TW201333010A - Imidazolone derivatives - Google Patents

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

Imidazolinone derivatives

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, which has a function of having a positive allosteric modulator for metabotropic glutamate receptor subtype 2 (mGlu2 receptor), and As an active ingredient selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD/HD (lack of attention/hyperactivity disorder), drug dependence, paralysis, shivering and sleep Medicine for the prevention or treatment of diseases in which the disorders are grouped.

The glutamate receptor is roughly classified into an ion channel type glutamate receptor and a metabotropic glutamate receptor (mGlu receptor) (Non-Patent Documents 1 and 2). The mGlu receptor was identified as a GPCR-type glutamate receptor conjugated to the G protein, and the contiguous receptor cDNA was cloned in the early 1990s (Non-Patent Documents 3 and 4). The report now indicates that there are 8 subtypes (mGlu1~mGlu8), which are classified into three groups by group structure, pharmacological characteristics and communication system (group I: mGlu1, mGlu5; group) Group II: mGlu2, mGlu3; group III: mGlu4, mGlu6, mGlu7, mGlu8) (Non-Patent Documents 5 to 7). Among them, the mGlu2 and mGlu3 receptors belonging to the group II are conjugated to the Gi/Go protein, and are regulated to inhibit adenylate cyclase activity, and the activation of the mGlu2 and mGlu3 receptors of the antagonist inhibits the Fushi Colin stimulation induces accumulation of cAMP (Non-Patent Documents 1, 8, and 9). For the central nervous system, mGlu2 and mGlu3 are subject to Most of the body is expressed in the cerebral cortex, the olfactory bulb, the linear body, the lateral nucleus, the ventricle, the hippocampus, the tonsil, etc. (Non-Patent Documents 10 to 14). These sites are related to brain functions such as emotion, cognition, motivation, and remuneration, and thus show the relationship between mGlu2 and mGlu3 receptors and mental disorders of anxiety disorders, schizophrenia, depression, and drug dependence (Non-Patent Documents 15-19) ).

From the analysis using a receptor-injured mouse, the antipsychotic action of the mGlu2/3 receptor antagonist is mainly related to the mGlu2 receptor (Non-Patent Documents 20 to 22). It has been reported that there are also active regulatory sites (heterologous binding sites) that differ from the glutamine binding sites (orthosteric binding sites) of the endogenous ligands, creating a selective mGlu2 receptor positive allosteric modulator. (PAM) (Non-Patent Documents 23 and 24). These selective mGlu2 receptors PAM exhibit an antipsychotic-like effect or a cognitive dysfunction improvement effect in various animal models in the same manner as the mGlu2/3 receptor, and thus show a possibility of being used as a therapeutic drug for schizophrenia (Non-Patent Document 25~) 32). Further, since the mGlu2 receptor PAM has been confirmed to have an anxiolytic effect on various animal models, it has also been shown to be a therapeutic drug for anxiety disorders (Non-Patent Documents 25, 28, 33, and 34).

Recently, there have been reports of compounds having the action of positive allosteric modulators of mGlu2 receptors (Non-Patent Documents 35 to 37). However, in these documents, the compound having a pyrrololidazolidinone skeleton or an imidazolidinone skeleton in the compound of the present invention is not described at all or disclosed.

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[Non-Patent Document 2] Psychopharmacology (Berl), 179(1), 4-29, 2005.

[Non-Patent Document 3] Nature, 349 (6312), 760-765, 1991.

[Non-Patent Document 4] Science, 252 (5010), 1318-1321, 1991.

[Non-Patent Document 5] Neuropharmacology, 34(1), 1-26, 1995

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[Non-Patent Document 7] Neuropharmacology, 38(10), 1431-1476, 1999.

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[Non-Patent Document 9] J Neurosci, 13(4), 1372-1378, 1993.

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[Non-Patent Document 18] Neuropharmacology. 2011 Jun 21. [Epub ahead of print] PMID: 21704048.

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[Non-Patent Document 23] J Med Chem., 46(15), 3189-3192, 2003.

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[Non-Patent Document 25] Psychopharmacology (Berl), 179(1), 271-283, 2005.

[Non-Patent Document 26] Bioorg Med Chem Lett., 15(18), 4068-4072, 2005.

[Non-Patent Document 27] J Pharmacol Exp Ther., 315(3), 1181-1187, 2005.

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[Non-Patent Document 30] Psychopharmacology (Berl), 192(4), 511-519, 2007.

[Non-Patent Document 31] Neuroscience, 168(1), 209-218, 2010.

[Non-Patent Document 32] ACS Med Chem Lett., 1(8), 406-410, 2010.

[Non-Patent Document 33] J Pharmacol Exp Ther., 336(1), 165-177, 2011.

[Non-Patent Document 34] Neuropharmacology, 62, 322-331, 2012.

[Non-Patent Document 35] Expert Opin. Ther. Patents, 19(9), 1259-1275, 2009.

[Non-Patent Document 35] Current Medicinal Chemistry, 18(1), 47-68, 2011.

[Non-Patent Document 36] ACS Chem. Neurosci., 2(8), 382-393, 2011.

The object of the present invention is to find novel compounds having positive allosteric modulators for the mGlu2 receptor, which can provide schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression , AD / HD (lack of attention / hyperactivity disorder), drug dependence, convulsions, trembling and sleep disorders such as preventive or therapeutic drugs.

The present inventors have examined the results in detail and found novel imidazolinone derivatives having the action of positive allosteric modulators of mGlu2 receptors, and completed the present invention.

That is, the present invention is (1) Formula (I) [In the formula (I), R ¹ represents a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from a halogen atom, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, and a phenyl group ( the same or different groups of the phenyl group may be selected from halogen atoms, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and C _1-6 alkoxy group having 1 to 3 substituents as Substituting) the same or different 1 to 3 groups in the group) or C _2-6 alkenyl; R ² represents a hydrogen atom or a C _1-6 alkyl group; or any of R ³ and R ⁴ And represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted by one hydroxyl group), a halogenated C _1-6 alkyl group, or a C _2-6 alkenyl group, and the other represents an aryl group. Or a heteroaryl group (the aryl group and the heteroaryl group may be substituted by the same or different 1-3 groups selected from the group of substituents A'below); the substituent group A' represents a halogen atom, a cyano group, a hydroxyl group , C _1-6 alkyl (the C _1-6 alkyl group may be selected from the group consisting of a halogen atom, a cyano group, a hydroxyl group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, a C ₃ group _{; -8} cycloalkyl, C _3-8 cycloalkoxy (the C _3-8 cycloalkyl, and C _3-8 cycloalkoxy may be the same or different from a C _1-6 alkyl group and a halogen atom 1~3 groups substituted), aryl, heteroaryl, An aryloxy group and a 1-5 group substituted by a saturated heterocyclic group), a C _1-6 alkoxy group (the C _1-6 alkoxy group may be the same group selected from a halogen atom and an aryl group) Or a different 1 to 3 substituents), a C _3-8 cycloalkyl group, a C _3-8 cycloalkoxy group (the C _3-8 cycloalkyl group and the C _3-8 cycloalkoxy group may be the same or Substituted by 1 to 3 halogen atoms), amine group, aminomethylmercapto group (the amine group and aminocarbamoyl group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups) , aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic group (the saturated or partially unsaturated heterocyclic group may be the same or different 1 or 2 C _1-6 Alkyla substituted), C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, cyclic aminocarbonyl, C _2-6 alkenyl, C _1-6 alkoxycarbonyl, and saturated a heterocyclic oxy group; X represents a nitrogen atom or an imidazolidinone derivative represented by the formula CH], or a pharmaceutically acceptable salt thereof, (2) in the above formula (I), R ¹ is a C _1-6 alkyl group (The C _1-6 alkyl group may be selected from a halogen atom, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, and a phenyl group (the phenyl group may be a halogen atom, a cyano group, a C _1-6 alkyl group) Halogenated C _1-6 alkane Substituted with the same or different 1-3 groups of C _1-6 alkoxy groups, substituted by the same or different 1-3 groups; R ³ and R ⁴ Any one of them is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a C _2-6 alkenyl group, and the other is an aryl group or a heteroaryl group (the aryl group and the heteroaryl group) It may be substituted by the same or different 1 to 3 groups selected from the following substituent group A; the substituent group A is a halogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group (the C _1-6 alkane) The group may be selected from the group consisting of a halogen atom, a cyano group, a hydroxyl group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, a C _3-8 cycloalkyl group, and a C _3-8 cycloalkoxy group. Substituting (the C _3-8 cycloalkyl group, and the C _3-8 cycloalkoxy group may be substituted by the same or different 1-3 halogen atoms) in groups of 1 to 5 groups), C _{1 -6} alkoxy group (the C _1-6 alkoxy group may be substituted by the same or different 1-3 groups selected from the group consisting of a halogen atom and an aryl group), a C _3-8 cycloalkyl group, C _{3 - 8-} cycloalkoxy (the C _3-8 cycloalkyl and C _3-8 cycloalkoxy may be substituted by the same or different 1-3 halogen atoms), an amine group, an aminomethyl fluorenyl group (the amine) And aminomethylmercapto can be the same or phase a heterocyclic 1 or 2 C _1-6 alkyl group substituted, an aryl group, a heteroaryl group, an aryloxy group, a heteroaryloxy group, a saturated or partially unsaturated heterocyclic group (the saturated and partially unsaturated heterocyclic group) The imidazolinone described in (1) which may be substituted by the same or different 1 or 2 C _1-6 alkyl groups, a C _1-6 alkylsulfanyl group, and a C _1-6 alkylsulfonyl group a derivative, or a pharmaceutically acceptable salt thereof, (3) in the above formula (I), R ³ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a C _{2 -6} alkenyl; R ⁴ is an aryl or heteroaryl group (the aryl and heteroaryl groups may be substituted by the same or different 1-3 groups selected from the substituent group A described in (2)) 1) or (2) an imidazolinone derivative, or a pharmaceutically acceptable salt thereof, (4) in the above formula (I), R ⁴ is an aryl group or a heteroaryl group (the aryl group and the hetero group) The aryl group may be substituted by the same or different 1-3 groups selected from the group of substituents A1 described below; the substituent group A1 is a halogen atom, a cyano group, a C _1-6 alkyl group (the C _1-6 alkane) The group may be formed by a halogen atom, a cyano group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, a C _3-8 cycloalkyl group, an aryl group, and a heteroaryl group. Group 1~ 5 substituents), C _1-6 alkoxy (the C _1-6 alkoxy group may be substituted by the same or different 1-3 groups selected from the group consisting of a halogen atom and an aryl group), C _{3 -8} cycloalkyl, C _3-8 cycloalkoxy, aminomethanyl (the aminomethyl thiol group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups), aryl, a heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic group (the saturated and partially unsaturated heterocyclic group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups) and C _1-6 alkylsulfanyl group of (1) to (3) an imidazoline derivative according to any of, or a pharmaceutically salt thereof can be licensed, (5) the above-mentioned formula (I), R ⁴ is an aryl group or a heteroaryl group (the aryl group and the heteroaryl group may be substituted by the same or different 1-3 groups selected from the group of substituents A2 described below); the substituent group A2 is a halogen atom, a cyano group, a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from the group consisting of a halogen atom, a cyano group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, and C _a group of 1 to 5 groups in which a _3-8 cycloalkyl group is substituted), a C _1-6 alkoxy group (the C _1-6 alkoxy group may be the same or different from a group selected from a halogen atom and an aryl group) 1~3 bases Substituted), C _3-8 cycloalkyl, C _3-8 cycloalkoxy, acyl urethane (urethane acyl which may be the same or different one or two C _1-6 alkyl substituted by , an aryl group, a heteroaryl group, an aryloxy group, a heteroaryloxy group, a saturated or partially unsaturated heterocyclic group (the saturated or partially unsaturated heterocyclic group may be the same or different 1 or 2 C _1-6) substituted alkyl), and C _1-6 alkylsulfanyl group of (imidazolidinone derivatives 1) to (4) described in any one of, or a pharmaceutically salt thereof can be licensed, (6) In the formula (I), X is a nitrogen atom of the imidazolinone derivative according to any one of (1) to (5), or a pharmaceutically acceptable salt thereof, and (7) contains the above (1) to (() (6) The pharmaceutical composition according to any one of the above (1) to (6), wherein the imidazolinone derivative according to any one of the above (1) to (6) is contained in the above-mentioned (1) to (6) A derivative, or a pharmaceutically acceptable salt thereof, is selected as an active ingredient selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depressed disease, AD/HD (lack of attention/ Hyperactivity disorder), drug dependence, paralysis, trembling, and sleep disorders Prevention or treatment of diseases with medicine groups.

It is known that the novel imidazolinone derivative of the present invention acts on the regulatory site of the activity of the mGlu2 receptor to enhance receptor stimulation by a physiological ligand (glutamine).

Type of implementation of the invention

The terms used in this specification have the following meanings.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The "C _1-6 alkyl group" represented by a straight chain or a branched chain of an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and the like.

The "halogenated C _1-6 alkyl group" means an alkyl group in which the above-mentioned "C _1-5 alkyl group" is substituted by 1 to 5 identical or different "halogen atoms", and examples thereof include monofluoromethyl group and Fluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2-fluoro-2-propyl, 1,1,1-trifluoromethyl-2-methyl-2 -propyl, 4,4,4-trifluorobutyl and the like.

The "C _3-8 cycloalkyl group" means a cycloalkyl group having 3 to 8 ring carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

The "C _2-6 alkenyl group" means a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include ethylene, allyl, 1-propenyl, isopropenyl and 1-butenyl. A group such as 1-methyl-2-propenyl, 1-ethyl-1-vinyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl or 4-pentenyl.

The "C _1-6 alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. , n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy Base and other bases.

The "C _3-8 cycloalkoxy group" means a group in which the above-mentioned "C _3-8 cycloalkyl group" is bonded to an oxygen atom, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group. Base, cycloheptyloxy, cyclooctyloxy.

The "C _2-6 alkanoylamino group" means a group in which a linear or branched chain alkyl group having 2 to 6 carbon atoms is bonded to an amine group, and examples thereof include an ethyl hydrazino group and a propyl decyl amine group. Base, butyl sulfhydryl group, isobutyl decyl amine group, pentammonylamino group, isoamylamino group, neopentylamino group.

The "aryl group" means a monocyclic to bicyclic aromatic carbocyclic ring, and examples thereof include a group such as a phenyl group and a naphthalene group.

The "heteroaryl group" means an aromatic group having 2 to 9 carbon atoms and having 1 to 2 rings of at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and examples thereof include a furyl group and a pyrrolyl group. , thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, fluorenyl, benzene And a furyl group and the like.

The "aryloxy group" means a group in which the above "aryl group" is bonded to an oxygen atom, and examples thereof include a group such as a phenoxy group and a naphthyloxy group.

The "heteroaryloxy group" means a group in which the above "heteroaryl group" is bonded to an oxygen atom, and examples thereof include a furyloxy group, a pyrroloxy group, a thienyloxy group, a pyrazolyloxy group, an imidazolyloxy group, and an oxazolyloxy group. a group such as isoxazolyloxy, thiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, quinolinyloxy, decyloxy, benzofuranyloxy .

The saturated heterocyclic group is represented by having an oxygen atom, a nitrogen atom and a sulfurogen. The saturated heterocyclic group having 2 to 9 carbon atoms of at least one hetero atom of the subunit may, for example, be tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. Equal base.

The saturated or partially unsaturated heterocyclic group means a saturated or partially unsaturated heterocyclic group having 2 to 9 carbon atoms and having at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and examples thereof include tetrahydrofuran and tetrahydrogen. A pyran, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyridyl or the like.

The "C _1-6 alkylsulfanyl group" means a group in which the above-mentioned "C _1-6 alkyl group" is bonded to a sulfur atom, and examples thereof include a methylsulfanyl group, an ethylsulfanyl group, and an n-propylsulfane group. Base, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isova A group such as a sulfinyl group, a neopentylsulfanyl group, a tert-pentylsulfanyl group, or an n-hexylsulfanyl group.

The "C _1-6 alkylsulfonyl group" means a sulfonyl group substituted by the above "C _1-6 alkyl group", and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, and an n-propylsulfonate. Sulfhydryl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, iso A group such as a pentylsulfonyl group, a neopentylsulfonyl group, a tert-pentylsulfonyl group, or an n-hexylsulfonyl group.

The "cyclic aminocarbonyl group" means a group in which a cyclic amine group of a 4 to 8 membered ring is bonded to a carbonyl group by a guanamine bond, and examples thereof include azetidinylcarbonyl group, pyrrolidinylcarbonyl group, and piperidinylcarbonyl group. A morpholinylcarbonyl group or the like.

The "C _1-6 alkoxycarbonyl group" means a group in which the above-mentioned "C _1-6 alkoxy group" is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an isopropyl group. A group such as an oxycarbonyl group, an n-butoxycarbonyl group, a tert-butoxycarbonyl group, an n-pentyloxycarbonyl group or an n-hexyloxycarbonyl group.

The "saturated heterocyclic oxy group" means a group in which the above-mentioned "saturated heterocyclic group" is bonded to an oxygen atom, and examples thereof include a group such as a tetrahydrofuranyloxy group or a tetrahydropyranyloxy group.

Preferred in the present invention, R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from the group consisting of a halogen atom, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, and a phenyl group). the groups of the phenyl group may be the same or different selected from halogen atoms, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and C _1-6 alkoxy group having 1 to 3 substituted with Substituting the same or different 1-3 groups of the group), more preferably R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from a halogen atom, a C _3-8 ring) The alkyl group and the C _1-6 alkoxy group are substituted by the same or different 1-3 groups.

Preferred R ² in the present invention is a hydrogen atom or a C _1-6 alkyl group. More preferably, R ² is a hydrogen atom or a methyl group.

Preferred R ³ in the present invention is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a C _2-6 alkenyl group.

Preferred R ⁴ in the present invention is an aryl group or a heteroaryl group (the aryl group and the heteroaryl group may be substituted by the same or different 1-3 groups selected from the group of substituents A below).

