyclyl” is bonded to an oxygen atom, and examples thereof include tetrahydrofuranyloxy, tetrahydropyranyloxy, and the like.
　本発明における好ましいＲ1は、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、Ｃ3-8シクロアルキル、Ｃ1-6アルコキシ、及びフェニル（該フェニルはハロゲン原子、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、及びＣ1-6アルコキシからなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）からなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり、
　さらに好ましいＲ1は、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、Ｃ3-8シクロアルキル、及びＣ1-6アルコキシからなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）である。 Preferred R 1 in the present invention is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, and the same or different 1 to 3 groups selected from the group consisting of C 1-6 alkoxy may be substituted. Or may be substituted with 1 to 3 different groups).
More preferable R 1 is C 1-6 alkyl (wherein the C 1-6 alkyl is the same or different 1 to 3 selected from the group consisting of a halogen atom, C 3-8 cycloalkyl, and C 1-6 alkoxy). It may be substituted with a group of
　本発明における好ましいＲ2は、水素原子、又はＣ1-6アルキルであり。さらに好ましいＲ2は、水素原子、又はメチルである。 Preferred R 2 in the present invention is a hydrogen atom or C 1-6 alkyl. More desirable R 2 is a hydrogen atom or methyl.
　本発明における好ましいＲ3は、水素原子、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、又はＣ2-6アルケニルである。
本発明における好ましいＲ4は、アリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａより選ばれる同一の又は異なる１～３個の基で置換されてもよい。）である。 Preferred R 3 in the present invention is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl.
Preferred R 4 in the present invention is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A).
　置換基群Ａはハロゲン原子、シアノ、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、ヒドロキシ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）からなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）、アミノ、カルバモイル（該アミノ及びカルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルキルスルファニル、及びＣ1-6アルキルスルホニルである。 Substituent group A is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3-6 From 8 cycloalkyl, and C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and C 3-8 cycloalkyloxy may be substituted with the same or different 1 to 3 halogen atoms). Which may be substituted with 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (wherein the C 1-6 alkoxy is the same or different 1 to 3 groups selected from the group of halogen atoms and aryl) A C 3-8 cycloalkyl, a C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and the C 3-8 cycloalkyloxy may be the same or different one to three). May be substituted with a halogen atom of ), Amino, carbamoyl (said amino and carbamoyl optionally substituted by the same or different one or two C 1-6 alkyl.), Aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated Saturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be substituted with the same or different 1 or 2 C 1-6 alkyl), C 1-6 alkylsulfanyl, and C 1-6 alkylsulfonyl It is.
　さらに好ましいＲ4は、アリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群A１より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）である。 More preferred R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A1).
　置換基群Ａ１はハロゲン原子、シアノ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、及びＣ3-8シクロアルキルからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ、カルバモイル（該カルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、及びＣ1-6アルキルスルファニルである。
　本発明における好ましいＸは、窒素原子である。 Substituent group A1 is a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, and C 3-8 cycloalkyl) Which may be substituted with 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (wherein the C 1-6 alkoxy is the same or different 1 to 3 selected from the group of halogen atoms and aryl) ), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, carbamoyl (wherein the carbamoyl is substituted with the same or different 1 or 2 C 1-6 alkyl). or.), aryl, heteroaryl, aryloxy, heteroaryloxy, heterocyclyl, saturated or partially unsaturated heterocyclyl (saturated and partially unsaturated identical or different one or two C 1-6 alkyl Substituted.), And a C 1-6 alkylsulfanyl.
Preferred X in the present invention is a nitrogen atom.
本発明化合物中の好ましい化合物の例として、
３－（ビフェニル－４－イル）－６－ブチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［４－（ピリジン－３－イル）フェニル］－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［４－（プロパン－２－イルオキシ）フェニル］－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－（４－フェノキシフェニル）－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［４－（プロパン－２－イル）フェニル］－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［６－（シクロペンチルオキシ）ピリジン－３－イル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［４－（３－フルオロプロポキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［４－（シクロプロピルオキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
２－メチル－６－（４，４，４－トリフルオロブチル）－３－［４－（トリフルオロメトキシ）フェニル］－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－｛４－［シクロプロピル（ジフルオロ）メチル］フェニル｝－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－（シクロブチルメチル）－３－｛４－［シクロプロピル（ジフルオロ）メチル］フェニル｝－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
３－｛４－［シクロプロピル（ジフルオロ）メチル］フェニル｝－６－（シクロプロピルメチル）－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
6-(シクロプロピルメチル)-3-{4-[ジフルオロ(1-メチルシクロプロピル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
６－（シクロプロピルメチル）－３－［４－（１，１－ジフルオロ－２－メチルプロピル）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［４－（シクロペンチルオキシ）－２－フルオロフェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［３－フルオロ－４－（ピリジン－２－イルオキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－（シクロブチルメチル）－３－［３－フルオロ－４－（ピリジン－２－イルオキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－ブチル－３－［３－フルオロ－４－（ピリダジン－３－イルオキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－（シクロプロピルメチル）－３－［３－フルオロ－４－（ピリダジン－３－イルオキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
６－（シクロブチルメチル）－３－［３－フルオロ－４－（ピリダジン－３－イルオキシ）フェニル］－２－メチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン、
又はその医薬上許容される塩が挙げられる。 Examples of preferred compounds in the compounds of the present invention include
3- (biphenyl-4-yl) -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [4- (pyridin-3-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [4- (propan-2-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- (4-phenoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [4- (propan-2-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [6- (cyclopentyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [4- (3-fluoropropoxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [4- (cyclopropyloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
2-Methyl-6- (4,4,4-trifluorobutyl) -3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on,
6-butyl-3- {4- [cyclopropyl (difluoro) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6- (cyclobutylmethyl) -3- {4- [cyclopropyl (difluoro) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
3- {4- [cyclopropyl (difluoro) methyl] phenyl} -6- (cyclopropylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6- (Cyclopropylmethyl) -3- {4- [difluoro (1-methylcyclopropyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On 6- (cyclopropylmethyl) -3- [4- (1,1-difluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Imidazol-7-one,
6-butyl-3- [4- (cyclopentyloxy) -2-fluorophenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6-butyl-3- [3-fluoro-4- (pyridin-2-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one,
6- (Cyclobutylmethyl) -3- [3-fluoro-4- (pyridin-2-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on,
6-butyl-3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one;
6- (Cyclopropylmethyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on,
6- (Cyclobutylmethyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on,
Or a pharmaceutically acceptable salt thereof.
　「医薬上許容される塩」とは、硫酸、塩酸、臭化水素酸、リン酸、硝酸等の無機酸との塩、ギ酸、トリフルオロ酢酸、酢酸、シュウ酸、乳酸、酒石酸、フマル酸、マレイン酸、クエン酸、ベンゼンスルホン酸、メタンスルホン酸、ｐ－トルエンスルホン酸、安息香酸、カンファースルホン酸、エタンスルホン酸、グルコヘプトン酸、グルコン酸、グルタミン酸、グリコール酸、リンゴ酸、マロン酸、マンデル酸、ガラクタル酸、ナフタレン－２－スルホン酸等の有機酸との塩、リチウムイオン、ナトリウムイオン、カリウムイオン、カルシウムイオン、マグネシウムイオン、亜鉛イオン、アルミニウムイオン等の１種又は複数の金属イオンとの塩、アンモニア、アルギニン、リシン、ピペラジン、コリン、ジエチルアミン、４－フェニルシクロヘキシルアミン、２－アミノエタノール、ベンザチン等のアミンとの塩が含まれる。 “Pharmaceutically acceptable salt” refers to salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, formic acid, trifluoroacetic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, Maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid , Salts with organic acids such as galactaric acid, naphthalene-2-sulfonic acid, salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion , Ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylsilane B hexylamine, 2-aminoethanol, salts with amines such as benzathine.
　なお、本発明の化合物は、各種溶媒和物としても存在し得る。また、医薬としての適用性の面から水和物の場合もある。 Note that the compound of the present invention may exist as various solvates. Moreover, it may be a hydrate from the viewpoint of applicability as a medicine.
　本発明の化合物は、エナンチオマー、ジアステレオマー、平衡化合物、これらの任意の割合の混合物、ラセミ体等を全て含む。 The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in arbitrary proportions, racemates, and the like.
　本発明の化合物は、一つ又は二つ以上の医薬的に許容される担体、賦形剤又は希釈剤と組み合せて医薬的製剤とすることができる。上記担体、賦形剤及び希釈剤として、水、乳糖、デキストロース、フラクトース、ショ糖、ソルビトール、マンニトール、ポリエチレングリコール、プロピレングリコール、デンプン、ガム、ゼラチン、アルギネート、ケイ酸カルシウム、リン酸カルシウム、セルロース、水シロップ、メチルセルロース、ポリビニルピロリドン、アルキルパラヒドロキシベンゾソルベート、タルク、ステアリン酸マグネシウム、ステアリン酸、グリセリン、ゴマ油、オリーブ油、大豆油等の各種油等が含まれる。 The compound of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation. As said carrier, excipient and diluent, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup And various oils such as methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil and soybean oil.
　また、上記の担体、賦形剤又は希釈剤に必要に応じて一般に使用される増量剤、結合剤、崩壊剤、ｐＨ調整剤、溶解剤等の添加剤が混合し、常用の製剤技術によって錠剤、丸剤、カプセル剤、顆粒剤、粉剤、液剤、乳剤、懸濁剤、軟膏剤、注射剤、皮膚貼付剤等の経口又は非経口用医薬として調製することができる。本発明の化合物は、成人患者に対して１回の投与量として０．００１～２０００ｍｇを１日１回又は数回に分けて経口又は非経口で投与することが可能である。なお、この投与量は治療対象となる疾病の種類、患者の年齢、体重、症状等により適宜増減することが可能である。 In addition, additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients, or diluents, and tablets are prepared by conventional formulation techniques. , Pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches and the like. The compound of the present invention can be orally or parenterally administered to an adult patient at a dose of 0.001 to 2000 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
　本発明の化合物には、一つ以上の水素原子、フッ素原子、炭素原子、窒素原子、酸素原子、硫黄原子が放射性同位元素や安定同位元素と置換された化合物も含まれる。これらの標識化合物は、代謝や薬物動態研究、受容体のリガンド等として生物学的分析等に有用である。 The compounds of the present invention also include compounds in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
　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、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）、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。
「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、10-カンファースルホン酸、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、ギ酸、酢酸等の有機酸、塩化亜鉛（ＩＩ）、塩化アルミニウム（ＩＩＩ）、塩化チタン（ＩＶ）、三フッ化ホウ素ジエチルエーテル錯体、三臭化ホウ素、トリメチルシリルヨージド、トリフルオロメタンスルホン酸トリメチルシリル等のルイス酸である。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 “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or alkaline earth metal carbonate; Sodium hydrogen carbonate, potassium hydrogen carbonate or other alkali metal or alkaline earth Metal bicarbonate; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3 0.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; quaternary ammonium salts such as tetra-n-butylammonium fluoride and benzyltrimethylammonium hydroxide; pyridine, imidazole, 2,6 -Basic heterocyclic compounds such as lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and the like. Lewis acids such as organic acids, zinc (II) chloride, aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
　本発明化合物は、例えば下記に示す方法によって製造することができる。 The compound of the present invention can be produced, for example, by the method shown below.
　式（Ｉ-Ｉ）で示される本発明化合物は下記スキーム１の方法にて製造することができる。 The compound of the present invention represented by the formula (II) can be produced by the method of the following scheme 1.
Figure JPOXMLDOC01-appb-C000003
 　式中、Ｒ1及びＲ2は前記と同義である。Ｒ3’はアリール、ヘテロアリールを示す。Ｍはカップリング反応で用いられる金属原子又は金属原子団を示し、化合物（４）の例としてマグネシウム反応剤、亜鉛反応剤、ホウ酸又はホウ酸エステルが結合したホウ素反応剤、スズ反応剤等が挙げられる。Ｘ1は塩素原子、臭素原子、ヨウ素原子、フッ素原子又は有機スルホニルオキシ（メタンスルホニルオキシ、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）等の脱離基を示す。Ｘ2及びＸ3は、同一又は異なって塩素原子、臭素原子、ヨウ素原子を示す。Ｒ5は、メチル、エチル、ｔｅｒｔ－ブチル、ベンジル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。
Figure JPOXMLDOC01-appb-C000003
 In the formula, R 1 and R 2 are as defined above. R 3 ′ represents aryl or heteroaryl. M represents a metal atom or a metal atomic group used in the coupling reaction, and examples of the compound (4) include magnesium reactant, zinc reactant, boron reactant bound with boric acid or borate ester, tin reactant, and the like. Can be mentioned. X 1 represents a leaving group such as chlorine atom, bromine atom, iodine atom, fluorine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.). X 2 and X 3 are the same or different and represent a chlorine atom, a bromine atom or an iodine atom. R 5 is a protecting group of a carboxy group such as methyl, ethyl, tert-butyl, benzyl, etc. {Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC. ) Reference} or a hydrogen atom.
　工程１：化合物（３）は不活性溶媒中、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、Ｒ5が水素原子の場合、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。或いはアミド化反応とは、Ｒ5がカルボキシ基の保護基の場合、例えば、不活性溶媒中又は無溶媒にて、塩基又は酸存在下若しくは非存在下、化合物（１）と化合物（２）の縮合反応である。
工程２：化合物（５）は不活性溶媒中、塩基存在下又は非存在下、パラジウム触媒及び必要に応じて配位子を用いて、化合物（３）と化合物（４）のカップリング反応により製造することができる。ここでカップリング反応としては、当業者に公知なカップリング反応の条件が挙げられ、例えば、｛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.）｝等に記載の方法、それに準じた方法、又はこれらと常法とを組み合わせることにより実施することができる。ここで化合物（３）及び化合物（４）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、パラジウム触媒とは、例えば酢酸パラジウム（ＩＩ）、塩化パラジウム（ＩＩ）、ビス（トリフェニルホスフィン）酢酸パラジウム（ＩＩ）、ビス（トリフェニルホスフィン）塩化パラジウム（ＩＩ）、(1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾリデン)(3-クロロピリジル)塩化パラジウム(ＩＩ)、トリス(ジベンジリデンアセトン)ジパラジウム（０）、ビス(ジベンジリデンアセトン)パラジウム（０）、テトラキストリフェニルホスフィンパラジウム（０）、塩化〔１，1’－ビス（ジフェニルホスフィノ）フェロセン〕パラジウム（ＩＩ）、塩化アリルパラジウム（ＩＩ）、ビス（アセトニトリル）塩化パラジウム（ＩＩ）等を挙げることができ、配位子とは例えばトリフェニルホスフィン、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、９，９－ジメチル－４，５－ビス（ジフェニルホスフィノ）キサンテン（Ｘａｎｔｐｈｏｓ）等を挙げることができる。
工程３：本発明化合物（Ｉ－Ｉ）は不活性溶媒中、塩基存在下、化合物（５）と化合物（６）のアルキル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（５）及び化合物（６）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。 Step 1: Compound (3) can be prepared by an amidation reaction known to those skilled in the art of Compound (1) and Compound (2) in an inert solvent {Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) See 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 means that when R 5 is a hydrogen atom, for example, O- (7-azabenzotriazol-1-yl) -N, N, N in an inert solvent in the presence or absence of a base. ', N'-tetramethyluronium hexafluorophosphoric acid (HATU), O- (benzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphoric acid (HBTU), Condensing agents such as N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI) Condensation reaction using mixed acid anhydride using ethyl chloroformate, isobutyl chloroformate, trimethylacetyl chloride, etc. , Thionyl chloride, oxalyl chloride, 1-chloro -N, N, 2-trimethyl-1-condensation reaction or the like via an acid halide using a propenyl amine. Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary. Alternatively, the amidation reaction means that when R 5 is a protecting group for a carboxy group, for example, in an inert solvent or without a solvent, in the presence or absence of a base or an acid, the compound (1) and the compound (2) It is a condensation reaction.
Step 2: Compound (5) is produced by a coupling reaction of Compound (3) and Compound (4) in an inert solvent, in the presence or absence of a base, using a palladium catalyst and optionally a ligand. can do. Here, examples of the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, {Comprehensive Organic Transformations Second Edition} {Comprehensive Organic Transformations Second Edition} 1999, John Willy and Sons (John Wiley & Sons, INC.)} Or the like, a method according to the method, or a combination thereof with a conventional method. Here, as the compound (3) and the compound (4), 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. Here, the palladium catalyst refers to, for example, palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium acetate (II), bis (triphenylphosphine) palladium chloride (II), (1,3- Bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenyl Phosphine palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), allyl palladium (II) chloride, bis (acetonitrile) palladium chloride (II), and the like. Examples of ligands include triphenylphosphine and 2,2-bis (diphenylphosphino). 1,1-binaphthyl (BINAP), 2-(di -tert- butylphosphino) biphenyl, 9,9-dimethyl-4,5-bis (diphenylphosphino) can be exemplified xanthene (Xantphos) or the like.
Step 3: The compound (II) of the present invention can be produced by an alkylation reaction of the compound (5) and the compound (6) in the presence of a base in an inert solvent {Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) 1999, see John Wiley & Sons, INC.}. Here, as the compound (5) and the compound (6), 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、式（Ｉ－ＩＩ）で示される本化合物は下記のスキーム２の方法にて製造することができる。 For example, the present compound represented by the formula (I-II) can be produced by the method of Scheme 2 below.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　式中、Ｒ1、Ｒ2、Ｒ3’、Ｒ5、Ｍ、Ｘ2及びＸ3は前記と同義である。Ｘ4は、塩素原子、臭素原子、ヨウ素原子を示す。
工程４：化合物（８）はスキーム１中の工程１と同様の手法により、化合物（７）と化合物（２）から製造することができる。ここで化合物（７）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。
工程５：化合物（９）は不活性溶媒中、酸存在下または非存在下、化合物（８）をＮ－クロロコハク酸イミド、Ｎ－ブロモコハク酸イミド、Ｎ－ヨードコハク酸イミド等のハロゲン化剤と反応させることにより製造することができる。或いは、化合物（９）は不活性溶媒中、塩基存在下または非存在下、化合物（８）を一塩化ヨウ素、ヨウ素、臭素等のハロゲン化剤と反応させることにより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。
工程６：化合物（１０）はスキーム１中の工程２と同様の手法により、化合物（９）と化合物（４）から製造することができる。ここで化合物（９）及び化合物（４）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７：本発明化合物（Ｉ－ＩＩ）はスキーム１中の工程３と同様の手法により、化合物（１０）と化合物（６）から製造することができる。ここで化合物（１０）及び化合物（６）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, R 1 , R 2 , R 3 ′, R 5 , M, X 2 and X 3 are as defined above. X 4 represents a chlorine atom, a bromine atom, or an iodine atom.
Step 4: Compound (8) can be produced from Compound (7) and Compound (2) by the same method as in Step 1 in Scheme 1. Here, as the compound (7) and the compound (2), 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 5: Compound (9) is reacted with a halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, etc. in an inert solvent in the presence or absence of an acid. Can be manufactured. Alternatively, compound (9) can be produced by reacting compound (8) with a halogenating agent such as iodine monochloride, iodine or bromine in an inert solvent in the presence or absence of a base. 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.
Step 6: Compound (10) can be produced from compound (9) and compound (4) by the same method as in Step 2 in Scheme 1. Here, as the compound (9) and the compound (4), 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: Compound (I-II) of the present invention can be produced from compound (10) and compound (6) by the same method as in step 3 in scheme 1. Here, as the compound (10) and the compound (6), 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.
　例えば、式（Ｉ－ＩＩ）で示される本発明化合物は下記のスキーム３の方法にても製造することができる。 For example, the compound of the present invention represented by the formula (I-II) can also be produced by the method of Scheme 3 below.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　式中、Ｒ1、Ｒ2、Ｒ3’、Ｍ、Ｘ2、Ｘ3及びＸ4は前記と同義である。
工程８：化合物（１１）はスキーム１中の工程３と同様の手法により、化合物（８）と化合物（６）から製造することができる。ここで化合物（８）及び化合物（６）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９：化合物（１２）はスキーム２中の工程５と同様の手法により、化合物（１１）から製造することができる。ここで化合物（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。
工程１０：本発明化合物（Ｉ－ＩＩ）はスキーム１中の工程２と同様の手法により、化合物（１２）と化合物（４）から製造することができる。ここで化合物（１２）及び化合物（４）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。
例えば、式（Ｉ－ＩＩＩ）で示される本発明化合物は下記のスキーム４の方法にて製造することができる。 In the formula, R 1 , R 2 , R 3 ′, M, X 2 , X 3 and X 4 are as defined above.
Step 8: Compound (11) can be produced from compound (8) and compound (6) by the same method as in Step 3 in Scheme 1. Here, as the compound (8) and the compound (6), 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 9: Compound (12) can be produced from compound (11) by the same method as in Step 5 in Scheme 2. Here, as the compound (11), 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.
Step 10: Compound (I-II) of the present invention can be produced from compound (12) and compound (4) by the same method as in step 2 in scheme 1. Here, as the compound (12) and the compound (4), 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.
For example, the compound of the present invention represented by the formula (I-III) can be produced by the method of Scheme 4 below.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
式中、Ｒ1、Ｒ2、Ｒ5、Ｍ、Ｘ1、Ｘ2及びＸ3は前記と同義である。Ｒ4’はアリール、ヘテロアリールを示す。化合物（１４）の例としてマグネシウム反応剤、亜鉛反応剤、ホウ酸又はホウ酸エステルが結合したホウ素反応剤、スズ反応剤等が挙げられる。 In the formula, R 1 , R 2 , R 5 , M, X 1 , X 2 and X 3 are as defined above. R 4 ′ represents aryl or heteroaryl. Examples of the compound (14) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, a tin reactant, and the like.
　工程１１：化合物（１５）はスキーム１中の工程２と同様の手法により、化合物（１３）と化合物（１４）から製造することができる。ここで化合物（１３）及び化合物（１４）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（１６）はスキーム１中の工程１と同様の手法により、化合物（１５）と化合物（２）から製造することができる。ここで化合物（１５）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。
工程１３：本発明化合物（Ｉ－ＩＩ）はスキーム１中の工程３と同様の手法により、化合物（１６）と化合物（６）から製造することができる。ここで化合物（１６）及び化合物（６）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。 Step 11: Compound (15) can be produced from compound (13) and compound (14) by the same method as in Step 2 in Scheme 1. Here, as the compound (13) and the compound (14), 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 12: Compound (16) can be produced from compound (15) and compound (2) by the same method as in Step 1 in Scheme 1. Here, as the compound (15) and the compound (2), 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 13: Compound (I-II) of the present invention can be produced from compound (16) and compound (6) by the same method as in Step 3 in Scheme 1. Here, as the compound (16) and the compound (6), 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.
　例えば、式（Ｉ－ＩＶ）で示される本発明化合物は下記のスキーム５の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (I-IV) can be produced by the method of Scheme 5 below.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4’、 Ｒ5、Ｍ、Ｘ2、Ｘ3及びＸ4は前記と同義である。
工程１４：化合物（１８）はスキーム１中の工程１と同様の手法により、化合物（１７）と化合物（２）から製造することができる。ここで化合物（１７）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。
工程１５：化合物（１９）はスキーム１中の工程３と同様の手法により、化合物（１８）と化合物（６）から製造することができる。ここで化合物（１８）及び化合物（６）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１６：化合物（２０）はスキーム２中の工程５と同様の手法により、化合物（１９）から製造することができる。ここで化合物（１９）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１７：本発明化合物（Ｉ－ＩＶ）はスキーム１中の工程２と同様の手法により、化合物（２０）と化合物（１４）から製造することができる。ここで化合物（２０）及び化合物（１４）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, R 1 , R 2 , R 3 , R 4 ′, R 5 , M, X 2 , X 3 and X 4 are as defined above.
Step 14: Compound (18) can be produced from compound (17) and compound (2) by the same method as in Step 1 in Scheme 1. Here, as the compound (17) and the compound (2), 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 15: Compound (19) can be produced from compound (18) and compound (6) by the same method as in Step 3 in Scheme 1. Here, as the compound (18) and the compound (6), 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.
Step 16: Compound (20) can be produced from compound (19) by the same method as in Step 5 in Scheme 2. Here, as the compound (19), 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 17: Compound (I-IV) of the present invention can be produced from compound (20) and compound (14) by the same method as in step 2 in scheme 1. Here, as the compound (20) and the compound (14), 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.
　例えば、式（Ｉ－Ｖ）及び式（Ｉ－ＶＩ）で示される本発明化合物は下記のスキーム６の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (IV) and the formula (I-VI) can be produced by the method of the following scheme 6.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
式中、Ｒ1、Ｒ2、Ｒ4’、Ｍ、Ｘ2及びＸ3は前記と同義である。Ｒ3”はＣ1-6アルキル、Ｃ2-6アルケニル、アリール、ヘテロアリールを示す。化合物（２２）の例としてマグネシウム反応剤、亜鉛反応剤、ホウ酸又はホウ酸エステルが結合したホウ素反応剤、スズ反応剤等が挙げられる。
工程１８：化合物（２１）はスキーム２中の工程５と同様の手法により、化合物（１１）から製造することができる。ここで化合物（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。
工程１９：本発明化合物（Ｉ－Ｖ）はスキーム１中の工程２と同様の手法により、化合物（２１）と化合物（１４）から製造することができる。ここで化合物（２１）及び化合物（１４）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２０：本発明化合物（Ｉ－ＶＩ）はスキーム１中の工程２と同様の手法により、本発明化合物（Ｉ－Ｖ）と化合物（２２）から製造することができる。ここで化合物（２２）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, R 1 , R 2 , R 4 ′, M, X 2 and X 3 are as defined above. R 3 ″ represents C 1-6 alkyl, C 2-6 alkenyl, aryl, heteroaryl. Examples of the compound (22) include a magnesium reactant, a zinc reactant, a boron reactant bound with boric acid or a borate ester. And tin reactants.
Step 18: Compound (21) can be produced from compound (11) by the same method as in Step 5 in Scheme 2. Here, as the compound (11), 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.
Step 19: Compound (IV) of the present invention can be produced from compound (21) and compound (14) by the same method as in Step 2 in Scheme 1. Here, as the compound (21) and the compound (14), 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 20: Compound (I-VI) of the present invention can be produced from compound (IV) of the present invention and compound (22) by the same method as in Step 2 in Scheme 1. Here, as the compound (22), 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、式（Ｉ－ＶＩＩ）で示される本発明化合物は下記のスキーム７の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (I-VII) can be produced by the method of Scheme 7 below.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
式中、Ｒ1、Ｒ2及びＲ3は前記と同義である。Ｒ6はＣ1-6アルキルを示す。
工程２１：本発明化合物（Ｉ－ＶＩＩ）は不活性溶媒中、酸存在下又は非存在下、化合物（１８）と化合物（２３）の反応により製造することができる。ここで化合物（１８）及び化合物（２３）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, R 1 , R 2 and R 3 are as defined above. R 6 represents C 1-6 alkyl.
Step 21: The compound (I-VII) of the present invention can be produced by reacting the compound (18) with the compound (23) in an inert solvent in the presence or absence of an acid. Here, as the compound (18) and the compound (23), 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.
　例えば、式（Ｉ－ＩＸ）で示される本発明化合物は下記のスキーム８の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (I-IX) can be produced by the method of Scheme 8 below.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
式中、Ｒ1、Ｒ2、Ｍ及びＸ2は前記と同義である。Ｒ3’’’は、Ｃ1-6アルキル（該Ｃ1-6アルキルは１個のヒドロキシで置換されてもよい。）、ハロＣ1-6アルキル、又はＣ2-6アルケニルを示し、Ｒ7はアリール、ヘテロアリール、ヘテロシクリルを示す。化合物（２５）の例としてマグネシウム反応剤、亜鉛反応剤、ホウ酸又はホウ酸エステルが結合したホウ素反応剤、スズ反応剤等が挙げられる。Ｘ5は有機スルホニルオキシ（メタンスルホニルオキシ、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）等の脱離基を示す。
工程２２：本発明化合物（Ｉ－ＩＸ）はスキーム１中の工程２と同様の手法により、化合物（２４）又は本発明化合物（Ｉ－ＶＩＩＩ）と、化合物（２５）から製造することができる。ここで化合物（２４）及び化合物（２５）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。
例えば、式（Ｉ－ＩＸ）で示される本発明化合物は下記のスキーム９の方法にて製造することができる。 In the formula, R 1 , R 2 , M and X 2 are as defined above. R 3 ′ ″ represents C 1-6 alkyl (wherein the C 1-6 alkyl may be substituted with 1 hydroxy), haloC 1-6 alkyl, or C 2-6 alkenyl; 7 represents aryl, heteroaryl, or heterocyclyl. Examples of the compound (25) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, a tin reactant, and the like. X 5 represents a leaving group such as organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.).
Step 22: Compound (I-IX) of the present invention can be produced from compound (24) or compound (I-VIII) of the present invention and compound (25) by the same method as in step 2 in scheme 1. Here, as the compound (24) and the compound (25), 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.
For example, the compound of the present invention represented by the formula (I-IX) can be produced by the method of Scheme 9 below.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
式中、Ｒ1、Ｒ2、Ｒ3’’’、Ｒ7、Ｍ及びＸ1は前記と同義である。。化合物（２６）の例としてマグネシウム反応剤、亜鉛反応剤、ホウ酸又はホウ酸エステルが結合したホウ素反応剤、スズ反応剤等が挙げられる。
工程２３：本発明化合物（Ｉ－ＩＸ）はスキーム１中の工程２と同様の手法により、化合物（２６）と化合物（２７）から製造することができる。ここで化合物（２６）及び化合物（２７）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。
例えば、式（Ｉ－ＸＩ）で示される本発明化合物は下記のスキーム１０の方法にて製造することができる。 In the formula, R 1 , R 2 , R 3 ′ ″, R 7 , M and X 1 are as defined above. . Examples of the compound (26) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, a tin reactant, and the like.
Step 23: Compound (I-IX) of the present invention can be produced from compound (26) and compound (27) by the same method as in Step 2 in Scheme 1. Here, as the compound (26) and the compound (27), 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.
For example, the compound of the present invention represented by the formula (I-XI) can be produced by the method of Scheme 10 below.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
式中、Ｒ1、Ｒ2、Ｒ3’’’及びＸ1は前記と同義である。Ｒ8はＣ1-6アルキル、Ｃ3-8シクロアルキル、ヘテロアリール、ヘテロシクリルを示し、ｎは０～６の整数を示す。
工程２４：本発明化合物（Ｉ－Ｘ）は不活性溶媒中、塩基存在下、本発明化合物（Ｉ－ＩＸ）と化合物（２７）の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（２７）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, R 1 , R 2 , R 3 ′ ″ and X 1 are as defined above. R 8 represents C 1-6 alkyl, C 3-8 cycloalkyl, heteroaryl, heterocyclyl, and n represents an integer of 0-6.
Step 24: The compound (IX) of the present invention can be produced by the reaction of the compound (IX) of the present invention and the compound (27) in the presence of a base in an inert solvent {Comprehensive Organic Transformations Second edition (Comprehensive Organic Transformations Second Edition) 1999, see John Wiley & Sons, INC.}. Here, as the compound (27), 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.
　例えば、式（Ｉ－ＸＩＩＩ）で示される本発明化合物は下記のスキーム１１の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (I-XIII) can be produced by the method of Scheme 11 below.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
式中、Ｒ1、Ｒ2、Ｒ3’’’、Ｒ8及びＸ1は前記と同義である。
工程２５：本発明化合物（Ｉ－ＸＩＩＩ）は不活性溶媒中、塩基存在下、本発明化合物（Ｉ－ＸＩＩ）と化合物（２８）を銅触媒及び必要に応じて配位子を用いて反応させることにより製造することができる。ここで化合物（２８）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。ここで銅触媒とは、例えば、銅（０）、ヨウ化銅（Ｉ）、塩化銅（Ｉ）、酸化銅（Ｉ）、臭化銅（Ｉ）トリストリフェニルホスフィン錯体、トリフルオロメタンスルホン酸銅（Ｉ）ベンゼン錯体等が挙げられる。配位子とは、銅触媒を用いたカップリング反応で当業者に公知な配位子、例えば、Ｎ，Ｎ’－ジメチルエチレンジアミン、１，２－シクロヘキサンジアミン、２－アミノピリジン、１，１０－フェナントロリン、２－ヒドロキシベンズアルデヒドオキシム、エチレングリコール、ピコリン酸等が挙げられる（Ｓｙｎｌｅｔｔ，１５，２４２８－２４３９，２００３）。
また、本発明化合物（Ｉ－ＸＩＩＩ）は不活性溶媒中、塩基存在下、本発明化合物（Ｉ－ＸＩＩ）と化合物（２８）の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（２８）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。
例えば、本発明化合物（Ｉ）に於いて、式中のＲ3又はＲ4がＣ2-6アルケニル基、若しくはＲ3又はＲ4の置換基が３，４－ジヒドロ－２Ｈ－ピラニル基等の場合、不活性溶媒中、遷移金属触媒存在下、水素雰囲気下、常圧又は加圧下に於いて本発明化合物（Ｉ）の接触還元反応により、本発明化合物（Ｉ）の還元体を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｝。該本発明化合物（Ｉ）の還元体も本発明化合物に包含される。ここで、還元反応で使用する遷移金属触媒とは例えば、パラジウム炭素、水酸化パラジウム、パラジウムブラック、パラジウム-フィブロイン、酸化白金（ＩＶ）、ラネーニッケル等が挙げられる。また例えば、本発明化合物（Ｉ）に於いて、式中のＲ3又はＲ4がハロゲン原子、若しくはＲ3又はＲ4の置換基がハロゲン原子の場合、同様の手法により本発明化合物（Ｉ）の還元体を製造することができる。該本発明化合物（Ｉ）の還元体も本発明化合物に包含される。 In the formula, R 1 , R 2 , R 3 ′ ″, R 8 and X 1 are as defined above.
Step 25: The compound (I-XIII) of the present invention is reacted with the compound (I-XII) of the present invention and the compound (28) in an inert solvent using a copper catalyst and, if necessary, a ligand in the presence of a base. Can be manufactured. Here, as the compound (28), 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, the copper catalyst is, for example, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I) tristriphenylphosphine complex, copper trifluoromethanesulfonate. (I) A benzene complex etc. are mentioned. The ligand is a ligand known to those skilled in the art in a coupling reaction using a copper catalyst, such as N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, 2-aminopyridine, 1,10- Examples include phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, picolinic acid and the like (Synlett, 15, 2428-2439, 2003).
The compound (I-XIII) of the present invention can be produced by reacting the compound (I-XII) of the present invention with a compound (28) in the presence of a base in an inert solvent. {See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.} Where compound (28) is a commercially available compound, a known compound or a Commercially available compounds or compounds synthesized from known compounds can be used using various organic synthesis methods known to those skilled in the art.
For example, in the compound (I) of the present invention, R 3 or R 4 in the formula is a C 2-6 alkenyl group, or the substituent of R 3 or R 4 is a 3,4-dihydro-2H-pyranyl group, etc. In this case, a reduced form of the compound (I) of the present invention is produced by a catalytic reduction reaction of the compound (I) of the present invention in an inert solvent in the presence of a transition metal catalyst, in a hydrogen atmosphere, at normal pressure or under pressure. {Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC.}. The reduced form of the compound (I) of the present invention is also encompassed in the compound of the present invention. Here, examples of the transition metal catalyst used in the reduction reaction include palladium carbon, palladium hydroxide, palladium black, palladium-fibroin, platinum (IV) oxide, Raney nickel, and the like. Further, for example, in the present invention Compound (I), R 3 or R 4 is a halogen atom in the formula, or when the substituent of R 3 or R 4 is a halogen atom, the same compounds of the present invention by a method (I) The reductant of can be produced. The reduced form of the compound (I) of the present invention is also encompassed in the compound of the present invention.
例えば、式（Ｉ－ＸＩＶ）で示される本発明化合物は下記のスキーム１２の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (I-XIV) can be produced by the method of Scheme 12 below.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　式中、Ｒ1、Ｒ2及びＲ3’’’は前記と同義である。Ｒ９はＣ1-6アルキル、Ｃ3-8シクロアルキル、飽和のヘテロシクリルを示す。
工程２６：本発明化合物（Ｉ－ＸＩＶ）は不活性溶媒中、本発明化合物（Ｉ－Ｘ’）と化合物（２９）の光延反応により製造することができる。ここで化合物（２９）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）。 In the formula, R 1 , R 2 and R 3 ′ ″ have the same meanings as described above. R 9 represents C 1-6 alkyl, C 3-8 cycloalkyl, or saturated heterocyclyl.
Step 26: The compound (I-XIV) of the present invention can be produced by Mitsunobu reaction of the compound (IX ′) of the present invention and the compound (29) in an inert solvent. Here, as the compound (29), 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).
例えば、式（Ｉ－ＸＶ）で示される本発明化合物は下記のスキーム１３の方法にて製造することができる。 For example, the compound of the present invention represented by the formula (I-XV) can be produced by the method of Scheme 13 below.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
式中、Ｒ1、Ｒ2、Ｒ3’’’及びＸ1は前記と同義である。Ｒ１０はヘテロアリールを示す。
工程２７：本発明化合物（Ｉ－ＸＶ）はスキーム１１中の工程２５と同様の手法により、本発明化合物（Ｉ－Ｘ’）と化合物（３０）から製造することができる。ここで化合物（３０）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, R 1 , R 2 , R 3 ′ ″ and X 1 are as defined above. R 10 represents heteroaryl.
Step 27: The compound of the present invention (I-XV) can be produced from the compound of the present invention (IX ′) and the compound (30) by the same method as in Step 25 in Scheme 11. Here, as the compound (30), 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.
また例えば、式（１８）で示される化合物は下記のスキーム１４の方法にて製造することができる。 For example, the compound shown by Formula (18) can be manufactured by the method of the following scheme 14.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
式中、Ｒ1及びＲ３及びＸ1は前記と同義である。Ｒ１１はアセチル基、メタンスルホニル基、ｐ－メトキシフェニルスルホニル基、ｐ－トルエンスルホニル基、ベンジルオキシカルボニル基、ｔ－ブチルオキシカルボニル基、ベンジル基、ｐ－メトキシベンジル基、トリチル基等のイミダゾール環上の窒素原子の保護基｛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｝を示す。
工程２８：化合物（３３）は不活性溶媒中、塩基存在下、化合物（３１）と化合物（３２）の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（３１）及び化合物（３２）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２９：化合物（１８）は不活性溶媒中、化合物（３３）の保護基Ｒ１１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。 In the formula, R 1, R 3 and X 1 are as defined above. R 11 is an imidazole ring such as an acetyl group, a methanesulfonyl group, a p-methoxyphenylsulfonyl group, a p-toluenesulfonyl group, a benzyloxycarbonyl group, a t-butyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group, or a trityl group. The protecting group for the nitrogen atom (see Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.) Is shown.
Step 28: Compound (33) can be produced by reacting compound (31) with compound (32) in the presence of a base in an inert solvent. {See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.} Where compound (31) and compound (32) are commercially available compounds A commercially available compound or a compound synthesized from a known compound can be used using known compounds or various organic synthesis methods known to those skilled in the art.
Step 29: Compound (18) in an inert solvent, various organic synthesis {Protective Groups's Inn Organic Synthesis protecting group R 11 of the compound (33) are known to those skilled in the art (Protective Groups in Organic Synthesis) 4 Plate, see John Wiley & Sons, Inc.}.
　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。
　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、グレース社製リベラリス（登録商標）Ｓｉｌｉｃａ、「ＩＳＯＬＵＴＥ（登録商標）　ＨＭ－Ｎ」にはバイオタージ社製のＩＳＯＬＵＴＥ（登録商標）　ＨＭ－Ｎ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「ＳｕｎＦｉｒｅ（登録商標）」にはＷａｔｅｒｓ社製のＳｕｎＦｉｒｅ（登録商標）　ｐｒｅｐ　Ｃ１８　ＯＢＤ（登録商標）５．０μｍ，φ３０×５０ｍｍ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。
　マイクロウェーブ反応装置にはＢｉｏｔａｇｅ社製のＩｎｉｔｉａｔｏｒを使用した。
　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。 Next, the present invention will be described in more detail with reference to production examples, examples and test examples. However, the present invention is not limited to these production examples, examples and test examples, and the scope of the present invention is not limited thereto. You may change in the range which does not deviate.
In the production examples and examples, the “NH silica gel cartridge” when purified by column chromatography is Biotage (registered trademark) SNAPPartridge KP-NH manufactured by Biotage, and the “silica gel cartridge” is manufactured by Biotage. Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil, Grace's Liberalis (registered trademark) Silica, and "ISOLUTE (registered trademark) HM-N" include Biotage's ISOLUTE (registered trademark) HM-N. Each commercially available product was used. For “SunFire (registered trademark)” when purified using reverse-phase column chromatography, SunFire (registered trademark) prep C18 OBD (registered trademark) 5.0 μm, φ30 × 50 mm manufactured by Waters was used. 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).
An Initiator manufactured by Biotage was used as the microwave reactor.
Each instrument data described in the production examples and examples was measured with the following measuring instruments.
　ＭＳスペクトル：ＬＣＭＳ－２０１０ＥＶ（島津製作所）、ＬＣＭＳ－ＩＴ－ＴＯＦ（島津製作所）、ｍｉｃｒｏｍａｓｓ　Ｐｌａｔｆｏｒｍ　ＬＣ又はｍｉｃｒｏｍａｓｓ　ＧＣＴ、Ａｇｉｌｅｎｔ　２９００及びＡｇｉｌｅｎｔ　６１５０
　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。
　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。 MS spectrum: LCMS-2010EV (Shimadzu Corporation), LCMS-IT-TOF (Shimadzu Corporation), micromass Platform LC or micromass GCT, Agilent 2900 and Agilent 6150
NMR spectrum: [ 1 H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL), 300 MHz: UNITYNOVA300 (Varian Inc.), 200 MHz: GEMINI 2000/200 (Varian Inc.)
The compound name in a manufacture example and an Example was named by ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).
Abbreviations in the nuclear magnetic resonance (NMR) spectra used in the production examples and examples are shown below.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, dq: double triplet, dq: double triplet, dq: double triplet, dq: double triplet (Double quartert), ddd: double doublet, m: multiplet, br: broad, J: coupling constant, Hz: hertz, DMSO-d 6 : deuterated dimethyl Sulfoxide.
　製造例１　N-ブチル-4-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキサミド
１）4-ブロモ-N-ブチル-1H-ピロール-2-カルボキサミド
　エチル 4-ブロモ-1H-ピロール-2-カルボキシラート（１．００　ｇ）及びｎ－ブチルアミン（３．００　ｍＬ）の混合物を８時間加熱還流した。室温にて２日間撹拌した後、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（７１２　ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.87 - 1.01 (m, 3 H) 1.31 - 1.66 (m, 4 H) 3.32 - 3.48 (m, 2 H) 5.77 (br. s., 1 H) 6.47 - 6.54 (m, 1 H) 6.86 - 6.94 (m, 1 H) 9.46 - 9.90 (m, 1 H)
２）N-ブチル-4-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキサミド
　4-ブロモ-N-ブチル-1H-ピロール-2-カルボキサミド（２２８　ｍｇ）、4-tert-ブチルフェニルボロン酸（３５６　ｍｇ）、炭酸セシウム（６５０　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（１２　ｍｇ）、エタノール（１．０　ｍＬ）、トルエン（１．０　ｍＬ）及び水（１．０　ｍＬ）の混合物をマイクロウェーブ照射下１３０　℃にて４５分間撹拌した。反応液に水を加え、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝９０：１０～２０：８０）にて精製し、表題化合物（９６　ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.90 - 1.00 (m, 3 H) 1.19 - 1.47 (m, 13 H) 3.36 - 3.49 (m, 2 H) 6.74 - 6.79 (m, 1 H) 7.14 - 7.19 (m, 1 H) 7.35 - 7.45 (m, 4 H); MS (ESI/APCI pos) m/z : 299 [M+H]+
製造例１と同様にして、以下の化合物を合成した。
N-ブチル-4-[4-(トリフルオロメチル)フェニル]-1H-ピロール-2-カルボキサミド
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.88 - 1.06 (m, 3 H) 1.32 - 1.74 (m, 4 H) 3.32 - 3.56 (m, 2 H) 6.76 - 6.99 (m, 2 H) 7.20 - 7.32 (m, 2 H)
4-[4-(ベンジルオキシ)フェニル]-N-ブチル-1H-ピロール-2-カルボキサミド
1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.97 (t, J=7.22 Hz, 2 H) 1.41 (s, 2 H) 1.56 - 1.65 (m, 2 H) 5.10 (s, 2 H) 6.73 - 7.85 (m, 11 H); MS (ESI/APCI pos) m/z : 349 [M+H]+ Production Example 1 N-butyl-4- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide 1) 4-bromo-N-butyl-1H-pyrrole-2-carboxamide ethyl 4-bromo-1H-pyrrole A mixture of -2-carboxylate (1.00 g) and n-butylamine (3.00 mL) was heated to reflux for 8 hours. After stirring at room temperature for 2 days, 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 (712 mg).
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.87-1.01 (m, 3 H) 1.31-1.66 (m, 4 H) 3.32-3.48 (m, 2 H) 5.77 (br. S., 1 H) 6.47 -6.54 (m, 1 H) 6.86-6.94 (m, 1 H) 9.46-9.90 (m, 1 H)
2) N-butyl-4- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide 4-bromo-N-butyl-1H-pyrrole-2-carboxamide (228 mg), 4-tert-butylphenyl Boronic acid (356 mg), cesium carbonate (650 mg), tetrakis (triphenylphosphine) palladium (0) (12 mg), ethanol (1.0 mL), toluene (1.0 mL) and water (1.0 mL) was stirred for 45 minutes at 130 ° C. under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-20: 80) to give the title compound (96 mg).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.90-1.00 (m, 3 H) 1.19-1.47 (m, 13 H) 3.36-3.49 (m, 2 H) 6.74-6.79 (m, 1 H) 7.14- 7.19 (m, 1 H) 7.35-7.45 (m, 4 H); MS (ESI / APCI pos) m / z: 299 [M + H] +
In the same manner as in Production Example 1, the following compounds were synthesized.
N-butyl-4- [4- (trifluoromethyl) phenyl] -1H-pyrrole-2-carboxamide
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.88-1.06 (m, 3 H) 1.32-1.74 (m, 4 H) 3.32-3.56 (m, 2 H) 6.76-6.99 (m, 2 H) 7.20- 7.32 (m, 2 H)
4- [4- (Benzyloxy) phenyl] -N-butyl-1H-pyrrole-2-carboxamide
1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.97 (t, J = 7.22 Hz, 2 H) 1.41 (s, 2 H) 1.56-1.65 (m, 2 H) 5.10 (s, 2 H) 6.73-7.85 (m, 11 H); MS (ESI / APCI pos) m / z: 349 [M + H] +
　製造例２　N-ブチル-4-(4-tert-ブチルフェニル)-1H-イミダゾール-2-カルボキサミド
１）N-ブチル-1H-イミダゾール-2-カルボキサミド
　エチル 1H-イミダゾール-2-カルボキシラート（１７．８　ｇ）、ｎ－ブチルアミン（５０．２　ｍＬ）及びエタノール（６４　ｍＬ）の混合物を８０　℃（オイルバス温度）にて４．５時間攪拌した。反応液を減圧下濃縮した後、残渣をヘキサンにて洗浄し、表題化合物（１７．７　ｇ）を淡褐色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.91 - 0.96 (3 H, m), 1.40 (2 H, dq, J=15.0, 7.4 Hz), 1.60 (2 H, quin, J=7.3 Hz), 3.44 (2 H, q, J=6.7 Hz), 7.11 (1 H, s), 7.15 (1 H, s), 7.54 (1 H, br. s.), 12.05 (1 H, br. s.); MS (ESI/APCI pos) m/z : 168 [M+H]+ 
２）4-ブロモ-N-ブチル-1H-イミダゾール-2-カルボキサミド
　N-ブチル-1H-イミダゾール-2-カルボキサミド（２２４　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．２　ｍＬ）溶液にＮ-ブロモスクシンイミド（２６２　ｍｇ）を加え、室温にて１時間攪拌した。反応液を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（６３　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.95 (3 H, t, J=7.4 Hz), 1.37 - 1.44 (2 H, m), 1.56 - 1.62 (2 H, m), 3.40 - 3.45 (2 H, m), 7.14 (1 H, s), 7.24 (1 H, br. s.), 11.63 (1 H, br. s); MS (ESI/APCI pos) m/z : 246 [M+H]+ 
３）N-ブチル-4-(4-tert-ブチルフェニル)-1H-イミダゾール-2-カルボキサミド
　4-ブロモ-N-ブチル-1H-イミダゾール-2-カルボキサミド（８３　ｍｇ）、4-tert-ブチルフェニルボロン酸（７２　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（７８　ｍｇ）、エタノール（０．８３　ｍＬ）、トルエン（０．８３　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（０．５１　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。反応液をセライト（登録商標）ろ過後、ろ液に水を加え酢酸エチルにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（６９　ｍｇ）を淡黄色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.94 - 0.99 (3 H, m), 1.34 (9 H, s), 1.40 - 1.48 (2 H, m), 1.56 - 1.67 (2 H, m), 3.44 - 3.49 (2 H, m), 7.30 - 7.38 (1 H, m), 7.40 - 7.47 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 7.70 (1 H, d, J=8.3 Hz); MS (ESI/APCI pos) m/z : 300 [M+H]+ Production Example 2 N-butyl-4- (4-tert-butylphenyl) -1H-imidazole-2-carboxamide 1) N-butyl-1H-imidazole-2-carboxamide ethyl 1H-imidazole-2-carboxylate (17. 8 g), a mixture of n-butylamine (50.2 mL) and ethanol (64 mL) was stirred at 80 ° C. (oil bath temperature) for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane to give the title compound (17.7 g) as a light brown solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.91-0.96 (3 H, m), 1.40 (2 H, dq, J = 15.0, 7.4 Hz), 1.60 (2 H, quin, J = 7.3 Hz), 3.44 (2 H, q, J = 6.7 Hz), 7.11 (1 H, s), 7.15 (1 H, s), 7.54 (1 H, br.s.), 12.05 (1 H, br.s.) ; MS (ESI / APCI pos) m / z: 168 [M + H] +
2) 4-Bromo-N-butyl-1H-imidazole-2-carboxamide N-bromo-1H-imidazole-2-carboxamide (224 mg) in N, N-dimethylformamide (2.2 mL) solution in N-bromo Succinimide (262 mg) was added and stirred at room temperature for 1 hour. The reaction solution was purified by reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title Compound (63 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, t, J = 7.4 Hz), 1.37-1.44 (2 H, m), 1.56-1.62 (2 H, m), 3.40-3.45 (2 H, m), 7.14 (1 H, s), 7.24 (1 H, br.s.), 11.63 (1 H, br.s); MS (ESI / APCI pos) m / z: 246 (M + H ] +
3) N-butyl-4- (4-tert-butylphenyl) -1H-imidazole-2-carboxamide 4-bromo-N-butyl-1H-imidazole-2-carboxamide (83 mg), 4-tert-butylphenyl A mixture of boronic acid (72 mg), tetrakis (triphenylphosphine) palladium (0) (78 mg), ethanol (0.83 mL), toluene (0.83 mL) and 2M aqueous sodium carbonate (0.51 mL) Was stirred at 150 ° C. for 30 minutes under microwave irradiation. The reaction mixture was filtered through Celite (registered trademark), water was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (69 mg) was obtained as a pale yellow solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94-0.99 (3 H, m), 1.34 (9 H, s), 1.40-1.48 (2 H, m), 1.56-1.67 (2 H, m), 3.44-3.49 (2 H, m), 7.30-7.38 (1 H, m), 7.40-7.47 (2 H, m), 7.53 (1 H, d, J = 8.3 Hz), 7.70 (1 H, d, J = 8.3 Hz); MS (ESI / APCI pos) m / z: 300 [M + H] +
　製造例３　3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
１）N-ブチル-1H-イミダゾール-2-カルボキサミド
1H-イミダゾール-2-カルボン酸（２．９０　ｇ）、ｎ－ブチルアミン（２．８４　ｇ）、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）（１４．８　ｇ）、ジイソプロピルエチルアミン（６．８０　ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（３７　ｍＬ）の混合物を室温にて２日間撹拌した。反応液に水（７４　ｍＬ）を加え、室温にて１５分間撹拌した後、生じた固体をろ取して、表題化合物（２．８０　ｇ）を無色固体として得た。
MS (ESI/APCI pos) m/z : 168 [M+H]+
２）6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　窒素雰囲気下、N-ブチル-1H-イミダゾール-2-カルボキサミド（３１．６　ｇ）のＮ，Ｎ－ジメチルホルムアミド（７６０　ｍＬ）溶液に、氷浴冷却下にて６０％水素化ナトリウム（２２．７　ｇ）を加え１５分間撹拌した後、室温にて３０分間攪拌した。氷浴冷却下、反応懸濁液にクロロヨードメタン（１００　ｇ）を滴下した後、室温にて１８時間攪拌した。反応懸濁液に室温にて水（５１　ｍＬ）を滴下し、３０分間攪拌した後、減圧下濃縮した。残渣にクロロホルム （１．０　Ｌ）を加え、室温にて１時間撹拌した。不溶物をセライト（登録商標）ろ過にてろ別し、クロロホルムにて洗浄した。ろ液を減圧下濃縮し、得られた残渣をメタノール（６００　ｍＬ）にて希釈後、ヘキサン（４００　ｍＬ）にて３回洗浄した。メタノール層を減圧下濃縮した。残渣をカラムクロマログラフィー（ＮＨシリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９７：３及びシリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９７：３ ）にて精製した。得られた固体をヘキサンにて洗浄して、表題化合物（１７．１　ｇ）を淡黄色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.0 Hz), 1.29 - 1.51 (2 H, m), 1.55 - 1.73 (2 H, m), 3.60 (2 H, t, J=7.5 Hz), 5.29 (2 H, s), 7.21 (1 H, d, J=1.3 Hz), 7.40 (1 H, d, J=1.3 Hz); MS (ESI/APCI pos) m/z : 180 [M+H]+ 
３）3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２３３　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．７　ｍＬ）溶液にＮ-ブロモスクシンイミド（２５５　ｍｇ）を加え、室温にて１４時間攪拌した。反応液を減圧下濃縮した。残渣をカラムクロマログラフィー（ヘキサン：酢酸エチル＝５０：５０～０：１００）にて精製して、表題化合物の混合物（１９９　ｍｇ）を淡褐色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93 - 0.99 (3 H, m), 1.35 - 1.45 (2 H, m), 1.60 - 1.69 (2 H, m), 3.58 - 3.64 (2 H, m), 5.18 (2 H×3/4, s), 5.29 (2 H×1/4, s), 7.21 (1 H×1/4, s), 7.31 (1 H×3/4, s); MS (ESI/APCI pos) m/z : 258 [M+H]+ Production Example 3 3-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2-bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 1) N-butyl-1H-imidazole-2-carboxamide
1H-imidazole-2-carboxylic acid (2.90 g), n-butylamine (2.84 g), uronium hexafluorophosphate 2- (1H-7-azabenzotriazol-1-yl) -1,1, A mixture of 3,3-tetramethylmethanaminium (HATU) (14.8 g), diisopropylethylamine (6.80 mL) and N, N-dimethylformamide (37 mL) was stirred at room temperature for 2 days. Water (74 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 min. The resulting solid was collected by filtration to give the title compound (2.80 g) as a colorless solid.
MS (ESI / APCI pos) m / z: 168 [M + H] +
2) 6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one N-butyl-1H-imidazole-2-carboxamide (31.6 g) N under nitrogen atmosphere , N-dimethylformamide (760 mL) was added with 60% sodium hydride (22.7 g) under ice bath cooling and stirred for 15 minutes, and then stirred at room temperature for 30 minutes. Under ice bath cooling, chloroiodomethane (100 g) was added dropwise to the reaction suspension, followed by stirring at room temperature for 18 hours. Water (51 mL) was added dropwise to the reaction suspension at room temperature, stirred for 30 minutes, and concentrated under reduced pressure. Chloroform (1.0 L) was added to the residue and stirred at room temperature for 1 hour. The insoluble material was filtered off through Celite (registered trademark) and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with methanol (600 mL) and then washed three times with hexane (400 mL). The methanol layer was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, chloroform: methanol = 100: 0 to 97: 3 and silica gel cartridge, chloroform: methanol = 100: 0 to 97: 3). The obtained solid was washed with hexane to give the title compound (17.1 g) as a pale yellow solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.0 Hz), 1.29-1.51 (2 H, m), 1.55-1.73 (2 H, m), 3.60 (2 H, t, J = 7.5 Hz), 5.29 (2 H, s), 7.21 (1 H, d, J = 1.3 Hz), 7.40 (1 H, d, J = 1.3 Hz); MS (ESI / APCI pos) m / z: 180 [M + H] +
3) 3-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2-bromo-6-butyl-5,6-dihydro-7H-imidazo [ 1,5-a] imidazol-7-one 6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (233 mg) N, N-dimethylformamide (3. 7-mL) solution was added with N-bromosuccinimide (255 mg) and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 50: 50-0: 100) to give a mixture of the title compounds (199 mg) as a light brown solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93-0.99 (3 H, m), 1.35-1.45 (2 H, m), 1.60-1.69 (2 H, m), 3.58-3.64 (2 H, m ), 5.18 (2 H × 3/4, s), 5.29 (2 H × 1/4, s), 7.21 (1 H × 1/4, s), 7.31 (1 H × 3/4, s); MS (ESI / APCI pos) m / z: 258 [M + H] +
　製造例４　N-ブチル-5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキサミド
１）メチル 5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキシラート
　メチル 5-ブロモ-1H-ピロール-2-カルボキシラート（２３２　ｍｇ）、4-tert-ブチルフェニルボロン酸（３０２　ｍｇ）、炭酸セシウム（４８０　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（４０　ｍｇ）、メタノール（１．０　ｍＬ）、トルエン（１．０　ｍＬ）及び水（１．０　ｍＬ）の混合物をマイクロウェーブ照射下１３０　℃にて３０分間撹拌した。反応液を酢酸エチルにて希釈した後、飽和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（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～７０：３０）にて精製し、表題化合物（１３８　ｍｇ）を得た。
２）N-ブチル-5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキサミド
メチル 5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキシラート（１７３　ｍｇ）及びｎ－ブチルアミン（３．７０　ｍＬ）の混合物を１３０　℃（オイルバス温度）にて３日間攪拌した。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、ヘキサン：酢酸エチル＝１００：０～７０：３０）にて精製し、表題化合物（１７４　ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.93 - 1.00 (m, 3 H) 1.37 - 1.47 (m, 2 H) 1.54 - 1.64 (m, 4 H) 3.40 - 3.49 (m, 2 H) 5.82 - 5.91 (m, 1 H) 6.73 - 6.79 (m, 1 H) 7.16 (dd, J=2.68, 1.44 Hz, 1 H) 7.35 - 7.47 (m, 4 H); MS (ESI/APCI pos) m/z : 299 [M+H]+ Production Example 4 N-butyl-5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide 1) methyl 5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxylate methyl 5- Bromo-1H-pyrrole-2-carboxylate (232 mg), 4-tert-butylphenylboronic acid (302 mg), cesium carbonate (480 mg), tetrakis (triphenylphosphine) palladium (0) (40 mg), A mixture of methanol (1.0 mL), toluene (1.0 mL) and water (1.0 mL) was stirred at 130 ° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (138 mg).
2) N-butyl-5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamidomethyl 5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxylate (173 mg) and n A mixture of butylamine (3.70 mL) was stirred at 130 ° C. (oil bath temperature) for 3 days. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (174 mg).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93-1.00 (m, 3 H) 1.37-1.47 (m, 2 H) 1.54-1.64 (m, 4 H) 3.40-3.49 (m, 2 H) 5.82- 5.91 (m, 1 H) 6.73-6.79 (m, 1 H) 7.16 (dd, J = 2.68, 1.44 Hz, 1 H) 7.35-7.47 (m, 4 H); MS (ESI / APCI pos) m / z : 299 [M + H] +
製造例４と同様にして、以下の化合物を合成した。
N-ブチル-5-(4-メトキシフェニル)-1H-ピロール-2-カルボキサミド
MS (ESI/APCI pos) m/z : 273 [M+H]+
N-ブチル-5-[4-(トリフルオロメトキシ)フェニル]-1H-ピロール-2-カルボキサミド
MS (ESI/APCI pos) m/z : 327 [M+H]+ In the same manner as in Production Example 4, the following compounds were synthesized.
N-butyl-5- (4-methoxyphenyl) -1H-pyrrole-2-carboxamide
MS (ESI / APCI pos) m / z: 273 [M + H] +
N-butyl-5- [4- (trifluoromethoxy) phenyl] -1H-pyrrole-2-carboxamide
MS (ESI / APCI pos) m / z: 327 [M + H] +
　製造例５　5-(4-tert-ブチルフェニル)-N-(3-メチルブチル)-1H-ピロール-2-カルボキサミド
１）5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボン酸
製造例４－１）で得られたメチル 5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキシラート（７８０　ｍｇ）のメタノール（１０　ｍＬ）溶液に２Ｍ　水酸化ナトリウム溶液（７．５　ｍＬ、メタノール溶液）を加え、室温にて３．５時間攪拌した後、　８０　℃（オイルバス温度）にて３時間攪拌した。反応液を減圧下濃縮した。残渣に１Ｍ　塩化水素水溶液（２０　ｍＬ）を加えた後、生じた固体をろ取して、表題化合物（５３２　ｍｇ）を無色固体として得た。
1H NMR (200 MHz, DMSO-d6)　δ　ppm 1.28 (9 H, s), 7.01 - 7.12 (1 H, m), 7.27 - 7.40 (3 H, m), 7.46 - 7.55 (2 H, m), 11.75 - 11.91 (1 H, m); MS (ESI/APCI pos) m/z : 244[M+H]+
２）5-(4-tert-ブチルフェニル)-N-(3-メチルブチル)-1H-ピロール-2-カルボキサミド
5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボン酸（１００　ｍｇ）、イソアミルアミン（５３　ｍｇ）、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）（２３０　ｍｇ）、ジイソプロピルエチルアミン（０．１００　ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（２．０　ｍＬ）の混合物を室温にて２１時間、及び８０　℃（オイルバス温度）にて５時間撹拌した。反応液にイソアミルアミン（５３　ｍｇ）、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）（２３０　ｍｇ）及びジイソプロピルエチルアミン（０．１００　ｍＬ）を加え、８０　℃（オイルバス温度）にて４時間撹拌した。反応液を酢酸エチルにて希釈した後、飽和食塩水にて２回洗浄した。有機層にＩＳＯＬＵＴＥ（登録商標）　ＨＭ－Ｎを加えた後、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＝７５：２５～５０：５０）にて精製し、表題化合物（１０４　ｍｇ）を無色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.95 (3 H, s), 0.98 (3 H, s), 1.34 (9 H, s), 1.43 - 1.57 (2 H, m), 1.59 - 1.80 (1 H, m), 3.38 - 3.54 (2 H, m), 5.76 - 5.91 (1 H, m), 6.74 - 6.78 (1 H, m), 7.14 - 7.19 (1 H, m), 7.33 - 7.49 (4 H, m), 9.26 - 9.36 (1 H, m); MS (ESI/APCI pos) m/z : 313[M+H]+
製造例５と同様にして、以下の化合物を合成した。
5-(4-tert-ブチルフェニル)-N-(シクロプロピルメチル)-1H-ピロール-2-カルボキサミド
MS (ESI/APCI pos) m/z : 297[M+H]+ Production Example 5 5- (4-tert-butylphenyl) -N- (3-methylbutyl) -1H-pyrrole-2-carboxamide 1) 5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxylic acid To a solution of methyl 5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxylate (780 mg) obtained in Production Example 4-1) in methanol (10 mL) was added 2M sodium hydroxide solution (7. (5 mL, methanol solution) was added, and the mixture was stirred at room temperature for 3.5 hours, and then stirred at 80 ° C. (oil bath temperature) for 3 hours. The reaction solution was concentrated under reduced pressure. 1M aqueous hydrogen chloride solution (20 mL) was added to the residue, and the resulting solid was collected by filtration to give the title compound (532 mg) as a colorless solid.
1H NMR (200 MHz, DMSO-d6) δ ppm 1.28 (9 H, s), 7.01-7.12 (1 H, m), 7.27-7.40 (3 H, m), 7.46-7.55 (2 H, m), 11.75-11.91 (1 H, m); MS (ESI / APCI pos) m / z: 244 [M + H] +
2) 5- (4-tert-butylphenyl) -N- (3-methylbutyl) -1H-pyrrole-2-carboxamide
5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxylic acid (100 mg), isoamylamine (53 mg), uronium hexafluorophosphate 2- (1H-7-azabenzotriazol-1-yl ) -1,1,3,3-tetramethylmethanaminium (HATU) (230 mg), diisopropylethylamine (0.100 mL) and N, N-dimethylformamide (2.0 mL) at room temperature The mixture was stirred for 21 hours and at 80 ° C. (oil bath temperature) for 5 hours. To the reaction mixture, isoamylamine (53 mg), uronium hexafluorophosphate 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethylmethanaminium (HATU) (230 mg) ) And diisopropylethylamine (0.100 mL) were added, and the mixture was stirred at 80 ° C. (oil bath temperature) for 4 hours. The reaction solution was diluted with ethyl acetate and washed twice with saturated brine. After adding ISOLUTE (registered trademark) HM-N to the organic layer, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 75: 25-50: 50) to obtain the title compound (104 mg) as a colorless solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, s), 0.98 (3 H, s), 1.34 (9 H, s), 1.43-1.57 (2 H, m), 1.59-1.80 ( 1 H, m), 3.38-3.54 (2 H, m), 5.76-5.91 (1 H, m), 6.74-6.78 (1 H, m), 7.14-7.19 (1 H, m), 7.33-7.49 ( 4 H, m), 9.26-9.36 (1 H, m); MS (ESI / APCI pos) m / z: 313 [M + H] +
The following compounds were synthesized in the same manner as in Production Example 5.