The substituent group A is a halogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from a halogen atom, a cyano group, a hydroxyl group, an oxo group, a C _1-6 alkoxy group, C _2-6 alkanoylamino, C _3-8 cycloalkyl, and C _3-8 cycloalkoxy (the C _3-8 cycloalkyl, and C _3-8 cycloalkoxy may be the same or phase Substituted by 1 to 3 halogen atoms) substituted by 1 to 5 groups of groups), C _1-6 alkoxy group (the C _1-6 alkoxy group may be selected from the group consisting of a halogen atom and an aryl group) Substituted by the same or different 1-3 groups), C _3-8 cycloalkyl, C _3-8 cycloalkoxy (the C _3-8 cycloalkyl group and the C _3-8 cycloalkoxy group may be Substituted by the same or different 1-3 halogen atoms), an amine group, an aminocarbamyl group (the amine group and the aminocarbamyl group may be the same or different 1 or 2 C _1-6 alkyl groups) Substituted), aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic group (the saturated and partially unsaturated heterocyclic group may be the same or different 1 or 2 C _{1- 6} alkyl substituted), C _1-6 alkylsulfanyl, and C _1-6 alkylsulfonyl.

Desirable R ⁴ is an aryl or heteroaryl group (the aryl and heteroaryl groups may be substituted by the same or different 1-3 groups selected from the group of substituents A1 described below).

The substituent group A1 is a halogen atom, a cyano group, a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from a halogen atom, a cyano group, an oxo group, a C _1-6 alkoxy group, a C _2-6 group). Alkalylamino group, and 1 to 5 groups of C _3-8 cycloalkyl groups substituted), C _1-6 alkoxy group (the C _1-6 alkoxy group may be selected from a halogen atom and a aryl group) Substituted by the same or different 1 to 3 groups of the group), C _3-8 cycloalkyl, C _3-8 cycloalkoxy, aminomethyl fluorenyl (the aminocarbamyl group may be the same or Substituted 1 or 2 C _1-6 alkyl substituted), aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic groups (saturated and partially unsaturated heterocyclic) The group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups), and a C _1-6 alkylsulfanyl group.

In the present invention, preferred X is a nitrogen atom.

As an example of a preferred compound in the compound of the present invention, 3-(biphenyl-4-yl)-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole is exemplified. -7-keto, 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-(propane- 2-yl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, 6-butyl-3-[6-(cyclopentyloxy)pyridine- 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-(cyclopropoxy) Phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, 2-methyl-6-(4,4,4-trifluoro Butyl)-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, 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]benzene }-2-Methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, 3-{4-[cyclopropyl(difluoro)methyl]phenyl} -6-(cyclopropyl A 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]imidazol-7-one 6-(cyclopropyl Methyl)-3-[4-(1,1-difluoro-2-methylpropyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-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]imidazol-7-one, 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-(哒Pyrazin-3-yloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, 6-(cyclobutylmethyl)-3- [3-fluoro-4-(pyridazin-3-yloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, or Its medicinally acceptable salt.

The "medicinally acceptable salt" is a salt containing a mineral acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, and formic acid, trifluoroacetic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, and horse. Acid, citric acid, benzenesulfonic acid, alkanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid , malonic acid, mandelic acid, mucic acid, naphthalene-2-sulfonic acid and other organic acid salts, and a salt of one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, and ammonia, arginine, lysine, piperazine, colin, diethyl a salt of an amine such as an amine, 4-phenylcyclohexylamine, 2-aminoethanol or benzathine.

Further, the compound of the present invention can exist as various solvates. There are also hydrates in terms of applicability as medicine.

The compounds of the present invention contain all of enantiomers, diastereomers, equilibrium compounds, mixtures thereof in any ratio, racemates and the like.

The compounds of the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation. As the above carrier, excipient and diluent, containing water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gelatin, alginate, calcium citrate, Calcium phosphate, cellulose, water syrup, methyl cellulose, polyvinylpyrrolidone, alkyl sorbic acid p-hydroxybenzene, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, etc. .

Further, the above-mentioned carrier, excipient or diluent may be mixed with an additive such as a bulking agent, a binding agent, a breaker, a pH adjuster or a dissolving agent which are generally used, and may be prepared into a tablet, a pill, or the like by a usual formulation technique. Oral or non-oral medicine such as capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, and skin patches. The compound of the present invention can be administered in an amount of 0.001 to 2000 mg once per adult patient, and can be administered once or several times a day orally or parenterally. Moreover, the dosage can be adapted according to the type of disease to be treated, the age, weight, and symptoms of the patient. Should increase or decrease.

The compound of the present invention also contains a compound in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms are substituted by a radioisotope or a stable isotope element. These labeled compounds are useful as metabolic or pharmacodynamic studies, ligands for receptors, and biological assays.

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

The "inert solvent" is, for example, an aromatic solvent such as benzene, toluene, xylene or pyridine; a hydrocarbon solvent such as hexane, pentane or cyclohexane; dichlorohexane, chloroform or 1,2-dichloroethane; Halogenated hydrocarbon solvent such as alkane or carbon tetrachloride; ether solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or 1,4-dioxane; ethyl acetate, ethyl formate, etc. Ester solvent; alcohol solvent such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol or ethylene glycol; ketone solvent such as acetone or methyl ethyl ketone; N, N-dimethylformamide, N - a mercapto solvent such as methylpyrrolidone or N,N-dimethylacetamide; an anthraquinone solvent such as dimethyl hydrazine; a nitrile solvent such as acetonitrile or propionitrile; and water, and their homogeneous systems and Evenly mixed solvent and the like. These inert solvents are suitably selected depending on 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, and calcium hydride; lithium decylamine, sodium decylamine, lithium diisopropyl decylamine, and lithium dicyclohexyl hydrazine; Alkali metal or alkaline earth gold such as amine, lithium hexamethyldiamine, sodium hexamethyldiamine, potassium hexamethyldiamine Guanidine; a lower alkoxide of an alkali or alkaline earth metal such as sodium methoxide, sodium ethoxide or potassium pentoxide; butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium Or an alkyl lithium; a hydroxide of an alkali metal or an alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide; or an alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate or barium carbonate; a salt; an alkali metal or an alkaline earth metal hydrogencarbonate such as sodium hydrogencarbonate or potassium hydrogencarbonate; triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, 1,8-di Azabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N,N-dimethylaniline, etc. Amine; a 4-grade ammonium salt such as tetra-n-butylammonium fluoride or benzyltrimethylammonium hydroxide; a basic heterocyclic compound such as pyridine, imidazole or 2,6-lutidine. These bases can be suitably selected in accordance with various reaction conditions known to those skilled in the art.

Examples of the "acid" include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, organic acids such as 10-camphorsulfonic acid, p-toluenesulfonic acid, alkanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid, and chlorine. Zinc (II), aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether, boron tribromide, trimethylformamidinium iodide, trifluoroalkanesulfonic acid Lewis acid such as trimethylformamido. These acids are suitably selected in accordance with 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 (I-I) can be produced by the method of the following Scheme 1.

In the formula, R ¹ and R ^{2 are the} same as defined above. R ^{3 '} represents an aryl group or a heteroaryl group. M represents a metal atom or a metal atom group used in the coupling reaction, and examples of the compound (4) include a magnesium reactant, a zinc reactant, a boron reactant in which boric acid or a boric acid ester is combined, a tin reactant, and the like. X ¹ represents a chlorine atom, a bromine atom, an iodine atom, a fluorine atom or an organic sulfonyloxy group (alkylsulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoroalkanesulfonyloxy group, etc.) Waiting for the base. X ² and X ³ are the same or different and each represents a chlorine atom, a bromine atom, and an iodine atom. R ⁵ represents a protecting group of a carboxyl group such as a methyl group, an ethyl group, a tert-butyl group or a benzyl group (refer to Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.) or a hydrogen atom.

Step 1: Compound (3) can be produced by an amidoximation reaction known to those skilled in the compound (1) and the compound (2) in an inert solvent {refer to Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC .}. The compound (1) and the compound (2) can be synthesized from a commercial compound or a known compound using a commercial compound, a known compound, or various organic synthetic methods known to those skilled in the art. The amidation reaction is such that when R ⁵ is a hydrogen atom, for example, in an inert solvent, in the presence or absence of a base, O-(7-azabenzotriazol-1-yl)-N,N is used. , N', N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) a condensation reaction of a condensing agent such as diphenylphosphonium azide (DPPA) or carbonyldiimidazole (CDI), by using ethyl chloroformate, isobutyl chloroformate or trimethylethenyl chloride. The condensation reaction of the mixed acid anhydride is carried out by a condensation reaction using an acid halide such as sulfinium chloride, grass chloroform, 1-chloro-N,N,2-trimethyl-1-propenylamine or the like. Further, in the case of a guanidation reaction using a condensing agent, an additive such as 1-hydroxybenzotriazole (HOBt) or hydroxybutaneimine (HOSu) may be used as necessary. Or the so-called guanidine reaction means that when R ⁵ is a protecting group of a carboxyl group, for example, in an inert solvent or without a solvent, the compound (1) and the compound (2) are subjected to a condensation reaction in the presence or absence of a base or an acid.

Step 2: Compound (5) can be produced by coupling reaction of compound (3) with compound (4) by using a palladium catalyst and optionally a ligand in an inert solvent in the presence or absence of a base. . The coupling reaction is exemplified by the conditions of the coupling reaction known to the skilled person, and for example, the method described in {Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}, the method according thereto, or the like can be applied. A combination with the common law. The compound (3) and the compound (4) can be synthesized from a commercial compound or a known compound using a commercial compound, a known compound, or a variety of organic synthesis methods known to those skilled in the art. Here, the palladium catalyst may, for example, be palladium (II) acetate, palladium (II) chloride or palladium (II) bis(triphenylphosphine) acetate. Bis(triphenylphosphine)palladium(II) chloride, (1,3-bis(2,6-diisopropylphenyl)imidazolyl) (3-chloropyridyl)palladium chloride ( II), ginseng (benzylideneacetone) dipalladium (0), bis(benzylideneacetone)palladium (0), triphenylphosphine palladium (0), chlorinated [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium (II), allyl palladium (II) chloride, bis(acetonitrile) palladium (II) chloride, and the like. Examples of the ligand include triphenylphosphine and 2, 2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), 2-(di-tert-butylphosphine)biphenyl, 9,9-dimethyl-4,5-bis (two Phenylphosphine) Xantphos and the like.

Step 3: The compound (II) of the present invention can be produced by alkylation reaction of the compound (5) with the compound (6) in the presence of a base in an inert solvent {refer to Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}. The compound (5) and the compound (6) can be synthesized from a commercial compound or a known compound using a commercially available compound, a known compound, or various organic synthetic methods known to those skilled in the art.

For example, the present compound represented by the formula (I-II) can be produced by the method of the following Scheme 2.

In the formula, R ¹ , R ² , R ^3' , R ⁵ , M, X ² and X ^{3 have the} same meanings as defined above. X ⁴ represents a chlorine atom, a bromine atom, and an iodine atom.

Step 4: Compound (8) is produced from Compound (7) and Compound (2) by the same procedure as in Step 1 in Scheme 1. The compound (7) and the compound (2) are compounds which can be synthesized from a commercially available compound or a known compound by using a commercially available compound, a known compound, or various organic synthesis methods known to those skilled in the art.

Step 5: Compound (9) can be obtained by reacting compound (8) with N-chloroosyl succinimide, N-bromosuccinate, N-iodoammonium in the presence or absence of an acid in an inert solvent. It is produced by reacting a halogenating agent such as hydrazine imine. Or the compound (9) can be produced by reacting the 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. The compound (8) can be sold from a commercial compound, a known compound, or a variety of organic synthetic methods known to those skilled in the art. A compound or a compound synthesized by a known compound.

Step 6: Compound (10) can be produced from Compound (9) and Compound (4) in the same manner as in Step 2 in Scheme 1. The compound (9) and the compound (4) can be synthesized by using a compound of a commercial product, a known compound, or a synthetic compound or a known compound by various organic synthesis methods known to those skilled in the art.

Step 7: The compound (I-II) of the present invention can be produced from the compound (10) and the compound (6) by the same procedure as in the step 3 of the scheme 1. The compound (10) and the compound (6) can be synthesized from a commodity compound or a known compound by using a commodity compound, a known compound, or various organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-II) can also be produced by the method of the following Scheme 3.

In the formula, R ¹ , R ² , R ^3' , M, X ² , X ³ and X ^{4 have the} same meanings as defined above.

Step 8: Compound (11) can be produced from Compound (8) and Compound (6) in the same manner as in Step 3 of Scheme 1. The compound (8) and the compound (6) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

Step 9: Compound (12) can be produced from Compound (11) by the same procedure as Step 5 in Scheme 2. The compound (11) can be a compound synthesized from a vending compound or a known compound by using a compound of a commercial product, a known compound, or various organic synthetic methods known to those skilled in the art.

Step 10: The compound (I-II) of the present invention can be produced from the compound (12) and the compound (4) by the same procedure as in the step 2 in the scheme 1. The compound (12) and the compound (4) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-III) can be produced by the method of the following Scheme 4.

In the formula, R ¹ , R ² , R ⁵ , M, X ¹ , X ² and X ^{3 have the} same meanings as defined above. R ^{4 '} represents an aryl group or a heteroaryl group. Examples of the compound (14) include a magnesium reactant, a zinc reactant, a boron reactant in which boric acid or a boric acid ester is combined, a tin reactant, and the like.

Step 11: Compound (15) can be produced from Compound (13) and Compound (14) by the same procedure as in Step 2 of Scheme 1. The compound (13) and the compound (14) can be used as a commercial compound, and are known. A compound or a compound synthesized from a commodity compound or a known compound by various organic synthesis methods known to those skilled in the art.

Step 12: Compound (16) is produced from Compound (15) and Compound (2) by the same procedure as in Step 1 in Scheme 1. The compound (15) and the compound (2) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

Step 13: The compound (I-II) of the present invention can be produced from the compound (16) and the compound (6) by the same procedure as in the step 3 in the scheme 1. The compound (16) and the compound (6) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or various organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-IV) can also be produced by the method of the following Scheme 5.

In the formula, R ¹ , R ² , R ³ , R ^4′ , R ⁵ , M, X ² , X ³ and X ^{4 have the} same meanings as defined above.

Step 14: Compound (18) is produced from Compound (17) and Compound (2) by the same procedure as in Step 1 in Scheme 1. The compound (17) and the compound (2) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or various organic synthesis methods known to those skilled in the art.

Step 15: Compound (19) can be produced from Compound (18) and Compound (6) by the same procedure as in Step 3 in Scheme 1. The compound (18) and the compound (6) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

Step 16: Compound (20) can be produced from Compound (19) by the same procedure as Step 5 in Scheme 2. The compound (19) can be synthesized from a commodity compound or a known compound by using a commodity compound, a known compound, or various organic synthesis methods known to those skilled in the art.

Step 17: The compound (I-IV) of the present invention can be produced from the compound (20) and the compound (14) by the same procedure as in the step 2 in the scheme 1. The compound (20) and the compound (14) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-V) and the formula (I-VI) can be produced by the method of the following Scheme 6.

In the formula, R ¹ , R ² , R ^4′ , M, X ² and X ^{3 have the} same meanings as defined above. R ^{3 "} represents a C _1-6 alkyl group, a C _2-6 alkenyl group, an aryl group or a heteroaryl group. Examples of the compound (22) include a magnesium reactant, a zinc reactant, a boric acid or a boric acid ester. A boron reactant, a tin reactant, and the like are combined.

Step 18: Compound (21) can be produced from Compound (11) by the same procedure as Step 5 in Scheme 2. The compound (11) can be a compound synthesized from a vending compound or a known compound by using a compound of a commercial product, a known compound, or various organic synthetic methods known to those skilled in the art.

Step 19: The compound (I-V) of the present invention can be produced from the compound (21) and the compound (14) by the same procedure as in the step 2 in the scheme 1. The compound (21) and the compound (14) can be synthesized from a commodity compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

Step 20: The compound (I-VI) of the present invention can be produced from the compound (I-V) of the present invention and the compound (22) by the same procedure as in the step 2 in the scheme 1. The compound (22) can be a compound synthesized from a vending compound or a known compound by using a compound of a commercial product, a known compound, or a variety of organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-VII) can be produced by the method of the following Scheme 7.

In the formula, R ¹ , R ² and R ^{3 have the} same meanings as defined above. R ⁶ represents a C _1-6 alkyl group.

Step 21: The compound (I-VII) of the present invention can be produced by reacting the compound (18) with the compound (23) in the presence or absence of an acid in an inert solvent. The compound (18) and the compound (23) can be synthesized from a commodity compound or a known compound by using a commodity compound, a known compound, or various organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-IX) can be produced by the method of the following Scheme 8.

Wherein R ¹ , R ² , M and X ^{2 are} synonymous with the above. R ^3''' represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted by one hydroxyl group), a halogenated C _1-6 alkyl group, or a C _2-6 alkenyl group, and R ⁷ represents an aryl group, Heteroaryl, heterocyclic group. Examples of the compound (25) include a magnesium reactant, a zinc reactant, a boron reactant in which boric acid or a boric acid ester is combined, a tin reactant, and the like. X ⁵ represents a cleavable group such as an organic sulfonyloxy group (alkylsulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoroalkanesulfonyloxy group, etc.).

Step 22: The compound (I-IX) of the present invention can be produced from the compound (24) or the compound (I-VIII) of the present invention and the compound (25) by the same procedure as in the step 2 in the scheme 1. The compound (24) and the compound (25) can be synthesized from a commodity compound or a known compound by using a commodity compound, a known compound, or various organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-IX) can be produced by the method of the following Scheme 9.

In the formula, R ¹ , R ² , R ^3''' , R ⁷ , M and X ^{1 have the} same meanings as defined above. Examples of the compound (26) include a magnesium reactant, a zinc reactant, a boron reactant in which boric acid or a boric acid ester is combined, a tin reactant, and the like.

Step 23: The compound (I-IX) of the present invention can be used in Scheme 1 The same procedure as in the step 2 was carried out from the compound (26) and the compound (27). The compound (26) and the compound (27) can be synthesized from a commodity compound or a known compound by using a commodity compound, a known compound, or various organic synthesis methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-XI) can be produced by the method of the following Scheme 10.

In the formula, R ¹ , R ² , R ^3′′′ and X ^{1 have the} same meanings as defined above. R ⁸ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a heteroaryl group or a heterocyclic group, and n represents an integer of 0 to 6.