5- (4-tert-Butylphenyl) -N- (cyclopropylmethyl) -1H-pyrrole-2-carboxamide
MS (ESI / APCI pos) m / z: 297 [M + H] +
　製造例６　3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン、2-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2,3-ジブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Production Example 6 3-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one, 2-bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2,3-dibromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
　製造例３－２）で得られた6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１７．０　ｇ）のＮ，Ｎ－ジメチルホルムアミド（２７０　ｍＬ）溶液に、氷浴冷却下にてＮ-ブロモスクシンイミド（１８．６　ｇ）を加え３０分間攪拌した後、室温にて１８時間攪拌した。反応液に氷浴冷却下にて１５％チオ硫酸ナトリウム水溶液（２８０　ｍＬ）を滴下した後、室温にて１５分間攪拌した。反応液に水を加え、クロロホルムにて３回抽出した。合わせ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、クロロホルム：メタノール＝１００：０～９７：３、ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝６０：４０～２５：７５及びシリカゲルカートリッジ、ヘキサン：酢酸エチル＝６０：４０～２５：７５）にて精製し、3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１０．２　ｇ）（無色固体）、２-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３．５７　ｇ）（淡黄色固体）及び2,3-ジブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１．７９　ｇ）（無色固体）を得た。
３-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン：1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.4 Hz), 1.35 - 1.44 (2 H, m), 1.60 - 1.69 (2 H, m), 3.61 (2 H, t, J=7.4 Hz), 5.16 (2 H, s), 7.31 (1 H, s); MS (ESI/APCI pos) m/z : 258 [M+H]+
２-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン：1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.94 (3 H, t, J=7.4 Hz), 1.30 - 1.42 (2 H, m), 1.57 - 1.66 (2 H, m), 3.58 (2 H, t, J=7.4 Hz), 5.28 (2 H, s), 7.20 (1 H, s); MS (ESI/APCI pos) m/z : 258 [M+H]+
（2,3-ジブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン：1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.97 (3 H, t, J=7.2 Hz), 1.33 - 1.46 (2 H, m), 1.60 - 1.72 (2 H, m), 3.62 (2 H, t, J=7.4 Hz), 5.19 (2 H, s);　MS (ESI/APCI pos) m/z : 336 [M+H]+ N, N-dimethylformamide (270) of 6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (17.0 g) obtained in Production Example 3-2) To the solution, N-bromosuccinimide (18.6 g) was added with cooling in an ice bath, and the mixture was stirred for 30 minutes and then stirred at room temperature for 18 hours. A 15% aqueous sodium thiosulfate solution (280 mL) was added dropwise to the reaction solution while cooling in an ice bath, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (NH silica gel cartridge, chloroform: methanol = 100: 0 to 97: 3, NH silica gel cartridge, hexane: ethyl acetate = 60: 40 to 25:75 and silica gel cartridge, hexane: ethyl acetate = 60: 40 To 25:75) and 3-bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (10.2 g) (colorless solid), 2-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (3.57 g) (pale yellow solid) and 2,3-dibromo-6-butyl -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (1.79 g) (colorless solid) was obtained.
3-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one: 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.4 Hz), 1.35-1.44 (2 H, m), 1.60-1.69 (2 H, m), 3.61 (2 H, t, J = 7.4 Hz), 5.16 (2 H, s), 7.31 (1 H , s); MS (ESI / APCI pos) m / z: 258 [M + H] +
2-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one: 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J = 7.4 Hz), 1.30-1.42 (2 H, m), 1.57-1.66 (2 H, m), 3.58 (2 H, t, J = 7.4 Hz), 5.28 (2 H, s), 7.20 (1 H , s); MS (ESI / APCI pos) m / z: 258 [M + H] +
(2,3-Dibromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one: 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.2 Hz), 1.33-1.46 (2 H, m), 1.60-1.72 (2 H, m), 3.62 (2 H, t, J = 7.4 Hz), 5.19 (2 H, s); MS (ESI / APCI pos) m / z: 336 [M + H] +
製造例６と同様にして、以下の化合物を合成した。
3-ブロモ-6-(シクロプロピルメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 256 [M+H]+
3-ブロモ-6-プロピル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 244 [M+H]+
3-ブロモ-6-(3-メチルブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 272 [M+H]+
3-ブロモ-6-ペンチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 272 [M+H]+
3-ブロモ-6-(プロパン-2-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 244 [M+H]+
2,3-ジブロモ-6-(2-メチルプロピル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 336 [M+H]+
2,3-ジブロモ-6-(2-メトキシエチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 338 [M+H]+
2,3-ジブロモ-6-(4,4,4-トリフルオロブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 390 [M+H]+
2,3-ジブロモ-6-(2-シクロプロピルエチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 348 [M+H]+
3-ブロモ-6-(4-メトキシベンジル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 322 [M+H]+
6-ベンジル-3-ブロモ-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 292 [M+H]+ In the same manner as in Production Example 6, the following compounds were synthesized.
3-Bromo-6- (cyclopropylmethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 256 [M + H] +
3-Bromo-6-propyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 244 [M + H] +
3-Bromo-6- (3-methylbutyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 272 [M + H] +
3-Bromo-6-pentyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 272 [M + H] +
3-Bromo-6- (propan-2-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 244 [M + H] +
2,3-Dibromo-6- (2-methylpropyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 336 [M + H] +
2,3-Dibromo-6- (2-methoxyethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 338 [M + H] +
2,3-Dibromo-6- (4,4,4-trifluorobutyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 390 [M + H] +
2,3-Dibromo-6- (2-cyclopropylethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 348 [M + H] +
3-Bromo-6- (4-methoxybenzyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 322 [M + H] +
6-Benzyl-3-bromo-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 292 [M + H] +
　製造例７　3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
１）N-ブチル-4-メチル-1H-イミダゾール-2-カルボキサミド
製造例５－２）と同様の手法を用いて、4-メチル-1H-イミダゾール-2-カルボン酸（６５３　ｍｇ）より、表題化合物（４５６　ｍｇ）をアモルファスとして得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.94 (3 H, t, J=6.6 Hz), 1.27 - 1.71 (4 H, m), 2.29 (3 H, s), 3.42 (2 H, q, J=6.6 Hz), 6.83 (1 H, br. s.), 7.19 (1 H, br. s.); MS (ESI/APCI pos) m/z : 182 [M+H]+
２）6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
製造例３－２）と同様の手法を用いて、N-ブチル-4-メチル-1H-イミダゾール-2-カルボキサミド（４５５　ｍｇ）より、表題化合物（１５６　ｍｇ）を無色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.3 Hz), 1.27 - 1.73 (4 H, m), 2.34 (3 H, d, J=0.9 Hz), 3.58 (2 H, t, J=7.3 Hz), 5.21 (2 H, s), 6.93 (1 H, s); MS (ESI/APCI pos) m/z : 194 [M+H]+
３）3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
製造例６と同様の手法を用いて、6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１５３　ｍｇ）より、表題化合物（１４６　ｍｇ）を無色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.3 Hz), 1.28 - 1.74 (4 H, m), 2.30 (3 H, s), 3.60 (2 H, t, J=7.3 Hz), 5.13 (2 H, s); MS (ESI/APCI pos) m/z : 272 [M+H]+ Production Example 7 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 1) N-butyl-4-methyl-1H-imidazole- The title compound (456 mg) was obtained as an amorphous form from 4-methyl-1H-imidazole-2-carboxylic acid (653 mg) using the same method as in 2-carboxamide Production Example 5-2).
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J = 6.6 Hz), 1.27-1.71 (4 H, m), 2.29 (3 H, s), 3.42 (2 H, q, J = 6.6 Hz), 6.83 (1 H, br.s.), 7.19 (1 H, br.s.); MS (ESI / APCI pos) m / z: 182 [M + H] +
2) 6-Butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one In the same manner as in Production Example 3-2), N-butyl-4 The title compound (156 mg) was obtained as a colorless solid from -methyl-1H-imidazole-2-carboxamide (455 mg).
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.3 Hz), 1.27-1.73 (4 H, m), 2.34 (3 H, d, J = 0.9 Hz), 3.58 ( 2 H, t, J = 7.3 Hz), 5.21 (2 H, s), 6.93 (1 H, s); MS (ESI / APCI pos) m / z: 194 [M + H] +
3) 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one In the same manner as in Production Example 6, The title compound (146 mg) was obtained as a colorless solid from 2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (153 mg).
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.3 Hz), 1.28-1.74 (4 H, m), 2.30 (3 H, s), 3.60 (2 H, t, J = 7.3 Hz), 5.13 (2 H, s); MS (ESI / APCI pos) m / z: 272 [M + H] +
　製造例８　3-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
１）6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
製造例３－１）で得られたN-ブチル-1H-イミダゾール-2-カルボキサミド（１５０　ｍｇ）及び1,1-ジエトキシエタン（０．５１１　ｍＬ）のトルエン（７．５　ｍＬ）懸濁液にp-トルエンスルホン酸一水和物（３４　ｍｇ）を加え、１８０　℃（オイルバス温度）にて１５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＝９９：１～９１：９）にて精製し、表題化合物（７０　ｍｇ）を褐色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.95 (3 H, t, J=7.4 Hz), 1.38 (2 H, dq, J=14.9, 7.4 Hz), 1.54 - 1.65 (2 H, m), 1.66 (3 H, d, J=6.2 Hz), 3.23 (1 H, ddd, J=14.2, 8.9, 5.4 Hz), 3.88 (1 H, ddd, J=14.4, 9.1, 7.0 Hz), 5.44 (1 H, q, J=6.2 Hz), 7.14 (1 H, d, J=0.8 Hz), 7.39 (1 H, d, J=1.2 Hz); MS (ESI/APCI pos) m/z : 194 [M+H]+
２）3-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
製造例６と同様の手法を用いて、6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２７５　ｍｇ）より、3-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オンの混合物（２１４　ｍｇ）を褐色油状物として得た。
MS (ESI/APCI pos) m/z : 272 [M+H]+ Production Example 8 3-Bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2-bromo-6-butyl-5-methyl-5 , 6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one 1) 6-Butyl-5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7- Suspension of N-butyl-1H-imidazole-2-carboxamide (150 mg) and 1,1-diethoxyethane (0.511 mL) obtained in On-Production Example 3-1) in toluene (7.5 mL) P-Toluenesulfonic acid monohydrate (34 mg) was added to the solution, and the mixture was stirred at 180 ° C. (oil bath temperature) for 15 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 91: 9) to give the title compound (70 mg) as a brown oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, t, J = 7.4 Hz), 1.38 (2 H, dq, J = 14.9, 7.4 Hz), 1.54-1.65 (2 H, m), 1.66 (3 H, d, J = 6.2 Hz), 3.23 (1 H, ddd, J = 14.2, 8.9, 5.4 Hz), 3.88 (1 H, ddd, J = 14.4, 9.1, 7.0 Hz), 5.44 (1 H, q, J = 6.2 Hz), 7.14 (1 H, d, J = 0.8 Hz), 7.39 (1 H, d, J = 1.2 Hz); MS (ESI / APCI pos) m / z: 194 (M + H] +
2) 3-Bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2-bromo-6-butyl-5-methyl-5, 6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one Using a method similar to that of Preparation Example 6, 6-butyl-5-methyl-5,6-dihydro-7H-imidazo [1, 5-a] imidazol-7-one (275 mg) from 3-bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2 A mixture (214 mg) of -bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one was obtained as a brown oil.
MS (ESI / APCI pos) m / z: 272 [M + H] +
　製造例９　2-ブロモ-6-(2-メトキシエチル)-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
製造例６で得られた2,3-ジブロモ-6-(2-メトキシエチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（９８　ｍｇ）、4-イソブチルフェニルボロン酸（６２　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（３４　ｍｇ）、エタノール（１．０　ｍＬ）、トルエン（１．０　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（０．４４　ｍＬ）の混合物を１００　℃（オイルバス温度）にて６時間撹拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（８２　ｍｇ）をアモルファスとして得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.95 (6 H, d, J=6.6 Hz), 1.88 - 1.96 (1 H, m), 2.54 (2 H, d, J=7.0 Hz), 3.35 (3 H, s), 3.62 (2 H, t, J=4.7 Hz), 3.79 (2 H, t, J=4.7 Hz), 5.48 (2 H, s), 7.29 (2 H, d, J=8.3 Hz), 7.52 (2 H, d, J=8.3 Hz); MS (ESI/APCI pos) m/z : 392 [M+H]+ Production Example 9 2-Bromo-6- (2-methoxyethyl) -3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7- 2,3-dibromo-6- (2-methoxyethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (98 mg) obtained in ON Example 6 -Isobutylphenylboronic acid (62 mg), tetrakis (triphenylphosphine) palladium (0) (34 mg), ethanol (1.0 mL), toluene (1.0 mL) and 2M aqueous sodium carbonate (0.44 mL) ) Was stirred at 100 ° C. (oil bath temperature) for 6 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (82 mg) was obtained as amorphous.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (6 H, d, J = 6.6 Hz), 1.88-1.96 (1 H, m), 2.54 (2 H, d, J = 7.0 Hz), 3.35 ( 3 H, s), 3.62 (2 H, t, J = 4.7 Hz), 3.79 (2 H, t, J = 4.7 Hz), 5.48 (2 H, s), 7.29 (2 H, d, J = 8.3 Hz), 7.52 (2 H, d, J = 8.3 Hz); MS (ESI / APCI pos) m / z: 392 [M + H] +
製造例９と同様にして、以下の化合物を合成した。
2-ブロモ-6-ブチル-3-[4-(シクロプロピルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 390 [M+H]+
2-ブロモ-6-ブチル-3-(4-フェノキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 426 [M+H]+
2-ブロモ-6-ブチル-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 390 [M+H]+
2-ブロモ-6-ブチル-3-[4-(プロパン-2-イルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 392 [M+H]+
2-ブロモ-3-(4-tert-ブトキシフェニル)-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 406 [M+H]+
2-ブロモ-6-ブチル-3-[4-(シクロブチルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 404 [M+H]+
2-ブロモ-6-ブチル-3-(4-プロポキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 392 [M+H]+
2-ブロモ-6-ブチル-3-[4-(2-フルオロエトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 396 [M+H]+
2-ブロモ-3-[4-(シクロプロピルオキシ)フェニル]-6-(2-メチルプロピル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 390 [M+H]+
2-ブロモ-6-(4,4,4-トリフルオロブチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 472 [M+H]+
2-ブロモ-6-(2-シクロプロピルエチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 430 [M+H]+
6-ブチル-3-(6-クロロピリジン-3-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI/APCI pos) m/z : 291 [M+H]+ In the same manner as in Production Example 9, the following compounds were synthesized.
2-Bromo-6-butyl-3- [4- (cyclopropyloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 390 [M + H] +
2-Bromo-6-butyl-3- (4-phenoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 426 [M + H] +
2-Bromo-6-butyl-3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 390 [M + H] +
2-Bromo-6-butyl-3- [4- (propan-2-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 392 [M + H] +
2-Bromo-3- (4-tert-butoxyphenyl) -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 406 [M + H] +
2-Bromo-6-butyl-3- [4- (cyclobutyloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 404 [M + H] +
2-Bromo-6-butyl-3- (4-propoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 392 [M + H] +
2-Bromo-6-butyl-3- [4- (2-fluoroethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 396 [M + H] +
2-Bromo-3- [4- (cyclopropyloxy) phenyl] -6- (2-methylpropyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 390 [M + H] +
2-Bromo-6- (4,4,4-trifluorobutyl) -3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on
MS (ESI / APCI pos) m / z: 472 [M + H] +
2-Bromo-6- (2-cyclopropylethyl) -3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 430 [M + H] +
6-Butyl-3- (6-chloropyridin-3-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI / APCI pos) m / z: 291 [M + H] +
　製造例１０　4,4,5,5-テトラメチル-2-[4-(1,1,1-トリフルオロ-2-メチルプロパン-2-イル)フェニル]-1,3,2-ジオキサボロラン　
窒素雰囲気下、4-(1,1,1-トリフルオロ-2-メチルプロパン-2-イル)フェノール（５００ｍｇ）及びトリエチルアミン（０．５９９　ｍＬ）のクロロホルム（６．１　ｍＬ）溶液に、氷浴冷却下にてトリフルオロメタンスルホン酸 無水物（０．４８２　ｍＬ）を滴下した。反応液を徐々に室温まで昇温しながら、１時間攪拌した。氷浴冷却下にて反応液に飽和炭酸水素ナトリウム水溶液を滴下した後、クロロホルムにて抽出した。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、ヘキサン：酢酸エチル＝９５：５～９０：１０）にて精製した。得られた淡黄色油状物（７１４　ｍｇ）、 ビス(ピナコラト)ジボロン（９３３　ｍｇ）、酢酸カリウム（７２１　ｍｇ）、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II) （１００　ｍｇ）及び１，４－ジオキサン（６．１　ｍＬ）の混合物を窒素雰囲気下、８０　℃（オイルバス温度）にて２時間撹拌した。反応液を酢酸エチルにて希釈した後、不溶物をセライト（登録商標）ろ過にてろ別した。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、ヘキサン：酢酸エチル＝９５：５～９０：１０）にて精製して、表題化合物（７２６　ｍｇ）を淡黄色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 1.34 (12 H, s), 1.58 (6 H, s), 7.50 (2 H, d, J=7.9 Hz), 7.81 (2 H, d, J=7.9 Hz); MS (EI pos) m/z : 314[M]+ Production Example 10 4,4,5,5-Tetramethyl-2- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,3,2-dioxaborolane
Under a nitrogen atmosphere, a solution of 4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenol (500 mg) and triethylamine (0.599 mL) in chloroform (6.1 mL) was added to an ice bath. Under cooling, trifluoromethanesulfonic anhydride (0.482 mL) was added dropwise. The reaction solution was stirred for 1 hour while gradually warming to room temperature. A saturated aqueous sodium hydrogen carbonate solution was added dropwise to the reaction mixture while cooling in an ice bath, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5 to 90:10). The resulting pale yellow oil (714 mg), bis (pinacolato) diboron (933 mg), potassium acetate (721 mg), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (100 mg) and 1,4-dioxane (6.1 mL) were stirred at 80 ° C. (oil bath temperature) for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered off through Celite (registered trademark) filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5 to 90:10) to give the title compound (726 mg) as a pale yellow solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.34 (12 H, s), 1.58 (6 H, s), 7.50 (2 H, d, J = 7.9 Hz), 7.81 (2 H, d, J = 7.9 Hz); MS (EI pos) m / z: 314 [M] +
製造例１０と同様にして、以下の化合物を合成した。
4,4,5,5-テトラメチル-2-[4-(2,2,2-トリフルオロエチル)フェニル]-1,3,2-ジオキサボロラン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.34 (12 H, s), 3.38 (2 H, d, J=10.7 Hz), 7.30 (2 H, d, J=7.8 Hz), 7.80 (2 H, d, J=7.8 Hz)
4,4,5,5-テトラメチル-2-[4-(3,3,3-トリフルオロプロピル)フェニル]-1,3,2-ジオキサボロラン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.34 (12 H, s), 2.34 - 2.43 (2 H, m), 2.86 - 2.90 (2 H, m), 7.21 (2 H, d, J=7.8 Hz), 7.76 (2 H, d, J=8.3 Hz) The following compounds were synthesized in the same manner as in Production Example 10.
4,4,5,5-tetramethyl-2- [4- (2,2,2-trifluoroethyl) phenyl] -1,3,2-dioxaborolane
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.34 (12 H, s), 3.38 (2 H, d, J = 10.7 Hz), 7.30 (2 H, d, J = 7.8 Hz), 7.80 (2 H , d, J = 7.8 Hz)
4,4,5,5-tetramethyl-2- [4- (3,3,3-trifluoropropyl) phenyl] -1,3,2-dioxaborolane
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.34 (12 H, s), 2.34-2.43 (2 H, m), 2.86-2.90 (2 H, m), 7.21 (2 H, d, J = 7.8 Hz), 7.76 (2 H, d, J = 8.3 Hz)
　製造例１１　2-[4-(2-フルオロ-2-メチルプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン　
１）1-ブロモ-4-(2-フルオロ-2-メチルプロピル)ベンゼン
　窒素雰囲気下、2-(4-ブロモフェニル)-2-メチルプロパン-1-オール（１．３０　ｇ）のクロロホルム（１３　ｍＬ）溶液に、氷浴冷却下にて(ジエチルアミノ)サルファートリフルオリド（１．３７　ｇ）を滴下した後、室温にて２．５時間攪拌した。氷浴冷却下にて反応液に飽和炭酸水素ナトリウム水溶液を滴下した後、クロロホルムにて抽出した。有機層を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、ヘキサン：酢酸エチル＝１００：０～９８：２）にて精製して、表題化合物（９２８　ｍｇ）を無色油状物として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 1.32 (6 H, d, J=21.1 Hz), 2.85 (2 H, d, J=21.1 Hz), 7.09 (2 H, d, J=8.4 Hz), 7.42 (2 H, d, J=8.4 Hz); MS (EI pos) m/z : 230 [M]+
２）2-[4-(2-フルオロ-2-メチルプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン　
　製造例１０と同様の手法を用いて、1-ブロモ-4-(2-フルオロ-2-メチルプロピル)ベンゼン（５００　ｍｇ）より、表題化合物（４６６　ｍｇ）を淡黄色油状物として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 1.33 (6 H, d, J=20.7 Hz), 1.34 (12 H, s), 2.92 (2 H, d, J=20.7 Hz), 7.23 (2 H, d, J=7.9 Hz), 7.74 (2 H, d, J=7.9 Hz) ; MS (ESI/APCI pos) m/z : 301 [M+Na]+ Production Example 11 2- [4- (2-Fluoro-2-methylpropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
1) 1-Bromo-4- (2-fluoro-2-methylpropyl) benzene Under nitrogen atmosphere, 2- (4-bromophenyl) -2-methylpropan-1-ol (1.30 g) in chloroform (13 (Diethylamino) sulfur trifluoride (1.37 g) was added dropwise to the solution under ice bath cooling, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added dropwise to the reaction mixture while cooling in an ice bath, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 98: 2) to give the title compound (928 mg) as a colorless oil.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.32 (6 H, d, J = 21.1 Hz), 2.85 (2 H, d, J = 21.1 Hz), 7.09 (2 H, d, J = 8.4 Hz) , 7.42 (2 H, d, J = 8.4 Hz); MS (EI pos) m / z: 230 [M] +
2) 2- [4- (2-Fluoro-2-methylpropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Using the same method as in Production Example 10, the title compound (466 mg) was obtained as a pale yellow oil from 1-bromo-4- (2-fluoro-2-methylpropyl) benzene (500 mg).
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.33 (6 H, d, J = 20.7 Hz), 1.34 (12 H, s), 2.92 (2 H, d, J = 20.7 Hz), 7.23 (2 H , d, J = 7.9 Hz), 7.74 (2 H, d, J = 7.9 Hz); MS (ESI / APCI pos) m / z: 301 [M + Na] +
　製造例１２　2-[4-(シクロブチルオキシ)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール　（５００　ｍｇ）、シクロブタノール　（２１４　μＬ）及びトリフェニルホスフィン（８９４　ｍｇ）のテトラヒドロフラン（１２　ｍＬ）溶液に、室温にてアゾジカルボン酸ジイソプロピル（１．８０　ｍＬ）を滴下した後、２時間攪拌した。反応液を５０　℃（オイルバス温度）にて１０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、ヘキサン：酢酸エチル＝９５：５～８５：１５）にて精製して、表題化合物（４２２　ｍｇ）を淡赤色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 1.32 (12 H, s), 1.64 - 1.73 (1 H, m), 1.82 - 1.89 (1 H, m), 2.12 - 2.20 (2 H, m), 2.41 - 2.48 (2 H, m), 4.68 (1 H, quin, J=7.1 Hz), 6.80 (2 H, d, J=8.7 Hz), 7.72 (2 H, d, J=8.7 Hz)
製造例１２と同様にして、以下の化合物を合成した。
4,4,5,5-テトラメチル-2-[4-(3,3,3-トリフルオロプロポキシ)フェニル]-1,3,2-ジオキサボロラン
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 1.33 (s, 12 H), 2.58 - 2.68 (m, 2 H), 4.22 (t, J=6.8 Hz, 2 H), 6.89 (d, J=8.7 Hz, 2 H), 7.76 (d, J=8.7 Hz, 2 H)
2-[4-(3-フルオロプロポキシ)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.33 (12 H, s), 2.17 (2 H, dquin, J=25.6, 5.8, 5.8, 5.8, 5.8 Hz), 4.12 (2 H, t, J=6.0 Hz), 4.64 (2 H, dt, J=47.9, 5.8 Hz), 6.89 (2 H, d, J=8.7 Hz), 7.75 (2 H, d, J=8.7 Hz) Production Example 12 2- [4- (Cyclobutyloxy) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (500 mg), cyclobutanol (214 μL) and triphenylphosphine (894 mg) in tetrahydrofuran (12 To the solution was added dropwise diisopropyl azodicarboxylate (1.80 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was stirred at 50 ° C. (oil bath temperature) for 10 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5-85: 15) to give the title compound (422 mg) as a pale red oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 (12 H, s), 1.64-1.73 (1 H, m), 1.82-1.89 (1 H, m), 2.12-2.20 (2 H, m), 2.41-2.48 (2 H, m), 4.68 (1 H, quin, J = 7.1 Hz), 6.80 (2 H, d, J = 8.7 Hz), 7.72 (2 H, d, J = 8.7 Hz)
In the same manner as in Production Example 12, the following compounds were synthesized.
4,4,5,5-tetramethyl-2- [4- (3,3,3-trifluoropropoxy) phenyl] -1,3,2-dioxaborolane
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 12 H), 2.58-2.68 (m, 2 H), 4.22 (t, J = 6.8 Hz, 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 7.76 (d, J = 8.7 Hz, 2 H)
2- [4- (3-Fluoropropoxy) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.33 (12 H, s), 2.17 (2 H, dquin, J = 25.6, 5.8, 5.8, 5.8, 5.8 Hz), 4.12 (2 H, t, J = 6.0 Hz), 4.64 (2 H, dt, J = 47.9, 5.8 Hz), 6.89 (2 H, d, J = 8.7 Hz), 7.75 (2 H, d, J = 8.7 Hz)
　製造例１３　2-(シクロペンチルオキシ)-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン　
窒素雰囲気下、6-ヒドロキシピリジン-3-ボロン酸 ピナコール エステル（６００　ｍｇ）、ヨードシクロペンタン（１．６０　ｇ）、炭酸銀(Ｉ) （２．２５　ｇ）及びトルエン（６．０　ｍＬ）の混合物を１２０　℃（オイルバス温度）にて２時間撹拌した。不溶物をセライト（登録商標）ろ過にてろ別した後、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、ヘキサン：酢酸エチル＝９８：２～９０：１０）にて精製して、表題化合物（４４０　ｍｇ）を無色油状物として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 1.33 (12 H, s), 1.42 - 2.03 (8 H, m), 4.97 - 5.52 (1 H, m), 6.57 - 6.88 (1 H, m), 7.43 - 7.95 (1 H, m), 8.08 - 8.59 (1 H, m) Production Example 13 2- (Cyclopentyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
Under a nitrogen atmosphere, 6-hydroxypyridine-3-boronic acid pinacol ester (600 mg), iodocyclopentane (1.60 g), silver carbonate (I) (2.25 g) and toluene (6.0 mL). The mixture was stirred at 120 ° C. (oil bath temperature) for 2 hours. The insoluble material was filtered off through Celite (registered trademark) filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 98: 2-90: 10) to give the title compound (440 mg) as a colorless oil.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.33 (12 H, s), 1.42-2.03 (8 H, m), 4.97-5.52 (1 H, m), 6.57-6.88 (1 H, m), 7.43-7.95 (1 H, m), 8.08-8.59 (1 H, m)
　製造例１４　5-ブチル-2-(4-tert-ブチルフェニル)-4,5-ジヒドロピロロ[3,4-c]ピラゾール-6(2H)-オン　
１）エチル 1-(4-tert-ブチルフェニル)-1H-ピラゾール-3-カルボキシラート
　エチル 1H-ピラゾール-3-カルボキシラート（２．３９　ｇ）のＮ，Ｎ－ジメチルホルムアミド（２４　ｍＬ）溶液に、1-ブロモ-4-tert-ブチルベンゼン（４．４０　ｍＬ）、N,N'-ジメチルエチレンジアミン（０．９１８　ｍＬ）、よう化銅（Ｉ）（３．２５　ｇ）及び炭酸セシウム（１１．１　ｇ）を加え、１１０　℃（オイルバス温度）にて１２時間撹拌した。反応液をセライト（登録商標）ろ過後、ろ液に水を加え酢酸エチルにて３回抽出した。合わせ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、ヘキサン：酢酸エチル＝９０：１０～８０：２０）にて精製し、表題化合物（２．４７　ｇ）を淡黄色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 1.35 (9 H, s), 1.42 (3 H, t, J=7.0 Hz), 4.44 (2 H, q, J=7.0 Hz), 6.98 (1 H, d, J=2.5 Hz), 7.46 - 7.49 (2 H, m), 7.65 - 7.68 (2 H, m), 7.90 (1 H, d, J=2.5 Hz); MS　(ESI/APCI pos) m/z : 273 [M+H]+
２）エチル 1-(4-tert-ブチルフェニル)-4-ホルミル-1H-ピラゾール-3-カルボキシラート
　－１０　℃にてＮ，Ｎ－ジメチルホルムアミド（３．９　ｍＬ）に、塩化ホスホリル（４．８０　ｍＬ）を加えた後、エチル 1-(4-tert-ブチルフェニル)-1H-ピラゾール-3-カルボキシラート（１．７４　ｇ）を加え、１００　℃（オイルバス温度）にて３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滴下し、ｐＨを５．５に調整した。反応液に水を加え酢酸エチルにて３回抽出した。合わせ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、ヘキサン：酢酸エチル＝９０：１０～８０：２０）にて精製し、表題化合物（３４　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 1.35 (9 H, s), 1.47 (3 H, t, J=7.2 Hz), 4.52 (2 H, q, J=7.0 Hz), 7.51 (2 H, d, J=8.7 Hz), 7.67 (2 H, d, J=8.7 Hz), 8.45 (1 H, s), 10.46 (1 H, s); MS (ESI/APCI pos) m/z : 301 [M+H]+
３）エチル 4-[(ブチルアミノ)メチル]-1-(4-tert-ブチルフェニル)-1H-ピラゾール-3-カルボキシラート
　エチル 1-(4-tert-ブチルフェニル)-4-ホルミル-1H-ピラゾール-3-カルボキシラート（３４　ｍｇ）のクロロホルム（１．４　ｍＬ）溶液に、室温にてｎ－ブチルアミン（１６　μＬ）を加え１．５時間攪拌した。反応液に室温にてナトリウムトリアセトキシボロヒドリド（４８　ｍｇ）を加え３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滴下した後、酢酸エチルにて３回抽出した。合わせ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＝９６：４～９２：８）にて精製し、表題化合物（４２　ｍｇ）を淡黄色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.93 (3 H, t, J=7.2 Hz), 1.32 - 1.41 (12 H, m), 1.44 (3 H, t, J=7.2 Hz), 1.56 - 1.63 (2 H, m), 2.75 - 2.79 (2 H, m), 4.06 (2 H, s), 4.46 (2 H, q, J=7.0 Hz), 7.45 - 7.49 (2 H, m), 7.61 - 7.65 (2 H, m), 8.00 (1 H, s); MS (ESI/APCI pos) m/z : 358 [M+H]+ [M+H]+
４）4-[(ブチルアミノ)メチル]-1-(4-tert-ブチルフェニル)-1H-ピラゾール-3-カルボン酸
　エチル 4-[(ブチルアミノ)メチル]-1-(4-tert-ブチルフェニル)-1H-ピラゾール-3-カルボキシラート（３６　ｍｇ）のテトラヒドロフラン（０．７２　ｍＬ）及び水（０．７２　ｍＬ）溶液に８Ｍ　水酸化ナトリウム水溶液（１４　μＬ）を加え、７０　℃（オイルバス温度）にて１２時間撹拌した。反応液に８Ｍ　水酸化ナトリウム水溶液（１４　μＬ）を加え、７０　℃（オイルバス温度）にて５時間撹拌した。反応液を減圧下濃縮した。残渣をクロロホルムにて希釈し、クエン酸及び水を加えた後、クロロホルムにて６回抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥した後、減圧下濃縮して、表題化合物（５３　ｍｇ）を無色油状物として得た。
MS (ESI/APCI pos) m/z : 330 [M+H]+
５）5-ブチル-2-(4-tert-ブチルフェニル)-4,5-ジヒドロピロロ[3,4-c]ピラゾール-6(2H)-オン　
　4-[(ブチルアミノ)メチル]-1-(4-tert-ブチルフェニル)-1H-ピラゾール-3-カルボン酸（５３　ｍｇ）のクロロホルム（２．１　ｍＬ）溶液に、室温にてトリエチルアミン（０．１１２　ｍＬ）、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）（６２　ｍｇ）及び１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）（４９　ｍｇ）を加え４日間攪拌した。反応液を酢酸エチルにて希釈し、水を加えた後、酢酸エチルにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（９　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.4 Hz), 1.35 (9 H, s), 1.36 - 1.44 (2 H, m), 1.65 (2 H, t, J=7.4 Hz), 3.60 (2 H, t, J=7.4 Hz), 4.33 (2 H, s), 7.48 (2 H, d, J=8.7 Hz), 7.68 (2 H, d, J=8.7 Hz), 7.81 (1 H, d, J=0.8 Hz) ; MS (ESI/APCI pos) m/z : 312 [M+H]+ Production Example 14 5-Butyl-2- (4-tert-butylphenyl) -4,5-dihydropyrrolo [3,4-c] pyrazol-6 (2H) -one
1) Ethyl 1- (4-tert-butylphenyl) -1H-pyrazole-3-carboxylate To a solution of ethyl 1H-pyrazole-3-carboxylate (2.39 g) in N, N-dimethylformamide (24 mL) , 1-bromo-4-tert-butylbenzene (4.40 mL), N, N′-dimethylethylenediamine (0.918 mL), copper (I) iodide (3.25 g) and cesium carbonate (11. 1 g) was added, and the mixture was stirred at 110 ° C. (oil bath temperature) for 12 hours. The reaction mixture was filtered through Celite (registered trademark), water was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-80: 20) to give the title compound (2.47 g) as a pale yellow oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 (9 H, s), 1.42 (3 H, t, J = 7.0 Hz), 4.44 (2 H, q, J = 7.0 Hz), 6.98 (1 H , d, J = 2.5 Hz), 7.46-7.49 (2 H, m), 7.65-7.68 (2 H, m), 7.90 (1 H, d, J = 2.5 Hz); MS (ESI / APCI pos) m / z: 273 [M + H] +
2) Ethyl 1- (4-tert-butylphenyl) -4-formyl-1H-pyrazole-3-carboxylate −10 ° C. to N, N-dimethylformamide (3.9 mL) and phosphoryl chloride (4. 80 mL), ethyl 1- (4-tert-butylphenyl) -1H-pyrazole-3-carboxylate (1.74 g) was added, and the mixture was stirred at 100 ° C. (oil bath temperature) for 3 days. . A saturated aqueous sodium hydrogen carbonate solution was added dropwise to the reaction solution to adjust the pH to 5.5. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-80: 20) to give the title compound (34 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 (9 H, s), 1.47 (3 H, t, J = 7.2 Hz), 4.52 (2 H, q, J = 7.0 Hz), 7.51 (2 H , d, J = 8.7 Hz), 7.67 (2 H, d, J = 8.7 Hz), 8.45 (1 H, s), 10.46 (1 H, s); MS (ESI / APCI pos) m / z: 301 [M + H] +
3) Ethyl 4-[(butylamino) methyl] -1- (4-tert-butylphenyl) -1H-pyrazole-3-carboxylate ethyl 1- (4-tert-butylphenyl) -4-formyl-1H- To a solution of pyrazole-3-carboxylate (34 mg) in chloroform (1.4 mL) was added n-butylamine (16 μL) at room temperature and stirred for 1.5 hours. Sodium triacetoxyborohydride (48 mg) was added to the reaction solution at room temperature, and the mixture was stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added dropwise to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 96: 4-92: 8) to give the title compound (42 mg) as a pale yellow oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93 (3 H, t, J = 7.2 Hz), 1.32-1.41 (12 H, m), 1.44 (3 H, t, J = 7.2 Hz), 1.56- 1.63 (2 H, m), 2.75-2.79 (2 H, m), 4.06 (2 H, s), 4.46 (2 H, q, J = 7.0 Hz), 7.45-7.49 (2 H, m), 7.61 -7.65 (2 H, m), 8.00 (1 H, s); MS (ESI / APCI pos) m / z: 358 [M + H] + [M + H] +
4) Ethyl 4-[(butylamino) methyl] -1- (4-tert-butylphenyl) -1H-pyrazole-3-carboxylate 4-[(butylamino) methyl] -1- (4-tert-butyl To a solution of phenyl) -1H-pyrazole-3-carboxylate (36 mg) in tetrahydrofuran (0.72 mL) and water (0.72 mL) was added 8M aqueous sodium hydroxide solution (14 μL), and 70 ° C. (oil bath Temperature) for 12 hours. An 8M aqueous sodium hydroxide solution (14 μL) was added to the reaction solution, and the mixture was stirred at 70 ° C. (oil bath temperature) for 5 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, citric acid and water were added, and the mixture was extracted 6 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (53 mg) as a colorless oil.