Step 24: The compound (IX) of the present invention can be produced by reacting the compound (I-IX) of the present invention with the compound (27) in the presence of a base in an inert solvent {refer to Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}. The compound (27) can be synthesized from a vending compound or a known compound using a commercial compound, a known compound, or various organic synthetic methods known to those skilled in the art.

For example, the compound of the present invention represented by the formula (I-XIII) can be subjected to the following scheme Manufactured by the method of 11.

In the formula, R ¹ , R ² , R ^3''' , R ⁸ and X ^{1 have the} same meanings as defined above.

Step 25: The compound (I-XIII) of the present invention can be reacted with a copper catalyst and, if necessary, a ligand by using a compound of the present invention (I-XII) and a compound (28) in the presence of a base in an inert solvent. And manufacturing. The compound (28) can be a compound synthesized from a commodity compound or a known compound using a commercial compound, a known compound, or various organic synthesis methods known to those skilled in the art. Examples of the copper catalyst include copper (0), copper (I) iodide, copper (I) chloride, copper (I) acid, copper (I) bromide, and triphenylphosphine. Copper (I) benzene sulfonate or the like. The ligand may be a ligand known to those skilled in the art of coupling reaction using a copper catalyst, and examples thereof include N,N'-dimethylethylidene diamine and 1,2-cyclohexane. Diamine, 2-aminopyridine, 1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, picopyridine, etc. (Synlett, 15, 2824-2439, 2003).

Further, the compound (I-XIII) of the present invention can be produced by reacting the compound (I-XII) of the present invention with the compound (28) in the presence of a base in an inert solvent. {Refer to Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.} This compound (28) can be synthesized from a vending compound or a known compound using a vending compound, a known compound, or various organic synthetic methods known to those skilled in the art.

For example, for the compound (I) of the present invention, R ³ or R ⁴ in the formula is a C _2-6 alkenyl group, or a substituent of R ³ or R ⁴ is a 3,4-dihydro-2H-pyranyl group or the like. The reducing body of the compound (I) of the present invention can be produced by a contact reduction reaction of the compound (I) of the present invention in an inert solvent in the presence of a transition metal catalyst under a hydrogen atmosphere under normal pressure or under pressure (refer to Comprehensive). Organic Transformations Second Edition 1999, John Wiley & Sons, INC.}. The reduced body of the compound (I) of the present invention is also contained in the compound of the present invention. Among them, examples of the transition metal catalyst used in the reduction reaction include palladium carbon, palladium hydroxide, palladium black, palladium-silk fibroin, platinum (IV) oxide, and Raney nickel. Further, for example, the compound (I) of the present invention, R ³ in the formula or R ⁴ is a halogen atom, or R ⁴ or R ³ substituent is a halogen atom, by the same technique, the compounds can be produced according to the present invention (I) The body of the reduction. The reduced body of the compound (I) of the present invention is also contained in the compound of the present invention.

For example, the compound of the present invention represented by the formula (I-XIV) can be produced by the method of the following Scheme 12.

In the formula, R ¹ , R ² and R ^{3''' are} synonymous with the above. R ⁹ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, or a saturated heterocyclic group.

Step 26: The compound (I-XIV) of the present invention can be produced by a light delay reaction of the compound (I-X') of the present invention and the compound (29) in an inert solvent. The compound (29) can be synthesized from a vending compound or a known compound using a commercial compound, a known compound, or various organic synthetic methods known to those skilled in the art. The photo-delay reaction is, for example, an organophosphorus compound such as triphenylphosphine or tributylphosphine, diethyl azodicarboxylate, diisopropyl azodicarboxylate or ditributyl azodicarboxylate. A method of using an azo compound or a method of using a phosphorus ylide reagent such as cyanomethyltributylphosphine is exemplified (see Chem. Rev. 2009. 109, 2551-2651).

For example, the compound of the present invention represented by the formula (I-XV) can be produced by the method of the following Scheme 13.

In the formula, R ¹ , R ² , R ^3′′′ and X ^{1 have the} same meanings as defined above. R ¹⁰ represents a heteroaryl group.

Step 27: The compound (I-XV) of the present invention can be produced from the compound (I-X') of the present invention and the compound (30) by the same procedure as in the step 25 in the scheme. The compound (30) can be a compound synthesized from a commercially available compound or a known compound using a commercial compound, a known compound, or various organic synthetic methods known to those skilled in the art.

For another example, the compound of the formula (18) can be produced by the method of the following Scheme 14.

In the formula, R ¹ and R ³ and X ^{1 are the} same as defined above. R ¹¹ represents ethyl hydrazino, alkane sulfonyl, p-methoxyphenylsulfonyl, p-toluenesulfonyl, benzyloxycarbonyl, t-butoxycarbonyl, benzyl, p-methyl A protecting group for a nitrogen atom on an imidazole ring such as an oxybenzyl group or a trityl group (refer to Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.).

Step 28: Compound (33) can be produced by reacting Compound (31) with Compound (32) in the presence of a base in an inert solvent. {Refer to Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC.} The compound (31) and the compound (32) can be sold as a commercial compound, a known compound, or a variety of organic synthetic methods known to those skilled in the art. A compound or a compound synthesized by a known compound.

Step 29: Compound (18) can be subjected to various organic synthesis methods known to those skilled in the art by using a protecting group R ^{11 of the} compound (33) in an inert solvent. {Refer to Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons , INC.} is manufactured and removed.

[Examples]

The invention is further illustrated by the following examples, examples, and examples, which are not to be construed as limited by the invention.

In the production example and the examples, "NHSilicagel Cartridge" used for purification by column chromatography is Biotage (registered trademark) SNAPCartridge KP-NH and "Silicagel Cartridge" manufactured by Biotage Co., Ltd. ) SNA PCartridge KP-Sil and HP-Sil, "Reveleris (registered trademark) Silica, "ISOLUTE (registered trademark) HM-N" manufactured by Grace Corporation, are sold under the ISOLUTE (registered trademark) HM-N manufactured by Biotage. "SunFire (registered trademark)" used in the purification by reverse phase column chromatography is SunFire (registered trademark) prep C18 OBD (registered trademark) 5.0 μm manufactured by Waters Corporation. 30 x 50mm. TLC (tank plate) at the time of purification using TLC was Silica gel 60F254 (Merck), TLC (NH plate) using TLC plate NH (Fuji Silysia).

The microwave reaction apparatus was an Initiator manufactured by Biotage.

Each device data described in the production examples and the examples was measured using the following measurement equipment.

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 (Japan Electronics), 500 MHz: JNM-ECA500 (Japan Electronics), 300 MHz: UNITY NOVA 300 (Varian Inc.), 200 MHz: GEMINI 2000/200 (Varian Inc.)

The names of the compounds in the production examples and examples are named by ACD/Name (ACD/Labs 12.0, Advanced Chemistry Development Inc.).

The abbreviations in the nuclear magnetic resonance (NMR) spectrum used in the production examples and examples are as follows.

s:singlet, d:doublet, t:triplet, q:quartet, dd:double doublet,dt:double triplet,dq:double quartet,ddd:double double doublet,m:multiplet,br:broad,J:coupling constant , Hz: Hertz, DMSO-d ₆ : heavy hydrogenated dimethyl hydrazine.

Production Example 1 N-butyl-4-(4-tert-butylphenyl)-1H-pyrrole-2-carboxamide 1) 4-bromo-N-butyl-1H-pyrrole-2-carboxamide

A mixture of ethyl 4-bromo-1H-pyrrole-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 EtOAc EtOAc EtOAc (EtOAc)

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.87-1.01 (m, 3H) 1.31-1.66 (m, 4H) 3.32-3.48 (m, 2H) 5.77 (br.s., 1H) 6.47-6.54 (m, 1H) 6.86-6.94 (m, 1H) 9.46-9.90 (m, 1H)

2) N-butyl-4-(4-tert-butylphenyl)-1H-pyrrole-2-carboxamide

4-Bromo-N-butyl-1H-pyrrole-2-carboxamide (228 mg), 4-tert-butylphenylboronic acid (356 mg), cesium carbonate (650 mg), hydrazine (triphenyl) A mixture of phosphine)palladium(0) (12 mg), ethanol (1.0 mL), toluene (1.0 mL) and water (1.0 mL) was stirred at 130 ° C for 45 minutes under microwave irradiation. Add water to the reaction solution to ethyl acetate Perform extraction. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.90-1.00(m,3H)1.19-1.47(m,13H)3.36-3.49(m,2H)6.74-6.79(m,1H)7.14-7.19(m,1H ) 7.35-7.45 (m, 4H); MS (ESI/APCI pos) m/z: 299 [M+H] ⁺

The following compounds were synthesized in the same manner as in Production Example 1.

N-butyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxamide

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.88-1.06 (m, 3H) 1.32-1.74 (m, 4H) 3.32-3.56 (m, 2H) 6.76-6.99 (m, 2H) 7.20-7.32 (m, 2H) )

4-[4-(benzyloxy)phenyl]-N-butyl-1H-pyrrole-2-carboxamide

1H NMR (600MHz, CHLOROFORM-d) d ppm 0.97 (t, J = 7.22 Hz, 2H) 1.41 (s, 2H) 1.56-1.65 (m, 2H) 5.10 (s, 2H) 6.73-7.85 (m, 11H) ;MS(ESI/APCI pos)m/z:349[M+H] ⁺

Preparation Example 2 N-butyl-4-(4-tert-butylphenyl)-1H-imidazole-2-carboxamide 1) N-butyl-1H-imidazole-2-carboxamide

A mixture of ethyl 1H-imidazole-2-carboxylate (17.8 g), n-butylamine (50.2 mL) and ethanol (64 mL) at 80 ° C (oil bath temperature) Degree) was stirred for 4.5 hours. The reaction mixture was concentrated under reduced pressure.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.91-0.96 (3H, m), 1.40 (2H, dq, J = 15.0, 7.4 Hz), 1.60 (2H, quin, J = 7.3 Hz), 3.44 (2H, q, J = 6.7 Hz), 7.11 (1H, s), 7.15 (1H, s), 7.54 (1H, br.s.), 12.05 (1H, br.s.); MS (ESI/APCI pos) m /z:168[M+H] ⁺

2) 4-bromo-N-butyl-1H-imidazole-2-carboxamide

Add N-bromobutaneimide (262 mg) to a solution of N-butyl-1H-imidazol-2-carbamide (224 mg) in N,N-dimethylformamide (2.2 mL). Stirring was carried out for 1 hour at room temperature. The reaction mixture was purified by reverse phase column chromatography (yield: </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; A colorless solid of mg).

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (3H, t, J = 7.4 Hz), 1.37-1.44 (2H, m), 1.56-1.62 (2H, m), 3.40-3.45 (2H, m), 7.14 (1H, s), 7.24 (1H, br.s.), 11.63 (1H, 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-imidazol-2-carboxamide (83 mg), 4-tert- a mixture of butylphenylboronic acid (72 mg), hydrazine (triphenylphosphine) palladium (0) (78 mg), ethanol (0.83 mL), toluene (0.83 mL) and 2M aqueous sodium carbonate (0.51 mL) The mixture was stirred at 150 ° C for 30 minutes under irradiation. After the reaction mixture was filtered through celite (registered trademark), water was added to the filtrate and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. 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 ) a pale yellow solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.94-0.99 (3H, m), 1.34 (9H, s), 1.40-1.48 (2H, m), 1.56-1.67 (2H, m), 3.44-3.49 (2H , m), 7.30-7.38 (1H, m), 7.40-7.47 (2H, m), 7.53 (1H, d, J = 8.3 Hz), 7.70 (1H, d, J = 8.3 Hz); MS (ESI/ APCI pos)m/z: 300[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-di Hydrogen-7H-imidazo[1,5-a]imidazol-7-one 1) N-butyl-1H-imidazol-2-carboxamide

1H-imidazole-2-carboxylic acid (2.90 g), n-butylamine (2.84 g), uronium hexafluorophosphate 2-(1H-7-azabenzotriazol-1-yl)-1, a mixture of 1,3,3-tetramethylammonium (HATU) (14.8 g), diisopropylethylamine (6.80 mL) and N,N-dimethylformamide (37 mL) at room temperature Stir for 2 days. Water (74 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, and the resulting solid was filtered to give the title compound. (2.80 g) of 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

A solution of N-butyl-1H-imidazole-2-carboxamide (31.6 g) in N,N-dimethylformamide (760 mL) under nitrogen, 60% sodium hydride (22.7 g), after stirring for 15 minutes, stirring was carried out for 30 minutes at room temperature. Under ice cooling, chloroiodane (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 mixture at room temperature, stirred for 30 minutes, and concentrated under reduced pressure. Chloroform (1.0 L) was added to the residue, and the mixture was stirred at room temperature for 1 hour. The insoluble matter was filtered through diatomaceous earth (registered trademark), separated by filtration, and washed with chloroform. The filtrate was concentrated under reduced pressure, and the obtained residue was diluted with methanol (600 mL) and washed three times with hexane (400 mL). The methanol layer was concentrated under reduced pressure. The residue was purified by column chromatography (NHSilicagel Cartridge, chloroform: methanol = 100:0 to 97:3 and Silicagel Cartridge, chloroform:methanol = 100:0 to 97:3). The obtained solid was washed with hexane toield

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.0 Hz), 1.29-1.51 (2H, m), 1.55-1.73 (2H, m), 3.60 (2H, t, J = 7.5 Hz), 5.29 (2H, s), 7.21 (1H, d, J = 1.3 Hz), 7.40 (1H, 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-dihydrogen -7H-imidazo[1,5-a]imidazol-7-one

In a solution of 6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (233 mg) in N,N-dimethylformamide (3.7 mL) N-bromobutaneimine (255 mg) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93-0.99 (3H, m), 1.35-1.45 (2H, m), 1.60-1.69 (2H, m), 3.58-3.64 (2H, m), 5.18 (2H ×3/4, s), 5.29 (2H × 1/4, s), 7.21 (1H × 1/4, s), 7.31 (1H × 3 / 4, s); MS (ESI / APCI pos) m / z:258[M+H] ⁺

Preparation 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), hydrazine (triphenylphosphine) palladium A mixture of (0) (40 mg), 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 solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (EtOAc EtOAc EtOAc)

2) N-butyl-5-(4-tert-butylphenyl)-1H-pyrrole-2-carboxamide

a mixture of methyl 5-(4-tert-butylphenyl)-1H-pyrrole-2-carboxylate (173 mg) and n-butylamine (3.70 mL) at 130 ° C (oil bath temperature) Stir for 3 days. The reaction solution was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93-1.00(m,3H)1.37-1.47(m,2H)1.54-1.64(m,4H)3.40-3.49(m,2H)5.82-5.91(m,1H 6.73-6.79(m,1H)7.16(dd,J=2.68,1.44Hz,1H)7.35-7.47(m,4H);MS(ESI/APCI pos)m/z:299[M+H] ⁺

The following compounds were synthesized in the same manner as in Production Example 4.

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] ⁺

Production Example 5 5-(4-tert-butylphenyl)-N-(3-methylbutyl)-1H-pyrrole-2-carboxamide 1) 5-(4-tert-butylphenyl)-1H-pyrrole-2-carboxylic acid

Add 2M sodium hydroxide to a solution of methyl 5-(4-tert-butylphenyl)-1H-pyrrole-2-carboxylate (780 mg) obtained in Preparation Example 4-1) in methanol (10 mL) The solution (7.5 mL, methanol solution) 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. After a 1 M aqueous solution of hydrogen chloride (20 mL) was obtained.

1H NMR (200MHz, DMSO-d6) δ ppm 1.28 (9H, s), 7.01-7.12 (1H, m), 7.27-7.40 (3H, m), 7.46-7.55 (2H, m), 11.75-11.91 (1H ,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), urea hexafluorophosphate 2-(1H-7-aza Benzotriazol-1-yl)-1,1,3,3-tetramethylammonium (HATU) (230 mg), diisopropylethylamine (0.100 mL) and N,N-dimethyl The mixture of formamide (2.0 mL) was stirred at room temperature for 21 hours and at 80 ° C (oil bath temperature) for 5 hours. Add isoamylamine (53 mg), uronium hexafluorophosphate 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylalkane to the reaction mixture. Ammonium (HATU) (230 mg) and diisopropylethylamine (0.100 mL) at 80 ° C (oil bath temperature) 4 Stir for hours. The reaction solution was diluted with ethyl acetate, and then washed twice with saturated brine. After adding ISOLUTE (registered trademark) HM-N to the organic layer, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjj(

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.95 (3H, s), 0.98 (3H, s), 1.34 (9H, s), 1.43-1.57 (2H, m), 1.59-1.80 (1H, m), 3.38-3.54(2H,m), 5.76-5.91(1H,m),6.74-6.78(1H,m),7.14-7.19(1H,m),7.33-7.49(4H,m),9.26-9.36(1H ,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] ⁺

Production Example 6 3-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one, 2-bromo-6-butyl-5,6-di Hydrogen-7H-imidazo[1,5-a]imidazol-7-one and 2,3-dibromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole -7-ketone

6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (17.0 g) of N,N-dimethylmethyl obtained in Preparation Example 3-2) A solution of guanamine (270 mL) was added to N-bromosuccinimide (18.6 g) under ice-cooling, and the mixture was stirred for 30 minutes, and then stirred at room temperature for 18 hours. Add 15% aqueous sodium thiosulfate solution (280 mL) to the reaction solution and ice-cooling. After that, stirring was carried out for 15 minutes at room temperature. Water was added to the reaction mixture, and extraction was carried out three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was subjected to column chromatography (NHSilicagel Cartridge, chloroform: methanol = 100:0 to 97:3, NHSilicagel Cartridge, hexane: ethyl acetate = 60:40 to 25:75 and Silicagel Cartridge, hexane:acetic acid). Ethyl ester = 60:40~25:75) After purification, 3-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one was obtained (10.2 g) (colorless solid), 2-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (3.57 g) (light yellow solid) and 2 , 3-Dibromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (1.79 g) (colorless solid).

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 (3H, t, J = 7.4 Hz), 1.35-1.44 (2H, m), 1.60-1.69 (2H, m), 3.61 (2H, t, J = 7.4 Hz), 5.16 (2H, s), 7.31 (1H, 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 (3H, t, J = 7.4 Hz), 1.30 - 1.42 (2H, m), 1.57-1.66 (2H, m), 3.58 (2H, t, J = 7.4 Hz), 5.28 (2H, s), 7.20 (1H, 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 ( 3H, t, J = 7.2 Hz), 1.33-1.46 (2H, m), 1.60-1.72 (2H, m), 3.62 (2H, t, J = 7.4 Hz), 5.19 (2H, s); MS (ESI) /APCI pos)m/z: 336[M+H] ⁺

The following compounds were synthesized in the same manner as in Production Example 6.

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] ⁺

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-2-carboxamide

The title compound (456 mg) was obtained as an amorphous material by the same procedure as in the preparation of the compound (5).

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.94 (3H, t, J = 6.6 Hz), 1.27-7.11 (4H, m), 2.29 (3H, s), 3.42 (2H, q, J = 6.6 Hz) , 6.83 (1H, br.s.), 7.19 (1H, 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

The title compound (156 mg) was obtained from N-butyl-4-methyl-1H-imidazol-2-carbamide (455 mg). Colorless solid.

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.3 Hz), 1.27-1.73 (4H, m), 2.34 (3H, d, J = 0.9 Hz), 3.58 (2H, t, J=7.3 Hz), 5.21 (2H, s), 6.93 (1H, 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

The title compound was obtained from 6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (153 mg). (146 mg) of a colorless solid.

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.3 Hz), 1.28-1.74 (4H, m), 2.30 (3H, s), 3.60 (2H, t, J = 7.3 Hz) , 5.13 (2H, s); 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]imidazol-7-one

A suspension of N-butyl-1H-imidazole-2-carboxamide (150 mg) obtained from Example 3-1) and 1,1-diethoxyethane (0.511 mL) in toluene (7.5 mL) Among them, p-toluenesulfonic acid monohydrate (34 mg) was added, and the mixture was stirred at 180 ° C (oil bath temperature) for 15 hours. The reaction solution is under reduced pressure concentrate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (3H, t, J = 7.4 Hz), 1.38 (2H, dq, J = 14.9, 7.4 Hz), 1.54-1.65 (2H, m), 1.66 (3H, d, J = 6.2 Hz), 3.23 (1H, ddd, J = 14.2, 8.9, 5.4 Hz), 3.88 (1H, ddd, J = 14.4, 9.1, 7.0 Hz), 5.44 (1H, q, J = 6.2 Hz) ), 7.14 (1H, d, J = 0.8 Hz), 7.39 (1H, 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 the same procedure as in Production Example 6, from 6-butyl-5-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (275 mg) gave 3 -Bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one and 2-bromo-6-butyl-5-methyl A mixture of -5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (214 mg) as a brown oil.

MS (ESI/APCI pos) m/z: 272 [M+H] ⁺

Production Example 9 2-bromo-6-(2-methoxyethyl)-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H-imidazo[1, 5-a]imidazol-7-one

2,3-dibromo-6-(2-methoxyethyl)-derived from Production Example 6. 5,6-Dihydro-7H-imidazo[1,5-a]imidazol-7-one (98 mg), 4-isobutylphenylboronic acid (62 mg), hydrazine (triphenylphosphine) palladium ( A mixture of 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 extraction was carried out three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. 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 Amorphous.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (6H, d, J = 6.6 Hz), 1.88-1.96 (1H, m), 2.54 (2H, d, J = 7.0 Hz), 3.35 (3H, s) , 3.62 (2H, t, J = 4.7 Hz), 3.79 (2H, t, J = 4.7 Hz), 5.48 (2H, s), 7.29 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J=8.3Hz); MS(ESI/APCI pos)m/z: 392[M+H] ⁺

The following compounds were synthesized in the same manner as in Production Example 9.

2-bromo-6-butyl-3-[4-(cyclopropoxy)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-yl)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-(cyclobutoxy)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-(cyclopropoxy)phenyl]-6-(2-methylpropyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone

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-one

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] Imidazole-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] ⁺

Preparation Example 10 4,4,5,5-tetramethyl-2-[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]-1,3,2- Dioxocyclopentane

4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenol (500 mg) and triethylamine (0.599 mL) in chloroform (6.1 mL) Anhydrous trifluorosulfane sulfonate (0.482 mL) was added dropwise under ice cooling. The reaction solution was stirred for 1 hour while gradually raising the temperature to room temperature. After the reaction solution was dropped into a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, hexane: ethyl acetate = 95:5 to 90:10). The resulting pale yellow oil (714 mg), bis (pinacol) diboron (933 mg), potassium acetate (721 mg), [1,1'-bis(diphenylphosphino)ferrocene] A mixture of dichloropalladium (II) (100 mg) and 1,4-dioxane (6.1 mL) was stirred at 80 ° C (oil bath temperature) for 2 hours under a nitrogen atmosphere. After the reaction mixture was diluted with ethyl acetate, the insoluble material was filtered through Celite (registered trademark), and then separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjj(

1H NMR (200MHz, CHLOROFORM-d) δ ppm 1.34 (12H, s), 1.58 (6H, s), 7.50 (2H, d, J = 7.9 Hz), 7.81 (2H, d, J = 7.9 Hz); MS (EI pos)m/z: 314[M] ⁺

Production Example 10 The following compounds were synthesized in the same manner.

4,4,5,5-tetramethyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-1,3,2-dioxacyclopentane

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.34 (12H, s), 3.38 (2H, d, J = 10.7 Hz), 7.30 (2H, d, J = 7.8 Hz), 7.80 (2H, d, J = 7.8Hz)

4,4,5,5-tetramethyl-2-[4-(3,3,3-trifluoropropyl)phenyl]-1,3,2-dioxacyclopentane

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.34 (12H, s), 2.34 - 2.43 (2H, m), 2.86-2.90 (2H, m), 7.21 (2H, d, J = 7.8 Hz), 7.76 ( 2H,d,J=8.3Hz)

Preparation 11 2-[4-(2-Fluoro-2-methylpropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane 1) 1-bromo-4-(2-fluoro-2-methylpropyl)benzene

2-(4-bromophenyl)-2-methylpropan-1-ol (1.30 g) in chloroform (13 mL), EtOAc (EtOAc) After sulfur trifluoride (1.37 g), it was stirred at room temperature for 2.5 hours. After the reaction solution was dropwise added to a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. Residue by column chromatography (Silicagel Cartridge, Alkane: ethyl acetate = 100:0 - 98:2).

1H NMR (200MHz, CHLOROFORM-d) δ ppm 1.32 (6H, d, J = 21.1 Hz), 2.85 (2H, d, J = 21.1 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.42 (2H) ,d,J=8.4Hz);MS(EI pos)m/z:230[M] ⁺

2) 2-[4-(2-Fluoro-2-methylpropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

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 (200MHz, CHLOROFORM-d) δ ppm 1.33 (6H, d, J = 20.7 Hz), 1.34 (12H, s), 2.92 (2H, d, J = 20.7 Hz), 7.23 (2H, d, J = 7.9 Hz), 7.74 (2H, d, J = 7.9 Hz); MS (ESI/APCI pos) m/z: 301 [M+Na] ⁺

Preparation Example 12 2-[4-(Cyclobutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

2-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenol (500 mg), cyclobutanol (214 μL) and triphenylphosphine A solution of (894 mg) in tetrahydrofuran (12 mL) was added dropwise to diisopropyl azodicarboxylate (1.80 mL) at room temperature, followed by stirring for 2 hours. The reaction solution was stirred at 50 ° C (oil bath temperature) for 10 hours. The reaction solution is under reduced pressure concentrate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.32 (12H, s), 1.64-1.73 (1H, m), 1.82-1.89 (1H, m), 2.12-2.20 (2H, m), 2.41-2.48 (2H , m), 4.68 (1H, quin, J = 7.1 Hz), 6.80 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz)

Production Example 12 The following compounds were synthesized in the same manner.

4,4,5,5-tetramethyl-2-[4-(3,3,3-trifluoropropoxy)phenyl]-1,3,2-dioxacyclopentane

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.33 (s, 12H), 2.58-2.68 (m, 2H), 4.22 (t, J = 6.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H) , 7.76 (d, J = 8.7 Hz, 2H)

2-[4-(3-Fluoropropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.33 (12H, s), 2.17 (2H, dquin, J = 25.6, 5.8, 5.8, 5.8, 5.8 Hz), 4.12 (2H, t, J = 6.0 Hz), 4.64 (2H, dt, J = 47.9, 5.8 Hz), 6.89 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.7 Hz)

Preparation Example 13 2-(Cyclopentyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridine

A mixture of 6-hydroxypyridine-3-boronic acid ester (600 mg), iodocyclopentane (1.60 g), silver carbonate (I) (2.25 g) and toluene (6.0 mL) in a nitrogen atmosphere at 120 °C (oil bath temperature) was stirred for 2 hours. After the insoluble matter was filtered through celite (registered trademark) and separated by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (200MHz, CHLOROFORM-d) δ ppm 1.33 (12H, s), 1.42-2.03 (8H, m), 4.97-5.52 (1H, m), 6.57-6.88 (1H, m), 7.43-7.95 (1H , m), 8.08-8.59 (1H, m)

Preparation Example 14 5-Butyl-2-(4-tert-butylphenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one 1) Ethyl 1-(4-tert-butylphenyl)-1H-pyrazole-3-carboxylate

Add 1-bromo-4-tert-butylbenzene (4.40 mL) to a solution of ethyl 1H-pyrazole-3-carboxylate (2.39 g) in N,N-dimethylformamide (24 mL) N,N'-dimethylethylidene diamine (0.918 mL), copper (I) iodide (3.25 g) and cesium carbonate (11.1 g) were stirred at 110 ° C (oil bath temperature) for 12 hours. After the reaction mixture was filtered through celite (registered trademark), water was added to the filtrate and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was subjected to column chromatography (Silicagel Cartridge, hexane: ethyl acetate = The title compound (2.47 g) was obtained as a pale yellow oil.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.35 (9H, s), 1.42 (3H, t, J = 7.0 Hz), 4.44 (2H, q, J = 7.0 Hz), 6.98 (1H, d, J = 2.5 Hz), 7.46-7.49 (2H, m), 7.65-7.68 (2H, m), 7.90 (1H, d, J = 2.5 Hz); MS (ESI/APCI pos) m/z: 273 [M+H ] ⁺

2) Ethyl 1-(4-tert-butylphenyl)-4-carboxy-1H-pyrazole-3-carboxylate

After adding phosphonium chloride (4.80 mL) to N,N-dimethylformamide (3.9 mL) at -10 ° C, ethyl 1-(4-tert-butylphenyl)-1H- was added. Pyrazole-3-carboxylate (1.74 g) was stirred at 100 ° C (oil bath temperature) for 3 days. The reaction was dropped into a saturated aqueous solution of sodium hydrogencarbonate, and the pH was adjusted to 5.5. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.35 (9H, s), 1.47 (3H, t, J = 7.2 Hz), 4.52 (2H, q, J = 7.0 Hz), 7.51 (2H, d, J = 8.7 Hz), 7.67 (2H, d, J = 8.7 Hz), 8.45 (1H, s), 10.46 (1H, s); MS (ESI/APCI pos) m/z: 301 [M+H] ⁺

3) Ethyl 4-[(butylamino)methyl]-1-(4-tert-butylphenyl)-1H-pyrazole-3-carboxylate

To a solution of ethyl 1-(4-tert-butylphenyl)-4-methylindol-1H-pyrazole-3-carboxylate (34 mg) in chloroform (1.4 mL) - Butylamine (16 μL) was stirred for 1.5 hours. Sodium triethoxy borohydride (48 mg) was added to the reaction mixture at room temperature and stirred for 3 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added dropwise to the mixture, the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93 (3H, t, J = 7.2 Hz), 1.32-1.41 (12H, m), 1.44 (3H, t, J = 7.2 Hz), 1.56-1.63 (2H, m), 2.75-2.79 (2H, m), 4.06 (2H, s), 4.46 (2H, q, J = 7.0 Hz), 7.45-7.49 (2H, m), 7.61-7.65 (2H, m), 8.00 (1H, s); MS (ESI/APCI pos) m/z: 358 [M+H] ⁺ [M+H] ⁺

4) 4-[(butylamino)methyl]-1-(4-tert-butylphenyl)-1H-pyrazole-3-carboxylic acid

Ethyl 4-[(butylamino)methyl]-1-(4-tert-butylphenyl)-1H-pyrazole-3-carboxylate (36 mg) in tetrahydrofuran (0.72 mL) Water (0.72 mL) solution, 8 M sodium hydroxide solution (14 μL) was stirred at 70 ° C (oil bath temperature) for 12 hours. An 8 M aqueous sodium hydroxide solution (14 μL) was added to the reaction mixture, 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, and then citric acid and water were added, and then extracted with chloroform for 6 times. The combined organic layer was dried over anhydrous sodium sulfate.

MS (ESI/APCI pos) m/z: 330 [M+H] ⁺

5) 5-Butyl-2-(4-tert-butylphenyl)-4,5-dihydropyrrolo[3,4-c]pyrazole-6(2H)-one

In a solution of 4-[(butylamino)methyl]-1-(4-tert-butylphenyl)-1H-pyrazole-3-carboxylic acid (53 mg) in chloroform (2.1 mL) Triethylamine (0.112 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (62 mg) and 1-hydroxyl group were added at room temperature. Benzotriazole (HOBt) (49 mg) was stirred for 4 days. The reaction mixture was diluted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. 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 ) a colorless solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.4 Hz), 1.35 (9H, s), 1.36-1.44 (2H, m), 1.65 (2H, t, J = 7.4 Hz) , 3.60 (2H, t, J = 7.4 Hz), 4.33 (2H, s), 7.48 (2H, d, J = 8.7 Hz), 7.68 (2H, d, J = 8.7 Hz), 7.81 (1H, d, J=0.8 Hz); MS (ESI/APCI pos) m/z: 312 [M+H] ⁺

Preparation 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-1H-imidazol-2-carboxamide

Under a nitrogen atmosphere, in a solution of 1-benzyl-4-methyl-1H-imidazole (97.0 g) in tetrahydrofuran (780 mL), n-butyllithium (220 mL, 2.69 M) was added dropwise at -40 °C. The hexane solution) was stirred for 35 minutes. After the reaction solution was dropwise added with n-butyl isocyanate (69.1 mL) at -40 ° C, the mixture was stirred at room temperature for 2.5 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture under ice cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjj:

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.89-0.99 (3H, m), 1.32-1.45 (2H, m), 1.49-1.65 (2H, m), 2.09-2.21 (3H, m), 3.22-3.42 (2H, m), 5.63-5.80 (2H, m), 6.65-6.86 (1H, m), 7.01-7.42 (6H, m); MS (ESI pos) m/z: 272 [M+H] ⁺

2) N-butyl-4-methyl-1H-imidazole-2-carboxamide

1-Benzyl-N-butyl-4-methyl-1H-imidazol-2-carboxamide 10% palladium carbon (4.39 g) was added to a solution of (43.9 g) in ethanol (220 mL), and the mixture was stirred at 40 ° C (oil bath temperature) for 18 hours under a hydrogen atmosphere. After filtering the reaction liquid with diatomaceous earth (registered trademark), the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc (EtOAc)

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.94 (3H, t, J = 6.6 Hz), 1.27-7.11 (4H, m), 2.29 (3H, s), 3.42 (2H, q, J = 6.6 Hz) , 6.83 (1H, br.s.), 7.19 (1H, 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

In a nitrogen atmosphere, N-butyl-4-methyl-1H-imidazol-2-carboxamide (26.9 g) in N,N-dimethylformamide (500 mL) was cooled in an ice bath 60% sodium hydride (14.8 g) was added thereto, and the mixture was stirred for 15 minutes, and then stirred at room temperature for 30 minutes. After cooling in an ice bath, the reaction suspension was dropped into chloroiodane (26.8 mL), and stirred at room temperature for 12 hours. The reaction suspension was diluted with ethyl acetate and washed with aqueous ammonium chloride. The aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was diluted with MeOH, washed with hexane and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.3 Hz), 1.27-1.73 (4H, m), 2.34 (3H, d, J = 0.9 Hz), 3.58 (2H, t, J=7.3 Hz), 5.21 (2H, s), 6.93 (1H, 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

N,N-dimethylformamide (6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (5.78 g) A solution of 86 mL) was added with N-bromosuccinimide (5.59 g) under ice cooling, and stirred at room temperature for 45 minutes. After a 15% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added dropwise to the reaction mixture, the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was diluted with ethyl acetate and washed with aqueous sodium hydrogen sulfate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained solid was washed with EtOAc (EtOAc m.

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.3 Hz), 1.28-1.74 (4H, m), 2.30 (3H, s), 3.60 (2H, t, J = 7.3 Hz) , 5.13 (2H, s); MS (ESI/APCI pos) m/z: 272 [M+H] ⁺

Production Example 15 The following compounds were synthesized in the same manner.

3-bromo-6-butyl-2-(trifluoromethyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.85-0.99 (m, 3H) 1.27-1.43 (m, 2H) 1.56-1.69 (m, 2H) 3.60 (t, J = 7.43 Hz, 2H) 5.19 (s, 2H)

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] ⁺

Preparation 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-imidazol-2-carboxamide

A mixture of ethyl 4-methyl-1H-imidazol-2-carboxylate (7.80 g), cyclopropylmethylamine (14.4 g) and ethanol (25 mL) was carried out at 110 ° C (oil bath temperature). Stir for hours. After allowing to cool, the reaction solution was concentrated under reduced pressure. The residue was washed with EtOAc (EtOAc)

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.21-0.32 (2H, m), 0.48-0.61 (2H, m), 0.93-1.15 (1H, m), 2.30 (3H, d, J = 0.9 Hz), 3.29 (2H, dd, J = 7.0, 5.7 Hz), 6.84 (1H, d, J = 0.9 Hz), 7.42 (1H, 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

N,N-dimethylformamide (49 mL) in N-(cyclopropylmethyl)-4-methyl-1H-imidazol-2-carboxamide (2.64 g) under nitrogen Add 60% sodium hydride (1.77 g) to the ice bath for 15 minutes. After stirring, stirring was carried out for 30 minutes at room temperature. The chloroiodane (3.19 mL) was added dropwise to the reaction suspension under ice cooling, and the mixture was stirred at room temperature for 12 hours. The reaction suspension was diluted with ethyl acetate and washed with aqueous ammonium chloride. The aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was diluted with MeOH, washed with hexane and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.29-0.33 (2H, m), 0.59-0.63 (2H, m), 0.98-1.06 (1H, m), 2.34 (3H, s), 3.46 (2H, d , J=7.0 Hz), 5.33 (2H, s), 6.94 (1H, 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

N,N-dimethyl at 6-(cyclopropylmethyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (455 mg) In a solution of carbamide (6.8 mL), N-bromosuccinimide (445 mg) was added thereto under ice cooling, and the mixture was stirred at room temperature for 45 minutes. After a 15% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added dropwise to the reaction mixture, the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (NHSilicagel Cartridge, chloroform). The resulting solid is diisopropyl ether The title compound (471 mg) was obtained as a brown solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.30-0.34 (2H, m), 0.60-0.65 (2H, m), 0.98-1.07 (1H, m), 2.29 (3H, s), 3.47 (2H, d , J=7.4Hz), 5.23(2H, s); MS(ESI pos)m/z: 270[M+H] ⁺

Production Example 16 The following compounds were synthesized in the same manner.