MS (ESI / APCI pos) m / z: 330 [M + H] +
5) 5-Butyl-2- (4-tert-butylphenyl) -4,5-dihydropyrrolo [3,4-c] pyrazol-6 (2H) -one
To a solution of 4-[(butylamino) methyl] -1- (4-tert-butylphenyl) -1H-pyrazole-3-carboxylic acid (53 mg) in chloroform (2.1 mL) at room temperature was added triethylamine (0 .112 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl) (62 mg) and 1-hydroxybenzotriazole (HOBt) (49 mg) were added and stirred for 4 days. The reaction mixture was diluted with ethyl acetate, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (9 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.4 Hz), 1.35 (9 H, s), 1.36-1.44 (2 H, m), 1.65 (2 H, t, J = 7.4 Hz), 3.60 (2 H, t, J = 7.4 Hz), 4.33 (2 H, s), 7.48 (2 H, d, J = 8.7 Hz), 7.68 (2 H, d, J = 8.7 Hz), 7.81 (1 H, d, J = 0.8 Hz); MS (ESI / APCI pos) m / z: 312 [M + H] +
製造例１５　3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
１）1-ベンジル-N-ブチル-4-メチル-1H-イミダゾール-2-カルボキサミド
窒素雰囲気下、1-ベンジル-4-メチル-1H-イミダゾール（９７．０　ｇ）のテトラヒドロフラン（７８０　ｍＬ）溶液に、－４０℃にてｎ－ブチルリチウム（２２０　ｍＬ、２．６９Ｍ　ヘキサン溶液）を滴下し、３５分間撹拌した。反応液に－４０　℃にてイソシアン酸n－ブチル（６９．１　ｍＬ）を滴下した後、室温にて２．５時間攪拌した。氷浴冷却下、反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルにて抽出した。有機層を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。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＝９５：５～５５：４５）にて精製して、表題化合物（６７．３　ｇ）を褐色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) 　δ　ppm 0.89 - 0.99 (3 H, m), 1.32 - 1.45 (2 H, m), 1.49 - 1.65 (2 H, m), 2.09 - 2.21 (3 H, m), 3.22 - 3.42 (2 H, m),
5.63 - 5.80 (2 H, m), 6.65 - 6.86 (1 H, m), 7.01 - 7.42 (6 H, m)；MS (ESI pos) m/z : 272[M+H]+
２）N-ブチル-4-メチル-1H-イミダゾール-2-カルボキサミド
1-ベンジル-N-ブチル-4-メチル-1H-イミダゾール-2-カルボキサミド（４３．９　ｇ）のエタノール（２２０　ｍＬ）溶液に１０％パラジウム炭素（４．３９　ｇ）を加え、水素雰囲気下、４０　℃（オイルバス温度）にて１８時間攪拌した。反応液をセライト（登録商標）ろ過後、ろ液を減圧下濃縮した。残渣をヘキサンにて洗浄して、表題化合物（２７．０　ｇ）を無色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.94 (3 H, t, J=6.6 Hz), 1.27 - 1.71 (4 H, m), 2.29 (3 H, s), 3.42 (2 H, q, J=6.6 Hz), 6.83 (1 H, br. s.), 7.19 (1 H, br. s.); MS (ESI/APCI pos) m/z : 182 [M+H]+
３）6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
窒素雰囲気下、N-ブチル-4-メチル-1H-イミダゾール-2-カルボキサミド（２６．９　ｇ）のＮ，Ｎ－ジメチルホルムアミド（５００　ｍＬ）溶液に、氷浴冷却下にて６０％水素化ナトリウム（１４．８　ｇ）を加え１５分間撹拌した後、室温にて３０分間攪拌した。氷浴冷却下、反応懸濁液にクロロヨードメタン（２６．８　ｍＬ）を滴下した後、室温にて１２時間攪拌した。反応懸濁液を酢酸エチルにて希釈し、塩化アンモニウム水溶液にて洗浄した。水層をクロロホルムにて抽出した。合わせ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。残渣をメタノールにて希釈し、ヘキサンにて洗浄した後、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＝９９：１～９７：３）にて精製して、表題化合物（５．９７　ｇ）を褐色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.3 Hz), 1.27 - 1.73 (4 H, m), 2.34 (3 H, d, J=0.9 Hz), 3.58 (2 H, t, J=7.3 Hz), 5.21 (2 H, s), 6.93 (1 H, s); MS (ESI/APCI pos) m/z : 194 [M+H]+
４）3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　
6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（５．７８　ｇ）のＮ，Ｎ－ジメチルホルムアミド（８６　ｍＬ）溶液に、氷浴冷却下にてＮ-ブロモスクシンイミド（５．５９　ｇ）を加えた後、室温にて４５分間攪拌した。反応液に氷浴冷却下にて１５％チオ硫酸ナトリウム水溶液及び飽和炭酸水素ナトリウム水溶液を滴下した後、室温にて１５分間攪拌した。反応液に水を加え、酢酸エチルにて３回抽出した。合わせ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。残渣を酢酸エチルにて希釈し、炭酸水素ナトリウム水溶液にて洗浄した。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。得られた固体をジイソプロピルエーテル及びヘキサンにて洗浄して、表題化合物（７．５０　ｇ）を褐色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d)　δ　ppm 0.96 (3 H, t, J=7.3 Hz), 1.28 - 1.74 (4 H, m), 2.30 (3 H, s), 3.60 (2 H, t, J=7.3 Hz), 5.13 (2 H, s); MS (ESI/APCI pos) m/z : 272 [M+H]+
製造例１５と同様にして、以下の化合物を合成した。
3-ブロモ-6-ブチル-2-(トリフルオロメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.85 - 0.99 (m, 3 H) 1.27 - 1.43 (m, 2 H) 1.56 - 1.69 (m, 2 H) 3.60 (t, J=7.43 Hz, 2 H) 5.19 (s, 2 H)
3-ブロモ-6-tert-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI pos) m/z : 272 [M+H]+ Production Example 15 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 1) 1-benzyl-N-butyl-4-methyl- To a solution of 1-benzyl-4-methyl-1H-imidazole (97.0 g) in tetrahydrofuran (780 mL) under a nitrogen atmosphere of 1H-imidazole-2-carboxamide was added n-butyllithium (220 mL, 2.69M hexane solution) was added dropwise and stirred for 35 minutes. To the reaction solution, n-butyl isocyanate (69.1 mL) was added dropwise at −40 ° C., followed by stirring at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution while cooling in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5-55: 45) to give the title compound (67.3 g) as a brown oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.89-0.99 (3 H, m), 1.32-1.45 (2 H, m), 1.49-1.65 (2 H, m), 2.09-2.21 (3 H, m ), 3.22-3.42 (2 H, m),
5.63-5.80 (2 H, m), 6.65-6.86 (1 H, m), 7.01-7.42 (6 H, m); MS (ESI pos) m / z: 272 [M + H] +
2) N-butyl-4-methyl-1H-imidazole-2-carboxamide
To a solution of 1-benzyl-N-butyl-4-methyl-1H-imidazole-2-carboxamide (43.9 g) in ethanol (220 mL) was added 10% palladium carbon (4.39 g). The mixture was stirred at 40 ° C. (oil bath temperature) for 18 hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was washed with hexane to give the title compound (27.0 g) as a colorless solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J = 6.6 Hz), 1.27-1.71 (4 H, m), 2.29 (3 H, s), 3.42 (2 H, q, J = 6.6 Hz), 6.83 (1 H, br.s.), 7.19 (1 H, br.s.); MS (ESI / APCI pos) m / z: 182 [M + H] +
3) 6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one under nitrogen atmosphere, N-butyl-4-methyl-1H-imidazole-2-carboxamide (26.9 g) in N, N-dimethylformamide (500 mL) was added 60% sodium hydride (14.8 g) under ice bath cooling and stirred for 15 minutes, then at room temperature for 30 minutes. Stir. Under ice bath cooling, chloroiodomethane (26.8 mL) was added dropwise to the reaction suspension, followed by stirring at room temperature for 12 hours. The reaction suspension was diluted with ethyl acetate and washed with an aqueous ammonium chloride solution. The aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was diluted with methanol, washed with hexane, 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 (5.97 g) as a brown solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.3 Hz), 1.27-1.73 (4 H, m), 2.34 (3 H, d, J = 0.9 Hz), 3.58 ( 2 H, t, J = 7.3 Hz), 5.21 (2 H, s), 6.93 (1 H, s); MS (ESI / APCI pos) m / z: 194 [M + H] +
4) 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
To a solution of 6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (5.78 g) in N, N-dimethylformamide (86 mL), ice N-bromosuccinimide (5.59 g) was added under bath cooling, and the mixture was stirred at room temperature for 45 minutes. A 15% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added dropwise to the reaction solution under ice bath cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether and hexane to give the title compound (7.50 g) as a brown solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.3 Hz), 1.28-1.74 (4 H, m), 2.30 (3 H, s), 3.60 (2 H, t, J = 7.3 Hz), 5.13 (2 H, s); MS (ESI / APCI pos) m / z: 272 [M + H] +
The following compounds were synthesized in the same manner as in Production Example 15.
3-Bromo-6-butyl-2- (trifluoromethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.85-0.99 (m, 3 H) 1.27-1.43 (m, 2 H) 1.56-1.69 (m, 2 H) 3.60 (t, J = 7.43 Hz, 2 H ) 5.19 (s, 2 H)
3-Bromo-6-tert-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI pos) m / z: 272 [M + H] +
製造例１６　3-ブロモ-6-(シクロプロピルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン 
１）N-(シクロプロピルメチル)-4-メチル-1H-イミダゾール-2-カルボキサミド 
エチル 4-メチル-1H-イミダゾール-2-カルボキシラート（７．８０　ｇ）、シクロプロピルメチルアミン（１４．４　ｇ）及びエタノール（２５　ｍＬ）の混合物を１１０　℃（オイルバス温度）にて９時間攪拌した。放冷後、反応液を減圧下濃縮した。残渣をヘキサンにて洗浄して、表題化合物（８．９１ｇ）を褐色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d) δ　ppm 0.21 - 0.32 (2 H, m), 0.48 - 0.61 (2 H, m), 0.93 - 1.15 (1 H, m), 2.30 (3 H, d, J=0.9 Hz), 3.29 (2 H, dd, J=7.0,
5.7 Hz), 6.84 (1 H, d, J=0.9 Hz), 7.42 (1 H, br. s)
MS (ESI pos) m/z : １８０ [M+H]+ 
２）6-(シクロプロピルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
窒素雰囲気下、N-(シクロプロピルメチル)-4-メチル-1H-イミダゾール-2-カルボキサミド（２．６４　ｇ）のＮ，Ｎ－ジメチルホルムアミド（４９　ｍＬ）溶液に、氷浴冷却下にて６０％水素化ナトリウム（１．７７　ｇ）を加え１５分間撹拌した後、室温にて３０分間攪拌した。氷浴冷却下、反応懸濁液にクロロヨードメタン（３．１９　ｍＬ）を滴下した後、室温にて１２時間攪拌した。反応懸濁液を酢酸エチルにて希釈し、塩化アンモニウム水溶液にて洗浄した。水層をクロロホルムにて抽出した。合わせ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。残渣をメタノールにて希釈し、ヘキサンにて洗浄した後、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＝９９：１～９５：５）にて精製して、表題化合物（７７６　ｍｇ）を褐色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.29 - 0.33 (2 H, m), 0.59 - 0.63 (2 H, m), 0.98 - 1.06 (1 H, m), 2.34 (3 H, s), 3.46 (2 H, d, J=7.0 Hz), 5.33 (2 H, s), 6.94 (1 H, s) ；　MS (ESI pos) m/z : １９２ [M+H]+
３）3-ブロモ-6-(シクロプロピルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
6-(シクロプロピルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（４５５　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（６．８　ｍＬ）溶液に、氷浴冷却下にてＮ-ブロモスクシンイミド（４４５　ｍｇ）を加えた後、室温にて４５分間攪拌した。反応液に氷浴冷却下にて１５％チオ硫酸ナトリウム水溶液及び飽和炭酸水素ナトリウム水溶液を滴下した後、室温にて１５分間攪拌した。反応液に水を加え、酢酸エチルにて３回抽出した。合わせ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、クロロホルム）にて精製した。得られた固体をジイソプロピルエーテル及びヘキサンにて洗浄して、表題化合物（４７１　ｍｇ）を褐色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.30 - 0.34 (2 H, m), 0.60 - 0.65 (2 H, m), 0.98 - 1.07 (1 H, m), 2.29 (3 H, s), 3.47 (2 H, d, J=7.4 Hz), 5.23 (2
H, s) ；　MS (ESI pos) m/z : ２７０ [M+H]+
製造例１６と同様にして、以下の化合物を合成した。
3-ブロモ-2-メチル-6-(4,4,4-トリフルオロブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI pos) m/z : ３２６ [M+H]+
3-ブロモ-6-(シクロブチルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 1.76 - 1.85 (2 H, m) 1.91 - 1.99 (2 H, m) 2.07 - 2.15 (2 H, m) 2.29 (3 H, s) 2.59 - 2.68 (1 H, m) 3.63 (2 H, d, J=7.4 Hz) 5.08 (2 H, s)
3-ブロモ-2-メチル-6-(プロパ-2-エン-1-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 2.27 - 2.35 (3 H, m) 4.22 (2 H, d, J=6.2 Hz) 5.10 (2 H, s) 5.27 - 5.37 (2 H, m) 5.78 - 5.91 (1 H, m)
2,3-ジブロモ-6-(シクロプロピルメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI pos) m/z : 334 [M+H]+
3-ブロモ-6-(2,2-ジメチルプロピル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
MS (ESI pos) m/z : 286[M+H]+ Production Example 16 3-Bromo-6- (cyclopropylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1) N- (cyclopropylmethyl) -4-methyl-1H-imidazole-2-carboxamide
Mixture of ethyl 4-methyl-1H-imidazole-2-carboxylate (7.80 g), cyclopropylmethylamine (14.4 g) and ethanol (25 mL) at 110 ° C. (oil bath temperature) for 9 hours. Stir. After allowing to cool, the reaction mixture was concentrated under reduced pressure. The residue was washed with hexane to give the title compound (8.91 g) as a brown solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.21-0.32 (2 H, m), 0.48-0.61 (2 H, m), 0.93-1.15 (1 H, m), 2.30 (3 H, d, J = 0.9 Hz), 3.29 (2 H, dd, J = 7.0,
5.7 Hz), 6.84 (1 H, d, J = 0.9 Hz), 7.42 (1 H, br.s)
MS (ESI pos) m / z: 180 [M + H] +
2) 6- (Cyclopropylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one under nitrogen atmosphere, N- (cyclopropylmethyl) -4-methyl To a solution of -1H-imidazole-2-carboxamide (2.64 g) in N, N-dimethylformamide (49 mL), 60% sodium hydride (1.77 g) was added with cooling in an ice bath and stirred for 15 minutes. Then, the mixture was stirred at room temperature for 30 minutes. Under ice bath cooling, chloroiodomethane (3.19 mL) was added dropwise to the reaction suspension, followed by stirring at room temperature for 12 hours. The reaction suspension was diluted with ethyl acetate and washed with an aqueous ammonium chloride solution. The aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was diluted with methanol, washed with hexane, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 95: 5) to give the title compound (776 mg) as a brown solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.29-0.33 (2 H, m), 0.59-0.63 (2 H, m), 0.98-1.06 (1 H, m), 2.34 (3 H, s), 3.46 (2 H, d, J = 7.0 Hz), 5.33 (2 H, s), 6.94 (1 H, s); MS (ESI pos) m / z: 192 [M + H] +
3) 3-Bromo-6- (cyclopropylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
6- (Cyclopropylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (455 mg) N, N-dimethylformamide (6.8 mL) N-bromosuccinimide (445 mg) was added to the solution while cooling in an ice bath, and the mixture was stirred at room temperature for 45 min. A 15% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added dropwise to the reaction solution under ice bath cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, chloroform). The obtained solid was washed with diisopropyl ether and hexane to give the title compound (471 mg) as a brown solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.30-0.34 (2 H, m), 0.60-0.65 (2 H, m), 0.98-1.07 (1 H, m), 2.29 (3 H, s), 3.47 (2 H, d, J = 7.4 Hz), 5.23 (2
H, s); MS (ESI pos) m / z: 270 [M + H] +
In the same manner as in Production Example 16, the following compounds were synthesized.
3-Bromo-2-methyl-6- (4,4,4-trifluorobutyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI pos) m / z: 326 [M + H] +
3-Bromo-6- (cyclobutylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.76-1.85 (2 H, m) 1.91-1.99 (2 H, m) 2.07-2.15 (2 H, m) 2.29 (3 H, s) 2.59-2.68 ( 1 H, m) 3.63 (2 H, d, J = 7.4 Hz) 5.08 (2 H, s)
3-Bromo-2-methyl-6- (prop-2-en-1-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.27-2.35 (3 H, m) 4.22 (2 H, d, J = 6.2 Hz) 5.10 (2 H, s) 5.27-5.37 (2 H, m) 5.78 -5.91 (1 H, m)
2,3-Dibromo-6- (cyclopropylmethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI pos) m / z: 334 [M + H] +
3-Bromo-6- (2,2-dimethylpropyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
MS (ESI pos) m / z: 286 [M + H] +
製造例１７　3-ブロモ-6-ブチル-2-(フルオロメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　
１）エチル 6-ブチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-2-カルボキシラート
一酸化炭素雰囲気下、製造例３で得られた2-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（９００　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（４０３　ｍｇ）、炭酸カリウム（７２３　ｍｇ）、エタノール（５．８　ｍＬ）及Ｎ，Ｎ－ジメチルホルムアミド（１２　ｍＬ）の混合物を７５　℃（オイルバス温度）にて４日間撹拌した。反応液を酢酸エチルにて希釈し、セライト（登録商標）ろ過後、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（ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝５０：５０）にて精製した。得られた固体をジイソプロピルエーテルにて洗浄して、表題化合物（５３７　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.94 - 1.00 (3 H, m), 1.35 - 1.45 (5 H, m), 1.62 - 1.70 (2 H, m), 3.62 (2 H, t, J=7.4 Hz), 4.41 (2 H, q, J=7.3 Hz), 5.35 (2 H, s), 7.87 (1 H, s)； MS　 (ESI/APCI pos) m/z : 252 [M+H]+
２）6-ブチル-2-(ヒドロキシメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
窒素雰囲気下、エチル 6-ブチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-2-カルボキシラート（１５０　ｍｇ）及び塩化カルシウム（１３２　ｍｇ）のエタノール（６．０　ｍＬ）溶液に、室温にて水素化ホウ素ナトリウム（９０　ｍｇ）を加えた後、３．５日間攪拌した。反応液に氷浴冷却下にて飽和塩化アンモニウム水溶液を滴下した後、室温にて１５分間攪拌した。反応液をセライト（登録商標）ろ過後、ろ液をクロロホルムにて５回抽出した。合わせ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（６２　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.97 (3 H, t, J=7.4 Hz), 1.35 - 1.45 (2 H, m), 1.53 - 1.69 (2 H, m), 3.61 (2 H, t, J=7.4 Hz), 4.70 (2 H, s), 5.27
(2 H, s), 7.18 (1 H, s)； MS　 (ESI/APCI pos) m/z : 210 [M+H]+
３）6-ブチル-2-(フルオロメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
窒素雰囲気下、6-ブチル-2-(ヒドロキシメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（４３　ｍｇ）のクロロホルム（１．７　ｍＬ）溶液に、氷浴冷却下にて（ジエチルアミノ）サルファートリフルオリド（３７　μＬ）を加えた後、室温にて１時間攪拌した。反応液に氷浴冷却下にて飽和炭酸水素ナトリウム水溶液を滴下した後、クロロホルムにて２回抽出した。合わせ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＝９８：２）にて精製して、表題化合物（１６　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.97 (3 H, t, J=7.4 Hz), 1.36 - 1.44 (2 H, m), 1.60 - 1.69 (2 H, m), 3.62 (2 H, t, J=7.4 Hz), 5.29 (2 H, s), 5.42
(1 H, d, J=49.1 Hz), 7.32 (1 H, d, J=3.3 Hz)； MS　 (ESI/APCI pos) m/z : 212 [M+H]+
４）3-ブロモ-6-ブチル-2-(フルオロメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
6-ブチル-2-(フルオロメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１５　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．２０　ｍＬ）溶液に、氷浴冷却下にてＮ-ブロモスクシンイミド（１５　ｍｇ）を加えた後、室温にて５時間攪拌した。反応液に氷浴冷却下にて１５％チオ硫酸ナトリウム水溶液を滴下した後、室温にて１５分間攪拌した。反応液に水を加え、クロロホルムにて２回抽出した。合わせ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＝８０：２０～５０：５０）にて精製して、表題化合物（２０　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.97 (3 H, t, J=7.4 Hz), 1.35 - 1.46 (2 H, m), 1.62 - 1.69 (2 H, m), 3.63 (2 H, t, J=7.4 Hz), 5.20 (2 H, s), 5.37
(2 H, d, J=48.7 Hz)； MS　(ESI/APCI pos) m/z : 290 [M+H]+ Production Example 17 3-Bromo-6-butyl-2- (fluoromethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1) Ethyl 6-butyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazole-2-carboxylate 2-bromo-obtained in Preparation Example 3 under carbon monoxide atmosphere 6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (900 mg), tetrakis (triphenylphosphine) palladium (0) (403 mg), potassium carbonate (723 mg) ), Ethanol (5.8 mL) and N, N-dimethylformamide (12 mL) were stirred at 75 ° C. (oil bath temperature) for 4 days. The reaction mixture was diluted with ethyl acetate, filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 50: 50). The obtained solid was washed with diisopropyl ether to give the title compound (537 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94-1.00 (3 H, m), 1.35-1.45 (5 H, m), 1.62-1.70 (2 H, m), 3.62 (2 H, t, J = 7.4 Hz), 4.41 (2 H, q, J = 7.3 Hz), 5.35 (2 H, s), 7.87 (1 H, s); MS (ESI / APCI pos) m / z: 252 (M + H ] +
2) 6-Butyl-2- (hydroxymethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one under nitrogen atmosphere, ethyl 6-butyl-7-oxo-6,7 -Dihydro-5H-imidazo [1,5-a] imidazole-2-carboxylate (150 mg) and calcium chloride (132 mg) in ethanol (6.0 mL) at room temperature with sodium borohydride (90 mg), and stirred for 3.5 days. A saturated aqueous ammonium chloride solution was added dropwise to the reaction solution while cooling in an ice bath, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was filtered through Celite (registered trademark), and the filtrate was extracted 5 times with chloroform. The combined organic layers were 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 (62 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.35-1.45 (2 H, m), 1.53-1.69 (2 H, m), 3.61 (2 H, t, J = 7.4 Hz), 4.70 (2 H, s), 5.27
(2 H, s), 7.18 (1 H, s); MS (ESI / APCI pos) m / z: 210 [M + H] +
3) 6-Butyl-2- (fluoromethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one under a nitrogen atmosphere, 6-butyl-2- (hydroxymethyl) -5 , 6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one (43 mg) in chloroform (1.7 mL) was cooled to (diethylamino) sulfur trifluoride (37 μL) under ice bath cooling. ) And then stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added dropwise to the reaction solution while cooling in an ice bath, and the mixture was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 98: 2) to give the title compound (16 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.36-1.44 (2 H, m), 1.60-1.69 (2 H, m), 3.62 (2 H, t, J = 7.4 Hz), 5.29 (2 H, s), 5.42
(1 H, d, J = 49.1 Hz), 7.32 (1 H, d, J = 3.3 Hz); MS (ESI / APCI pos) m / z: 212 [M + H] +
4) 3-Bromo-6-butyl-2- (fluoromethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
6-Butyl-2- (fluoromethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (15 mg) in N, N-dimethylformamide (0.20 mL) N-bromosuccinimide (15 mg) was added to the solution while cooling in an ice bath, and the mixture was stirred at room temperature for 5 hours. A 15% aqueous sodium thiosulfate solution was added dropwise to the reaction solution under ice bath cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution and extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 80: 20-50: 50) to give the title compound (20 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.35-1.46 (2 H, m), 1.62-1.69 (2 H, m), 3.63 (2 H, t, J = 7.4 Hz), 5.20 (2 H, s), 5.37
(2 H, d, J = 48.7 Hz); MS (ESI / APCI pos) m / z: 290 [M + H] +
製造例１８　2-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
１）1-ブロモ-4-[シクロプロピル(ジフルオロ)メチル]ベンゼン
窒素雰囲気下、(4-ブロモフェニル)(シクロプロピル)メタノン（８００　ｍｇ）及びビス(2-メトキシエチル)アミノサルファートリフルオリド（２．３６　ｇ）の混合物を８０　℃（オイルバス温度）にて２日間攪拌した。反応液をクロロホルムにて希釈し、氷浴冷却下にて飽和炭酸水素ナトリウム水溶液を滴下した後、クロロホルムにて抽出した。有機層を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（ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝９８：２）にて精製して、表題化合物（１３６　ｍｇ）を無色油状物として得た。
1H NMR (200 MHz, CHLOROFORM-d) δ　ppm 0.57 - 0.82 (4 H, m), 1.32 - 1.63 (1 H, m), 7.41 (2 H, d, J=9.2 Hz), 7.55 (2 H, d, J=9.2 Hz)； MS (EI pos) m/z: ２４６ [M]+
２）2-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
1-ブロモ-4-[シクロプロピル(ジフルオロ)メチル]ベンゼン（１３４　ｍｇ）、ビス(ピナコラト)ジボロン（１８６　ｍｇ）、酢酸カリウム（１４４　ｍｇ）、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II) （２０　ｍｇ）及び１，４－ジオキサン（１．２　ｍＬ）の混合物を窒素雰囲気下、８０　℃（オイルバス温度）にて３時間撹拌した。反応液を酢酸エチルにて希釈した後、不溶物をセライト（登録商標）ろ過にてろ別した。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、ヘキサン：酢酸エチル＝９５：５）にて精製して、表題化合物（９８　ｍｇ）を淡黄色固体として得た。
1H NMR (200 MHz, CHLOROFORM-d) δ　ppm 0.55 - 0.82 (4 H, m), 1.35 (12 H, s), 1.38 - 1.61 (1 H, m), 7.52 (2 H, d, J=8.4 Hz), 7.85 (2 H, d, J=8.4 Hz)； MS (EI pos) m/z: ２９４ [M]+
製造例１８と同様にして、以下の化合物を合成した。
2-[4-(1,1-ジフルオロエチル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 1.35 (12 H, s), 1.91 ( 3 H, t, J=18 Hz), 7.50 (2 H, d, J=7.8 Hz), 7.86 (2 H, d, J=7.8 Hz)
2-[4-(1,1-ジフルオロプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 282 [M]+
2-[4-(1,1-ジフルオロ-3-メチルブチル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 310 [M]+
2-[4-(1,1-ジフルオロ-2-メチルプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (ESI pos) m/z : 297 [M+H]+
2-{ジフルオロ[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]メチル}ピリジン
MS (ESI pos) m/z : 332 [M+H]+
2-[4-(1,1-ジフルオロ-2-フェニルエチル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (ESI pos) m/z : 345 [M+H]+
2-[4-(2,2-ジフルオロプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 282 [M]+
2-[ジフルオロ(フェニル)メチル]-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン
MS (ESI pos) m/z : 332 [M+H]+
2-[4-(1,1-ジフルオロブチル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 296 [M]+
2-{4-[ジフルオロ(1-メチルシクロプロピル)メチル]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (ESI/APCI pos) m/z : 331[M+Na]+
2-[4-(1,1-ジフルオロ-2,2-ジメチルプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 310 [M]+
2-{4-[シクロペンチル(ジフルオロ)メチル]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 322 [M]+
2-(4-(ジフルオロ(フェニル)メチル)フェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (EI pos) m/z: 330 [M]+
2-(1,1-ジフルオロ-3-メチルブチル)-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン
MS (ESI/APCI pos) m/z : 312[M+H]+ Production Example 18 2- {4- [Cyclopropyl (difluoro) methyl] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1) 1-bromo-4- [cyclopropyl (difluoro ) Methyl] benzene under nitrogen atmosphere, a mixture of (4-bromophenyl) (cyclopropyl) methanone (800 mg) and bis (2-methoxyethyl) aminosulfur trifluoride (2.36 g) was heated to 80 ° C. (oil bath temperature ) For 2 days. The reaction solution was diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added dropwise with cooling in an ice bath, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 98: 2) to give the title compound (136 mg) as a colorless oil.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.57-0.82 (4 H, m), 1.32-1.63 (1 H, m), 7.41 (2 H, d, J = 9.2 Hz), 7.55 (2 H, d, J = 9.2 Hz); MS (EI pos) m / z: 246 [M] +
2) 2- {4- [cyclopropyl (difluoro) methyl] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
1-bromo-4- [cyclopropyl (difluoro) methyl] benzene (134 mg), bis (pinacolato) diboron (186 mg), potassium acetate (144 mg), [1,1'-bis (diphenylphosphino) ferrocene A mixture of dichloropalladium (II) (20 mg) and 1,4-dioxane (1.2 mL) was stirred at 80 ° C. (oil bath temperature) for 3 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered off through Celite (registered trademark) filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5) to give the title compound (98 mg) as a pale yellow solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.55-0.82 (4 H, m), 1.35 (12 H, s), 1.38-1.61 (1 H, m), 7.52 (2 H, d, J = 8.4 Hz), 7.85 (2 H, d, J = 8.4 Hz); MS (EI pos) m / z: 294 [M] +
In the same manner as in Production Example 18, the following compounds were synthesized.
2- [4- (1,1-Difluoroethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 (12 H, s), 1.91 (3 H, t, J = 18 Hz), 7.50 (2 H, d, J = 7.8 Hz), 7.86 (2 H , d, J = 7.8 Hz)
2- [4- (1,1-Difluoropropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 282 [M] +
2- [4- (1,1-Difluoro-3-methylbutyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 310 [M] +
2- [4- (1,1-Difluoro-2-methylpropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (ESI pos) m / z: 297 [M + H] +
2- {Difluoro [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methyl} pyridine
MS (ESI pos) m / z: 332 [M + H] +
2- [4- (1,1-Difluoro-2-phenylethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (ESI pos) m / z: 345 [M + H] +
2- [4- (2,2-Difluoropropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 282 [M] +
2- [Difluoro (phenyl) methyl] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
MS (ESI pos) m / z: 332 [M + H] +
2- [4- (1,1-Difluorobutyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 296 [M] +
2- {4- [Difluoro (1-methylcyclopropyl) methyl] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (ESI / APCI pos) m / z: 331 [M + Na] +
2- [4- (1,1-Difluoro-2,2-dimethylpropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 310 [M] +
2- {4- [cyclopentyl (difluoro) methyl] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 322 [M] +
2- (4- (Difluoro (phenyl) methyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (EI pos) m / z: 330 [M] +
2- (1,1-Difluoro-3-methylbutyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
MS (ESI / APCI pos) m / z: 312 [M + H] +
製造例１９　1-(5-ブロモピリジン-2-イル)-3-メチルブタン-1-オン
1-(5-ブロモピリジン-2-イル)-3-メチルブタン-1-オール（３．００　ｇ）のクロロホルム（３０　ｍＬ）溶液に、室温にて二酸化マンガン（１．６０　ｇ）を加えた後、室温にて３時間、５０　℃（オイルバス温度）にて１４時間撹拌した。放冷後、不溶物をセライト（登録商標）ろ過にてろ別した。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、ヘキサン：酢酸エチル＝９５：５～７０：３０）にて精製して、表題化合物（１．８２　ｇ）を黄色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.99 (6 H, d, J=6.6 Hz), 2.26 - 2.33 (1 H, m), 3.05 (2 H, d, J=7.0 Hz), 7.91 - 7.97 (2 H, m), 8.71 - 8.73 (1 H, m); MS (ESI pos) m/z : 242 [M+H]+ Production Example 19 1- (5-Bromopyridin-2-yl) -3-methylbutan-1-one
To a solution of 1- (5-bromopyridin-2-yl) -3-methylbutan-1-ol (3.00 g) in chloroform (30 mL) was added manganese dioxide (1.60 g) at room temperature. The mixture was stirred at room temperature for 3 hours and at 50 ° C. (oil bath temperature) for 14 hours. After standing to cool, the insoluble material was filtered off through Celite (registered trademark) filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5-70: 30) to give the title compound (1.82 g) as a yellow oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.99 (6 H, d, J = 6.6 Hz), 2.26-2.33 (1 H, m), 3.05 (2 H, d, J = 7.0 Hz), 7.91- 7.97 (2 H, m), 8.71-8.73 (1 H, m); MS (ESI pos) m / z: 242 [M + H] +
製造例２０　3-[2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]ピリジン
3-(4-ブロモ-2-フルオロフェノキシ)ピリジン（１００　ｍｇ）、 ビス(ピナコラト)ジボロン（１１５　ｍｇ）、酢酸カリウム（１１１　ｍｇ）、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II) （３１　ｍｇ）及び１，４－ジオキサン（１０　ｍＬ）の混合物を窒素雰囲気下、１００　℃（オイルバス温度）にて４時間撹拌した。反応液を酢酸エチルにて希釈した後、不溶物をセライト（登録商標）ろ過にてろ別した。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、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製して、表題化合物（２５　ｍｇ）を黄色油状物として得た。
MS (ESI pos) m/z : 316 [M+H]+
製造例２０と同様にして、以下の化合物を合成した。
2-(シクロブチルオキシ)-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン
1H NMR (200 MHz, CHLOROFORM-d) δ　ppm 1.33 (s, 12 H), 1.56 - 1.93 (m, 2 H), 2.02 - 2.25 (m, 2 H), 2.37 - 2.56 (m, 2 H), 5.21 (quin, J=7.5 Hz, 1 H),
6.60 - 6.69 (m, 1 H), 7.91 (dd, J=8.4, 1.8 Hz, 1 H), 8.48 - 8.54 (m, 1 H) 
2-(4-tert-ブトキシ-3-フルオロフェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (ESI/pos) m/z : 294 [M]+
2-フェニル-1-[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]エタノン
MS (ESI/APCI pos) m/z : 323[M+H]+
2-[3-フルオロ-4-(2-メチルプロパ-1-エン-1-イル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
MS (ESI/APCI pos) m/z : 277[M+H]+ Production Example 20 3- [2-Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] pyridine
3- (4-Bromo-2-fluorophenoxy) pyridine (100 mg), bis (pinacolato) diboron (115 mg), potassium acetate (111 mg), [1,1'-bis (diphenylphosphino) ferrocene] dichloro A mixture of palladium (II) (31 mg) and 1,4-dioxane (10 mL) was stirred at 100 ° C. (oil bath temperature) for 4 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered off through Celite (registered trademark) filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50) to give the title compound (25 mg) as a yellow oil.
MS (ESI pos) m / z: 316 [M + H] +
In the same manner as in Production Example 20, the following compounds were synthesized.
2- (Cyclobutyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 12 H), 1.56-1.93 (m, 2 H), 2.02-2.25 (m, 2 H), 2.37-2.56 (m, 2 H), 5.21 (quin, J = 7.5 Hz, 1 H),
6.60-6.69 (m, 1 H), 7.91 (dd, J = 8.4, 1.8 Hz, 1 H), 8.48-8.54 (m, 1 H)
2- (4-tert-Butoxy-3-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (ESI / pos) m / z: 294 [M] +
2-Phenyl-1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethanone
MS (ESI / APCI pos) m / z: 323 [M + H] +
2- [3-Fluoro-4- (2-methylprop-1-en-1-yl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
MS (ESI / APCI pos) m / z: 277 [M + H] +
製造例２１　5-フェニル-2-(トリブチルスタンナニル)ピリジン　
窒素雰囲気下、2-ブロモ-5-フェニルピリジン（２００　ｍｇ）のテトラヒドロフラン（２.０　ｍＬ）溶液に、－７８℃にてｎ－ブチルリチウム（２２０　ｍＬ、２．６０Ｍ　ヘキサン溶液）を滴下し、２０分間撹拌した。反応液に－７８℃にてトリブチルチンクロリド（０.２４３　ｍＬ）を滴下した後、４℃にて８０分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルにて抽出した。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＝１００：０～８０：２０）にて精製して、表題化合物（２３０　ｍｇ）を褐色油状物として得た。
MS (ESI pos) m/z : 446 [M+H]+ Production Example 21 5-Phenyl-2- (tributylstannanyl) pyridine
Under a nitrogen atmosphere, n-butyllithium (220 mL, 2.60 M hexane solution) was added dropwise to a solution of 2-bromo-5-phenylpyridine (200 mg) in tetrahydrofuran (2.0 mL) at −78 ° C. Stir for 20 minutes. Tributyltin chloride (0.243 mL) was added dropwise to the reaction solution at −78 ° C., followed by stirring at 4 ° C. for 80 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 80:20) to give the title compound (230 mg) as a brown oil.
MS (ESI pos) m / z: 446 [M + H] +
　実施例１：2-ブチル-6-(4-tert-ブチルフェニル)-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン Example 1: 2-Butyl-6- (4-tert-butylphenyl) -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　製造例１で得られたN-ブチル-4-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキサミド（９４　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０　ｍＬ）溶液に室温にて６０％水素化ナトリウム（３８　ｍｇ）を加え１時間撹拌した。反応液に室温にてクロロヨードメタン（１０７　ｍｇ）を加え、２時間攪拌した。反応液に水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝９０：１０～５０：５０）にて精製した。得られた固体をヘキサン/酢酸エチル（１０/１）にて洗浄して、表題化合物（５　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93 - 1.01 (m, 3 H) 1.34 (s, 9 H) 1.37 - 1.45 (m, 2 H) 1.57 - 1.67 (m, 2 H) 3.51 - 3.58 (m, 2 H) 5.28 (s, 2 H) 6.84 (s, 1 H) 7.20 (s, 1 H) 7.36 - 7.47 (m, 4 H); MS (ESI/APCI pos) m/z : 311 [M+H]+ To a solution of N-butyl-4- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide (94 mg) obtained in Production Example 1 in N, N-dimethylformamide (1.0 mL) at room temperature. 60% sodium hydride (38 mg) was added and stirred for 1 hour. Chloroiodomethane (107 mg) was added to the reaction solution at room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 to 50:50). The obtained solid was washed with hexane / ethyl acetate (10/1) to give the title compound (5 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93-1.01 (m, 3 H) 1.34 (s, 9 H) 1.37-1.45 (m, 2 H) 1.57-1.67 (m, 2 H) 3.51-3.58 ( m, 2 H) 5.28 (s, 2 H) 6.84 (s, 1 H) 7.20 (s, 1 H) 7.36-7.47 (m, 4 H); MS (ESI / APCI pos) m / z: 311 (M + H] +
　実施例２：2-ブチル-6-[4-(トリフルオロメチル)フェニル]-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン Example 2: 2-Butyl-6- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
実施例１と同様の手法を用いて、製造例１で得られたN-ブチル-4-[4-(トリフルオロメチル)フェニル]-1H-ピロール-2-カルボキサミド（９３　ｍｇ）より、表題化合物（１３　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94 - 1.02 (m, 3 H) 1.37 - 1.46 (m, 2 H) 1.58 - 1.68 (m, 2 H) 3.52 - 3.62 (m, 2 H) 5.31 (s, 2 H) 6.89 (s, 1 H) 7.29 (s, 1 H) 7.55 - 7.65 (m, 5 H) ; MS (ESI/APCI pos) m/z : 323[M+H]+ Using the same method as in Example 1, the title compound was obtained from N-butyl-4- [4- (trifluoromethyl) phenyl] -1H-pyrrole-2-carboxamide (93 mg) obtained in Production Example 1. (13 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94-1.02 (m, 3 H) 1.37-1.46 (m, 2 H) 1.58-1.68 (m, 2 H) 3.52-3.62 (m, 2 H) 5.31 ( s, 2 H) 6.89 (s, 1 H) 7.29 (s, 1 H) 7.55-7.65 (m, 5 H); MS (ESI / APCI pos) m / z: 323 [M + H] +
　実施例３：6-[4-(ベンジルオキシ)フェニル]-2-ブチル-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン Example 3: 6- [4- (Benzyloxy) phenyl] -2-butyl-2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
実施例１と同様の手法を用いて、製造例１で得られた4-[4-(ベンジルオキシ)フェニル]-N-ブチル-1H-ピロール-2-カルボキサミド（１７５　ｍｇ）より、表題化合物（２０　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.93 - 0.99 (m, 3 H) 1.36 - 1.45 (m, 2 H) 1.58 - 1.66 (m, 2 H) 3.50 - 3.59 (m, 2 H) 5.10 (s, 2 H) 5.27 (s, 2 H) 6.80 - 6.88 (m, 2 H) 7.07 - 7.14 (m, 2 H) 7.20 (s, 1 H) 7.26 - 7.48 (m, 6 H) ; MS (ESI/APCI pos) m/z : 361[M+H]+ Using a method similar to that in Example 1, 4- [4- (benzyloxy) phenyl] -N-butyl-1H-pyrrole-2-carboxamide (175 mg) obtained in Production Example 1 was used to give the title compound ( 20 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93-0.99 (m, 3 H) 1.36-1.45 (m, 2 H) 1.58-1.66 (m, 2 H) 3.50-3.59 (m, 2 H) 5.10 ( s, 2 H) 5.27 (s, 2 H) 6.80-6.88 (m, 2 H) 7.07-7.14 (m, 2 H) 7.20 (s, 1 H) 7.26-7.48 (m, 6 H); MS (ESI / APCI pos) m / z: 361 [M + H] +
　実施例４：6-ブチル-2-(4-tert-ブチルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 4: 6-Butyl-2- (4-tert-butylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
実施例１と同様の手法を用いて、製造例２で得られたN-ブチル-4-(4-tert-ブチルフェニル)-1H-イミダゾール-2-カルボキサミド（６９　ｍｇ）より、表題化合物（６　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J=7.4 Hz), 1.34 (9 H, s), 1.37 - 1.45 (2 H, m), 1.62 - 1.69 (2 H, m), 3.61 (2 H, t, J=7.4 Hz), 5.31 (2 H, s), 7.41 - 7.44 (2 H, m), 7.45 (1 H, s), 7.76 - 7.81 (2 H, m); MS (ESI/APCI pos) m/z : 312 [M+H]+ Using the same method as in Example 1, from the N-butyl-4- (4-tert-butylphenyl) -1H-imidazole-2-carboxamide (69 mg) obtained in Production Example 2, the title compound (6 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.34 (9 H, s), 1.37-1.45 (2 H, m), 1.62-1.69 (2 H, m), 3.61 (2 H, t, J = 7.4 Hz), 5.31 (2 H, s), 7.41-7.44 (2 H, m), 7.45 (1 H, s), 7.76-7.81 (2 H, m ); MS (ESI / APCI pos) m / z: 312 [M + H] +
　実施例５：6-ブチル-3-(4-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 5: 6-Butyl-3- (4-methoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
製造例３で得られた２－ブロモ－６－ブチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オン及び３－ブロモ－６－ブチル－５，６－ジヒドロ－７Ｈ－イミダゾ［１，５－ａ］イミダゾール－７－オンの混合物（１００　ｍｇ）、４－メトキシフェニルボロン酸（８８　ｍｇ）、炭酸カリウム（１６０　ｍｇ）、(1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾリデン)(3-クロロピリジル)塩化パラジウム(ＩＩ)（ＰＥＰＰＳＩ（登録商標）－ＩＰｒ）（２６　ｍｇ）、エタノール（０．４９　ｍＬ）、トルエン（０．４９　ｍＬ）及び水（０．３３　ｍＬ）の混合物を１００　℃（オイルバス温度）にて３０分間攪拌した。反応液を酢酸エチルにて希釈した後、水にて２回洗浄した。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＝５０：５０～０：１００及びシリカゲルカートリッジ、ヘキサン：酢酸エチル＝１０：９０～０：１００）にて精製し、6-ブチル-3-(4-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（４４　ｍｇ）を無色固体として、6-ブチル-2-(4-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１４　ｍｇ）を無色固体として得た。 2-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 3-bromo-6-butyl-5,6-dihydro obtained in Preparation Example 3 -7H-imidazo [1,5-a] imidazol-7-one mixture (100 mg), 4-methoxyphenylboronic acid (88 mg), potassium carbonate (160 mg), (1,3-bis (2, 6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride (PEPPSI®-IPr) (26 mg), ethanol (0.49 mL), toluene (0.49 mL) and water The mixture (0.33 mL) was stirred at 100 ° C. (oil bath temperature) for 30 minutes. The reaction solution was diluted with ethyl acetate and then washed twice with water. 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 = 50: 50 to 0: 100 and silica gel cartridge, hexane: ethyl acetate = 10: 90 to 0: 100) to give 6-butyl-3- (4-Methoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (44 mg) as a colorless solid, 6-butyl-2- (4-methoxyphenyl)- 5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one (14 mg) was obtained as a colorless solid.
　6-ブチル-3-(4-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J=7.4 Hz), 1.42 (2 H, sxt, J=7.5 Hz), 1.68 (2 H, quin, J=7.0 Hz), 3.65 (2 H, t, J=7.4 Hz), 3.86 (3 H, s), 5.41 (2 H, s), 7.00 (2 H, dt, J=8.7, 2.1 Hz), 7.41 (2 H, dt, J=8.7, 2.5 Hz), 7.52 (1 H, s); MS (ESI/APCI pos) m/z : 286[M+H]+
　6-ブチル-2-(4-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J=7.4 Hz), 1.41 (2 H, sxt, J=7.4 Hz), 1.65 (2 H, quin, J=7.5 Hz), 3.62 (2 H, t, J=7.4 Hz), 3.84 (3 H, s), 5.30 (2 H, s), 6.93 (2 H, d, J=9.1 Hz), 7.39 (1 H, s), 7.78 (2 H, d, J=8.7 Hz); MS (ESI/APCI pos) m/z : 286[M+H]+ 6-Butyl-3- (4-methoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.42 (2 H, sxt, J = 7.5 Hz), 1.68 (2 H, quin, J = 7.0 Hz) , 3.65 (2 H, t, J = 7.4 Hz), 3.86 (3 H, s), 5.41 (2 H, s), 7.00 (2 H, dt, J = 8.7, 2.1 Hz), 7.41 (2 H, dt, J = 8.7, 2.5 Hz), 7.52 (1 H, s); MS (ESI / APCI pos) m / z: 286 [M + H] +
6-Butyl-2- (4-methoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.41 (2 H, sxt, J = 7.4 Hz), 1.65 (2 H, quin, J = 7.5 Hz) , 3.62 (2 H, t, J = 7.4 Hz), 3.84 (3 H, s), 5.30 (2 H, s), 6.93 (2 H, d, J = 9.1 Hz), 7.39 (1 H, s) , 7.78 (2 H, d, J = 8.7 Hz); MS (ESI / APCI pos) m / z: 286 [M + H] +
　実施例６：2-ブチル-5-(4-tert-ブチルフェニル)-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン Example 6: 2-Butyl-5- (4-tert-butylphenyl) -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
製造例４で得られたN-ブチル-5-(4-tert-ブチルフェニル)-1H-ピロール-2-カルボキサミド（１１９　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０　ｍＬ）溶液に氷浴冷却下にて６０％水素化ナトリウム（４８　ｍｇ）を加え３０分間撹拌した後、室温にて１５分間攪拌した。氷浴冷却下、反応液にクロロヨードメタン（８５　ｍｇ）を加え、２時間攪拌した。反応液に水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝１００：０～７０：３０）にて精製した。得られた固体をヘキサンにて洗浄して、表題化合物（１０　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.92 - 1.00 (m, 3 H) 1.30 (s, 9 H) 1.37 - 1.45 (m, 2 H) 1.57 - 1.66 (m, 2 H) 3.49 - 3.59 (m, 2 H) 5.27 (s, 2 H) 6.84 (s, 1 H) 7.35 - 7.41 (m, 2 H) 7.42 - 7.46 (m, 2 H); MS (ESI/APCI pos) m/z : 311 [M+H]+ The N-butyl-5- (4-tert-butylphenyl) -1H-pyrrole-2-carboxamide (119 mg) obtained in Production Example 4 was added to an N, N-dimethylformamide (1.0 mL) solution in an ice bath. Under cooling, 60% sodium hydride (48 mg) was added and stirred for 30 minutes, and then stirred at room temperature for 15 minutes. Under ice bath cooling, chloroiodomethane (85 mg) was added to the reaction solution, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 70:30). The obtained solid was washed with hexane to give the title compound (10 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.92-1.00 (m, 3 H) 1.30 (s, 9 H) 1.37-1.45 (m, 2 H) 1.57-1.66 (m, 2 H) 3.49-3.59 ( m, 2 H) 5.27 (s, 2 H) 6.84 (s, 1 H) 7.35-7.41 (m, 2 H) 7.42-7.46 (m, 2 H); MS (ESI / APCI pos) m / z: 311 [M + H] +
実施例６と同様の手法を用いて、実施例７～１０の化合物を得た。
実施例７：2-ブチル-5-(4-メトキシフェニル)-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン
実施例８：2-ブチル-5-[4-(トリフルオロメトキシ)フェニル]-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン
実施例９：5-(4-tert-ブチルフェニル)-2-(3-メチルブチル)-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン
実施例１０：5-(4-tert-ブチルフェニル)-2-(シクロプロピルメチル)-2,3-ジヒドロ-1H-ピロロ[1,2-c]イミダゾール-1-オン
　実施例７～１０の化合物の構造式及び機器データを表１に示す。 In the same manner as in Example 6, the compounds of Examples 7 to 10 were obtained.
Example 7: 2-Butyl-5- (4-methoxyphenyl) -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one Example 8: 2-Butyl-5- [4 -(Trifluoromethoxy) phenyl] -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one Example 9: 5- (4-tert-Butylphenyl) -2- (3- Methylbutyl) -2,3-dihydro-1H-pyrrolo [1,2-c] imidazol-1-one Example 10: 5- (4-tert-butylphenyl) -2- (cyclopropylmethyl) -2,3 -Dihydro-1H-pyrrolo [1,2-c] imidazol-1-one The structural formulas and instrument data of the compounds of Examples 7 to 10 are shown in Table 1.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　実施例１１：6-ブチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 11: 6-Butyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
製造例６で得られた3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３０　ｍｇ）、４－トリフルオロメトキシフェニルボロン酸（３６　ｍｇ）、炭酸カリウム（４８　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（８　ｍｇ）、エタノール（０．１５　ｍＬ）、トルエン（０．１５　ｍＬ）及び水（０．１０　ｍＬ）の混合物を１００　℃（オイルバス温度）にて1時間攪拌した。反応液をクロロホルムにて希釈した後、不溶物をセライト（登録商標）ろ過にてろ別した。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（ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝６０：４０～３０：７０）にて精製し、6-ブチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３０　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J=7.2 Hz), 1.42 (2 H, sxt, J=7.3 Hz), 1.69 (2 H, quin, J=7.5 Hz), 3.66 (2 H, t, J=7.4 Hz), 5.45 (2 H, s), 7.33 (2 H, d, J=8.3 Hz), 7.52 (2 H, d, J=8.7 Hz), 7.62 (1 H, s); MS (ESI/APCI pos) m/z : 340[M+H]+ 3-Bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (30 mg), 4-trifluoromethoxyphenylboronic acid (30 mg) obtained in Production Example 6 36 mg), potassium carbonate (48 mg), PEPPSI®-IPr (8 mg), ethanol (0.15 mL), toluene (0.15 mL) and water (0.10 mL) The mixture was stirred at ℃ (oil bath temperature) for 1 hour. After diluting the reaction solution with chloroform, insoluble matters were filtered off by Celite (registered trademark) filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 60: 40-30: 70) to give 6-butyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro -7H-imidazo [1,5-a] imidazol-7-one (30 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.2 Hz), 1.42 (2 H, sxt, J = 7.3 Hz), 1.69 (2 H, quin, J = 7.5 Hz) , 3.66 (2 H, t, J = 7.4 Hz), 5.45 (2 H, s), 7.33 (2 H, d, J = 8.3 Hz), 7.52 (2 H, d, J = 8.7 Hz), 7.62 ( 1 H, s); MS (ESI / APCI pos) m / z: 340 [M + H] +
実施例１１と同様の手法を用いて、実施例１２～５５の化合物を得た。
実施例１２：6-ブチル-3-(4-tert-ブチルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３：3-(ビフェニル-4-イル)-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４：3-(ビフェニル-3-イル)-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１５：6-ブチル-3-[3-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１６：6-ブチル-3-[4-(トリフルオロメチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１７：6-ブチル-3-[3-(トリフルオロメチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１８：3-[3-(ベンジルオキシ)フェニル]-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１９：3-[4-(ベンジルオキシ)フェニル]-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２０：4-(6-ブチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)ベンゾニトリル
実施例２１：6-ブチル-3-(4-シクロヘキシルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２２：6-ブチル-3-[4-(4-メチルピペラジン-1-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２３：6-ブチル-3-[4-(ピリジン-3-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２４：3-[4-(ブタン-2-イル)フェニル]-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２５：6-ブチル-3-[3-フルオロ-4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２６：6-ブチル-3-[4-(プロパン-2-イルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２７：6-ブチル-3-(4-フェノキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２８：6-ブチル-3-(4-プロピルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例２９：6-ブチル-3-[4-(プロパン-2-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３０：2-[4-(6-ブチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)フェニル]-2-メチルプロパンニトリル
実施例３１：6-ブチル-3-[4-(シクロプロピルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３２：6-ブチル-3-[4-(ジフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３３：6-ブチル-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３４：6-ブチル-3-[4-(ピペリジン-1-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３５：6-ブチル-3-[6-(プロパン-2-イルオキシ)ピリジン-3-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３６：6-ブチル-3-[4-(プロパン-2-イルスルファニル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３７：6-ブチル-3-(4-ヒドロキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３７：6-ブチル-3-(4-シクロペンチルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例３９：3-(4-tert-ブトキシフェニル)-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４０：6-ブチル-3-[2-フルオロ-4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４１：6-ブチル-3-[4-(シクロペンチルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４２：6-ブチル-3-[4-(シクロブチルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４３：6-ブチル-3-[6-(シクロペンチルオキシ)ピリジン-3-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４４：6-ブチル-3-[4-(ヒドロキシメチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４５：3-[4-(tert-ブトキシメチル)フェニル]-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４６：6-ブチル-3-(4-クロロ-2-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４７：6-ブチル-3-(4-クロロ-3-メトキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４８：6-ブチル-3-[6-(ピペリジン-1-イル)ピリジン-3-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例４９：3-(4-tert-ブチルフェニル)-6-(シクロプロピルメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５５：3-[4-(シクロプロピルオキシ)フェニル]-6-プロピル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５１：3-[4-(シクロプロピルオキシ)フェニル]-6-(3-メチルブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５２：3-[4-(シクロプロピルオキシ)フェニル]-6-ペンチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５３：3-(4-tert-ブチルフェニル)-6-(プロパン-2-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５４：6-ブチル-3-(4-クロロフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５５：6-ベンジル-3-(4-tert-ブチルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例１２～５５の化合物の構造式及び機器データを表２－１～２－９に示す。 Using the same method as in Example 11, the compounds of Examples 12 to 55 were obtained.
Example 12: 6-Butyl-3- (4-tert-butylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 13: 3- (Biphenyl-4 -Yl) -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 14: 3- (Biphenyl-3-yl) -6-butyl-5,6 -Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 15: 6-Butyl-3- [3- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1 , 5-a] imidazol-7-one Example 16: 6-Butyl-3- [4- (trifluoromethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On Example 17: 6-Butyl-3- [3- (trifluoromethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 18: 3- [3- (Benzyloxy) phenyl] -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 19: 3- [4- (Benzyloxy) Nenyl] -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 20: 4- (6-Butyl-7-oxo-6,7-dihydro-5H -Imidazo [1,5-a] imidazol-3-yl) benzonitrile Example 21: 6-Butyl-3- (4-cyclohexylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] Imidazol-7-one Example 22: 6-Butyl-3- [4- (4-methylpiperazin-1-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On Example 23: 6-Butyl-3- [4- (pyridin-3-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 24: 3- [4- (Butan-2-yl) phenyl] -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 25: 6-Butyl-3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 26: 6-Butyl-3- [4- ( Propan-2-y Ruoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 27: 6-Butyl-3- (4-phenoxyphenyl) -5,6-dihydro-7H -Imidazo [1,5-a] imidazol-7-one Example 28: 6-Butyl-3- (4-propylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On Example 29: 6-Butyl-3- [4- (propan-2-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 30: 2- [4- (6-Butyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) phenyl] -2-methylpropanenitrile Example 31: 6- Butyl-3- [4- (cyclopropyloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 32: 6-Butyl-3- [4- ( Difluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 33: 6-Butyl-3- [4- (2-methylpropiyl) ) Phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 34: 6-butyl-3- [4- (piperidin-1-yl) phenyl] -5, 6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 35: 6-Butyl-3- [6- (propan-2-yloxy) pyridin-3-yl] -5,6- Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 36: 6-Butyl-3- [4- (propan-2-ylsulfanyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 37: 6-Butyl-3- (4-hydroxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 37: 6-Butyl-3- (4-cyclopentylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 39: 3- (4-tert-butoxy Phenyl) -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 40: 6-Butyl-3- [2-fluoro-4- (trifluoro) Romethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 41: 6-butyl-3- [4- (cyclopentyloxy) phenyl] -5,6- Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 42: 6-Butyl-3- [4- (cyclobutyloxy) phenyl] -5,6-dihydro-7H-imidazo [1, 5-a] imidazol-7-one Example 43: 6-Butyl-3- [6- (cyclopentyloxy) pyridin-3-yl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole -7-one Example 44: 6-Butyl-3- [4- (hydroxymethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 45: 3 -[4- (tert-Butoxymethyl) phenyl] -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 46: 6-Butyl-3- (4 -Chloro-2-methoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 47: 6-Butyl-3- (4 -Chloro-3-methoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 48: 6-Butyl-3- [6- (piperidin-1-yl) Pyridin-3-yl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 49: 3- (4-tert-butylphenyl) -6- (cyclopropylmethyl) -5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 55: 3- [4- (Cyclopropyloxy) phenyl] -6-propyl-5,6-dihydro-7H -Imidazo [1,5-a] imidazol-7-one Example 51: 3- [4- (Cyclopropyloxy) phenyl] -6- (3-methylbutyl) -5,6-dihydro-7H-imidazo [1 , 5-a] imidazol-7-one Example 52: 3- [4- (Cyclopropyloxy) phenyl] -6-pentyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -ON Example 53: 3- (4-tert-Butylphenyl) -6- (propan-2-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazo -7-one Example 54: 6-Butyl-3- (4-chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 55: 6-Benzyl-3 -(4-tert-Butylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Shown in 2-9.
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
　実施例５６：3-(4-tert-ブチルフェニル)-6-(4-メトキシベンジル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 56: 3- (4-tert-butylphenyl) -6- (4-methoxybenzyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
製造例６で得られた3-ブロモ-6-(4-メトキシベンジル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１１６　ｍｇ）、4-tert-ブチルフェニルボロン酸（７７　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（４２　ｍｇ）、エタノール（１．２　ｍＬ）、トルエン（１．２　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（０．５４　ｍＬ）の混合物を１００　℃（オイルバス温度）にて３時間撹拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）及び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：酢酸エチル＝９０：１０～８０：２０）にて精製して、表題化合物（２９　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 (9 H, s), 3.80 (3 H, s), 4.77 (2 H, s), 5.26 (2 H, s), 6.90 (2 H, d, J=8.3 Hz), 7.26 - 7.29 (2 H, m), 7.34 (2 H, d, J=8.3 Hz), 7.45 (2 H, d, J=8.3 Hz), 7.58 (1 H, s); MS (ESI/APCI pos) m/z : 376 [M+H]+ 3-bromo-6- (4-methoxybenzyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (116 mg) obtained in Preparation Example 6, 4-tert- Butylphenylboronic acid (77 mg), tetrakis (triphenylphosphine) palladium (0) (42 mg), ethanol (1.2 mL), toluene (1.2 mL) and 2M aqueous sodium carbonate (0.54 mL) The mixture was stirred at 100 ° C. (oil bath temperature) for 3 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) and column chromatography (silica gel cartridge, chloroform: ethyl acetate). = 90:10 to 80:20) to give the title compound (29 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 (9 H, s), 3.80 (3 H, s), 4.77 (2 H, s), 5.26 (2 H, s), 6.90 (2 H, d , J = 8.3 Hz), 7.26-7.29 (2 H, m), 7.34 (2 H, d, J = 8.3 Hz), 7.45 (2 H, d, J = 8.3 Hz), 7.58 (1 H, s) ; MS (ESI / APCI pos) m / z: 376 [M + H] +
　実施例５６と同様の手法を用いて、実施例５７～６２の化合物を得た。
実施例５７：6-ブチル-3-(3-クロロフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５８：6-ブチル-3-(2-クロロフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例５９：6-ブチル-3-(2,4-ジクロロフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例６０：6-ブチル-3-(3,4-ジクロロフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例６１：6-ブチル-3-[4-(2-メチルプロポキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例６２：6-ブチル-3-[4-(2,2,2-トリフルオロエトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例５７～６２の化合物の構造式及び機器データを表３に示す。 Using a method similar to that of Example 56, the compounds of Examples 57 to 62 were obtained.