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 (600MHz, CHLOROFORM-d) δ ppm 1.76-1.85 (2H, m) 1.91-1.99 (2H, m) 2.07-2.15 (2H, m) 2.29 (3H, s) 2.59-2.68 (1H, m) 3.63 (2H,d,J=7.4Hz)5.08(2H,s)

3-bromo-2-methyl-6-(propan-2-ylidene-1-yl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

1H NMR (600MHz, CHLOROFORM-d) δ ppm 2.27-2.35 (3H, m) 4.22 (2H, d, J = 6.2 Hz) 5.10 (2H, s) 5.27-5.37 (2H, m) 5.78-5.91 (1H, 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-imidazole And [1,5-a]imidazol-7-one

MS (ESI pos) m/z: 286 [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]imidazol-2-carboxylate

The 2-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (900 mg) obtained in Example 3 was prepared under a carbon monoxide atmosphere. a mixture of triphenylphosphine)palladium(0) (403 mg), potassium carbonate (723 mg), ethanol (5.8 mL) and N,N-dimethylformamide (12 mL) at 75 ° C (oil bath temperature) ) Stir for 4 days. The reaction solution was diluted with ethyl acetate and filtered over Celite (trade), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NHSilicagel Cartridge, hexane: ethyl acetate = 50: 50). The obtained solid was washed with diisopropyl ether to give the title compound (537 mg).

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.94-1.00 (3H, m), 1.35-1.45 (5H, m), 1.62-1.70 (2H, m), 3.62 (2H, t, J = 7.4 Hz), 4.41 (2H, q, J = 7.3 Hz), 5.35 (2H, s), 7.87 (1H, 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 a nitrogen atmosphere, ethyl 6-butyl-7-oxo-6,7-dihydro-5H-imidazo[1,5-a]imidazol-2-carboxylate (150 mg) and chlorine To a solution of calcium (132 mg) in ethanol (6.0 mL), sodium borohydride (90 mg) was added at room temperature, followed by stirring for 3.5 days. The reaction solution was added dropwise with a saturated aqueous solution of ammonium chloride under ice cooling, and then stirred at room temperature for 15 minutes. After the reaction liquid was filtered through diatomaceous earth (registered trademark), the filtrate was extracted with chloroform five times. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.35-1.45 (2H, m), 1.53-1.69 (2H, m), 3.61 (2H, t, J = 7.4 Hz), 4.70 (2H, s), 5.27 (2H, s), 7.18 (1H, 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

Chloroform (1.7) in 6-butyl-2-(hydroxymethyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (43 mg) under nitrogen atmosphere In a solution of mL), (diethylamino)sulfur trifluoride (37 μL) was added thereto under ice cooling, and the mixture was stirred at room temperature for 1 hour. After a saturated aqueous solution of sodium hydrogencarbonate was added dropwise to the reaction mixture in an ice bath, the mixture was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. Will be disabled The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.36-1.44 (2H, m), 1.60-1.69 (2H, m), 3.62 (2H, t, J = 7.4 Hz), 5.29 (2H, s), 5.42 (1H, d, J = 49.1 Hz), 7.32 (1H, 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

N,N-dimethyl A to 6-butyl-2-(fluoromethyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (15 mg) A solution of decylamine (0.20 mL) was added to N-bromosuccinimide (15 mg) under ice-cooling, and then stirred at room temperature for 5 hours. The reaction solution was added dropwise to a 15% aqueous sodium thiosulfate solution under ice cooling, and then stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and extraction was carried out twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.35-1.46 (2H, m), 1.62-1.69 (2H, m), 3.63 (2H, t, J = 7.4 Hz), 5.20 (2H, s), 5.37 (2H, d, J = 48.7 Hz); MS (ESI/APCI pos) m/z: 290 [M+H] ⁺

Preparation Example 18 2-{4-[Cyclopropyl(difluoro)methyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane 1) 1-bromo-4-[cyclopropyl(difluoro)methyl]benzene

a mixture of (4-bromophenyl)(cyclopropyl)methanone (800 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (2.36 g) at 80 ° C under nitrogen atmosphere (Oil bath temperature) was stirred for 2 days. The reaction solution was diluted with chloroform, and a saturated aqueous solution of sodium hydrogencarbon The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjj(

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.57-0.82 (4H, m), 1.32-1.63 (1H, m), 7.41 (2H, d, J = 9.2 Hz), 7.55 (2H, 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-dioxacyclopentane

1-Bromo-4-[cyclopropyl(difluoro)methyl]benzene (134 mg), bis(pinacol) diboron (186 mg), potassium acetate (144 mg), [1,1'- a mixture of bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg) and 1,4-dioxane (1.2 mL) under nitrogen at 80 ° C (oil bath temperature) Degree) was stirred for 3 hours. After the reaction mixture was diluted with ethyl acetate, the insoluble material was filtered over Celite (registered trademark) and separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjli

1H NMR (200MHz, CHLOROFORM-d) δ ppm 0.55-0.82 (4H, m), 1.35 (12H, s), 1.38-1.61 (1H, m), 7.52 (2H, d, J = 8.4 Hz), 7.85 ( 2H,d,J=8.4Hz);MS(EI pos)m/z:294[M] ⁺

The following compounds were synthesized in the same manner as in Production Example 18.

2-[4-(1,1-difluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.35 (12H, s), 1.91 (3H, t, J = 18 Hz), 7.50 (2H, d, J = 7.8 Hz), 7.86 (2H, d, J = 7.8 Hz)

2-[4-(1,1-difluoropropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS(EI pos)m/z: 282[M] ⁺

2-[4-(1,1-Difluoro-3-methylbutyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS(EI pos)m/z:310[M] ⁺

2-[4-(1,1-Difluoro-2-methylpropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS (ESI pos) m/z: 297 [M+H] ⁺

2-{Difluoro[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-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-dioxacyclopentane

MS (ESI pos) m/z: 345 [M+H] ⁺

2-[4-(2,2-difluoropropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS(EI pos)m/z: 282[M] ⁺

2-[Difluoro(phenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-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-dioxacyclopentane

MS(EI pos)m/z:296[M] ⁺

2-{4-[Difluoro(1-methylcyclopropyl)methyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

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-dioxacyclopentyl boron alkyl

MS(EI pos)m/z:310[M] ⁺

2-{4-[cyclopentyl(difluoro)methyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS(EI pos)m/z: 322[M] ⁺

2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS(EI pos)m/z:330[M] ⁺

2-(1,1-Difluoro-3-methylbutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl) Pyridine

MS (ESI/APCI pos) m/z: 312 [M+H] ⁺

Preparation Example 19 1-(5-Bromopyridin-2-yl)-3-methylbutan-1-one

After adding manganese dioxide (1.60 g) to a solution of 1-(5-bromopyridin-2-yl)-3-methylbutan-1-ol (3.00 g) in chloroform (30 mL) The mixture was stirred at room temperature for 3 hours and at 50 ° C (oil bath temperature) for 14 hours. After cooling, the insoluble matter was filtered with diatomaceous earth (registered trademark) and separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.99 (6H, d, J = 6.6 Hz), 2.26-2.33 (1H, m), 3.05 (2H, d, J = 7.0 Hz), 7.91-7.97 (2H, m), 8.71 - 8.73 (1H, m); MS (ESI pos) m/z: 242 [M+H] ⁺

Preparation Example 20 3-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)phenoxy]pyridine

3-(4-Bromo-2-fluorophenoxy)pyridine (100 mg), double (frequency) Diol (115 mg), potassium acetate (111 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg) and 1,4-di A mixture of oxane (10 mL) was stirred at 100 ° C (oil bath temperature) for 4 hours under nitrogen. After the reaction mixture was diluted with ethyl acetate, the insoluble material was filtered over Celite (registered trademark) and separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

MS (ESI pos) m/z: 316 [M+H] ⁺

The following compounds were synthesized in the same manner as in Production Example 20.

2-(cyclobutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridine

1H NMR (200MHz, CHLOROFORM-d) δ ppm 1.33 (s, 12H), 1.56-1.93 (m, 2H), 2.02-2.25 (m, 2H), 2.37-2.56 (m, 2H), 5.21 (quin, J = 7.5 Hz, 1H), 6.60-6.69 (m, 1H), 7.91 (dd, J = 8.4, 1.8 Hz, 1H), 8.48-8.54 (m, 1H)

2-(4-tert-butoxy-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane

MS (ESI/pos) m/z: 294 [M] ⁺

2-phenyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-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 Base-1,3,2-dioxacyclopentane

MS (ESI/APCI pos) m/z: 277 [M+H] ⁺

Production Example 21 5-phenyl-2-(tributylstannyl)pyridine

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 under nitrogen atmosphere. Stir for 20 minutes. After the reaction solution was dropwise added with tributyltin chloride (0.243 mL) at -78 ° C, the mixture was stirred at 4 ° C for 80 minutes. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

MS (ESI pos) m/z: 446 [M+H] ⁺

Example 1: 2-butyl-6-(4-tert-butylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one

N,N-dimethylformamide (1.0 mg) of N-butyl-4-(4-tert-butylphenyl)-1H-pyrrole-2-carboxamide (94 mg) obtained in Preparation Example 1. mL) solution, add 60% sodium hydride (38 mg) at room temperature and carry out 1 small Stir when. The reaction solution was added with chloroiodane (107 mg) at room temperature, and stirred for 2 hours. After water was added to the reaction mixture, extraction was carried out with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, hexane: ethyl acetate = 90:10 to 50:50). The obtained solid was washed with EtOAc/EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93-1.01(m,3H)1.34(s,9H)1.37-1.45(m,2H)1.57-1.67(m,2H)3.51-3.58(m,2H)5.28 (s, 2H) 6.84 (s, 1H) 7.20 (s, 1H) 7.36-7.47 (m, 4H); MS (ESI/APCI pos) m/z: 311 [M+H] ⁺

Example 2: 2-butyl-6-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one

Using the same procedure as in Example 1, the title was obtained from N-butyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxamide (93 mg) obtained in Preparation Example 1. Compound (13 mg) as a colorless solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.94-1.02(m,3H)1.37-1.46(m,2H)1.58-1.68(m,2H)3.52-3.62(m,2H)5.31(s,2H)6.89 (s, 1H) 7.29 (s, 1H) 7.55-7.65 (m, 5H); MS (ESI/APCI pos) m/z: 323 [M+H] ⁺

Example 3: 6-[4-(Benzyloxy)phenyl]-2-butyl-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one

Using the same procedure as in Example 1, 4-[4-(benzyloxy)phenyl]-N-butyl-1H-pyrrole-2-carboxamide (175 mg) obtained in Production Example 1 gave the title. Compound (20 mg) as a colorless solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93-0.99(m,3H)1.36-1.45(m,2H)1.58-1.66(m,2H)3.50-3.59(m,2H)5.10(s,2H)5.27 (s, 2H) 6.80-6.88 (m, 2H) 7.07-7.14 (m, 2H) 7.20 (s, 1H) 7.26-7.48 (m, 6H); MS (ESI/APCI pos) m/z: 361 [M +H] ⁺

Example 4: 6-Butyl-2-(4-tert-butylphenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

Using the same procedure as in Example 1, N-butyl-4-(4-tert-butylphenyl)-1H-imidazol-2-carboxamide (69 mg) obtained in Preparation 2 gave the title compound. 6 mg) of a colorless solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.34 (9H, s), 1.37-1.45 (2H, m), 1.62-1.69 (2H, m), 3.61 ( 2H, t, J = 7.4 Hz), 5.31 (2H, s), 7.41-7.44 (2H, m), 7.45 (1H, s), 7.76-7.81 (2H, m); MS (ESI/APCI pos) m /z:312[M+H] ⁺

Example 5: 6-Butyl-3-(4-methoxyphenyl)-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 3-bromo-6-butyl-5 obtained in Preparation Example 3, a mixture of 6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (100 mg), 4-methoxyphenylboronic acid (88 mg), potassium carbonate (160 mg), (1 ,3-bis(2,6-diisopropylbenzene (Imidazolyl) (3-chloropyridyl) palladium(II) chloride (PEPPSI (registered trademark)-IPr) (26 mg), ethanol (0.49 mL), toluene (0.49 mL) and water ( The mixture of 0.33 mL) was stirred at 100 ° C (oil bath temperature) for 30 minutes. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (NHSilicagel Cartridge, hexane: ethyl acetate = 50:50 to 0:100 and Silicagel Cartridge, hexane: ethyl acetate = 10:90 to 0:100). 6-butyl-3-(4-methoxyphenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (44 mg) as a colorless solid, 6 a colorless solid of -butyl-2-(4-methoxyphenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (14 mg).

6-butyl-3-(4-methoxyphenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.42 (2H, sxt, J = 7.5 Hz), 1.68 (2H, quin, J = 7.0 Hz), 3.65 (2H) , t, J = 7.4 Hz), 3.86 (3H, s), 5.41 (2H, s), 7.00 (2H, dt, J = 8.7, 2.1 Hz), 7.41 (2H, dt, J = 8.7, 2.5 Hz) , 7.52 (1H, 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 (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.41 (2H, sxt, J = 7.4 Hz), 1.65 (2H, quin, J = 7.5 Hz), 3.62 (2H) , t, J = 7.4 Hz), 3.84 (3H, s), 5.30 (2H, s), 6.93 (2H, d, J = 9.1 Hz), 7.39 (1H, s), 7.78 (2H, d, J = 8.7 Hz); MS (ESI/APCI pos) m/z: 286 [M+H] ⁺

Example 6: 2-Butyl-5-(4-tert-butylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one

N,N-dimethylformamide (1.0 mg) of N-butyl-5-(4-tert-butylphenyl)-1H-pyrrole-2-carboxamide (119 mg) obtained in Preparation 4. In a solution of mL), 60% sodium hydride (48 mg) was added under ice cooling, and the mixture was stirred for 30 minutes, and then stirred at room temperature for 15 minutes. Under ice cooling, chloroiodane (85 mg) was added to the reaction mixture, followed by stirring for 2 hours. After water was added to the reaction mixture, extraction was carried out with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, hexane: ethyl acetate = 100:0 to 70:30). The obtained solid was washed with hexane to give the title compound (10 mg).

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.92-1.00 (m, 3H) 1.30 (s, 9H) 1.37-1.45 (m, 2H) 1.57-1.66 (m, 2H) 3.49-3.59 (m, 2H) 5.27 (s, 2H) 6.84 (s, 1H) 7.35-7.41 (m, 2H) 7.42-7.46 (m, 2H); MS (ESI/APCI pos) m/z: 311 [M+H] ⁺

The compounds of Examples 7 to 10 were obtained in the same manner as in Example 6.

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]imidazole-1- ketone Example 10: 5-(4-tert-butylphenyl)-2-(cyclopropylmethyl)-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one

The structural formula and machine data of the compounds of Examples 7 to 10 are shown in Table 1.

Example 11: 6-Butyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

3-Bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (30 mg) obtained in Preparation Example 6 and 4-trifluoromethoxy a mixture of phenylboronic acid (36 mg), potassium carbonate (48 mg), PEPPSI (registered trademark)-IPr (8 mg), ethanol (0.15 mL), toluene (0.15 mL), and water (0.10 mL) at 100 ° C (oil bath temperature) was stirred for 1 hour. After the reaction liquid was diluted with chloroform, the insoluble matter was filtered and separated by filtration through diatomaceous earth (registered trademark). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NHSilicagel Cartridge, hexane: ethyl acetate = 60: 40 to 30: 70) to give 6-butyl-3-[4-(trifluoromethoxy) Phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (30 mg) as a colorless solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.2 Hz), 1.42 (2H, sxt, J = 7.3 Hz), 1.69 (2H, quin, J = 7.5 Hz), 3.66 (2H) , t, J = 7.4 Hz), 5.45 (2H, s), 7.33 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.62 (1H, s); MS (ESI) /APCI pos)m/z: 340[M+H] ⁺

The compounds of Examples 12 to 55 were obtained in the same manner as in Example 11.

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-7-one 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)phenyl]-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one Example 20: 4-(6-Butyl-7-oxoyl-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-ketone 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-(Butane-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]imidazole-7 -ketone Example 26: 6-Butyl-3-[4-(propan-2-yl)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]imidazol-7-one 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-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)phenyl]-2 -methylpropanonitrile Example 31: 6-Butyl-3-[4-(cyclopropoxy)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-methylpropyl)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-oxy)pyridin-3-yl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7 -ketone Example 36: 6-Butyl-3-[4-(propan-2-ylsulfanyl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7- ketone 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-Butoxyphenyl)-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one Example 40: 6-Butyl-3-[2-fluoro-4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7 -ketone 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-(cyclobutoxy)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]imidazol-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]imidazole-7 -ketone Example 49: 3-(4-tert-butylphenyl)-6-(cyclopropylmethyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one Example 55: 3-[4-(Cyclopropoxy)phenyl]-6-propyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one Example 51: 3-[4-(Cyclopropoxy)phenyl]-6-(3-methylbutyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone Example 52: 3-[4-(Cyclopropoxy)phenyl]-6-pentyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one Example 53: 3-(4-tert-butylphenyl)-6-(propan-2-yl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-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

The structural formula and machine data of the compounds of Examples 12 to 55 are shown in Tables 2-1 to 2-9.

Example 56: 3-(4-tert-butylphenyl)-6-(4-methoxybenzyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone

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), hydrazine (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 extracted three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. 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 (Silicagel Cartridge, chloroform: acetic acid). Ethyl ester = 90:10 - 80:20) After purification, the title compound (29 mg)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 1.32 (9H, s), 3.80 (3H, s), 4.77 (2H, s), 5.26 (2H, s), 6.90 (2H, d, J = 8.3 Hz) , 7.26-7.29 (2H, m), 7.34 (2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.58 (1H, s); MS (ESI/APCI pos) m/ z:376[M+H] ⁺

The compounds of Examples 57 to 62 were obtained in the same manner as in Example 56.

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-imidazole And [1,5-a]imidazol-7-one Example 60: 6-Butyl-3-(3,4-dichlorophenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one 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]imidazole -7-ketone

The structural formula and machine data of the compounds of Examples 57 to 62 are shown in Table 3.

Example 63: 6-Butyl-3-(3-fluoro-4-methylphenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

Under a nitrogen atmosphere, a solution of 2-fluoro-4-iodotoluene (106 mg) in tetrahydrofuran (1.0 mL) was added dropwise at -78 °C to di-tert-butyl butyl zincate (0.820 mL, 0.55 M, tetrahydrofuran). After the solution, the mixture was stirred at room temperature for 1.5 hours. 3-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (77 mg) obtained in Preparation Example 6 was added to the reaction mixture at room temperature. Tris(triphenylphosphine)palladium(0) (14 mg) 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 evaporated. The residue was subjected to reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid/water: 0.1% trifluoroacetic acid/acetonitrile = 90:10 to 0:100) and column chromatography (NHSilicagel Cartridge). The title compound (8 mg) was obtained as white crystals.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95-1.01(m,3H)1.38-1.47(m,2H)1.66-1.71(m,2H)2.32(s,3H)3.63-3.69(m,2H)5.44 (s, 2H) 7.07-7.70 (m, 4H)

Example 64: 6-Butyl-3-(4-tert-butylphenyl)-5-methyl-5,6-di Hydrogen-7H-imidazo[1,5-a]imidazol-7-one

3-Bromo-6-butyl-5-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one and 2-bromo-6- obtained in Production Example 8. Mixture of butyl-5-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (84 mg), 4-tert-butylphenylboronic acid (66 mg A mixture of PEPPSI (registered trademark)-IPr (21 mg), ethanol (0.84 mL), toluene (0.84 mL), and 2M sodium carbonate aqueous solution (0.46 mL) was stirred at 100 ° C (oil bath temperature) for 2 hours. Water was added to the reaction mixture and extracted three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc .

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.99 (3H, t, J = 7.4 Hz), 1.36 (9H, s), 1.38-1.47 (2H, m), 1.53 (3H, d, J = 5.8 Hz) , 1.60-1.75 (2H, m), 3.17-3.24 (1H, m), 3.91-3.98 (1H, m), 5.77-5.82 (1H, m), 7.40-7.43 (2H, m), 7.45-7.48 ( 2H, m), 7.48-7.49 (1H, m); MS (ESI/APCI pos) m/z: 326 [M+H] ⁺

Example 65: 6-Butyl-3-(6-phenoxypyridin-3-yl)-5,6-dihydro- 7H-imidazo[1,5-a]imidazol-7-one

1) 6-Butyl-3-(6-chloropyridin-3-yl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

Using the same procedure as in Example 56, 3-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one obtained in Production Example 6 (103 The title compound (45 mg) was obtained as a white crystal.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.39-1.47 (2H, m), 1.66-1.72 (2H, m), 3.67 (2H, t, J = 7.4 Hz), 5.46 (2H, s), 7.45 (1H, d, J = 8.3 Hz), 7.69 (1H, s), 7.79 (1H, dd, J = 8.3, 2.5 Hz), 8.52 (1H, 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) of N,N-dimethylformamide (0.40 mL), copper (0.4 mg) and cesium carbonate (67 mg), stirring was carried out for 1 hour at 100 ° C under microwave irradiation. Water was added to the reaction mixture and extracted three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc:EtOAc .

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.37-1.45 (2H, m), 1.62-1.69 (2H, m), 3.64 (2H, t, J = 7.4 Hz), 5.39 (2H, s), 7.03-7.06 (1H, m), 7.15-7.18 (2H, m), 7.24-7.27 (1H, m), 7.42-7.46 (2H, m), 7.57 (1H, s), 7.85 (1H, dd, J = 8.5, 2.7 Hz), 8.27-8.30 (1H, m); MS (ESI/APCI pos) m/z: 349 [M+H] ⁺

Example 66: 6-Butyl-3-[4-(pyridin-2-yloxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

1) 6-Butyl-3-(4-hydroxyphenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

3-[4-(Benzyloxy)phenyl]-6-butyl group obtained in Example 19 Add 5% palladium on carbon (30%) to a solution of 5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (376 mg) in methanol (1.3 mL) and ethyl acetate (6.7 mL) Mg), stirring under a hydrogen atmosphere at room temperature for 15 hours. After filtering the reaction liquid with diatomaceous earth (registered trademark), the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

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) A mixture of mg), potassium carbonate (46 mg) and N,N-dimethylformamide (0.60 mL) was stirred at 150 ° C for 1.5 hours under microwave irradiation. The title compound (12) was obtained after purification by reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid/water: 0.1% trifluoroacetic acid / acetonitrile = 90:10 to 0:100) A colorless solid of mg).

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.42 (2H, sxt, J = 7.0 Hz), 1.65-1.72 (2H, m), 3.66 (2H, t, J = 7.4 Hz), 5.45 (2H, s), 6.99 (1H, d, J = 8.3 Hz), 7.04-7.07 (1H, m), 7.24-7.28 (2H, m), 7.49-7.53 (2H, m ), 7.58 (1H, s), 7.72-7.76 (1H, m), 8.19-8.22 (1H, m); MS (ESI/APCI pos) m/z: 349 [M+H] ⁺

Example 67: 6-Butyl-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-5,6-dihydro-7H-imidazo[1,5 -a]imidazole-7-one

Using the same procedure as in Example 11, the 6-butyl-3-(4-chlorophenyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazole obtained from Example 54 was used. 7-ketone (100 mg) and 3,6-dihydro-2H-pyran-4-boronic acid ester (87 mg) gave the title compound (80 mg).

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.39-1.47 (2H, m), 1.65-1.72 (2H, m), 2.52-2.57 (2H, m), 3.66 (2H, t, J = 7.4 Hz), 3.96 (2H, t, J = 5.4 Hz), 4.34 - 4.38 (2H, m), 5.46 (2H, s), 6.21-6.24 (1H, m), 7.44 -7.52 (4H, m), 7.64 (1H, s); MS (ESI/APCI pos) m/z: 338 [M+H] ⁺

Example 68: 6-Butyl-3-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole -7-ketone

6-Butyl-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-5,6-dihydro-7H-imidazo[6] obtained in Example 67 To a solution of 5-a]imidazol-7-one (70 mg) in methanol (1.4 mL), 10% palladium carbon (35 mg) was added and stirred at room temperature for 1 hour under hydrogen atmosphere. After the reaction mixture was filtered over EtOAc (EtOAc),

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.39-1.46 (2H, m), 1.65-1.71 (2H, m), 1.77-1.88 (4H, m), 2.77-2.85 (1H, m), 3.53-3.58 (2H, m), 3.65 (2H, t, J = 7.4 Hz), 4.11 (2H, dd, J = 10.9, 3.9 Hz), 5.44 (2H, s) , 7.34 (2H, d, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.60 (1H, s); MS (ESI/APCI pos) m/z: 340 [M+H] ⁺

Example 69: 6-Butyl-2-methyl-3-[6-(piperidin-1-yl)pyridin-3-yl]-5,6-dihydro-7H-imidazo[1,5- a] imidazole-7-one

3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (20 mg) obtained in Preparation Example 7 and 6- (piperidin-1-yl)pyridine-3-boronic acid ester (27 mg), potassium carbonate (32 mg), PEPPSI (registered trademark)-IPr (2.6 mg), ethanol (0.23 mL), toluene (0.23 mL) The mixture with water (0.15 mL) was stirred at 100 ° C (oil bath temperature) for 3 hours. Water was added to the reaction mixture and extracted three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.94 (3H, t, J = 7.4 Hz), 1.33-1.41 (2H, m), 1.58-1.73 (8H, m), 2.40 (3H, s), 3.56- 3.61 (6H, m), 5.21 (2H, s), 6.72 (1H, d, J = 9.1 Hz), 7.47 (1H, dd, J = 8.7, 2.5 Hz), 8.21 (1H, d, J = 2.1 Hz) ); MS (ESI/APCI pos) m/z: 354 [M+H] ⁺

The compounds of Examples 70 to 74 were obtained in the same manner as in Example 69.

Example 70: 6-Butyl-3-[6-(cyclopentyloxy)pyridin-3-yl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a] Imidazole-7-one Example 71: 6-Butyl-3-[4-(cyclopentyloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7 -ketone 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] Imidazole-7-one Example 74: 6-Butyl-3-[4-(3-fluoropropoxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole -7-ketone

The structural formula and machine data of the compounds of Examples 70 to 74 are shown in Table 4.

Example 75: 2-Bromo-6-butyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7 -ketone

2,3-Dibromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (316 mg) obtained in Preparation Example 6 and 4-trifluoro a mixture of methoxyphenylboronic acid (193 mg), hydrazine (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 hydrazine (triphenylphosphine)palladium(0) (54 mg) were added to the reaction mixture, and the mixture was stirred at 100 ° C (oil bath temperature) for 7 hours. Water was added to the reaction mixture and extracted three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was subjected to column chromatography (Silicagel Cartridge, chloroform: ethyl acetate = 95:5 to 90:10) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid/water: 0.1% trifluoron). Acetic acid / acetonitrile = 90:10 - 0: 100) After purification, the title compound (26 mg) was obtained.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.4 Hz), 1.35-1.44 (2H, m), 1.60-1.68 (2H, m), 3.62 (2H, t, J = 7.4 Hz), 5.34 (2H, s), 7.36 (2H, d, J = 8.7 Hz), 7.64 - 7.68 (2H, m); MS (ESI/APCI pos) m/z: 418 [M+H] ⁺

Example 76: 3-(Biphenyl-4-yl)-2-bromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

Using the same procedure 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) gave the title compound (416 mg).

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.97 (3H, t, J = 7.4 Hz), 1.37-1.44 (2H, m), 1.63-1.69 (2H, m), 3.63 (2H, t, J = 7.4 Hz), 5.39 (2H, s), 7.39-7.43 (1H, m), 7.46-7.51 (2H, m), 7.61-7.65 (2H, m), 7.68-7.71 (2H, m), 7.72-7.75 ( 2H,m);MS(ESI/APCI pos)m/z:410[M+H] ⁺

Example 77: 6-Butyl-2-vinyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone

2-Bromo-6-butyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole obtained in Example 75 a solution of -7-ketone (83 mg) in N,N-dimethylformamide (1.7 mL) with cesium fluoride (60 mg), bis(triphenylphosphine)palladium(II) dichloride (14) Mg) and tributyltintin (87 μL) were stirred at 100 ° C (oil bath temperature) for 12 hours. After filtering the reaction liquid with diatomaceous earth (registered trademark), the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjj(

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.2 Hz), 1.36-1.43 (2H, m), 1.64 (2H, t, J = 7.6 Hz), 3.62 (2H, t, J = 7.6 Hz), 5.27 (2H, s), 5.33 (1H, dd, J = 10.9, 1.9 Hz), 6.26 (1H, dd, J = 17.1, 1.9 Hz), 6.69 (1H, dd, J = 17.1) , 10.9 Hz), 7.36 (2H, d, J = 8.7 Hz), 7.47 (2H, d, J = 8.7 Hz); MS (ESI/APCI pos) m/z: 366 [M+H] ⁺

Example 78: 6-Butyl-2-ethyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone

6-butyl-2-vinyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a] obtained in Example 77 A solution of imidazole-7-one (17 mg) in methanol (1.4 mL) was added to 10% palladium carbon (17 mg), and stirred at room temperature for 1 hour under hydrogen atmosphere. After filtering the reaction liquid with diatomaceous earth (registered trademark), the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc .

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (3H, t, J = 7.4 Hz), 1.32 (3H, t, J = 7.6 Hz), 1.36-1.43 (2H, m), 1.60-1.66 (2H, m), 2.76 (2H, q, J = 7.4 Hz), 3.61 (2H, t, J = 7.4 Hz), 5.26 (2H, s), 7.34 (2H, d, J = 8.3 Hz), 7.41 - 7.45 ( 2H,m);MS(ESI/APCI pos)m/z:368[M+H] ⁺

Example 79: 6-Butyl-2-methyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone

The 2-bromo-6-butyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole obtained in Example 75. -7-ketone (55 Mixture of mg), methylboronic acid (12 mg), PEPPSI (registered trademark)-IPr (9 mg), ethanol (0.55 mL), toluene (0.55 mL) and 2M aqueous sodium carbonate (0.20 mL) at 100 ° C (oil) Bath temperature) was stirred for 3 hours. Water was added to the reaction mixture, and extraction was carried out three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc .

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.4 Hz), 1.36-1.44 (2H, m), 1.60-1.68 (2H, m), 2.46 (3H, s), 3.61 ( 2H,t,J=7.4Hz), 5.28(2H,s),7.33-7.37(2H,m),7.42-7.47(2H,m);MS(ESI/APCI pos)m/z:354[M+ H] ⁺

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] Imidazole-7-one Example 81: 6-Butyl-3-[4-(cyclopentyloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7 -ketone 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] Imidazole-7-one Example 84: 6-Butyl-3-[4-(3-fluoropropoxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole -7-ketone

The structural formula and machine data of the compounds of Examples 80 to 85 are shown in Table 5.

Example 86: 6-(2-Methoxyethyl)-2-methyl-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H-imidazo[ 1,5-a]imidazol-7-one and 6-(2-methoxyethyl)-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H- Imidazo[1,5-a]imidazol-7-one

2-Bromo-6-(2-methoxyethyl)-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H-imidazole obtained in Preparation Example 9 [1,5-a]imidazol-7-one (82 mg), methylboronic acid (37 mg), PEPPSI (registered trademark)-IPr (28 mg), ethanol (0.82 mL), toluene (0.82 mL) and 2M A mixture of 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 extraction was carried out three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was subjected to column chromatography (Silicagel Cartridge, chloroform: ethyl acetate = 75: 25 to 50: 50) and reverse phase column chromatography (SunFire (registered trademark), 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90:10 ~ 0: 100) after purification to obtain 6-(2-methoxy Benzyl)-2-methyl-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (26 mg) of a colorless solid, and 6-(2-methoxyethyl)-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H-imidazo[ 1,5-a]imidazole-7-one (16 mg) as a colorless solid.

6-(2-methoxyethyl)-2-methyl-3-[4-(2-methylpropyl)phenyl]-5,6-dihydro-7H-imidazo[1,5- a] imidazole-7-one

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (6H, d, J = 6.6 Hz), 1.91 (1H, dt, J = 13.4, 6.9 Hz), 2.46 (3H, s), 2.53 (2H, d, J = 7.0 Hz), 3.35 (3H, s), 3.61 (2H, t, J = 4.7 Hz), 3.77 (2H, t, J = 4.7 Hz), 5.42 (2H, s), 7.25-7.29 (2H, m), 7.30-7.34 (2H, 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]imidazole-7 -ketone

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93 (6H, d, J = 6.6 Hz), 1.86-1.94 (1H, m), 2.52 (2H, d, J = 7.0 Hz), 3.38 (3H, s) , 3.65 (2H, t, J = 4.7 Hz), 3.82 (2H, t, J = 4.7 Hz), 5.58 (2H, s), 7.25 (2H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.3 Hz), 7.61 (1H, s); MS (ESI/APCI pos) m/z: 314 [M+H] ⁺

The compounds of Examples 87 to 96 were obtained in the same manner as in Example 86.

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]imidazole -7-ketone Example 90: 6-Butyl-3-[4-(2-fluoroethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one Example 91: 3-[4-(Cyclopropoxy)phenyl]-2-methyl-6-(2-methylpropyl)-5,6-dihydro-7H-imidazo[1,5 -a]imidazole-7-one Example 92: 3-[4-(Cyclopropoxy)phenyl]-6-(2-methylpropyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone Example 93: 2-Methyl-6-(4,4,4-trifluorobutyl)-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazole And [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]imidazole-7-one Example 95: 6-(2-Cyclopropylethyl)-2-methyl-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1 , 5-a]imidazole-7-one Example 96: 6-(2-Cyclopropylethyl)-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a] Imidazole-7-one

The structural formula and machine data of the compounds of Examples 87 to 96 are shown in Tables 6-1 to 6-2.

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

The 2,3-dibromo-6-butyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (100 mg) obtained in Production Example 6 was obtained in Production Example 10. 4,4,5,5-tetramethyl-2-[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]-1,3,2-dioxin Cyclopentane (102 mg), hydrazine (triphenylphosphine) palladium (0) (34 mg), potassium carbonate (123 mg), ethanol (0.45 mL), toluene (0.45 mL), and water (0.30 mL) The mixture was stirred at 100 ° C (oil bath temperature) for 2 hours under a nitrogen atmosphere. 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. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc .

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.94 (3H, t, J = 7.4 Hz), 1.38 (2H, sxt, J = 7.5 Hz), 1.54-1.66 (8H, m), 2.46 (3H, s) , 3.60 (2H, t, J = 7.4 Hz), 5.28 (2H, s), 7.37-7.42 (2H, m), 7.60 (2H, d, J = 8.3 Hz); MS (ESI/APCI pos) m/ z:380[M+H] ⁺

The compounds of Examples 98 to 101 were obtained in the same manner as in Example 97.

Example 98: 6-Butyl-2-methyl-3-[4-(2,2,2-trifluoroethyl)phenyl]-5,6-dihydro-7H-imidazo[1,5 -a]imidazole-7-one 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]imidazole-7-one Example 101: 6-Butyl-3-[6-(cyclobutoxy)pyridin-3-yl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a] Imidazole-7-one

The structural formula and machine data of the compounds of Examples 98 to 101 are shown in Table 7.

The compounds of Examples 102 to 149 were obtained in the same manner as in Example 69.