Example 57: 6-Butyl-3- (3-chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 58: 6-Butyl-3- (2- Chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 59: 6-Butyl-3- (2,4-dichlorophenyl) -5,6-dihydro-7H- Imidazo [1,5-a] imidazol-7-one Example 60: 6-Butyl-3- (3,4-dichlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On Example 61: 6-Butyl-3- [4- (2-methylpropoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 62: 6 -Butyl-3- [4- (2,2,2-trifluoroethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Compounds of Examples 57-62 Table 3 shows the structural formula and device data.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
　実施例６３：6-ブチル-3-(3-フルオロ-4-メチルフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 63: 6-butyl-3- (3-fluoro-4-methylphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
窒素雰囲気下、2-フルオロ-4-ヨードトルエン（１０６　ｍｇ）のテトラヒドロフラン（１．０　ｍＬ）溶液に－７８　℃にてテトラ‐tert-ブチル亜鉛酸ジリチウム（０．８２０　ｍＬ、０．５５Ｍ、テトラヒドロフラン溶液）を滴下した後、室温にて１．５時間攪拌した。反応液に室温にて製造例６で得られた3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（７７　ｍｇ）及びテトラキス(トリフェニルホスフィン)パラジウム(０)（１４　ｍｇ）を加え、２時間攪拌した。反応液に水を加え酢酸エチルにて抽出した。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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）及び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＝８０：２０～２０：８０）にて精製して、表題化合物（８　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 - 1.01 (m, 3 H) 1.38 - 1.47 (m, 2 H) 1.66 - 1.71 (m, 2 H) 2.32 (s, 3 H) 3.63 - 3.69 (m, 2 H) 5.44 (s, 2 H) 7.07 - 7.70 (m, 4 H) Under a nitrogen atmosphere, a solution of 2-fluoro-4-iodotoluene (106 mg) in tetrahydrofuran (1.0 mL) at −78 ° C. with tetra-tert-butylzinc zincate (0.820 mL, 0.55 M, tetrahydrofuran) Solution) was added dropwise, followed by stirring at room temperature for 1.5 hours. To the reaction solution, 3-bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (77 mg) and tetrakis (tri Phenylphosphine) palladium (0) (14 mg) was added and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (SunFire®, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) and column chromatography (NH silica gel cartridge) Hexane: ethyl acetate = 80: 20 to 20:80) to give the title compound (8 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95-1.01 (m, 3 H) 1.38-1.47 (m, 2 H) 1.66-1.71 (m, 2 H) 2.32 (s, 3 H) 3.63-3.69 ( m, 2 H) 5.44 (s, 2 H) 7.07-7.70 (m, 4 H)
　実施例６４：6-ブチル-3-(4-tert-ブチルフェニル)-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 64: 6-butyl-3- (4-tert-butylphenyl) -5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
製造例８で得られた3-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び2-ブロモ-6-ブチル-5-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オンの混合物（８４　ｍｇ）、4-tert-ブチルフェニルボロン酸（６６　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（２１　ｍｇ）、エタノール（０．８４　ｍＬ）、トルエン（０．８４　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（０．４６　ｍＬ）の混合物を１００　℃（オイルバス温度）にて２時間攪拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（６５　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d)　δ ppm 0.99 (3 H, t, J=7.4 Hz), 1.36 (9 H, s), 1.38 - 1.47 (2 H, m), 1.53 (3 H, d, J=5.8 Hz), 1.60 - 1.75 (2 H, m), 3.17 - 3.24 (1 H, m), 3.91 - 3.98 (1 H, m), 5.77 - 5.82 (1 H, m), 7.40 - 7.43 (2 H, m), 7.45 - 7.48 (2 H, m), 7.48 - 7.49 (1 H, m) ; MS (ESI/APCI pos) m/z : 326 [M+H]+ 3-Bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one and 2-bromo-6-butyl-5 obtained in Preparation Example 8 -Methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one mixture (84 mg), 4-tert-butylphenylboronic acid (66 mg), PEPPSI (registered trademark)- A mixture of IPr (21 mg), ethanol (0.84 mL), toluene (0.84 mL) and 2M aqueous sodium carbonate solution (0.46 mL) was stirred at 100 ° C. (oil bath temperature) for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (65 mg) Was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.99 (3 H, t, J = 7.4 Hz), 1.36 (9 H, s), 1.38-1.47 (2 H, m), 1.53 (3 H, d, J = 5.8 Hz), 1.60-1.75 (2 H, m), 3.17-3.24 (1 H, m), 3.91-3.98 (1 H, m), 5.77-5.82 (1 H, m), 7.40-7.43 ( 2 H, m), 7.45-7.48 (2 H, m), 7.48-7.49 (1 H, m); MS (ESI / APCI pos) m / z: 326 [M + H] +
　実施例６５：6-ブチル-3-(6-フェノキシピリジン-3-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 65: 6-butyl-3- (6-phenoxypyridin-3-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
１）6-ブチル-3-(6-クロロピリジン-3-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例５６と同様の手法を用いて、製造例６で得られた3-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１０３　ｍｇ）及び4-クロロ-５-ピリジンボロン酸（７５　ｍｇ）より、表題化合物（４５　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J=7.4 Hz), 1.39 - 1.47 (2 H, m), 1.66 - 1.72 (2 H, m), 3.67 (2 H, t, J=7.4 Hz), 5.46 (2 H, s), 7.45 (1 H, d, J=8.3 Hz), 7.69 (1 H, s), 7.79 (1 H, dd, J=8.3, 2.5 Hz), 8.52 (1 H, d, J=2.5 Hz); MS (ESI/APCI pos) m/z : 291 [M+H]+
２）6-ブチル-3-(6-フェノキシピリジン-3-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
6-ブチル-3-(6-クロロピリジン-3-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２０　ｍｇ）及びフェノール（１０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．４０　ｍＬ）溶液に、銅（０．４　ｍｇ）及び炭酸セシウム（６７　ｍｇ）を加えマイクロウェーブ照射下１００　℃にて１時間撹拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（６　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J=7.4 Hz), 1.37 - 1.45 (2 H, m), 1.62 - 1.69 (2 H, m), 3.64 (2 H, t, J=7.4 Hz), 5.39 (2 H, s), 7.03 - 7.06 (1 H, m), 7.15 - 7.18 (2 H, m), 7.24 - 7.27 (1 H, m), 7.42 - 7.46 (2 H, m), 7.57 (1 H, s), 7.85 (1 H, dd, J=8.5, 2.7 Hz), 8.27 - 8.30 (1 H, m); MS (ESI/APCI pos) m/z : 349 [M+H]+ 1) 6-Butyl-3- (6-chloropyridin-3-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Using a procedure similar to that in Example 56 3-bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (103 mg) and 4-chloro-5-pyridineboron obtained in Preparation Example 6 The title compound (45 mg) was obtained as a colorless solid from the acid (75 mg).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.39-1.47 (2 H, m), 1.66-1.72 (2 H, m), 3.67 (2 H, t, J = 7.4 Hz), 5.46 (2 H, s), 7.45 (1 H, d, J = 8.3 Hz), 7.69 (1 H, s), 7.79 (1 H, dd, J = 8.3, 2.5 Hz ), 8.52 (1 H, d, J = 2.5 Hz); MS (ESI / APCI pos) m / z: 291 [M + H] +
2) 6-Butyl-3- (6-phenoxypyridin-3-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
6-butyl-3- (6-chloropyridin-3-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (20 mg) and phenol (10 mg) N , N-dimethylformamide (0.40 mL) was added copper (0.4 mg) and cesium carbonate (67 mg), and the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (6 mg) Was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.37-1.45 (2 H, m), 1.62-1.69 (2 H, m), 3.64 (2 H, t, J = 7.4 Hz), 5.39 (2 H, s), 7.03-7.06 (1 H, m), 7.15-7.18 (2 H, m), 7.24-7.27 (1 H, m), 7.42-7.46 ( 2 H, m), 7.57 (1 H, s), 7.85 (1 H, dd, J = 8.5, 2.7 Hz), 8.27-8.30 (1 H, m); MS (ESI / APCI pos) m / z: 349 [M + H] +
　実施例６６：6-ブチル-3-[4-(ピリジン-2-イルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 66: 6-Butyl-3- [4- (pyridin-2-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
１）6-ブチル-3-(4-ヒドロキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例１９で得られた3-[4-(ベンジルオキシ)フェニル]-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３７６　ｍｇ）のメタノール（１．３　ｍＬ）及び酢酸エチル（６．７　ｍＬ）溶液に１０％パラジウム炭素（３０　ｍｇ）を加え、水素雰囲気下、室温にて１５時間撹拌した。反応液をセライト（登録商標）ろ過後、ろ液を減圧下濃縮した。残渣をカラムクロマログラフィー（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）にて精製して、表題化合物（３１　ｍｇ）を無色固体として得た。
MS ((ESI/APCI pos) m/z : 272 [M+H]+
２）6-ブチル-3-[4-(ピリジン-2-イルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
6-ブチル-3-(4-ヒドロキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３７　ｍｇ）、2-フルオロピリジン（３０　ｍｇ）、炭酸カリウム（４６　ｍｇ）及びＮ，Ｎ－ジメチルホルムアミド（０．６０　ｍＬ）の混合物をマイクロウェーブ照射下１５０　℃にて１．５時間撹拌した。反応液を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（１２　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J=7.4 Hz), 1.42 (2 H, sxt, J=7.0 Hz), 1.65 - 1.72 (2 H, m), 3.66 (2 H, t, J=7.4 Hz), 5.45 (2 H, s), 6.99 (1 H, d, J=8.3 Hz), 7.04 - 7.07 (1 H, m), 7.24 - 7.28 (2 H, m), 7.49 - 7.53 (2 H, m), 7.58 (1 H, s), 7.72 - 7.76 (1 H, m), 8.19 - 8.22 (1 H, m) ; MS (ESI/APCI pos) m/z : 349[M+H]+ 1) 6-butyl-3- (4-hydroxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 3- [4- (benzyl) obtained in Example 19 Oxy) phenyl] -6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (376 mg) in methanol (1.3 mL) and ethyl acetate (6.7 mL) ) 10% palladium carbon (30 mg) was added to the solution, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was 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 (31 mg) as a colorless solid.
MS ((ESI / APCI pos) m / z: 272 [M + H] +
2) 6-Butyl-3- [4- (pyridin-2-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
6-butyl-3- (4-hydroxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (37 mg), 2-fluoropyridine (30 mg), potassium carbonate (46 mg) and N, N-dimethylformamide (0.60 mL) were stirred at 150 ° C. for 1.5 hours under microwave irradiation. The reaction solution was purified by reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title The compound (12 mg) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.42 (2 H, sxt, J = 7.0 Hz), 1.65-1.72 (2 H, m), 3.66 ( 2 H, t, J = 7.4 Hz), 5.45 (2 H, s), 6.99 (1 H, d, J = 8.3 Hz), 7.04-7.07 (1 H, m), 7.24-7.28 (2 H, m ), 7.49-7.53 (2 H, m), 7.58 (1 H, s), 7.72-7.76 (1 H, m), 8.19-8.22 (1 H, m); MS (ESI / APCI pos) m / z : 349 [M + H] +
　実施例６７：6-ブチル-3-[4-(3,6-ジヒドロ-2H-ピラン-4-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 67: 6-Butyl-3- [4- (3,6-dihydro-2H-pyran-4-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　実施例１１と同様の手法を用いて、実施例５４で得られた6-ブチル-3-(4-クロロフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１００　ｍｇ）及び3,6-ジヒドロ-2H-ピラン-4-ボロン酸 ピナコール エステル（８７　ｍｇ）より、表題化合物（８０　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J=7.4 Hz), 1.39 - 1.47 (2 H, m), 1.65 - 1.72 (2 H, m), 2.52 - 2.57 (2 H, m), 3.66 (2 H, t, J=7.4 Hz), 3.96 (2 H, t, J=5.4 Hz), 4.34 - 4.38 (2 H, m), 5.46 (2 H, s), 6.21 - 6.24 (1 H, m), 7.44 - 7.52 (4 H, m), 7.64 (1 H, s); MS (ESI/APCI pos) m/z : 338 [M+H]+ Using a method similar to that of Example 11, 6-butyl-3- (4-chlorophenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7- obtained in Example 54 was used. The title compound (80 mg) was obtained as a colorless solid from ON (100 mg) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (87 mg).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.39-1.47 (2 H, m), 1.65-1.72 (2 H, m), 2.52-2.57 (2 H, m), 3.66 (2 H, t, J = 7.4 Hz), 3.96 (2 H, t, J = 5.4 Hz), 4.34-4.38 (2 H, m), 5.46 (2 H, s), 6.21 -6.24 (1 H, m), 7.44-7.52 (4 H, m), 7.64 (1 H, s); MS (ESI / APCI pos) m / z: 338 [M + H] +
　実施例６８：6-ブチル-3-[4-(テトラヒドロ-2H-ピラン-4-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 68: 6-Butyl-3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
実施例６７で得られた6-ブチル-3-[4-(3,6-ジヒドロ-2H-ピラン-4-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（７０　ｍｇ）のメタノール（１．４　ｍＬ）溶液に１０％パラジウム炭素（３５　ｍｇ）を加え、水素雰囲気下、室温にて１時間撹拌した。反応液をセライト（登録商標）ろ過後、ろ液を減圧下濃縮して、表題化合物（６６　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.98 (3 H, t, J=7.4 Hz), 1.39 - 1.46 (2 H, m), 1.65 - 1.71 (2 H, m), 1.77 - 1.88 (4 H, m), 2.77 - 2.85 (1 H, m), 3.53 - 3.58 (2 H, m), 3.65 (2 H, t, J=7.4 Hz), 4.11 (2 H, dd, J=10.9, 3.9 Hz), 5.44 (2 H, s), 7.34 (2 H, d, J=8.3 Hz), 7.44 (2 H, d, J=8.3 Hz), 7.60 (1 H, s); MS (ESI/APCI pos) m/z : 340 [M+H]+ 6-Butyl-3- [4- (3,6-dihydro-2H-pyran-4-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] obtained in Example 67 To a solution of imidazol-7-one (70 mg) in methanol (1.4 mL) was added 10% palladium carbon (35 mg), and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give the title compound (66 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.39-1.46 (2 H, m), 1.65-1.71 (2 H, m), 1.77-1.88 (4 H, m), 2.77-2.85 (1 H, m), 3.53-3.58 (2 H, m), 3.65 (2 H, t, J = 7.4 Hz), 4.11 (2 H, dd, J = 10.9, 3.9 Hz), 5.44 (2 H, s), 7.34 (2 H, d, J = 8.3 Hz), 7.44 (2 H, d, J = 8.3 Hz), 7.60 (1 H, s); MS (ESI / APCI pos) m / z: 340 [M + H] +
　実施例６９：6-ブチル-2-メチル-3-[6-(ピペリジン-1-イル)ピリジン-3-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 69: 6-Butyl-2-methyl-3- [6- (piperidin-1-yl) pyridin-3-yl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
製造例７で得られた3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２０　ｍｇ）、6-(ピペリジン-1-イル)ピリジン-3-ボロン酸 ピナコール エステル（２７　ｍｇ）、炭酸カリウム（３２　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（２．６　ｍｇ）、エタノール（０．２３　ｍＬ）、トルエン（０．２３　ｍＬ）及び水（０．１５　ｍＬ）の混合物を１００　℃（オイルバス温度）にて３時間攪拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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＝６０：４０～２０：８０）にて精製し、、表題化合物（１０　ｍｇ）を淡黄色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J=7.4 Hz), 1.33 - 1.41 (2 H, m), 1.58 - 1.73 (8 H, m), 2.40 (3 H, s), 3.56 - 3.61 (6 H, m), 5.21 (2 H, s), 6.72 (1 H, d, J=9.1 Hz), 7.47 (1 H, dd, J=8.7, 2.5 Hz), 8.21 (1 H, d, J=2.1 Hz) ; MS (ESI/APCI pos) m/z : 354 [M+H]+ 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (20 mg) obtained in Preparation Example 7, 6- (piperidine- 1-yl) pyridine-3-boronic acid pinacol ester (27 mg), potassium carbonate (32 mg), PEPPSI®-IPr (2.6 mg), ethanol (0.23 mL), toluene (0. 23 mL) and water (0.15 mL) were stirred at 100 ° C. (oil bath temperature) for 3 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 60: 40-20: 80) to obtain the title compound (10 mg) as a pale yellow solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J = 7.4 Hz), 1.33-1.41 (2 H, m), 1.58-1.73 (8 H, m), 2.40 (3 H, s), 3.56-3.61 (6 H, m), 5.21 (2 H, s), 6.72 (1 H, d, J = 9.1 Hz), 7.47 (1 H, dd, J = 8.7, 2.5 Hz), 8.21 (1 H, d, J = 2.1 Hz); MS (ESI / APCI pos) m / z: 354 [M + H] +
実施例６９と同様の手法を用いて、実施例７０～７４の化合物を得た。
実施例７０：6-ブチル-3-[6-(シクロペンチルオキシ)ピリジン-3-イル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例７１：6-ブチル-3-[4-(シクロペンチルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例７２：6-ブチル-2-メチル-3-[4-(3,3,3-トリフルオロプロポキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例７３：3-[4-(tert-ブトキシメチル)フェニル]-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例７４：6-ブチル-3-[4-(3-フルオロプロポキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例７０～７４の化合物の構造式及び機器データを表４に示す。 Using a method similar to that in Example 69, the compounds of Examples 70 to 74 were obtained.
Example 70: 6-Butyl-3- [6- (cyclopentyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 71: 6-Butyl-3- [4- (cyclopentyloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 72: 6- Butyl-2-methyl-3- [4- (3,3,3-trifluoropropoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 73: 3- [4- (tert-Butoxymethyl) phenyl] -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 74: 6-Butyl -3- [4- (3-Fluoropropoxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Structural formula of the compounds of Examples 70-74 Table 4 shows the device data.
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
　実施例７５：2-ブロモ-6-ブチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 75: 2-Bromo-6-butyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
製造例６で得られた2,3-ジブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３１６　ｍｇ）、４－トリフルオロメトキシフェニルボロン酸（１９３　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（１０８　ｍｇ）、エタノール（３．２　ｍＬ）、トルエン（３．２　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（１．４　ｍＬ）の混合物を１００　℃（オイルバス温度）にて５時間撹拌した。反応液に４－トリフルオロメトキシフェニルボロン酸（１９　ｍｇ）及びテトラキス(トリフェニルホスフィン)パラジウム(０)（５４　ｍｇ）を加え、１００　℃（オイルバス温度）にて７時間撹拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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：酢酸エチル＝９５：５～９０：１０）及び逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（２６　ｍｇ）をアモルファスとして得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J=7.4 Hz), 1.35 - 1.44 (2 H, m), 1.60 - 1.68 (2 H, m), 3.62 (2 H, t, J=7.4 Hz), 5.34 (2 H, s), 7.36 (2 H, d, J=8.7 Hz), 7.64 - 7.68 (2 H, m); MS (ESI/APCI pos) m/z : 418 [M+H]+ 2,3-Dibromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (316 mg), 4-trifluoromethoxyphenylboron obtained in Production Example 6 A mixture of acid (193 mg), tetrakis (triphenylphosphine) palladium (0) (108 mg), ethanol (3.2 mL), toluene (3.2 mL) and 2M aqueous sodium carbonate (1.4 mL). The mixture was stirred at 100 ° C. (oil bath temperature) for 5 hours. 4-Trifluoromethoxyphenylboronic acid (19 mg) and tetrakis (triphenylphosphine) palladium (0) (54 mg) were added to the reaction solution, and the mixture was stirred at 100 ° C. (oil bath temperature) for 7 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel cartridge, chloroform: ethyl acetate = 95: 5 to 90:10) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile). = 90:10 to 0: 100) to give the title compound (26 mg) as amorphous.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.4 Hz), 1.35-1.44 (2 H, m), 1.60-1.68 (2 H, m), 3.62 (2 H, t, J = 7.4 Hz), 5.34 (2 H, s), 7.36 (2 H, d, J = 8.7 Hz), 7.64-7.68 (2 H, m); MS (ESI / APCI pos) m / z: 418 [M + H] +
　実施例７６：3-(ビフェニル-4-イル)-2-ブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 76: 3- (biphenyl-4-yl) -2-bromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
実施例７５と同様の手法を用いて、製造例６で得られた2,3-ジブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３５９　ｍｇ）より、表題化合物（４１６　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J=7.4 Hz), 1.37 - 1.44 (2 H, m), 1.63 - 1.69 (2 H, m), 3.63 (2 H, t, J=7.4 Hz), 5.39 (2 H, s), 7.39 - 7.43 (1 H, m), 7.46 - 7.51 (2 H, m), 7.61 - 7.65 (2 H, m), 7.68 - 7.71 (2 H, m), 7.72 - 7.75 (2 H, m); MS (ESI/APCI pos) m/z : 410 [M+H]+ In the same manner as in Example 75, 2,3-dibromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Production Example 6 ( 359 mg) to give the title compound (416 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.97 (3 H, t, J = 7.4 Hz), 1.37-1.44 (2 H, m), 1.63-1.69 (2 H, m), 3.63 (2 H, t, J = 7.4 Hz), 5.39 (2 H, s), 7.39-7.43 (1 H, m), 7.46-7.51 (2 H, m), 7.61-7.65 (2 H, m), 7.68-7.71 ( 2 H, m), 7.72-7.75 (2 H, m); MS (ESI / APCI pos) m / z: 410 [M + H] +
　実施例７７：6-ブチル-2-エテニル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 77: 6-Butyl-2-ethenyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　実施例７５で得られた2-ブロモ-6-ブチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（８３　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．７　ｍＬ）溶液に、フッ化セシウム（６０　ｍｇ）、ビス（トリフェニルホスフィン）パラジウム（II）ジクロリド（１４　ｍｇ）及びトリブチルビニルスズ（８７　μＬ）を加え、１００　℃（オイルバス温度）にて１２時間撹拌した。反応液をセライト（登録商標）ろ過した後、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（ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝８５：１５～７０：３０）にて精製し、表題化合物（２４　ｍｇ）を淡黄色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J=7.2 Hz), 1.36 - 1.43 (2 H, m), 1.64 (2 H, t, J=7.6 Hz), 3.62 (2 H, t, J=7.6 Hz), 5.27 (2 H, s), 5.33 (1 H, dd, J=10.9, 1.9 Hz), 6.26 (1 H, dd, J=17.1, 1.9 Hz), 6.69 (1 H, dd, J=17.1, 10.9 Hz), 7.36 (2 H, d, J=8.7 Hz), 7.47 (2 H, d, J=8.7 Hz); MS (ESI/APCI pos) m/z : 366 [M+H]+ 2-Bromo-6-butyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Example 75 ( 83 mg) in N, N-dimethylformamide (1.7 mL) was added to cesium fluoride (60 mg), bis (triphenylphosphine) palladium (II) dichloride (14 mg) and tributylvinyltin (87 μL). And stirred at 100 ° C. (oil bath temperature) for 12 hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 85: 15 to 70:30) to obtain the title compound (24 mg) as a pale yellow solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.2 Hz), 1.36-1.43 (2 H, m), 1.64 (2 H, t, J = 7.6 Hz), 3.62 ( 2 H, t, J = 7.6 Hz), 5.27 (2 H, s), 5.33 (1 H, dd, J = 10.9, 1.9 Hz), 6.26 (1 H, dd, J = 17.1, 1.9 Hz), 6.69 (1 H, dd, J = 17.1, 10.9 Hz), 7.36 (2 H, d, J = 8.7 Hz), 7.47 (2 H, d, J = 8.7 Hz); MS (ESI / APCI pos) m / z : 366 [M + H] +
　実施例７８：6-ブチル-2-エチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 78: 6-Butyl-2-ethyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
実施例７７で得られた6-ブチル-2-エテニル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１７　ｍｇ）のメタノール（１．４　ｍＬ）溶液に１０％パラジウム炭素（１７　ｍｇ）を加え、水素雰囲気下、室温にて１時間撹拌した。反応液をセライト（登録商標）ろ過後、ろ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（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（１５　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, t, J=7.4 Hz), 1.32 (3 H, t, J=7.6 Hz), 1.36 - 1.43 (2 H, m), 1.60 - 1.66 (2 H, m), 2.76 (2 H, q, J=7.4 Hz), 3.61 (2 H, t, J=7.4 Hz), 5.26 (2 H, s), 7.34 (2 H, d, J=8.3 Hz), 7.41 - 7.45 (2 H, m); MS (ESI/APCI pos) m/z : 368 [M+H]+ 6-Butyl-2-ethenyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Example 77 ( 17 mg) in methanol (1.4 mL) was added 10% palladium carbon (17 mg), and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (15 mg) Was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, t, J = 7.4 Hz), 1.32 (3 H, t, J = 7.6 Hz), 1.36-1.43 (2 H, m), 1.60- 1.66 (2 H, m), 2.76 (2 H, q, J = 7.4 Hz), 3.61 (2 H, t, J = 7.4 Hz), 5.26 (2 H, s), 7.34 (2 H, d, J = 8.3 Hz), 7.41-7.45 (2 H, m); MS (ESI / APCI pos) m / z: 368 [M + H] +
　実施例７９：6-ブチル-2-メチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 79: 6-butyl-2-methyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
実施例７５で得られた2-ブロモ-6-ブチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（５５　ｍｇ）、メチルボロン酸（１２　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（９　ｍｇ）、エタノール（０．５５　ｍＬ）、トルエン（０．５５　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（０．２０　ｍＬ）の混合物を１００　℃（オイルバス温度）にて３時間撹拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（１３　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J=7.4 Hz), 1.36 - 1.44 (2 H, m), 1.60 - 1.68 (2 H, m), 2.46 (3 H, s), 3.61 (2 H, t, J=7.4 Hz), 5.28 (2 H, s), 7.33 - 7.37 (2 H, m), 7.42 - 7.47 (2 H, m); MS (ESI/APCI pos) m/z : 354 [M+H]+ 2-Bromo-6-butyl-3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Example 75 ( 55 mg), methylboronic acid (12 mg), PEPPSI®-IPr (9 mg), ethanol (0.55 mL), toluene (0.55 mL) and 2M aqueous sodium carbonate (0.20 mL). The mixture was stirred at 100 ° C. (oil bath temperature) for 3 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (13 mg) Was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.4 Hz), 1.36-1.44 (2 H, m), 1.60-1.68 (2 H, m), 2.46 (3 H, s), 3.61 (2 H, t, J = 7.4 Hz), 5.28 (2 H, s), 7.33-7.37 (2 H, m), 7.42-7.47 (2 H, m); MS (ESI / APCI pos ) m / z: 354 [M + H] +
実施例７９と同様の手法を用いて、実施例８０～８５の化合物を得た。
実施例８０：6-ブチル-3-[6-(シクロペンチルオキシ)ピリジン-3-イル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例８１：6-ブチル-3-[4-(シクロペンチルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例８２：6-ブチル-2-メチル-3-[4-(3,3,3-トリフルオロプロポキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例８３：3-[4-(tert-ブトキシメチル)フェニル]-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例８４：6-ブチル-3-[4-(3-フルオロプロポキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例８０～８５の化合物の構造式及び機器データを表５に示す。 The compounds of Examples 80 to 85 were obtained in the same manner as in Example 79.
Example 80: 6-Butyl-3- [6- (cyclopentyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 81: 6-Butyl-3- [4- (cyclopentyloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 82: 6- Butyl-2-methyl-3- [4- (3,3,3-trifluoropropoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 83: 3- [4- (tert-Butoxymethyl) phenyl] -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 84: 6-Butyl -3- [4- (3-Fluoropropoxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Structural formulas of the compounds of Examples 80-85 Table 5 shows the device data.
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
実施例８６：6-(2-メトキシエチル)-2-メチル-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン及び6-(2-メトキシエチル)-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 86: 6- (2-methoxyethyl) -2-methyl-3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -One and 6- (2-methoxyethyl) -3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
製造例９で得られた2-ブロモ-6-(2-メトキシエチル)-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（８２　ｍｇ）、メチルボロン酸（３７　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（２８　ｍｇ）、エタノール（０．８２　ｍＬ）、トルエン（０．８２　ｍＬ）及び２Ｍ　炭酸ナトリウム水溶液（０．４２　ｍＬ）の混合物を１００　℃（オイルバス温度）にて１時間撹拌した。反応液に水を加えクロロホルムにて３回抽出した。合わせ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：酢酸エチル＝７５：２５～５０：５０）及び逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ（登録商標）、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、6-(2-メトキシエチル)-2-メチル-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２６　ｍｇ）を無色固体として、及び6-(2-メトキシエチル)-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１６　ｍｇ）を無色固体として得た。
6-(2-メトキシエチル)-2-メチル-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (6 H, d, J=6.6 Hz), 1.91 (1 H, dt, J=13.4, 6.9 Hz), 2.46 (3 H, s), 2.53 (2 H, d, J=7.0 Hz), 3.35 (3 H, s), 3.61 (2 H, t, J=4.7 Hz), 3.77 (2 H, t, J=4.7 Hz), 5.42 (2 H, s), 7.25 - 7.29 (2 H, m), 7.30 - 7.34 (2 H, m) ; MS (ESI/APCI pos) m/z : 328 [M+H]+
6-(2-メトキシエチル)-3-[4-(2-メチルプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93 (6 H, d, J=6.6 Hz), 1.86 - 1.94 (1 H, m), 2.52 (2 H, d, J=7.0 Hz), 3.38 (3 H, s), 3.65 (2 H, t, J=4.7 Hz), 3.82 (2 H, t, J=4.7 Hz), 5.58 (2 H, s), 7.25 (2 H, d, J=8.3 Hz), 7.40 (2 H, d, J=8.3 Hz), 7.61 (1 H, s); MS (ESI/APCI pos) m/z : 314 [M+H]+ 2-Bromo-6- (2-methoxyethyl) -3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] obtained in Production Example 9 Imidazole-7-one (82 mg), methylboronic acid (37 mg), PEPPSI®-IPr (28 mg), ethanol (0.82 mL), toluene (0.82 mL) and 2M aqueous sodium carbonate ( 0.42 mL) was stirred at 100 ° C. (oil bath temperature) for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel cartridge, chloroform: ethyl acetate = 75: 25 to 50:50) and reverse phase column chromatography (SunFire®, 0.1% trifluoroacetic acid / water: 0.1% 6)-(2-methoxyethyl) -2-methyl-3- [4- (2-methylpropyl) phenyl] -5,6- Dihydro-7H-imidazo [1,5-a] imidazol-7-one (26 mg) as a colorless solid and 6- (2-methoxyethyl) -3- [4- (2-methylpropyl) phenyl]- 5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one (16 mg) was obtained as a colorless solid.
6- (2-methoxyethyl) -2-methyl-3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (6 H, d, J = 6.6 Hz), 1.91 (1 H, dt, J = 13.4, 6.9 Hz), 2.46 (3 H, s), 2.53 ( 2 H, d, J = 7.0 Hz), 3.35 (3 H, s), 3.61 (2 H, t, J = 4.7 Hz), 3.77 (2 H, t, J = 4.7 Hz), 5.42 (2 H, s), 7.25-7.29 (2 H, m), 7.30-7.34 (2 H, m); MS (ESI / APCI pos) m / z: 328 [M + H] +
6- (2-methoxyethyl) -3- [4- (2-methylpropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93 (6 H, d, J = 6.6 Hz), 1.86-1.94 (1 H, m), 2.52 (2 H, d, J = 7.0 Hz), 3.38 ( 3 H, s), 3.65 (2 H, t, J = 4.7 Hz), 3.82 (2 H, t, J = 4.7 Hz), 5.58 (2 H, s), 7.25 (2 H, d, J = 8.3 Hz), 7.40 (2 H, d, J = 8.3 Hz), 7.61 (1 H, s); MS (ESI / APCI pos) m / z: 314 [M + H] +
実施例８６と同様の手法を用いて、実施例８７～９６の化合物を得た。
実施例８７：6-ブチル-2-メチル-3-(4-プロポキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例８８：6-ブチル-3-(4-プロポキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例８９：6-ブチル-3-[4-(2-フルオロエトキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９０：6-ブチル-3-[4-(2-フルオロエトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９１：3-[4-(シクロプロピルオキシ)フェニル]-2-メチル-6-(2-メチルプロピル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９２：3-[4-(シクロプロピルオキシ)フェニル]-6-(2-メチルプロピル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９３：2-メチル-6-(4,4,4-トリフルオロブチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９４：6-(4,4,4-トリフルオロブチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９５：6-(2-シクロプロピルエチル)-2-メチル-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９６：6-(2-シクロプロピルエチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例８７～９６の化合物の構造式及び機器データを表６－１～６－２に示す。 Using a method similar to that of Example 86, the compounds of Examples 87 to 96 were obtained.
Example 87: 6-Butyl-2-methyl-3- (4-propoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 88: 6-Butyl- 3- (4-propoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 89: 6-Butyl-3- [4- (2-fluoroethoxy) phenyl ] -2-Methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 90: 6-Butyl-3- [4- (2-fluoroethoxy) phenyl] -5 , 6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 91: 3- [4- (Cyclopropyloxy) phenyl] -2-methyl-6- (2-methylpropyl)- 5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 92: 3- [4- (Cyclopropyloxy) phenyl] -6- (2-methylpropyl) -5,6 -Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 93: 2-Methyl-6- (4,4,4-trifluorobutyl) -3- [4- (trifluoro Methoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 94: 6- (4,4,4-trifluorobutyl) -3- [4- ( Trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 95: 6- (2-Cyclopropylethyl) -2-methyl-3- [4 -(Trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 96: 6- (2-Cyclopropylethyl) -3- [4- ( Trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one The structural formulas and instrumental data of the compounds of Examples 87 to 96 are shown in Tables 6-1 to 6-2. Shown in
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
　実施例９７：6-ブチル-2-メチル-3-[4-(1,1,1-トリフルオロ-2-メチルプロパン-2-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 97: 6-Butyl-2-methyl-3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -5,6-dihydro-7H-imidazo [1 , 5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
製造例６で得られた2,3-ジブロモ-6-ブチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１００　ｍｇ）、製造例１０で得られた4,4,5,5-テトラメチル-2-[4-(1,1,1-トリフルオロ-2-メチルプロパン-2-イル)フェニル]-1,3,2-ジオキサボロラン（１０２　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（３４　ｍｇ）、炭酸カリウム（１２３　ｍｇ）、エタノール（０．４５　ｍＬ）、トルエン（０．４５　ｍＬ）及び水（０．３０　ｍＬ）の混合物を窒素雰囲気下、１００　℃（オイルバス温度）にて２時間撹拌した。反応液にメチルボロン酸（３６　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（２０　ｍｇ）、炭酸カリウム（１２３　ｍｇ）及び水（０．３０　ｍＬ）を加え、１００　℃（オイルバス温度）にて４時間撹拌した。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（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（２８　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J=7.4 Hz), 1.38 (2 H, sxt, J=7.5 Hz), 1.54 - 1.66 (8 H, m), 2.46 (3 H, s), 3.60 (2 H, t, J=7.4 Hz), 5.28 (2 H, s), 7.37 - 7.42 (2 H, m), 7.60 (2 H, d, J=8.3 Hz); MS (ESI/APCI pos) m/z : 380 [M+H]+ 2,3-Dibromo-6-butyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (100 mg) obtained in Preparation Example 6, obtained in Preparation Example 10 4,4,5,5-tetramethyl-2- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,3,2-dioxaborolane (102 mg), A mixture of tetrakis (triphenylphosphine) palladium (0) (34 mg), potassium carbonate (123 mg), ethanol (0.45 mL), toluene (0.45 mL) and water (0.30 mL) was added to a nitrogen atmosphere. The mixture was stirred at 100 ° C. (oil bath temperature) for 2 hours. Methylboronic acid (36 mg), PEPPSI (registered trademark) -IPr (20 mg), potassium carbonate (123 mg) and water (0.30 mL) were added to the reaction mixture, and the mixture was stirred at 100 ° C. (oil bath temperature) for 4 hours. Stir. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (28 mg) Was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94 (3 H, t, J = 7.4 Hz), 1.38 (2 H, sxt, J = 7.5 Hz), 1.54-1.66 (8 H, m), 2.46 ( 3 H, s), 3.60 (2 H, t, J = 7.4 Hz), 5.28 (2 H, s), 7.37-7.42 (2 H, m), 7.60 (2 H, d, J = 8.3 Hz); MS (ESI / APCI pos) m / z: 380 [M + H] +
実施例９７と同様の手法を用いて、実施例９８～１０１の化合物を得た。
実施例９８：6-ブチル-2-メチル-3-[4-(2,2,2-トリフルオロエチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例９９：6-ブチル-2-メチル-3-[4-(3,3,3-トリフルオロプロピル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１００：6-ブチル-3-[4-(2-フルオロ-2-メチルプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１０１：6-ブチル-3-[6-(シクロブチルオキシ)ピリジン-3-イル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例９８～１０１の化合物の構造式及び機器データを表７に示す。 Using a method similar to that in Example 97, the compounds of Examples 98 to 101 were obtained.
Example 98: 6-Butyl-2-methyl-3- [4- (2,2,2-trifluoroethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -ON Example 99: 6-Butyl-2-methyl-3- [4- (3,3,3-trifluoropropyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole -7-one Example 100: 6-Butyl-3- [4- (2-fluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Imidazol-7-one Example 101: 6-Butyl-3- [6- (cyclobutyloxy) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Table 7 shows the structural formulas and instrument data of the compounds of Examples 98-101.