Example 102: 6-Butyl-3-[4-(1,1-difluoroethyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 103: 6-Butyl-3-[4-(cyclopropylcarbonyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7 -ketone Example 104: 2-[4-(6-Butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl) Phenyl]-2-methylpropanonitrile Example 105: 6-Butyl-3-{4-[cyclopropyl(difluoro)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[1,5- a] imidazole-7-one Example 106: 4-(6-Butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)-N- (2-methylpropyl)benzamide Example 107: N-[4-(6-butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl) Benzyl]acetamide Example 108: 4-(6-Butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)-N- Methyl benzamide Example 109: 4-(6-Butyl-2-methyl-7-oxoyl-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]imidazole-7- ketone Example 111: 6-Butyl-3-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 112: 6-Butyl-3-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7- ketone Example 113: 6-Butyl-2-methyl-3-[2-(piperidin-1-yl)pyrimidin-5-yl]-5,6-dihydro-7H-imidazo[1,5- a] imidazole-7-one Example 114: 3-(4-tert-Butoxy-3-fluorophenyl)-6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a] Imidazole-7-one Example 115: 6-Butyl-3-[4-(1,1-difluoropropyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 116: 6-Butyl-2-methyl-3-[4-(phenylethenyl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole- 7-ketone Example 117: 3-[4-(Benzyloxy)-3-fluorophenyl]-6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 118: 6-Butyl-2-methyl-3-[4-(morpholin-4-yl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a]imidazole -7-ketone Example 119: 6-Butyl-2-methyl-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a] Imidazole-7-one Example 120: 6-Butyl-2-(fluoromethyl)-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 121: 6-Butyl-2-(hydroxymethyl)-3-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 122: 6-Butyl-3-[4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-5,6-dihydro-7H-imidazo[1,5- a] imidazole-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 Imidazole-7-ketone Example 125: 6-Butyl-3-{4-[difluoro(phenyl)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 126: 6-Butyl-3-[4-(1,1-difluoro-3-methylbutyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[ 1,5-a]imidazole-7-one Example 127: 6-Butyl-2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-5,6-dihydro-7H-imidazo[ 1,5-a]imidazole-7-one Example 128: 6-Butyl-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7- ketone 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-trifluorobutyl)-5,6-dihydro- 7H-imidazo[1,5-a]imidazol-7-one Example 131: 3-[4-(1,1-Difluoro-3-methylbutyl)phenyl]-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]imidazole-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]imidazole-7-one Example 135: 6-Butyl-3-[4-(2,2-difluoropropyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 136: 6-Butyl-3-[6-(1,1-difluoro-3-methylbutyl)pyridin-3-yl]-2-methyl-5,6-dihydro-7H- Imidazo[1,5-a]imidazol-7-one Example 137: 6-Butyl-3-{6-[difluoro(phenyl)methyl]pyridin-3-yl}-2-methyl-5,6-dihydro-7H-imidazo[1, 5-a]imidazol-7-one Example 138: 3-(6-Butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)benzamide amine Example 139: 3-(6-Butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)-N- Methyl benzamide Example 140: 3-(6-Butyl-2-methyl-7-oxoyl-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 Imidazole-7-ketone Example 142: 6-tert-butyl-3-[4-(1,1-difluoro-2-methylpropyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazole And [1,5-a]imidazol-7-one Example 143: 6-Butyl-3-[4-(hydroxymethyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7- ketone Example 144: 6-Butyl-3-{4-[difluoro(1-methylcyclopropyl)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[ 1,5-a]imidazole-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]imidazole-7- ketone 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]imidazol-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

The structural formula and machine data of the compounds of Examples 102 to 149 are as follows. Tables 8-1 to 8-10 are shown.

Example 150: 6-(Cyclobutylmethyl)-3-{4-[cyclopropyl(difluoro)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[1 , 5-a]imidazole-7-one hydrochloride

3-Bromo-6-(cyclobutylmethyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (50 mg) obtained in Preparation Example 16. Preparation of 2-{4-[cyclopropyl(difluoro)methyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane borane obtained in Example 18. a mixture of (54 mg), potassium carbonate (73 mg), PEPPSI (registered trademark)-IPr (12 mg), 1,4-dioxane (0.75 mL) and water (0.25 mL) at 100 ° C (oil bath temperature) ), stirring for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, chloroform: methanol = 100:0 to 95:5). To a solution of the obtained solid in ethyl acetate (1.0 mL), 4M hydrochloric acid / ethyl acetate (0.5 mL). The title compound (10 mg) was obtained.

1H NMR (600MHz, DMSO-d6) δ ppm 0.66-0.75 (4H, m) 1.70-1.88 (6H, m) 1.99-2.07 (2H, m) 2.40 (3H, s) 2.60-2.68 (2H, m) 5.62 (2H, s) 7.67-7.73 (4H, m); MS (ESI pos) m/z: 372 [M+H] ⁺

The compounds of Examples 151 to 160 were obtained in the same manner as in Example 150.

Example 151: 3-{4-[Cyclopropyl(difluoro)methyl]phenyl}-2-methyl-6-(prop-2-yl-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-imidazole [1,5-a]imidazole-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] imidazole-7-ketone 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 salt Acid salt Example 157: 6-Butyl-3-[3-fluoro-4-(pyridin-3-yloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5 -a]imidazol-7-one 2 hydrochloride Example 158: 6-(Cyclopropylmethyl)-3-[3-fluoro-4-(pyridin-3-yloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazole And [1,5-a]imidazol-7-one 2 hydrochloride 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 2 hydrochloride

The structural formula and machine data of the compounds of Examples 151 to 160 are shown in Tables 9-1 to 9-2.

Example 161: 6-(Cyclopropylmethyl)-3-{4-[difluoro(phenyl)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[ 1,5-a]imidazole-7-keto salt Acid salt and 6-(cyclopropylmethyl)-3-{4-[difluoro(phenyl)methyl]phenyl}-5,6-dihydro-7H-imidazo[1,5-a] Imidazole-7-one hydrochloride

1) 2-Bromo-6-(cyclopropylmethyl)-3-{4-[difluoro(phenyl)methyl]phenyl}-5,6-dihydro-7H-imidazo[1,5 -a]imidazole-7-one

The 2,3-dibromo-6-(cyclopropylmethyl)-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one obtained in Preparation Example 16 (100 mg) ,2-(1,1-Difluoro-3-methylbutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl a mixture of pyridine (103 mg), hydrazine (triphenylphosphine) palladium (0) (34 mg), ethanol (0.6 mL), toluene (0.6 mL) and water (0.4 mL) at 100 ° C (oil bath temperature) Stir for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, chloroform: methanol = 100:0 to 95:5) to give the title compound (140 mg) as amorphous.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.31- 0.35 (2H, m) 0.61-0.68 (2H, m) 1.00-1.07 (1H, m) 3.50 (2H, d, J = 7.0 Hz) 5.46 (2H, s) 7.44-7.48 (3H, m) 7.55 (2H, dd, J = 7.2, 1.9 Hz) 7.65-7.70 (4H, 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 Imidazole-7-ketone (70 mg), 2,4,6-trimethylboroxine (19 mg), PEPPSI (registered trademark)-IPr (21 mg), cesium carbonate (42 mg) and N, A mixture of N-dimethylformamide (1.0 mL) was stirred at 100 ° C (oil bath temperature) for 5 hours. The reaction mixture was diluted with EtOAc. The residue was subjected to column chromatography (Silicagel Cartridge, chloroform: methanol = 100:0 to 95:5) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / Purification was carried out with acetonitrile = 90:10 to 0:100. 6-(cyclopropylmethyl)-3-{4-[difluoro(phenyl)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[1] A solution of 5-a]imidazole-7-one in ethyl acetate (1.0 mL) was added dropwise 4M hydrochloric acid / ethyl acetate (0.5 mL) at room temperature and then stirred for 10 min. The solid was filtered off 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) as a colorless solid. Further, in the obtained 6-(cyclopropylmethyl)-3-{4-[difluoro(phenyl)methyl]phenyl}-5,6-dihydro-7H-imidazo[1,5- A] A solution of the imidazole-7-one in ethyl acetate (1.0 mL) was added dropwise 4M hydrochloric acid / ethyl acetate (0.5 mL) at room temperature and stirred for 10 min. The solid was filtered off 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) as a colorless solid.

6-(cyclopropylmethyl)-3-{4-[difluoro(phenyl)methyl]phenyl}-2-methyl-5,6-dihydro-7H-imidazo[1,5- a] imidazole-7-ketone hydrochloride

1H NMR (600MHz, DMSO-d6) δ ppm 0.31 (2H, d, J = 4.1 Hz) 0.50 (2H, d, J = 7.4 Hz) 1.01-1.12 (1H, m) 2.41 (3H, s) 3.36 (2H , d, J = 7.0 Hz) 5.75 (2H, s) 6.55 (1H, s) 7.50 - 7.63 (4H, m) 7.64 - 7.79 (4H, 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]imidazole-7 -ketone hydrochloride

1H NMR (600MHz, DMSO-d6) δ ppm 0.29-0.37 (2H, m) 0.47-0.57 (2H, m) 1.06-1.16 (1H, m) 3.40 (2H, s) 5.86 (2H, s) 7.47-7.68 (7H,m) 7.78-7.89(3H,m);MS(ESI pos)m/z:380[M+H] ⁺

Using the same procedure as in Example 161, the compound of Example 162 was obtained.

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

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.30-0.35(2H,m) 0.60-0.64(2H,m)1.03-1.06(7H,m)2.32-2.42(1H,m)2.49(3H,s)3.50 (2H, d, J = 7.4 Hz) 5.42 (2H, s) 7.47 (2H, d, J = 8.3 Hz) 7.57 (2H, d, J = 8.3 Hz); MS (ESI pos) m/z: 360 [ M+H] ⁺

Example 163: 6-Butyl-3-[3-fluoro-4-(2-methylpropyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5 -a]imidazole-7-one

6-Butyl-3-[3-fluoro-4-(2-methylprop-1-en-1-yl)phenyl]-2-methyl-5,6-dihydrofurate obtained in Example 123 To a solution of -7H-imidazo[1,5-a]imidazol-7-one (28 mg) in ethyl acetate (1.0 mL), 10% palladium carbon (10 mg). Stir for 75 minutes. After filtering the reaction solution with diatomaceous earth (registered trademark), the filtrate was subjected to reduced pressure. concentrate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.93-0.98 (9H, m), 1.36-1.43 (2H, m), 1.61-1.68 (2H, m), 1.91-1.98 (1H, m), 2.47 (3H , s), 2.56 (2H, d, J = 7.0 Hz), 3.61 (2H, t, J = 7.4 Hz), 5.30 (2H, s), 7.04-7.12 (2H, m), 7.24-7.28 (1H, m);MS(ESI pos)m/z:344[M+H] ⁺

The compounds of Examples 164 to 167 were obtained in the same manner as in Example 163.

Example 164: 6-Butyl-3-(2-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7- ketone Example 165: 6-(Cyclopropylmethyl)-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 166: 6-(Cyclobutylmethyl)-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole -7-ketone Example 167: 6-(2,2-Dimethylpropyl)-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1 , 5-a]imidazole-7-one

The structural formula and machine data of the compounds of Examples 164 to 167 are shown in Table 10.

Example 168: 6-Butyl-3-[3-fluoro-4-(tetrahydro-2H-pyran-4-oxy)phenyl]-2-methyl-5,6-dihydro-7H- Imidazo[1,5-a]imidazol-7-one

6-Butyl-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole obtained in Example 128 A solution of 7-ketone (20 mg), tetrahydro-2H-pyran-4-ol (15 mg) and triphenylphosphine (39 mg) in tetrahydrofuran (1.0 mL), azodicarboxylate dropwise at room temperature After diisopropyl isopropyl (80 μL, 1.9 M in toluene), the mixture was stirred for 12 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, ethyl acetate was evaporated. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to TLC (silicone 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). After purification, the title compound (7.2 mg) was obtained as an amorphous material.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.2 Hz), 1.34-1.46 (2H, m), 1.60-1.69 (2H, m), 1.80-1.92 (2H, m), 2.00-2.12(2H,m), 2.44(3H,s),3.55-3.67(4H,m),3.98-4.06(2H,m),4.50-4.59(1H,m),5.26(2H,s), 7.06-7.18(3H,m);MS(ESI pos)m/z:388[M+H] ⁺

The compounds of Examples 169 to 173 were obtained in the same manner as in Example 168.

Example 169: 6-Butyl-3-[4-(cyclopentyloxy)-2-fluorophenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 170: 6-Butyl-3-[4-(cyclopentyloxy)-3-fluorophenyl]-2-methyl-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone Example 171: 6-Butyl-3-[2-fluoro-4-(tetrahydro-2H-pyran-4-oxy)phenyl]-2-methyl-5,6-dihydro-7H- Imidazo[1,5-a]imidazol-7-one hydrochloride Example 172: 6-(Cyclopropylmethyl)-3-[3-fluoro-4-(tetrahydro-2H-pyran-4-oxy)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-oxy)phenyl]-2-methyl-5,6- Dihydro-7H-imidazo[1,5-a]imidazol-7-one

The structural formula and machine data of the compounds of Examples 169 to 173 are shown in Table 11.

Example 174: 6-Butyl-2-methyl-3-[4-(piperazin-1-ylmethyl)phenyl]-5,6-dihydro-7H-imidazo[1,5-a Imidazole-7-ketone

1) tert-butyl 4-[4-(6-butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazole-3- Phenylmethyl]piperazine-1-carboxylate

3-Bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (80 mg) obtained in Preparation Example 7 and tert- Butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)benzyl]piperazine-1-carboxylate ( a mixture of 142 mg), potassium carbonate (122 mg), PEPPSI (registered trademark)-IPr (20 mg), ethanol (0.38 mL), toluene (0.38 mL) and water (0.25 mL) at 100 ° C (oil bath temperature) Stir for 1 hour. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (3H, t, J = 7.2 Hz), 1.36-1.43 (2H, m), 1.46 (9H, s), 1.61-1.67 (2H, m), 2.40- 2.44 (4H, m), 2.47 (3H, s), 3.43-3.47 (4H, m), 3.55 (2H, s), 3.61 (2H, t, J = 7.4 Hz), 5.29 (2H, s), 7.35 -7.38(2H,m),7.42-7.46(2H,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]imidazole -7-ketone

Tert-butyl 4-[4-(6-butyl-2-methyl-7-oxo-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl A solution of benzylidene-piperazine-l-carboxylate (134 mg) in chloroform (2.0 mL) was added dropwise to trifluoroacetic acid (1.0 mL), and the mixture was stirred for 2 hours. After adding 1 M aqueous sodium hydroxide solution to the reaction mixture under ice cooling and neutralizing, extraction was carried out 10 times with chloroform. The combined organic layers were dried with anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.95 (3H, t, J = 7.4 Hz), 1.35-1.43 (2H, m), 1.60-1.67 (2H, m), 2.43-2.50 (7H, m), 2.90-2.94(4H,m), 3.54(2H,s), 3.61(2H,t,J=7.4Hz), 5.28(2H,s),7.34-7.37(2H,m),7.43-7.46(2H, m);MS(ESI pos)m/z:368[M+H] ⁺

Example 175: 6-Butyl-2-methyl-3-(5-phenylpyridin-2-yl)-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7- ketone

Production example of 3-bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (30 mg) obtained in Production Example 7. a mixture of the obtained 5-phenyl-2-(tributylstannyl)pyridine (59 mg), hydrazine (triphenylphosphine)palladium(0) (25 mg) and toluene (1.0 mL) at 110 ° C ( The oil bath temperature was stirred for 14 hours. After filtering the reaction liquid with diatomaceous earth (registered trademark), the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (Silicagel Cartridge, hexane: ethyl acetate = 70:30 to 25:75) and reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid/water: 0.1% After purification by fluoroacetic acid / acetonitrile = 90:10 - 0: 100),

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.39-1.47 (2H, m), 1.68-1.74 (2H, m), 2.70 (3H, s), 3.66 ( 2H, t, J = 7.4 Hz), 5.65 (2H, s), 7.42-7.46 (1H, m), 7.50-7.54 (2H, m), 7.61-7.64 (2H, m), 7.72 (1H, d, J=8.3 Hz), 7.97-8.01 (1H, m), 8.86-8.88 (1H, m); MS (ESI pos) m/z: 347 [M+H] ⁺

Example 176: ethyl 5-(6-butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)- 1,2-oxazole-3-carboxylate

1) 6-Butyl-2-methyl-3-[(trimethylformamido)acetylene]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

The 3-bromo-6-butyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (200 mg) obtained in Preparation Example 7 and the top three Methyl decyl acetylene (0.125 mL), bis(triphenylphosphine)palladium(II) dichloride (52 mg), triphenylphosphine (19 mg), copper (I) iodide (5 mg), three A mixture of ethylamine (0.154 mL) and N,N-dimethylformamide (2.0 mL) was stirred at 75 ° C (oil bath temperature) for 3 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.27 (9H, s), 0.96 (3H, t, J = 7.2 Hz), 1.35-1.42 (2H, m), 1.61-1.67 (2H, m), 2.38 ( 3H, s), 3.59 (2H, t, J = 7.4 Hz), 5.21 (2H, 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

To 6-butyl-2-methyl-3-[(trimethylformamido)acetylene]-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one (196 A solution of mg of ethanol (2.0 mL) was added to a 0.1 M aqueous potassium hydroxide solution (0.500 mL) at room temperature, followed by stirring for 35 minutes. The reaction solution was concentrated under reduced pressure. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjj:

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.96 (3H, t, J = 7.4 Hz), 1.36-1.43 (2H, m), 1.61-1.67 (2H, m), 2.40 (3H, s), 3.60 ( 2H, t, J = 7.4 Hz), 3.63 (1H, s), 5.22 (2H, s)

3) Ethyl 5-(6-butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl)-1, 2-oxazole-3-carboxylate

6-butyl-3-ethynyl-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one

To a solution of (55 mg) of ethyl acetate (2.0 mL) and water (0.50 mL), ethyl hydrogen carbonate (253 mg) and ethyl 2-chloro-2-(hydroxyimide) Mg), stirring for 6 hours. After water was added to the reaction mixture, extraction was carried out with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (EtOAc EtOAc EtOAc:EtOAc Things.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.2 Hz), 1.38-1.48 (5H, m), 1.66-1.72 (2H, m), 2.57 (3H, s), 3.66 ( 2H, t, J = 7.4 Hz), 4.50 (2H, q, J = 7.2 Hz), 5.53 (2H, s), 6.79 (1H, s); MS (ESI pos) m/z: 333 [M+H ] ⁺

Example 177: 6-Butyl-2-methyl-3-[3-(phenoxymethyl)-1,2-oxazol-5-yl]-5,6-dihydro-7H-imidazole [1,5-a]imidazole-7-one

1) 6-Butyl-3-[3-(hydroxymethyl)-1,2-oxazol-5-yl]-2-methyl-5,6-dihydro-7H-imidazo[1,5 -a]imidazole-7-one

Ethyl 5-(6-butyl-2-methyl-7-oxoyl-6,7-dihydro-5H-imidazo[1,5-a]imidazol-3-yl obtained in Example 176 A solution of-1,2-oxazol-3-carboxylate (70 mg) in ethanol (2.3 mL) was stirred at room temperature with sodium borohydride (24 mg). After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, it was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.38-1.45 (2H, m), 1.65-1.71 (2H, m), 2.54 (3H, s), 3.65 ( 2H, t, J = 7.2 Hz), 4.85 (2H, s), 552 (2H, s), 6.49 (1H, 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-one

To 6-butyl-3-[3-(hydroxymethyl)-1,2-oxazol-5-yl]-2-methyl-5,6-dihydro-7H-imidazo[1,5- a] Imidazolyl-7-one (23 mg), phenol (9 mg) and triphenylphosphine (25 mg) in tetrahydrofuran (2.0 mL), and diisopropyl azodicarboxylate (50) After μL and 1.9 M toluene solution, stirring was carried out for 1 hour. After water was added to the reaction mixture, extraction was carried out with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, hexane: ethyl acetate = 90:10 to 35:65) and TLC (NH. The title compound (11 mg) was obtained as a colourless solid.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.98 (3H, t, J = 7.4 Hz), 1.38-1.45 (2H, m), 1.65-1.71 (2H, m), 2.54 (3H, s), 3.65 ( 2H, t, J = 7.4 Hz), 5.21 (2H, s), 5.52 (2H, s), 6.53 (1H, s), 6.99-7.04 (3H, m), 7.30-7.35 (2H, m); (ESI pos)m/z: 367[M+H] ⁺

Example 178: 6-Butyl-3-[4-(methoxymethyl)phenyl]-2-methyl- 5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one hydrochloride

6-Butyl-3-[4-(hydroxymethyl)phenyl]-2-methyl-5,6-dihydro-7H-imidazole [1,5] obtained in Example 143 under nitrogen atmosphere. -a]A solution of imidazole-7-one (50 mg) in N,N-dimethylformamide (1.0 mL), adding 60% sodium hydride (7.4 mg) at room temperature for 10 minutes, then adding iodine Methyl (36 mg) was added and stirred for 3 hours. After water was added to the reaction mixture, it was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90:10 - 0: 100). To a solution of the obtained solid 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.