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
　実施例６９と同様の手法を用いて、実施例１０２～１４９の化合物を得た。
実施例１０２：6-ブチル-3-[4-(1,1-ジフルオロエチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１０３：6-ブチル-3-[4-(シクロプロピルカルボニル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１０４：2-[4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)フェニル]-2-メチルプロパンニトリル
実施例１０５：6-ブチル-3-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１０６：4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-N-(2-メチルプロピル)ベンズアミド
実施例１０７：N-[4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)ベンジル]アセトアミド
実施例１０８：4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-N-メチルベンズアミド
実施例１０９：4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-N,N-ジメチルベンズアミド
実施例１１０：6-ブチル-3-(4-クロロ-3-フルオロフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１１：6-ブチル-3-[4-クロロ-3-(トリフルオロメチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１２：6-ブチル-3-(4-クロロ-2-フルオロフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１３：6-ブチル-2-メチル-3-[2-(ピペリジン-1-イル)ピリミジン-5-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１４：3-(4-tert-ブトキシ-3-フルオロフェニル)-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１５：6-ブチル-3-[4-(1,1-ジフルオロプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１６：6-ブチル-2-メチル-3-[4-(フェニルアセチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１７：3-[4-(ベンジルオキシ)-3-フルオロフェニル]-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１８：6-ブチル-2-メチル-3-[4-(モルホリン-4-イル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１１９：6-ブチル-2-メチル-3-[4-(ピロリジン-1-イルカルボニル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２０：6-ブチル-2-(フルオロメチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２１：6-ブチル-2-(ヒドロキシメチル)-3-[4-(トリフルオロメトキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２２：6-ブチル-3-[4-(トリフルオロメトキシ)フェニル]-2-(トリフルオロメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２３：6-ブチル-3-[3-フルオロ-4-(2-メチルプロパ-1-エン-1-イル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２４：3-[4-(ベンジルオキシ)-2-フルオロフェニル]-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２５：6-ブチル-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２６：6-ブチル-3-[4-(1,1-ジフルオロ-3-メチルブチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２７：6-ブチル-2-メチル-3-[1-(2-メチルプロピル)-1H-ピラゾール-4-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２８：6-ブチル-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１２９：3-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-2-メチル-6-(4,4,4-トリフルオロブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３０：3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-6-(4,4,4-トリフルオロブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３１：3-[4-(1,1-ジフルオロ-3-メチルブチル)フェニル]-2-メチル-6-(4,4,4-トリフルオロブチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３２：6-ブチル-3-[4-(1,1-ジフルオロ-2-メチルプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３３：6-ブチル-3-{4-[ジフルオロ(ピリジン-2-イル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３４：6-ブチル-3-[4-(1,1-ジフルオロ-2-フェニルエチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３５：6-ブチル-3-[4-(2,2-ジフルオロプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３６：6-ブチル-3-[6-(1,1-ジフルオロ-3-メチルブチル)ピリジン-3-イル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３７：6-ブチル-3-{6-[ジフルオロ(フェニル)メチル]ピリジン-3-イル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１３８：3-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)ベンズアミド
実施例１３９：3-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-N-メチルベンズアミド
実施例１４０：3-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-N,N-ジメチルベンズアミド
実施例１４１：6-ブチル-3-[4-(1,1-ジフルオロブチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４２：6-tert-ブチル-3-[4-(1,1-ジフルオロ-2-メチルプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４３：6-ブチル-3-[4-(ヒドロキシメチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４４：6-ブチル-3-{4-[ジフルオロ(1-メチルシクロプロピル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４５：6-(シクロプロピルメチル)-3-{4-[ジフルオロ(1-メチルシクロプロピル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４６：6-ブチル-3-(2-クロロ-4-フルオロフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４７：2-ブロモ-6-ブチル-3-(4-フェノキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４８：3-[4-(ベンジルオキシ)-3-フルオロフェニル]-6-(シクロブチルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１４９：3-[4-(ベンジルオキシ)-3-フルオロフェニル]-6-(2,2-ジメチルプロピル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　実施例１０２～１４９の化合物の構造式及び機器データを表８－１～８－１０に示す。 Using a method similar to that in Example 69, the compounds of Examples 102 to 149 were obtained.
Example 102: 6-Butyl-3- [4- (1,1-difluoroethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 103: 6-Butyl-3- [4- (cyclopropylcarbonyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 104: 2 -[4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) phenyl] -2-methylpropanenitrile Example 105 6-butyl-3- {4- [cyclopropyl (difluoro) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 106: 4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -N- (2-methylpropyl) benzamide Example 107 : N- [4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) benzi Acetamide Example 108: 4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -N-methylbenzamide Example 109: 4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -N, N-dimethylbenzamide Example 110: 6-Butyl-3- (4-chloro-3-fluorophenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 111: 6-Butyl- 3- [4-Chloro-3- (trifluoromethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 112: 6-Butyl- 3- (4-Chloro-2-fluorophenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 113: 6-Butyl-2-methyl- 3- [2- (Piperidin-1-yl) pyrimidin-5-yl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 1 4: 3- (4-tert-Butoxy-3-fluorophenyl) -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 115: 6-Butyl-3- [4- (1,1-difluoropropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 116: 6 -Butyl-2-methyl-3- [4- (phenylacetyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 117: 3- [4- ( [Benzyloxy) -3-fluorophenyl] -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 118: 6-Butyl-2-methyl -3- [4- (morpholin-4-yl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 119: 6-Butyl-2-methyl-3 -[4- (Pyrrolidin-1-ylcarbonyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 120: 6-Butyl-2- ( Fluoromethyl) -3- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 121: 6-Butyl-2- (hydroxymethyl) ) -3- [4- (Trifluoromethoxy) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 122: 6-Butyl-3- [4- ( Trifluoromethoxy) phenyl] -2- (trifluoromethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 123: 6-Butyl-3- [3-fluoro -4- (2-Methylprop-1-en-1-yl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 124: 3- [4- (Benzyloxy) -2-fluorophenyl] -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 125: 6-Butyl -3- {4- [Difluoro (phenyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Dazol-7-one Example 126: 6-Butyl-3- [4- (1,1-difluoro-3-methylbutyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5- a] imidazol-7-one Example 127: 6-Butyl-2-methyl-3- [1- (2-methylpropyl) -1H-pyrazol-4-yl] -5,6-dihydro-7H-imidazo [ 1,5-a] imidazol-7-one Example 128: 6-Butyl-3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5- a] imidazol-7-one Example 129: 3- {4- [cyclopropyl (difluoro) methyl] phenyl} -2-methyl-6- (4,4,4-trifluorobutyl) -5,6-dihydro -7H-imidazo [1,5-a] imidazol-7-one Example 130: 3- {4- [Difluoro (phenyl) methyl] phenyl} -2-methyl-6- (4,4,4-trifluoro Butyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 131: 3- [4- (1,1-Difluoro-3-methylbutyl) fe Nyl] -2-methyl-6- (4,4,4-trifluorobutyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 132: 6-Butyl- 3- [4- (1,1-Difluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 133: 6 -Butyl-3- {4- [difluoro (pyridin-2-yl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 134 : 6-butyl-3- [4- (1,1-difluoro-2-phenylethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 135: 6-Butyl-3- [4- (2,2-difluoropropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 136: 6-Butyl-3- [6- (1,1-difluoro-3-methylbutyl) pyridin-3-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Imidazole-7-one Example 137: 6-butyl-3- {6- [difluoro (phenyl) methyl] pyridin-3-yl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On Example 138: 3- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) benzamide Example 139: 3- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -N-methylbenzamide Example 140: 3- (6-Butyl -2-Methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -N, N-dimethylbenzamide Example 141: 6-Butyl-3- [4 -(1,1-Difluorobutyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 142: 6-tert-butyl-3- [ 4- (1,1-Difluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 143 6-Butyl-3- [4- (hydroxymethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 144: 6-Butyl-3 -{4- [Difluoro (1-methylcyclopropyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 145: 6- ( Cyclopropylmethyl) -3- {4- [difluoro (1-methylcyclopropyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 146: 6-Butyl-3- (2-chloro-4-fluorophenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 147: 2 -Bromo-6-butyl-3- (4-phenoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 148: 3- [4- (Benzyloxy) -3-Fluorophenyl] -6- (cyclobutylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] Midazol-7-one Example 149: 3- [4- (Benzyloxy) -3-fluorophenyl] -6- (2,2-dimethylpropyl) -2-methyl-5,6-dihydro-7H-imidazo [ 1,5-a] imidazol-7-one Structural formulas and instrument data of the compounds of Examples 102 to 149 are shown in Tables 8-1 to 8-10.
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
実施例１５０：6-(シクロブチルメチル)-3-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩 Example 150: 6- (cyclobutylmethyl) -3- {4- [cyclopropyl (difluoro) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole- 7-one hydrochloride
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
製造例１６で得られた3-ブロモ-6-(シクロブチルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（５０　ｍｇ）、製造例１８で得られた2-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン（５４　ｍｇ）、炭酸カリウム（７３　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（１２　ｍｇ）、１，４－ジオキサン（０．７５　ｍＬ）及び水（０．２５　ｍＬ）の混合物を１００　℃（オイルバス温度）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＝１００：０～９５：５）にて精製した。得られた固体の酢酸エチル（１．０　ｍＬ）溶液に室温にて４Ｍ　塩酸/酢酸エチル（０．５　ｍＬ）を滴下し、１０分間撹拌した。反応液を減圧下濃縮して、表題化合物（１０　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ　ppm 0.66 - 0.75 (4 H, m) 1.70 - 1.88 (6 H, m) 1.99 - 2.07 (2 H, m) 2.40 (3 H, s) 2.60 - 2.68 (2 H, m) 5.62 (2 H, s) 7.67 - 7.73 (4 H, m)；　MS　(ESI pos) m/z : 372 [M+H]+   3-bromo-6- (cyclobutylmethyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (50 mg) obtained in Production Example 16 2- {4- [cyclopropyl (difluoro) methyl] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg), potassium carbonate (73 mg) obtained in Example 18 ), PEPPSI®-IPr (12 mg), 1,4-dioxane (0.75 mL) and water (0.25 mL) were stirred at 100 ° C. (oil bath temperature) for 5 hours. Water was added to the reaction solution and extracted with chloroform. 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 = 100: 0 to 95: 5). 4M Hydrochloric acid / ethyl acetate (0.5 mL) was added dropwise to a solid ethyl acetate (1.0 mL) solution at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (10 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 0.66-0.75 (4 H, m) 1.70-1.88 (6 H, m) 1.99-2.07 (2 H, m) 2.40 (3 H, s) 2.60-2.68 ( 2 H, m) 5.62 (2 H, s) 7.67-7.73 (4 H, m); MS (ESI pos) m / z: 372 [M + H] +
実施例１５０と同様の手法を用いて、実施例１５１～１６０の化合物を得た。
実施例１５１：3-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-2-メチル-6-(プロパ-2-エン-1-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１５２：3-{4-[シクロプロピル(ジフルオロ)メチル]フェニル}-6-(シクロプロピルメチル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１５３：6-ブチル-3-[4-(1,1-ジフルオロ-2,2-ジメチルプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１５４：6-ブチル-3-{4-[シクロペンチル(ジフルオロ)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１５５：6-ブチル-3-(4-フルオロフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１５６：6-ブチル-2-メチル-3-(3-フェノキシフェニル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１５７：6-ブチル-3-[3-フルオロ-4-(ピリジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　２塩酸塩
実施例１５８：6-(シクロプロピルメチル)-3-[3-フルオロ-4-(ピリジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　２塩酸塩
実施例１５９：6-(シクロブチルメチル)-3-[3-フルオロ-4-(ピリジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　２塩酸塩
実施例１６０：6-(2,2-ジメチルプロピル)-3-[3-フルオロ-4-(ピリジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　２塩酸塩
実施例１５１～１６０の化合物の構造式及び機器データを表９－１～９－２に示す。 Using the same method as in Example 150, the compounds of Examples 151 to 160 were obtained.
Example 151 1: 3- {4- [cyclopropyl (difluoro) methyl] phenyl} -2-methyl-6- (prop-2-en-1-yl) -5,6-dihydro-7H-imidazo [1, 5-a] imidazol-7-one hydrochloride Example 152: 3- {4- [cyclopropyl (difluoro) methyl] phenyl} -6- (cyclopropylmethyl) -2-methyl-5,6-dihydro-7H -Imidazo [1,5-a] imidazol-7-one hydrochloride Example 153: 6-Butyl-3- [4- (1,1-difluoro-2,2-dimethylpropyl) phenyl] -2-methyl- 5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride Example 154: 6-Butyl-3- {4- [cyclopentyl (difluoro) methyl] phenyl} -2-methyl- 5,6-Dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride Example 155: 6-Butyl-3- (4-fluorophenyl) -2-methyl-5,6-dihydro- 7H-imidazo [1,5-a] imidazol-7-one hydrochloride Example 156: 6-Butyl-2-methyl-3- ( 3-phenoxyphenyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride Example 157: 6-Butyl-3- [3-fluoro-4- (pyridine-3) -Yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one dihydrochloride Example 158: 6- (cyclopropylmethyl) -3- [3 -Fluoro-4- (pyridin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one dihydrochloride Example 159: 6- ( Cyclobutylmethyl) -3- [3-fluoro-4- (pyridin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 2 Hydrochloride Example 160: 6- (2,2-Dimethylpropyl) -3- [3-fluoro-4- (pyridin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [ 1,5-a] imidazol-7-one dihydrochloride Structural formulas and instrument data of the compounds of Examples 151-160 Tables 9-1 and 9-2 show the data.
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
実施例１６1：6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩　及び6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩 Example 161 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On hydrochloride and 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloric acid salt
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000070
 １）2-ブロモ-6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　製造例１６で得られた2,3-ジブロモ-6-(シクロプロピルメチル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１００　ｍｇ）、2-(1,1-ジフルオロ-3-メチルブチル)-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン（１０３　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（３４　ｍｇ）、エタノール（０．６　ｍＬ）、トルエン（０．６　ｍＬ）及び水（０．４　ｍＬ）の混合物を１００　℃（オイルバス温度）にて５時間撹拌した。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＝１００：０～９５：５）にて精製して、表題化合物（１４０　ｍｇ）をアモルファスとして得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.31 - 0.35 (2 H, m) 0.61 - 0.68 (2 H, m) 1.00 - 1.07 (1 H, m) 3.50 (2 H, d, J=7.0 Hz) 5.46 (2 H, s) 7.44 - 7.48 (3 H, m) 7.55 (2 H, dd, J=7.2, 1.9 Hz) 7.65 - 7.70 (4 H, m); MS (ESI pos) m/z : 458 [M+H]+
２）6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩　及び6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
2-ブロモ-6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（７０　ｍｇ）、2,4,6-トリメチルボロキシン（１９　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（２１　ｍｇ）、炭酸セシウム（４２　ｍｇ）及Ｎ，Ｎ－ジメチルホルムアミド（１．０　ｍＬ）の混合物を１００　℃（オイルバス温度）にて５時間撹拌した。反応液を酢酸エチルにて希釈し、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、クロロホルム：メタノール＝１００：０～９５：５）及び逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製した。得られた6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オンの酢酸エチル（１．０　ｍＬ）溶液に室温にて４Ｍ　塩酸/酢酸エチル（０．５　ｍＬ）を滴下し、１０分間撹拌した。固体をろ取し、ジイソプロピルエーテルにて洗浄して、6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩　（１５　ｍｇ）を無色固体として得た。また、得られた6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オンの酢酸エチル（１．０　ｍＬ）溶液に室温にて４Ｍ　塩酸/酢酸エチル（０．５　ｍＬ）を滴下し、１０分間撹拌した。固体をろ取し、ジイソプロピルエーテルにて洗浄して、6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩（２．１　ｍｇ）を無色固体として得た。
6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
1H NMR (600 MHz, DMSO-d6) δ　ppm 0.31 (2 H, d, J=4.1 Hz) 0.50 (2 H, d, J=7.4 Hz) 1.01 - 1.12 (1 H, m) 2.41 (3 H, s) 3.36 (2 H, d, J=7.0 Hz) 5.75 (2 H, s) 6.55 (1 H, s) 7.50 - 7.63 (4 H, m) 7.64 - 7.79 (4 H, m) ; MS (ESI pos) m/z : 394 [M+H]+
6-(シクロプロピルメチル)-3-{4-[ジフルオロ(フェニル)メチル]フェニル}-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン 塩酸塩
1H NMR (600 MHz, DMSO-d6) δ　ppm 0.29 - 0.37 (2 H, m) 0.47 - 0.57 (2 H, m) 1.06 - 1.16 (1 H, m) 3.40 (2 H, s) 5.86 (2 H, s) 7.47 - 7.68 (7 H, m) 7.78 - 7.89 (3 H, m) ; MS (ESI pos) m/z : 380 [M+H]+
Figure JPOXMLDOC01-appb-C000070
 1) 2-Bromo-6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 2,3-Dibromo-6- (cyclopropylmethyl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (100 mg) obtained in Preparation Example 16, 2- ( 1,1-difluoro-3-methylbutyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (103 mg), tetrakis (triphenylphosphine) palladium A mixture of (0) (34 mg), ethanol (0.6 mL), toluene (0.6 mL) and water (0.4 mL) was stirred at 100 ° C. (oil bath temperature) for 5 hours. Water was added to the reaction solution and extracted with chloroform. 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 = 100: 0 to 95: 5) to obtain the title compound (140 mg) as amorphous.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.31-0.35 (2 H, m) 0.61-0.68 (2 H, m) 1.00-1.07 (1 H, m) 3.50 (2 H, d, J = 7.0 Hz ) 5.46 (2 H, s) 7.44-7.48 (3 H, m) 7.55 (2 H, dd, J = 7.2, 1.9 Hz) 7.65-7.70 (4 H, m); MS (ESI pos) m / z: 458 [M + H] +
2) 6- (Cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Hydrochloride and 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride
2-Bromo-6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (70 mg), 2,4,6-trimethylboroxine (19 mg), PEPPSI®-IPr (21 mg), cesium carbonate (42 mg) and N, N-dimethylformamide (1.0 mL) Was stirred at 100 ° C. (oil bath temperature) for 5 hours. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 95: 5) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90:10 to 0: 100). The resulting 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7- 4M Hydrochloric acid / ethyl acetate (0.5 mL) was added dropwise to an ethyl acetate (1.0 mL) solution at room temperature, and the mixture was stirred for 10 minutes. The solid was collected by filtration and washed with diisopropyl ether to give 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride (15 mg) was obtained as a colorless solid. In addition, the obtained 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one To a solution of ethyl acetate (1.0 mL), 4M hydrochloric acid / ethyl acetate (0.5 mL) was added dropwise at room temperature, and the mixture was stirred for 10 minutes. The solid was collected by filtration and washed with diisopropyl ether to give 6- (cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5 -a] imidazol-7-one hydrochloride (2.1 mg) was obtained as a colorless solid.
6- (Cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride
1H NMR (600 MHz, DMSO-d6) δ ppm 0.31 (2 H, d, J = 4.1 Hz) 0.50 (2 H, d, J = 7.4 Hz) 1.01-1.12 (1 H, m) 2.41 (3 H, s) 3.36 (2 H, d, J = 7.0 Hz) 5.75 (2 H, s) 6.55 (1 H, s) 7.50-7.63 (4 H, m) 7.64-7.79 (4 H, m); MS (ESI pos) m / z: 394 [M + H] +
6- (Cyclopropylmethyl) -3- {4- [difluoro (phenyl) methyl] phenyl} -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride
1H NMR (600 MHz, DMSO-d6) δ ppm 0.29-0.37 (2 H, m) 0.47-0.57 (2 H, m) 1.06-1.16 (1 H, m) 3.40 (2 H, s) 5.86 (2 H , s) 7.47-7.68 (7 H, m) 7.78-7.89 (3 H, m); MS (ESI pos) m / z: 380 [M + H] +
実施例１６１と同様の手法を用いて、実施例１６２の化合物を得た。
実施例１６２：6-(シクロプロピルメチル)-3-[4-(1,1-ジフルオロ-2-メチルプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン The compound of Example 162 was obtained in the same manner as in Example 161.
Example 162: 6- (cyclopropylmethyl) -3- [4- (1,1-difluoro-2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5- a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000071
 1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.30 - 0.35 (2 H, m) 0.60 - 0.64 (2 H, m) 1.03 - 1.06 (7 H, m) 2.32 - 2.42 (1 H, m) 2.49 (3 H, s) 3.50 (2 H, d, J=7.4 Hz) 5.42 (2 H, s) 7.47 (2 H, d, J=8.3 Hz) 7.57 (2 H, d, J=8.3 Hz); MS (ESI pos) m/z : 360 [M+H]+
Figure JPOXMLDOC01-appb-C000071
 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.30-0.35 (2 H, m) 0.60-0.64 (2 H, m) 1.03-1.06 (7 H, m) 2.32-2.42 (1 H, m) 2.49 ( 3 H, s) 3.50 (2 H, d, J = 7.4 Hz) 5.42 (2 H, s) 7.47 (2 H, d, J = 8.3 Hz) 7.57 (2 H, d, J = 8.3 Hz); MS (ESI pos) m / z: 360 [M + H] +
実施例１６３：6-ブチル-3-[3-フルオロ-4-(2-メチルプロピル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　 Example 163: 6-butyl-3- [3-fluoro-4- (2-methylpropyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7- ON
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
実施例１２３で得られた6-ブチル-3-[3-フルオロ-4-(2-メチルプロパ-1-エン-1-イル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２８　ｍｇ）の酢酸エチル（１．０　ｍＬ）溶液に１０％パラジウム炭素（１０　ｍｇ）を加え、水素雰囲気下、室温にて７５分間撹拌した。反応液をセライト（登録商標）ろ過後、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、ヘキサン：酢酸エチル＝６０：４０～３０：７０）にて精製して、表題化合物（２５　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.93 - 0.98 (9 H, m), 1.36 - 1.43 (2 H, m), 1.61 - 1.68 (2 H, m), 1.91 - 1.98 (1 H, m), 2.47 (3 H, s), 2.56 (2 H, d, J=7.0 Hz), 3.61 (2 H, t, J=7.4 Hz), 5.30 (2 H, s), 7.04 - 7.12 (2 H, m), 7.24 - 7.28 (1 H, m); MS  (ESI pos) m/z : 344 [M+H]+
実施例１６３と同様の手法を用いて、実施例１６４～１６７の化合物を得た。
実施例１６４：6-ブチル-3-(2-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１６５：6-(シクロプロピルメチル)-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１６６：6-(シクロブチルメチル)-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１６７：6-(2,2-ジメチルプロピル)-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１６４～１６７の化合物の構造式及び機器データを表１０に示す。 6-Butyl-3- [3-fluoro-4- (2-methylprop-1-en-1-yl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo obtained in Example 123 To a solution of 1,5-a] imidazol-7-one (28 mg) in ethyl acetate (1.0 mL) was added 10% palladium carbon (10 mg), and the mixture was stirred at room temperature for 75 minutes in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 60: 40-30: 70) to give the title compound (25 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93-0.98 (9 H, m), 1.36-1.43 (2 H, m), 1.61-1.68 (2 H, m), 1.91-1.98 (1 H, m ), 2.47 (3 H, s), 2.56 (2 H, d, J = 7.0 Hz), 3.61 (2 H, t, J = 7.4 Hz), 5.30 (2 H, s), 7.04-7.12 (2 H , m), 7.24-7.28 (1 H, m); MS (ESI pos) m / z: 344 [M + H] +
Using the same method as in Example 163, the compounds of Examples 164 to 167 were obtained.
Example 164: 6-Butyl-3- (2-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 165: 6- (Cyclopropylmethyl) -3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 166: 6- (Cyclobutylmethyl) -3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 167: 6- (2,2-dimethylpropyl) -3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one The structural formulas and instrument data of the compounds of Examples 164 to 167 are shown in Table 10.
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
実施例１６８：6-ブチル-3-[3-フルオロ-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　 Example 168: 6-butyl-3- [3-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a ] Imidazole-7-one
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
実施例１２８で得られた6-ブチル-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２０　ｍｇ）、テトラヒドロ-2H-ピラン-4-オール（１５　ｍｇ）及びトリフェニルホスフィン（３９　ｍｇ）のテトラヒドロフラン（１．０　ｍＬ）溶液に、室温にてアゾジカルボン酸ジイソプロピル（８０　μＬ、１．９Ｍ　トルエン溶液）を滴下した後、１２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た後、酢酸エチルにて抽出した。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ＴＬＣ（シリカゲルプレート、クロロホルム：メタノール＝９：１）及び逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製して、表題化合物（７．２　ｍｇ）をアモルファスとして得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.96 (3 H, t, J=7.2 Hz), 1.34 - 1.46 (2 H, m), 1.60 - 1.69 (2 H, m), 1.80 - 1.92 (2 H, m), 2.00 - 2.12 (2 H, m), 2.44 (3 H, s), 3.55 - 3.67 (4 H, m), 3.98 - 4.06 (2 H, m), 4.50 - 4.59 (1 H, m), 5.26 (2 H, s), 7.06 - 7.18 (3 H, m); MS (ESI pos) m/z : 388 [M+H]+
実施例１６８と同様の手法を用いて、実施例１６９～１７３の化合物を得た。
実施例１６９：6-ブチル-3-[4-(シクロペンチルオキシ)-2-フルオロフェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１７０：6-ブチル-3-[4-(シクロペンチルオキシ)-3-フルオロフェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１７１：6-ブチル-3-[2-フルオロ-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１７２：6-(シクロプロピルメチル)-3-[3-フルオロ-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１７３：6-(シクロプロピルメチル)-3-[2-フルオロ-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１６９～１７３の化合物の構造式及び機器データを表１１に示す。 6-Butyl-3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Example 128 ( 20 mg), tetrahydro-2H-pyran-4-ol (15 mg) and triphenylphosphine (39 mg) in tetrahydrofuran (1.0 mL) at room temperature and diisopropyl azodicarboxylate (80 μL, 1.9 M). The solution was stirred for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to TLC (silica gel plate, chloroform: methanol = 9: 1) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100) to give the title compound (7.2 mg) as amorphous.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.2 Hz), 1.34-1.46 (2 H, m), 1.60-1.69 (2 H, m), 1.80-1.92 (2 H, m), 2.00-2.12 (2 H, m), 2.44 (3 H, s), 3.55-3.67 (4 H, m), 3.98-4.06 (2 H, m), 4.50-4.59 (1 H, m), 5.26 (2 H, s), 7.06-7.18 (3 H, m); MS (ESI pos) m / z: 388 [M + H] +
Using the same method as in Example 168, the compounds of Examples 169 to 173 were obtained.
Example 169: 6-butyl-3- [4- (cyclopentyloxy) -2-fluorophenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 170: 6-Butyl-3- [4- (cyclopentyloxy) -3-fluorophenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 171: 6-Butyl-3- [2-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole -7-one hydrochloride Example 172: 6- (cyclopropylmethyl) -3- [3-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl] -2-methyl-5,6-dihydro -7H-imidazo [1,5-a] imidazol-7-one Example 173: 6- (Cyclopropylmethyl) -3- [2-fluoro-4- (tetrahydro-2H-pyran-4-yloxy) phenyl] -2-Methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one Structure and equipment data of the compound of 施例 169-173 shown in Table 11.
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
実施例１７４：6-ブチル-2-メチル-3-[4-(ピペラジン-1-イルメチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　 Example 174: 6-Butyl-2-methyl-3- [4- (piperazin-1-ylmethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
１）tert-ブチル 4-[4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)ベンジル]ピペラジン-1-カルボキシラート
製造例７で得られた3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（８０　ｍｇ）、tert-ブチル 4-[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル]ピペラジン-1-カルボキシラート（１４２　ｍｇ）、炭酸カリウム（１２２　ｍｇ）、ＰＥＰＰＳＩ（登録商標）－ＩＰｒ（２０　ｍｇ）、エタノール（０．３８　ｍＬ）、トルエン（０．３８　ｍＬ）及び水（０．２５　ｍＬ）の混合物を１００　℃（オイルバス温度）にて１時間攪拌した。反応液に水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝６０：４０～１５：８５）にて精製し、表題化合物（１３０　ｍｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.95 (3 H, t, J=7.2 Hz), 1.36 - 1.43 (2 H, m), 1.46 (9 H, s), 1.61 - 1.67 (2 H, m), 2.40 - 2.44 (4 H, m), 2.47 (3 H, s), 3.43 - 3.47 (4 H, m), 3.55 (2 H, s), 3.61 (2 H, t, J=7.4 Hz), 5.29 (2 H, s), 7.35 - 7.38 (2 H, m), 7.42 - 7.46 (2 H, m); MS (ESI pos) m/z : 468 [M+H]+
２）6-ブチル-2-メチル-3-[4-(ピペラジン-1-イルメチル)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
　tert-ブチル 4-[4-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)ベンジル]ピペラジン-1-カルボキシラート（１３４　ｍｇ）のクロロホルム（２．０　ｍＬ）溶液に、氷浴冷却下にてトリフルオロ酢酸（１．０　ｍＬ）を滴下した後、２時間攪拌した。氷浴冷却下にて反応液に１Ｍ　水酸化ナトリウム水溶液を加え中和した後、クロロホルムにて１０回抽出した。合わせた有機層を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（ＮＨシリカゲルカートリッジ、クロロホルム：メタノール＝９７：３～９５：５）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, CHLOROFORM-d) δ　ppm 0.95 (3 H, t, J=7.4 Hz), 1.35 - 1.43 (2 H, m), 1.60 - 1.67 (2 H, m), 2.43 - 2.50 (7 H, m), 2.90 - 2.94 (4 H, m), 3.54 (2 H, s), 3.61 (2 H, t, J=7.4 Hz), 5.28 (2 H, s), 7.34 - 7.37 (2 H, m), 7.43 - 7.46 (2 H, m) ; MS (ESI pos) m/z : 368 [M+H]+ 1) tert-butyl 4- [4- (6-butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) benzyl] piperazine-1 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (80 mg), tert- Butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl] piperazine-1-carboxylate (142 mg), potassium carbonate (122 mg), A mixture of PEPPSI®-IPr (20 mg), ethanol (0.38 mL), toluene (0.38 mL) and water (0.25 mL) was stirred at 100 ° C. (oil bath temperature) for 1 hour. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 60: 40-15: 85) to give the title compound (130 mg) as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, t, J = 7.2 Hz), 1.36-1.43 (2 H, m), 1.46 (9 H, s), 1.61-1.67 (2 H, m), 2.40-2.44 (4 H, m), 2.47 (3 H, s), 3.43-3.47 (4 H, m), 3.55 (2 H, s), 3.61 (2 H, t, J = 7.4 Hz ), 5.29 (2 H, s), 7.35-7.38 (2 H, m), 7.42-7.46 (2 H, m); MS (ESI pos) m / z: 468 [M + H] +
2) 6-Butyl-2-methyl-3- [4- (piperazin-1-ylmethyl) phenyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one tert-butyl 4 -[4- (6-Butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) benzyl] piperazine-1-carboxylate (134 mg ) In chloroform (2.0 mL) was added dropwise trifluoroacetic acid (1.0 mL) with cooling in an ice bath and stirred for 2 hours. The reaction solution was neutralized by adding a 1M aqueous sodium hydroxide solution while cooling in an ice bath, and extracted 10 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel cartridge, chloroform: methanol = 97: 3-95: 5) to obtain the title compound (17 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 (3 H, t, J = 7.4 Hz), 1.35-1.43 (2 H, m), 1.60-1.67 (2 H, m), 2.43-2.50 (7 H, m), 2.90-2.94 (4 H, m), 3.54 (2 H, s), 3.61 (2 H, t, J = 7.4 Hz), 5.28 (2 H, s), 7.34-7.37 (2 H , m), 7.43-7.46 (2 H, m); MS (ESI pos) m / z: 368 [M + H] +
実施例１７５：6-ブチル-2-メチル-3-(5-フェニルピリジン-2-イル)-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン Example 175: 6-Butyl-2-methyl-3- (5-phenylpyridin-2-yl) -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
製造例７で得られた3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３０　ｍｇ）、製造例２１で得られた5-フェニル-2-(トリブチルスタンナニル)ピリジン（５９　ｍｇ）、テトラキス(トリフェニルホスフィン)パラジウム(０)（２５　ｍｇ）及びトルエン（１．０　ｍＬ）の混合物を１１０　℃（オイルバス温度）にて１４時間攪拌した。反応液をセライト（登録商標）ろ過後、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、ヘキサン：酢酸エチル＝７０：３０～２５：７５）及び逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製し、表題化合物（１６　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.98 (3 H, t, J=7.4 Hz), 1.39 - 1.47 (2 H, m), 1.68 - 1.74 (2 H, m), 2.70 (3 H, s), 3.66 (2 H, t, J=7.4 Hz), 5.65 (2 H, s), 7.42 - 7.46 (1 H, m), 7.50 - 7.54 (2 H, m), 7.61 - 7.64 (2 H, m), 7.72 (1 H, d, J=8.3 Hz), 7.97 - 8.01 (1 H, m), 8.86 - 8.88 (1 H, m)；　MS (ESI pos) m/z : 347 [M+H]+ 3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (30 mg) obtained in Preparation Example 7, obtained in Preparation Example 21 A mixture of 5-phenyl-2- (tributylstannanyl) pyridine (59 mg), tetrakis (triphenylphosphine) palladium (0) (25 mg) and toluene (1.0 mL) was added at 110 ° C. (oil bath temperature). ) For 14 hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30 to 25:75) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile. = 90:10 to 0: 100) to give the title compound (16 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.39-1.47 (2 H, m), 1.68-1.74 (2 H, m), 2.70 (3 H, s), 3.66 (2 H, t, J = 7.4 Hz), 5.65 (2 H, s), 7.42-7.46 (1 H, m), 7.50-7.54 (2 H, m), 7.61-7.64 (2 H , m), 7.72 (1 H, d, J = 8.3 Hz), 7.97-8.01 (1 H, m), 8.86-8.88 (1 H, m); MS (ESI pos) m / z: 347 [M + H] +
実施例１７６：エチル 5-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-1,2-オキサゾール-3-カルボキシラート Example 176: Ethyl 5- (6-butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -1,2-oxazole-3 -Carboxylate
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
１）6-ブチル-2-メチル-3-[(トリメチルシリル)エチニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
製造例７で得られた3-ブロモ-6-ブチル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２００　ｍｇ）、トリメチルシリルアセチレン（０．１２５　ｍＬ）、ビス(トリフェニルホスフィン)パラジウム(ＩＩ)ジクロリド（５２　ｍｇ）、トリフェニルホスフィン（１９　ｍｇ）、ヨウ化銅　（Ｉ）（５　ｍｇ）、トリエチルアミン（０．１５４　ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（２．０　ｍＬ）の混合物を７５　℃（オイルバス温度）にて３時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝７０：３０～６０：４０）にて精製して、表題化合物（１９６　ｍｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.27 (9 H, s), 0.96 (3 H, t, J=7.2 Hz), 1.35 - 1.42 (2 H, m), 1.61 - 1.67 (2 H, m), 2.38 (3 H, s), 3.59 (2 H, t, J=7.4 Hz), 5.21 (2 H, s); MS (ESI pos) m/z : 290 [M+H]+
２）6-ブチル-3-エチニル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
6-ブチル-2-メチル-3-[(トリメチルシリル)エチニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（１９６　ｍｇ）のエタノール（２．０　ｍＬ）溶液に、室温にて０．１Ｍ　水酸化カリウム水溶液（０．５００　ｍＬ）を加えた後、３５分間攪拌した。反応液を減圧下濃縮し、水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝７０：３０～４０：６０）にて精製して、表題化合物（９７　ｍｇ）を褐色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.96 (3 H, t, J=7.4 Hz), 1.36 - 1.43 (2 H, m), 1.61 - 1.67 (2 H, m), 2.40 (3 H, s), 3.60 (2 H, t, J=7.4 Hz), 3.63 (1 H, s), 5.22 (2 H, s)
３）エチル 5-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-1,2-オキサゾール-3-カルボキシラート
　6-ブチル-3-エチニル-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
（５５　ｍｇ）の酢酸エチル（２．０　ｍＬ）及び水（０．５０　ｍＬ）溶液に、室温にて炭酸水素カリウム（２５３　ｍｇ）及び2-クロロ-2-(ヒドロキシイミノ)酢酸エチル（１５３　ｍｇ）を加え、６時間撹拌した。反応液に水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝９０：１０～５０：５０）にて精製して、表題化合物（７２　ｍｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.98 (3 H, t, J=7.2 Hz), 1.38 - 1.48 (5 H, m), 1.66 - 1.72 (2 H, m), 2.57 (3 H, s), 3.66 (2 H, t, J=7.4 Hz), 4.50 (2 H, q, J=7.2 Hz), 5.53 (2 H, s), 6.79 (1 H, s); MS (ESI pos) m/z : 333 [M+H]+ 1) 6-butyl-2-methyl-3-[(trimethylsilyl) ethynyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one 3-bromo obtained in Preparation Example 7 -6-butyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (200 mg), trimethylsilylacetylene (0.125 mL), bis (triphenylphosphine) Of palladium (II) dichloride (52 mg), triphenylphosphine (19 mg), copper (I) iodide (5 mg), triethylamine (0.154 mL) and N, N-dimethylformamide (2.0 mL). The mixture was stirred at 75 ° C. (oil bath temperature) for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30-60: 40) to give the title compound (196 mg) as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.27 (9 H, s), 0.96 (3 H, t, J = 7.2 Hz), 1.35-1.42 (2 H, m), 1.61-1.67 (2 H, m), 2.38 (3 H, s), 3.59 (2 H, t, J = 7.4 Hz), 5.21 (2 H, s); MS (ESI pos) m / z: 290 [M + H] +
2) 6-Butyl-3-ethynyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one
6-Butyl-2-methyl-3-[(trimethylsilyl) ethynyl] -5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (196 mg) in ethanol (2.0 mL) A 0.1 M aqueous potassium hydroxide solution (0.500 mL) was added to the solution at room temperature, and the mixture was stirred for 35 minutes. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30-40: 60) to give the title compound (97 mg) as a brown solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.96 (3 H, t, J = 7.4 Hz), 1.36-1.43 (2 H, m), 1.61-1.67 (2 H, m), 2.40 (3 H, s), 3.60 (2 H, t, J = 7.4 Hz), 3.63 (1 H, s), 5.22 (2 H, s)
3) Ethyl 5- (6-butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -1,2-oxazole-3-carboxy Rat 6-butyl-3-ethynyl-2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (55 mg) in ethyl acetate (2.0 mL) and water ( To the 0.50 mL) solution were added potassium bicarbonate (253 mg) and ethyl 2-chloro-2- (hydroxyimino) acetate (153 mg) at room temperature, and the mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 (72 mg) as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.2 Hz), 1.38-1.48 (5 H, m), 1.66-1.72 (2 H, m), 2.57 (3 H, s), 3.66 (2 H, t, J = 7.4 Hz), 4.50 (2 H, q, J = 7.2 Hz), 5.53 (2 H, s), 6.79 (1 H, s); MS (ESI pos) m / z: 333 [M + H] +
実施例１７７：6-ブチル-2-メチル-3-[3-(フェノキシメチル)-1,2-オキサゾール-5-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　 Example 177: 6-Butyl-2-methyl-3- [3- (phenoxymethyl) -1,2-oxazol-5-yl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole -7-on
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
１）6-ブチル-3-[3-(ヒドロキシメチル)-1,2-オキサゾール-5-イル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１７６で得られたエチル 5-(6-ブチル-2-メチル-7-オキソ-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-3-イル)-1,2-オキサゾール-3-カルボキシラート（７０　ｍｇ）のエタノール（２．３　ｍＬ）溶液に、室温にて水素化ホウ素ナトリウム（２４　ｍｇ）を加え、１時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、クロロホルムにて抽出した。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＝１００：０～９７：３）にて精製して、表題化合物（５４　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.98 (3 H, t, J=7.4 Hz), 1.38 - 1.45 (2 H, m), 1.65 - 1.71 (2 H, m), 2.54 (3 H, s), 3.65 (2 H, t, J=7.2 Hz), 4.85 (2 H, s), 5.52 (2 H, s), 6.49 (1 H, s)；MS (ESI pos) m/z : 291 [M+H]+
２）6-ブチル-2-メチル-3-[3-(フェノキシメチル)-1,2-オキサゾール-5-イル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　
6-ブチル-3-[3-(ヒドロキシメチル)-1,2-オキサゾール-5-イル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（２３　ｍｇ）、フェノール（９　ｍｇ）及びトリフェニルホスフィン（２５　ｍｇ）のテトラヒドロフラン（２．０　ｍＬ）溶液に、室温にてアゾジカルボン酸ジイソプロピル（５０　μＬ、１．９Ｍ　トルエン溶液）を滴下した後、１時間攪拌した。反応液に水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝９０：１０～３５：６５）及びＴＬＣ（ＮＨシリカゲルプレート、ヘキサン：酢酸エチル＝１：２）にて精製して、表題化合物（１１　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.98 (3 H, t, J=7.4 Hz), 1.38 - 1.45 (2 H, m), 1.65 - 1.71 (2 H, m), 2.54 (3 H, s), 3.65 (2 H, t, J=7.4 Hz), 5.21 (2 H, s), 5.52 (2 H, s), 6.53 (1 H, s), 6.99 - 7.04 (3 H, m), 7.30 - 7.35 (2 H, m); MS (ESI pos) m/z : 367 [M+H]+ 1) 6-Butyl-3- [3- (hydroxymethyl) -1,2-oxazol-5-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On ethyl 5- (6-butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo [1,5-a] imidazol-3-yl) -1, obtained in Example 176 To a solution of 2-oxazole-3-carboxylate (70 mg) in ethanol (2.3 mL) was added sodium borohydride (24 mg) at room temperature and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. 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 = 100: 0 to 97: 3) to obtain the title compound (54 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.38-1.45 (2 H, m), 1.65-1.71 (2 H, m), 2.54 (3 H, s), 3.65 (2 H, t, J = 7.2 Hz), 4.85 (2 H, s), 5.52 (2 H, s), 6.49 (1 H, s); MS (ESI pos) m / z: 291 [M + H] +
2) 6-Butyl-2-methyl-3- [3- (phenoxymethyl) -1,2-oxazol-5-yl] -5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -on
6-Butyl-3- [3- (hydroxymethyl) -1,2-oxazol-5-yl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one (23 mg), phenol (9 mg) and triphenylphosphine (25 mg) in tetrahydrofuran (2.0 mL) were added dropwise with diisopropyl azodicarboxylate (50 μL, 1.9 M toluene solution) at room temperature. Stir for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 to 35:65) and TLC (NH silica gel plate, hexane: ethyl acetate = 1: 2) to give the title compound (11 mg) Was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (3 H, t, J = 7.4 Hz), 1.38-1.45 (2 H, m), 1.65-1.71 (2 H, m), 2.54 (3 H, s), 3.65 (2 H, t, J = 7.4 Hz), 5.21 (2 H, s), 5.52 (2 H, s), 6.53 (1 H, s), 6.99-7.04 (3 H, m), 7.30-7.35 (2 H, m); MS (ESI pos) m / z: 367 [M + H] +
実施例１７８：6-ブチル-3-[4-(メトキシメチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩　 Example 178: 6-butyl-3- [4- (methoxymethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one hydrochloride
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
窒素雰囲気下、実施例１４３で得られた6-ブチル-3-[4-(ヒドロキシメチル)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（５０　ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０　ｍＬ）溶液に、室温にて６０％水素化ナトリウム（７．４　ｍｇ）を加え１０分間撹拌した後、ヨウ化メチル（３６　ｍｇ）を加え３間攪拌した。反応液に水を加えた後、クロロホルムにて抽出した。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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製した。得られた固体の酢酸エチル（１．０　ｍＬ）溶液に、室温にて４Ｍ　塩酸/酢酸エチル（０．５　ｍＬ）を滴下し、１時間撹拌した。反応液を減圧下濃縮し、得られた固体をジイソプロピルエーテルにて洗浄して、表題化合物（８　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ　ppm 0.90 - 0.96 (3 H, m) 1.34 - 1.43 (2 H, m) 1.61 - 1.71 (2 H, m) 2.58 (3 H, s) 3.45 (3 H, s) 3.64 - 3.73 (2 H, m) 4.53 (2 H, s) 5.73 - 5.85 (2 H, m) 7.51 - 7.55 (2 H, m) 7.58 - 7.65 (2 H, m); MS (ESI pos) m/z : 314 [M+H]+ 6-Butyl-3- [4- (hydroxymethyl) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 obtained in Example 143 under nitrogen atmosphere -On (50 mg) in N, N-dimethylformamide (1.0 mL) was added 60% sodium hydride (7.4 mg) at room temperature and stirred for 10 minutes, then methyl iodide (36 mg ) Was added and stirred for 3 minutes. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100). To a solution of the obtained solid in ethyl acetate (1.0 mL), 4M hydrochloric acid / ethyl acetate (0.5 mL) was added dropwise at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (8 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.90-0.96 (3 H, m) 1.34-1.43 (2 H, m) 1.61-1.71 (2 H, m) 2.58 (3 H, s) 3.45 (3 H , s) 3.64-3.73 (2 H, m) 4.53 (2 H, s) 5.73-5.85 (2 H, m) 7.51-7.55 (2 H, m) 7.58-7.65 (2 H, m); MS (ESI pos) m / z: 314 [M + H] +
実施例１７９：6-ブチル-3-[3-フルオロ-4-(ピリジン-2-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩　 Example 179: 6-butyl-3- [3-fluoro-4- (pyridin-2-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On hydrochloride
Figure JPOXMLDOC01-appb-C000081
 実施例１２８で得られた6-ブチル-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（３０　ｍｇ）、２－ブロモピリジン（１６　ｍｇ）、ヨウ化銅　（Ｉ）（３　ｍｇ）、ピコリン酸（Ｉ）（３　ｍｇ）、リン酸カリウム（４２　ｍｇ）及びジメチルスルホキシド（１．０　ｍＬ）の混合物を１０５　℃（オイルバス温度）にて２４時間攪拌した。反応液に水を加えた後、酢酸エチルにて抽出した。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、ヘキサン：酢酸エチル＝７０：３０～３０：７０）にて精製した。得られた固体の酢酸エチル（１．０　ｍＬ）溶液に室温にて４Ｍ　塩酸/酢酸エチル（０．５　ｍＬ）を滴下し、１時間撹拌した。反応液を減圧下濃縮して、表題化合物（７　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) δ　ppm 0.91 (3 H, t, J=7.4 Hz), 1.28 - 1.36 (2 H, m), 1.57 - 1.63 (2 H, m), 2.41 (3 H, s), 3.49 (2 H, t, J=7.2 Hz), 5.67 (2 H, s), 7.15 - 7.20 (2 H, m), 7.45 - 7.50 (2 H, m), 7.60 - 7.65 (1 H, m), 7.89 - 7.93 (1 H, m), 8.12 - 8.15 (1 H, m); MS (ESI pos) m/z : 381 [M+H]+
実施例１７９と同様の手法を用いて、実施例１８０～１８３の化合物を得た。
実施例１８０：6-ブチル-3-[3-フルオロ-4-(ピリジン-4-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　２塩酸塩
実施例１８１：6-ブチル-2-メチル-3-[3-メチル-4-(ピリダジン-4-イルオキシ)フェニル]-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１８２：6-(シクロブチルメチル)-3-[3-フルオロ-4-(ピリジン-2-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１８３：6-(2,2-ジメチルプロピル)-3-[3-フルオロ-4-(ピリジン-2-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１８０～１８３の化合物の構造式及び機器データを表１２に示す。
Figure JPOXMLDOC01-appb-C000081
 6-Butyl-3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Example 128 ( 30 mg), 2-bromopyridine (16 mg), copper (I) iodide (3 mg), picolinic acid (I) (3 mg), potassium phosphate (42 mg) and dimethyl sulfoxide (1.0 mL) The mixture was stirred at 105 ° C. (oil bath temperature) for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30 to 30:70). To a solution of the obtained solid in ethyl acetate (1.0 mL), 4M hydrochloric acid / ethyl acetate (0.5 mL) was added dropwise at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (7 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 0.91 (3 H, t, J = 7.4 Hz), 1.28-1.36 (2 H, m), 1.57-1.63 (2 H, m), 2.41 (3 H, s), 3.49 (2 H, t, J = 7.2 Hz), 5.67 (2 H, s), 7.15-7.20 (2 H, m), 7.45-7.50 (2 H, m), 7.60-7.65 (1 H , m), 7.89-7.93 (1 H, m), 8.12-8.15 (1 H, m); MS (ESI pos) m / z: 381 [M + H] +
The compounds of Examples 180 to 183 were obtained in the same manner as in Example 179.
Example 180: 6-butyl-3- [3-fluoro-4- (pyridin-4-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -One dihydrochloride Example 181: 6-Butyl-2-methyl-3- [3-methyl-4- (pyridazin-4-yloxy) phenyl] -5,6-dihydro-7H-imidazo [1,5- a] Imidazol-7-one hydrochloride Example 182: 6- (Cyclobutylmethyl) -3- [3-fluoro-4- (pyridin-2-yloxy) phenyl] -2-methyl-5,6-dihydro- 7H-imidazo [1,5-a] imidazol-7-one Example 183: 6- (2,2-Dimethylpropyl) -3- [3-fluoro-4- (pyridin-2-yloxy) phenyl] -2 -Methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one The structural formulas and instrumental data of the compounds of Examples 180-183 are shown in Table 12.
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
実施例１８４：6-ブチル-3-[3-フルオロ-4-(ピリダジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩　 Example 184: 6-butyl-3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -On hydrochloride
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
実施例１２８で得られた6-ブチル-3-(3-フルオロ-4-ヒドロキシフェニル)-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン（５０　ｍｇ）、３－クロロピリダジン（３８　ｍｇ）、炭酸カリウム（５７　ｍｇ）及びＮ，Ｎ－ジメチルホルムアミド（１．２　ｍＬ）の混合物を１００　℃（オイルバス温度）にて１８時間攪拌した。反応液に水を加えた後、クロロホルムにて抽出した。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。残渣を逆相カラムクロマトグラフィー（ＳｕｎＦｉｒｅ、０．１％トリフルオロ酢酸/水：０．１％トリフルオロ酢酸/アセトニトリル＝９０：１０～０：１００）にて精製した。得られた固体の酢酸エチル（１．０　ｍＬ）溶液に室温にて４Ｍ　塩酸/酢酸エチル（０．５　ｍＬ）を滴下し、１時間撹拌した。反応液を減圧下濃縮し、得られた固体をジイソプロピルエーテルにて洗浄して、表題化合物（２１　ｍｇ）を無色固体として得た。
1H NMR (600 MHz, DMSO-d6) d ppm 0.91 (3 H, t, J=7.2 Hz) 1.29 - 1.36 (2 H, m) 1.57 - 1.64 (2 H, m) 2.45 (3 H, s) 3.51 (2 H, t, J=7.2 Hz) 5.74 (2 H, s) 7.52 - 7.56 (1 H, m) 7.59 - 7.64 (1 H, m) 7.64 - 7.68 (1 H, m) 7.69 - 7.74 (1 H, m) 7.79 - 7.91 (1 H, m) 9.06 (1 H, d, J=3.3 Hz); MS (ESI pos) m/z : 382 [M+H]+
実施例１８４と同様の手法を用いて、実施例１８５～１８８の化合物を得た。
実施例１８５：6-ブチル-3-[3-フルオロ-4-(ピラジン-2-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１８６：6-(シクロプロピルメチル)-3-[3-フルオロ-4-(ピリダジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン　塩酸塩
実施例１８７：6-(シクロブチルメチル)-3-[3-フルオロ-4-(ピリダジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１８８：6-(2,2-ジメチルプロピル)-3-[3-フルオロ-4-(ピリダジン-3-イルオキシ)フェニル]-2-メチル-5,6-ジヒドロ-7H-イミダゾ[1,5-a]イミダゾール-7-オン
実施例１８５～１８８の化合物の構造式及び機器データを表１３に示す。 6-Butyl-3- (3-fluoro-4-hydroxyphenyl) -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one obtained in Example 128 ( 50 mg), 3-chloropyridazine (38 mg), potassium carbonate (57 mg) and N, N-dimethylformamide (1.2 mL) were stirred at 100 ° C. (oil bath temperature) for 18 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90: 10 to 0: 100). To a solution of the obtained solid in ethyl acetate (1.0 mL), 4M hydrochloric acid / ethyl acetate (0.5 mL) was added dropwise at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (21 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) d ppm 0.91 (3 H, t, J = 7.2 Hz) 1.29-1.36 (2 H, m) 1.57-1.64 (2 H, m) 2.45 (3 H, s) 3.51 (2 H, t, J = 7.2 Hz) 5.74 (2 H, s) 7.52-7.56 (1 H, m) 7.59-7.64 (1 H, m) 7.64-7.68 (1 H, m) 7.69-7.74 (1 H, m) 7.79-7.91 (1 H, m) 9.06 (1 H, d, J = 3.3 Hz); MS (ESI pos) m / z: 382 [M + H] +
Using the same method as in Example 184, the compounds of Examples 185 to 188 were obtained.
Example 185: 6-butyl-3- [3-fluoro-4- (pyrazin-2-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazole-7 -ONE Hydrochloride Example 186: 6- (Cyclopropylmethyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6-dihydro-7H-imidazo [1 , 5-a] imidazol-7-one hydrochloride Example 187: 6- (Cyclobutylmethyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl] -2-methyl-5,6 -Dihydro-7H-imidazo [1,5-a] imidazol-7-one Example 188: 6- (2,2-Dimethylpropyl) -3- [3-fluoro-4- (pyridazin-3-yloxy) phenyl ] -2-Methyl-5,6-dihydro-7H-imidazo [1,5-a] imidazol-7-one The structural formula and instrument data of the compounds of Examples 185 to 188 are shown in Table 13.
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
　各実施例化合物は、ラット型もしくはヒト型ｍＧｌｕ２受容体に作用して、受容体反応を増強させた。
　試験例１　[35Ｓ]ＧＴＰγＳ結合試験（１）
（ラッ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）
　ラット型ｍＧｌｕ２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、１ｍＭ　ｓｏｄｉｕｍ　Ｐｙｒｕｖａ
ｔｅ、１ｍＭ　Ｓｕｃｃｉｎｉｃ　ａｃｉｄ、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。 Each Example compound acted on the rat-type or human-type mGlu2 receptor to enhance the receptor response.
Test Example 1 [ 35 S] GTPγS binding test (1)
(Preparation of crude membrane fraction of CHO cells stably expressing rat metabotropic glutamate receptor (mGlu2))
Rat-type mGlu2 stably expressing CHO cells were mixed with Dulbecco's modified Eagle's medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 μg / mL streptomycin, 1 mM sodium Pyruba.
te, 1 mM succinic acid, 2 mM L-glutamine (added when used)], 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 homogenizer, and centrifuged again at 4 ° C., 48,000 × g for 20 minutes, thereby again. Got sunk. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at −80 ° C.
（[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。
実施例化合物を膜タンパク質１０μｇ／ａｓｓａｙの膜画分に添加して、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３μＭ）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ＧＦ／Ｃフィルタ－上に吸引濾過し、氷冷２０ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）でＧＦ／Ｃフィルタ－を洗浄した。乾燥後、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。 ([ 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 3 μM) and [ 35 S] GTPγS (final concentration 0.15 nM) were added, and incubation was performed at 30 ° C. for 1 hour. After incubation, the reaction solution was suction filtered onto a GF / C filter, and the GF / C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a scintillation cocktail was added to the filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.
　上記反応において、グルタミン酸非存在下で得られた[35Ｓ]ＧＴＰγＳ結合量を非特異的結合量として、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量とした。３μＭグルタミン酸と様々な濃度における各実施例化合物共存下における特異的結合量との差から、各実施例化合物のＥＣ50値を非線形最小二乗法を用いた回帰曲線により算出した。 In the above reaction, the amount of [ 35 S] GTPγS binding obtained in the absence of glutamic acid is defined as the nonspecific binding amount, and the difference from the amount of [ 35 S] GTPγS binding obtained in the presence of glutamic acid is defined as the specific binding amount. did. From the difference between 3 μM glutamic acid and the specific binding amount in the presence of each compound at various concentrations, the EC 50 value of each compound was calculated by a regression curve using a nonlinear least square method.
　本発明化合物のＥＣ50値を表１４に例示する。 The EC 50 values of the compounds of the present invention are exemplified in Table 14.
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
試験例２　[35Ｓ]ＧＴＰγＳ結合試験（２）
(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、２ｍＭ Ｌ－ｇｌｕｔａｍｉｎｅ（用時添加）、４００μｇ／ｍＬ　ＨｙｇｒｏｍｙｃｉｎＢ（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℃、１，０００ｒｐｍ、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 2 [ 35 S] GTPγS binding test (2)
(Preparation of crude membrane fraction of CHO cells stably expressing human metabotropic glutamate receptor (mGlu2))
Human-type mGlu2 stably expressing CHO cells were treated with Dulbecco's modified Eagle's medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 μg / mL streptomycin, 2 mM L-glutamine (when added), 400 μg / mL Hygromycin B Was added at the time of use)] 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 1,000 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 homogenizer, and centrifuged again at 4 ° C., 48,000 × g for 20 minutes, thereby again. Got sunk. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at −80 ° C.
（[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。実施例化合物を膜タンパク質１０μｇ／ａｓｓａｙの膜画分に添加して、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１μＭ）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ＧＦ／Ｃフィルタ－上に吸引濾過し、氷冷２０ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）でＧＦ／Ｃフィルタ－を洗浄した。乾燥後、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。
　上記反応において、グルタミン酸非存在下で得られた[35Ｓ]ＧＴＰγＳ結合量を非特異的結合量として、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量とした。１μＭグルタミン酸と様々な濃度における各実施例化合物共存下における特異的結合量との差から、各実施例化合物のＥＣ50値を非線形最小二乗法を用いた回帰曲線により算出した。 ([ 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 1 μM) and [ 35 S] GTPγS (final concentration 0.15 nM) were added, and incubation was performed at 30 ° C. for 1 hour. After incubation, the reaction solution was suction filtered onto a GF / C filter, and the GF / C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a scintillation cocktail was added to the filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.
In the above reaction, the amount of [ 35 S] GTPγS binding obtained in the absence of glutamic acid is defined as the nonspecific binding amount, and the difference from the amount of [ 35 S] GTPγS binding obtained in the presence of glutamic acid is defined as the specific binding amount. did. From the difference between 1 μM glutamic acid and the specific binding amount in the presence of each compound at various concentrations, the EC 50 value of each compound was calculated by a regression curve using a nonlinear least square method.
　本発明化合物のＥＣ50値を表１５に例示する。 The EC 50 values of the compounds of the present invention are exemplified in Table 15.
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
　本発明により、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、ＡＤ／ＨＤ（注意欠如/多動性障害）、薬物依存、痙攣、振戦及び睡眠障害等の治療又は予防剤を提供することが可能となる。 According to the present invention, treatment of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorder Or it becomes possible to provide a preventive agent.

Claims (8)

  1. 式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
     ［式（Ｉ）中、
    Ｒ1は、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、Ｃ3-8シクロアルキル、Ｃ1-6アルコキシ、及びフェニル（該フェニルはハロゲン原子、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、及びＣ1-6アルコキシからなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）からなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、又はＣ2-6アルケニルを示し；
    Ｒ2は、水素原子、又はＣ1-6アルキルを示し；
    Ｒ3及びＲ4は、いずれか一方が水素原子、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは１個のヒドロキシで置換されてもよい。）、ハロＣ1-6アルキル、又はＣ2-6アルケニルを示し、他方がアリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａ’より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）を示し；
    置換基群Ａ’はハロゲン原子、シアノ、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、ヒドロキシ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルキルオキシはＣ1-6アルキル及びハロゲン原子より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、及び飽和のヘテロシクリルからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）、アミノ、カルバモイル（該アミノ及びカルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルキルスルファニル、Ｃ1-6アルキルスルホニル、環状アミノカルボニル、Ｃ2-6アルケニル、Ｃ1-6アルコキシカルボニル、及び飽和のヘテロシクリルオキシを示し；
    Ｘは窒素原子又は式ＣＨを示す。]
    で表されるイミダゾロン誘導体、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 is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl , C 1-6 alkyl, and C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: 3 may be substituted with three groups), or C 2-6 alkenyl;
    R 2 represents a hydrogen atom or C 1-6 alkyl;
    Any one of R 3 and R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy), halo C 1-6 alkyl, Or C 2-6 alkenyl, the other being aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A ′). Show;
    Substituent group A ′ is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3 -8 cycloalkyl, C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and C 3-8 cycloalkyloxy are the same or different 1 to 3 groups selected from C 1-6 alkyl and a halogen atom) And optionally substituted with 1 to 5 groups selected from the group consisting of aryl, heteroaryl, aryloxy, and saturated heterocyclyl), C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group of halogen atom and aryl.), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy (the C 3-8 Shikuroa Kill and C 3-8 cycloalkyloxy optionally substituted by the same or different 1 to 3 halogen atoms.), Amino, carbamoyl (said amino and carbamoyl same or different one or two C 1 -6 alkyl may be substituted.), Aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be the same or different 1 or 2 C 1-6 alkyl may be substituted.), C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, cyclic aminocarbonyl, C 2-6 alkenyl, C 1-6 alkoxycarbonyl, and saturated heterocyclyloxy Indicates;
    X represents a nitrogen atom or the formula CH. ]
    Or an pharmaceutically acceptable salt thereof.
  2. 上記式（Ｉ）において、
    Ｒ1が、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、Ｃ3-8シクロアルキル、Ｃ1-6アルコキシ、及びフェニル（該フェニルはハロゲン原子、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、及びＣ1-6アルコキシからなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）からなる群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
    Ｒ3及びＲ4が、いずれか一方が水素原子、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、又はＣ2-6アルケニルであり、他方がアリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａより選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
    置換基群Ａがハロゲン原子、シアノ、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、ヒドロキシ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル、及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）からなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルキルオキシは同一の又は異なる１～３個のハロゲン原子で置換されてもよい。）、アミノ、カルバモイル（該アミノ及びカルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルキルスルファニル、及びＣ1-6アルキルスルホニルである
    請求項１に記載のイミダゾロン誘導体、又はその医薬上許容される塩。     In the above formula (I),
    R 1 is C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C 1-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C 1-6 alkyl , C 1-6 alkyl, and C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: May be substituted with three groups);
    One of R 3 and R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl, and the other is aryl or heteroaryl (the aryl and heteroaryl Aryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A):
    Substituent group A is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3-6 From 8 cycloalkyl, and C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and C 3-8 cycloalkyloxy may be substituted with the same or different 1 to 3 halogen atoms). 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (the C 1-6 alkoxy is the same or different 1 to 3 groups selected from the group of halogen atoms and aryl) A C 3-8 cycloalkyl, a C 3-8 cycloalkyloxy (the C 3-8 cycloalkyl and the C 3-8 cycloalkyloxy may be the same or different one to three). May be substituted with a halogen atom of ), Amino, carbamoyl (said amino and carbamoyl optionally substituted by the same or different one or two C 1-6 alkyl.), Aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated Saturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be substituted with the same or different 1 or 2 C 1-6 alkyl), C 1-6 alkylsulfanyl, and C 1-6 alkylsulfonyl The imidazolone derivative according to claim 1, or a pharmaceutically acceptable salt thereof.
  3. 上記式（Ｉ）において、
    Ｒ3が、水素原子、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、又はＣ2-6アルケニルであり；
    Ｒ4が、アリール又はヘテロアリール（該アリール及びヘテロアリールは請求項２記載の置換基群Ａより選ばれる同一の又は異なる１～３個の基で置換されてもよい。）である請求項１又は２に記載のイミダゾロン誘導体、又はその医薬上許容される塩。     In the above formula (I),
    R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 2-6 alkenyl;
    The R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the substituent group A according to claim 2). Or the imidazolone derivative according to 2, or a pharmaceutically acceptable salt thereof.
  4. 上記式（Ｉ）において、
    Ｒ4が、アリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａ１より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
    置換基群Ａ１がハロゲン原子、シアノ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、Ｃ3-8シクロアルキル、アリール、及びヘテロアリールからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ、カルバモイル（該カルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、及びＣ1-6アルキルスルファニルである請求項１～３いずれか一項に記載のイミダゾロン誘導体、又はその医薬上許容される塩。     In the above formula (I),
    R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A1);
    Substituent group A1 is a halogen atom, cyano, C 1-6 alkyl (wherein C 1-6 alkyl is a halogen atom, cyano, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3-8 cycloalkyl, Optionally substituted with 1 to 5 groups selected from the group consisting of aryl and heteroaryl.), C 1-6 alkoxy (the C 1-6 alkoxy is the same selected from the group of halogen atoms and aryl) Or may be substituted with 1 to 3 different groups), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, carbamoyl (wherein the carbamoyl is the same or different 1 or 2 C 1-6 May be substituted with alkyl), aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be the same or different) The imidazolone derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with 1 or 2 C 1-6 alkyls), and C 1-6 alkylsulfanyl. Salt.
  5. 上記式（Ｉ）において、
    Ｒ4が、アリール又はヘテロアリール（該アリール及びヘテロアリールは下記置換基群Ａ２より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）であり；
    置換基群Ａ２がハロゲン原子、シアノ、Ｃ1-6アルキル（該Ｃ1-6アルキルはハロゲン原子、シアノ、オキソ、Ｃ1-6アルコキシ、Ｃ2-6アルカノイルアミノ、及びＣ3-8シクロアルキルからなる群より選ばれる１～５個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシはハロゲン原子及びアリールの群より選ばれる同一の又は異なる１～３個の基で置換されてもよい。）、Ｃ3-8シクロアルキル、Ｃ3-8シクロアルキルオキシ、カルバモイル（該カルバモイルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、アリール、ヘテロアリール、アリールオキシ、ヘテロアリールオキシ、飽和又は部分不飽和のヘテロシクリル（該飽和及び部分不飽和のヘテロシクリルは同一の又は異なる１又は２個のＣ1-6アルキルで置換されてもよい。）、及びＣ1-6アルキルスルファニルである請求項１～４いずれか一項に記載のイミダゾロン誘導体、又はその医薬上許容される塩。     In the above formula (I),
    R 4 is aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A2);
    Substituent group A2 is a halogen atom, cyano, C 1-6 alkyl (wherein C 1-6 alkyl is a halogen atom, cyano, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, and C 3-8 cycloalkyl) Which may be substituted with 1 to 5 groups selected from the group consisting of: C 1-6 alkoxy (wherein the C 1-6 alkoxy is the same or different 1 to 3 selected from the group of halogen atoms and aryl) ), C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, carbamoyl (wherein the carbamoyl is substituted with the same or different 1 or 2 C 1-6 alkyl). or.), aryl, heteroaryl, aryloxy, heteroaryloxy, heterocyclyl, saturated or partially unsaturated heterocyclyl (saturated and partially unsaturated identical or different one or two C 1-6 alkyl Substituted.), And C 1-6 alkylsulfanyl imidazolone derivative according to any one of claims 1 to 4, which is Le, or a pharmaceutically acceptable salt thereof.
  6. 上記式（Ｉ）において、
    Ｘが窒素原子である請求項１～５いずれか一項に記載のイミダゾロン誘導体、又はその医薬上許容される塩。     In the above formula (I),
    6. The imidazolone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein X is a nitrogen atom.
  7. 請求項１～６のいずれか一項に記載のイミダゾロン誘導体、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組成物。 A pharmaceutical composition comprising the imidazolone derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
  8. 請求項１～６のいずれか一項に記載のイミダゾロン誘導体、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ことを特徴とする、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、ＡＤ／ＨＤ（注意欠如/多動性障害）、薬物依存、痙攣、振戦及び睡眠障害からなる群から選択される疾患の予防又は治療用医薬。 A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, comprising the imidazolone derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient. A medicament for the prevention or treatment of a disease selected from the group consisting of anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders.
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