1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.90-0.96(3H,m)1.34-1.43(2H,m)1.61-1.71(2H,m)2.58(3H,s)3.45(3H,s)3.64-3.73 (2H,m)4.53(2H,s)5.73-5.85(2H,m)7.51-7.55(2H,m)7.58-7.65(2H,m);MS(ESI pos)m/z:314[M+H ] ⁺

Example 179: 6-Butyl-3-[3-fluoro-4-(pyridin-2-yloxy)phenyl]-2- Methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazol-7-one hydrochloride

The 6-butyl-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole obtained in Example 128 was obtained. 7-ketone (30 mg), 2-bromopyridine (16 mg), copper (I) iodide (3 mg), picolinic acid (I) (3 mg), potassium phosphate (42 mg) and dimethyl The mixture of Aachen (1.0 mL) was stirred at 105 ° C (oil bath temperature) for 24 hours. After water was added to the reaction mixture, extraction was carried out with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (Silicagel Cartridge, hexane: ethyl acetate = 70:30 to 30:70). To a solution of the obtained solid 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 title compound (7 mg) was obtained.

1H NMR (600MHz, DMSO-d6) δ ppm 0.91 (3H, t, J = 7.4 Hz), 1.28-1.36 (2H, m), 1.57-1.63 (2H, m), 2.41 (3H, s), 3.49 ( 2H, t, J = 7.2 Hz), 5.67 (2H, s), 7.15-7.20 (2H, m), 7.45-7.50 (2H, m), 7.60-7.65 (1H, m), 7.89-7.93 (1H, m), 8.12 - 8.15 (1H, 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]imidazol-7-one 2 hydrochloride Example 181: 6-Butyl-2-methyl-3-[3-methyl-4-(pyridazin-4-yloxy)phenyl]-5,6-dihydro-7H-imidazo[1 , 5-a]imidazole-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]imidazole-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 formula and machine data of the compounds of Examples 180 to 183 are shown in Table 12.

Example 184: 6-Butyl-3-[3-fluoro-4-(pyridazin-3-yloxy)phenyl]-2-methyl-5,6-dihydro-7H-imidazo[1, 5-a]imidazole-7-one hydrochloride

The 6-butyl-3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole obtained in Example 128 was obtained. A mixture of 7-ketone (50 mg), 3-chloropyridazine (38 mg), potassium carbonate (57 mg) and N,N-dimethylformamide (1.2 mL) at 100 ° C (oil bath temperature) Stir for 18 hours. After adding water to the reaction mixture, it was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase column chromatography (SunFire, 0.1% trifluoroacetic acid / water: 0.1% trifluoroacetic acid / acetonitrile = 90:10 - 0: 100). To a solution of the obtained solid 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.

1H NMR (600MHz, DMSO-d6) d ppm 0.91 (3H, t, J = 7.2 Hz) 1.29-1.36 (2H, m) 1.57-1.64 (2H, m) 2.45 (3H, s) 3.51 (2H, t, J=7.2Hz)5.74(2H,s)7.52-7.56(1H,m)7.59-7.64(1H,m)7.64-7.68(1H,m)7.69-7.74(1H,m)7.79-7.91(1H,m ) 9.06 (1H, d, J = 3.3 Hz); MS (ESI pos) m / z: 382 [M + H] ⁺

Using the same procedure as in Example 184, Examples 185 to 188 were obtained. compound of.

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-imidazole [1,5-a]imidazole-7-one Example 188: 6-(2,2-Dimethylpropyl)-3-[3-fluoro-4-(pyridazin-3-yloxy)phenyl]-2-methyl-5,6-di Hydrogen-7H-imidazo[1,5-a]imidazol-7-one

The structural formula and machine data of the compounds of Examples 185 to 188 are shown in Table 13.

Each of the example compounds acted on a rat type or human type mGlu2 receptor to enhance receptor response.

Test Example 1 [ ³⁵ S]GTP γ S binding test (1) (The rat type metabotropic glutamate receptor (mGlu2) is stable and expresses the coarse membrane fraction of CHO cells)

Rat type mGlu2 was stabilized to express CHO cells, using Dulbecco's Modified Eagle's Medium with 10% dialysis bovine embryo serum [1% proline, 50 units/mL penicillin, 50 μg/mL streptomycin, 1 mM sodium pyruvate, 1 mM succinic acid and 2 mM L-glutamine (added in time) were cultured at 37 ° C under 5% CO ₂ . The cells in the merged state were washed twice with PBS(-), and then exfoliated with a cell spatula, and centrifuged at 1000 rpm for 5 minutes at 4 ° C to collect the cells. The obtained precipitate was suspended in a 20 mM HEPES buffer (pH 7.4), and the suspension was homogenized by a homogenizer, and then centrifuged at 48,000 × g at 4 ° C for 20 minutes to obtain a precipitate again. Further, the obtained precipitate was washed twice by centrifugation, and then homogenized by the above buffer to obtain a crude membrane portion. The resulting crude film fraction was stored at -80 °C.

([ ³⁵ S]GTP γ S binding test)

The frozen membrane fraction prepared above was thawed at the time of use and diluted with a binding assay buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , 8.4 μM GDP, 10 μg/mL saponin, 0.1% BSA).

The compound of the example was added to a membrane portion of a membrane protein of 10 μg/assay, and cultured at 30 ° C for 20 minutes under constant temperature. Thereafter, glutamic acid (final concentration: 3 μM) and [ ³⁵ S]GTP γ S (final concentration: 0.15 nM) were added, and the mixture was cultured at 30 ° C for 1 hour under constant temperature. After constant temperature incubation, the above reaction solution was suction-filtered on 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 the membrane-bound radioactivity was measured by a liquid scintillation cytometer.

For the above reaction, the [ ³⁵ S]GTP γ S binding amount obtained in the absence of glutamic acid was used as the non-specific (specific) binding amount, and [ ³⁵ S]GTP γ S obtained in the presence of glutamic acid. The difference in binding amount is taken as the specific (specific) binding amount. Specific (specificity) in the coexistence of the compound represented by the following Example 3μM with various concentrations of the glutamate binding difference of embodiments, each of the embodiments of the compound of Example EC ₅₀ value was calculated using non-linear least square method from the regression line.

The EC ₅₀ values of the compounds of the invention are as illustrated in Table 14.

Test Example 2 [ ³⁵ S]GTP γ S binding test (2) (Human type metabotropic glutamate receptor (mGlu2) stability shows the coarse membrane fraction of CHO cells)

Human type mGlu2 is stable. CHO cells use Dulbecco's Modified Eagle's Medium with 10% dialyzed bovine serum. [1% proline, 50 units/mL penicillin, 50 μg/mL streptomycin, 2 mM L-glutamine. (added at time), 400 μg/mL Hygromycin B (added in time), and cultured at 37 ° C under 5% CO ₂ . The cells in the merged state were washed twice with PBS(-), and then exfoliated by a cell scraper, and centrifuged at 1,000 rpm for 5 minutes at 4 ° C to collect the cells. The obtained precipitate was suspended in a 20 mM HEPES buffer (pH 7.4), and the suspension was homogenized by a homogenizer, and then centrifuged at 48,000 × g for 20 minutes at 4 ° C to obtain a precipitate again. The precipitate obtained again was washed by centrifugation twice, and then homogenized with the above buffer to obtain a crude membrane portion. The resulting crude film fraction was maintained at -80 °C.

([ ³⁵ S]GTP γ S binding test)

The frozen membrane fraction prepared above was thawed at the time of use, and diluted with a 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). The compound of the example was added to a membrane portion of a membrane protein of 10 μg/assay, and incubation was carried out at 30 ° C for 20 minutes under constant temperature. Thereafter, glutamic acid (final concentration: 1 μM) and [ ³⁵ S]GTP γ S (final concentration: 0.15 nM) were added, and incubation was carried out at 30 ° C for 1 hour under constant temperature. After the incubation at a constant temperature, the above reaction solution was suction-filtered on a GF/C filter, and the GF/C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a filter scintillation cocktail was added, and membrane-bound radioactivity was measured by a liquid scintillation cytometer.

For the above reaction, the [ ³⁵ S]GTP γ S binding amount obtained in the absence of glutamic acid is regarded as the non-specific (specific) binding amount, and the [ ³⁵ S]GTP γ obtained in the presence of glutamic acid The difference in the amount of S binding is taken as the specific (specific) binding amount. Difference of specific binding (specific) embodiment of the compound represented by the coexistence of various concentrations of glutamate 1μM of each of the embodiments, the respective embodiments of the compound of Example EC ₅₀ value was calculated using non-linear least square method from the regression line.

The EC ₅₀ values of the compounds of the invention are as illustrated in Table 15.

[Industrial availability]

By the present invention, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD/HD (lack of attention/hyperactivity disorder), drug dependence, paralysis, trembling, and sleep disorders can be provided. Such as therapeutic or preventive agents.

Claims (8)

An imidazolinone derivative of the formula (I), or a pharmaceutically acceptable salt thereof, of the formula (I) [In the formula (I), R ¹ represents a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from a halogen atom, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, and a phenyl group ( the same or different groups of the phenyl group may be selected from halogen atoms, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, and C _1-6 alkoxy group having 1 to 3 substituents as Substituting) the same or different 1 to 3 groups in the group) or C _2-6 alkenyl; R ² represents a hydrogen atom or a C _1-6 alkyl group; or any of R ³ and R ⁴ And represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted by one hydroxyl group), a halogenated C _1-6 alkyl group, or a C _2-6 alkenyl group, and the other represents an aryl group. Or a heteroaryl group (the aryl group and the heteroaryl group may be substituted by the same or different 1-3 groups selected from the group of substituents A'below); the substituent group A' represents a halogen atom, a cyano group, a hydroxyl group , C _1-6 alkyl (the C _1-6 alkyl group may be selected from the group consisting of a halogen atom, a cyano group, a hydroxyl group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, a C ₃ group _{; -8} cycloalkyl, C _3-8 cycloalkoxy (the C _3-8 cycloalkyl and C _3-8 cycloalkoxy may be the same or different from a C _1-6 alkyl group and a halogen atom 1~3 groups substituted), aryl, heteroaryl, aromatic An oxy group and a group of 1 to 5 groups in which a saturated heterocyclic group is substituted), a C _1-6 alkoxy group (the C _1-6 alkoxy group may be the same or a group selected from a halogen atom and an aryl group) Substituted 1 to 3 substituents, C _3-8 cycloalkyl, C _3-8 cycloalkoxy (the C _3-8 cycloalkyl and C _3-8 cycloalkoxy may be the same or phase Substituted by 1 to 3 halogen atoms), an amine group, an aminocarbamyl group (the amine group and the aminocarbamoyl group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups), An aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic group (the saturated and partially unsaturated heterocyclic group may be the same or different 1 or 2 C _1-6 alkyl) Substituted), C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, cyclic aminocarbonyl, C _2-6 alkenyl, C _1-6 alkoxycarbonyl, and saturated heterocyclic Oxy; X represents a nitrogen atom or a formula CH]. An imidazolinone derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group may be selected from halogen atoms, C _3-8 cycloalkyl, C _1-6 alkoxy, and phenyl (the phenyl group may be selected from halogen atoms, cyano, C _1-6 alkyl, halogenated C _1-6 alkoxy Substituted with the same or different 1-3 groups of C _1-6 alkoxy groups, substituted by the same or different 1-3 groups; R ³ and R ⁴ Any one of them is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a C _2-6 alkenyl group, and the other is an aryl group or a heteroaryl group (the aryl group and the heteroaryl group) Substituted by the same or different 1-3 groups selected from the following substituent group A); the substituent group A is a halogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group (the C _1-6 alkane) The group may be selected from the group consisting of a halogen atom, a cyano group, a hydroxyl group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, a C _3-8 cycloalkyl group, and a C _3-8 cycloalkoxy group. Substituting (the C _3-8 cycloalkyl group, and the C _3-8 cycloalkoxy group may be substituted by the same or different 1-3 halogen atoms) in groups of 1 to 5 groups), C _{1 -6} alkoxy (this C _{The 1-6} alkoxy group may be substituted by the same or different 1-3 groups selected from the group consisting of a halogen atom and an aryl group, a C _3-8 cycloalkyl group, a C _3-8 cycloalkoxy group (the C _3-8 cycloalkyl and C _3-8 cycloalkoxy may be substituted by the same or different 1 to 3 halogen atoms), an amine group, an aminomethyl group (the amine group and the aminocarbamyl group may be Alternate or different 1 or 2 C _1-6 alkyl substituted), aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic groups (saturated and partially unsaturated) The heterocyclic group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups), a C _1-6 alkylsulfanyl group, and a C _1-6 alkylsulfonyl group. An imidazolinone derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R ³ is a hydrogen atom, a halogen atom or a C _1-6 alkane a halogenated C _1-6 alkyl group or a C _2-6 alkenyl group; R ⁴ is an aryl group or a heteroaryl group (the aryl group and the heteroaryl group may be selected from the group A of substituents as set forth in claim 2) Replaced by the same or different 1~3 bases). The imidazolinone derivative, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein in the above formula (I), R ⁴ is an aryl group or a heteroaryl group ( The aryl group and the heteroaryl group may be substituted by the same or different 1 to 3 groups selected from the group of substituents A1 described below; the substituent group A1 is a halogen atom, a cyano group, a C _1-6 alkyl group (this The C _1-6 alkyl group may be selected from the group consisting of a halogen atom, a cyano group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, a C _3-8 cycloalkyl group, an aryl group, and a hetero group. a group of 1 to 5 groups in which an aryl group is substituted), a C _1-6 alkoxy group (the C _1-6 alkoxy group may be the same or different from the group selected from a halogen atom and an aryl group) 3 substituents), C _3-8 cycloalkyl, C _3-8 cycloalkoxy, aminomethyl fluorenyl (the aminomethyl thiol group may be the same or different 1 or 2 C _1-6 Alkyla substituted), aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic group (the saturated and partially unsaturated heterocyclic group may be the same or different 1 or 2) a C _1-6 alkyl group substituted), and a C _1-6 alkyl sulfanyl group. The imidazolinone derivative, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein, in the above formula (I), R ⁴ is an aryl group or a heteroaryl group ( The aryl group and the heteroaryl group may be substituted by the same or different 1-3 groups selected from the group of substituents A2 described below; the substituent group A2 is a halogen atom, a cyano group, a C _1-6 alkyl group (this The C _1-6 alkyl group may be a group selected from the group consisting of a halogen atom, a cyano group, an oxo group, a C _1-6 alkoxy group, a C _2-6 alkanoylamino group, and a C _3-8 cycloalkyl group. ~5 groups substituted), C _1-6 alkoxy (the C _1-6 alkoxy group may be substituted by the same or different 1-3 groups selected from the group consisting of a halogen atom and an aryl group), C _3-8 cycloalkyl, C _3-8 cycloalkoxy, aminomethanyl (the aminocarbamoyl group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups), aryl group a heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclic group (the saturated and partially unsaturated heterocyclic group may be substituted by the same or different 1 or 2 C _1-6 alkyl groups) And C _1-6 alkylsulfanyl. The imidazolinone derivative, or a pharmaceutically acceptable salt thereof, according to any one of the items 1 to 5, wherein X is a nitrogen atom in the above formula (I). A pharmaceutical composition comprising an imidazolinone derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient. A medicine for preventing or treating diseases selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depressed disease, AD/HD (lack of attention/hyperactivity disorder), and medicine A medicine for the prophylaxis or treatment of a disease in which a group of diseases, a sputum, a trembling, and a sleep disorder are contained, which is characterized by containing an imidazolinone derivative according to any one of claims 1 to 6, or a pharmaceutical thereof A salt that can be licensed as an active ingredient.