JP2014214130A - Medicine containing dihydroimidazo oxazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine for prevention or treatment of diseases, such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD/HD (attention deficit/hyperactivity disorder), drug dependence, convulsions, tremor, sleep disorder, or the like.SOLUTION: A medicine contains a novel dihydroimidazo oxazole derivative represented by the general formula (IA) having a positive allosteric modulator effect against a metabotropic glutamate receptor subtype 2 (mGlu2 receptor) or a pharmaceutically acceptable salt thereof as an active ingredient for prevention or treatment of diseases selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD/HD (attention deficit/hyperactivity disorder), drug dependence, convulsions, a tremor, and sleep disorder.

Description

  The present invention relates to a novel compound having a positive allosteric modulator action on metabotropic glutamate receptor subtype 2 (mGlu2 receptor) or a pharmaceutically acceptable salt thereof, and schizophrenia containing them as an active ingredient, Prevention or prevention of a disease selected from the group consisting of Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders The present invention relates to a therapeutic drug.

  Glutamate receptors are broadly classified into ion channel glutamate receptors and metabotropic glutamate receptors (mGlu receptors) (Non-patent Documents 1 and 2). Among these, the mGlu receptor was identified as a GPCR-type glutamate receptor coupled to G protein, but receptor cDNAs were successively cloned in the early 1990s (Non-patent Documents 3 and 4). Currently, the existence of eight subtypes (mGlu1 to mGlu8) has been reported, and these are classified into three groups (group I: mGlu1, mGlu5; group II :) due to differences in receptor structure, pharmacological properties and signal transduction system. mGlu2, mGlu3; Group III: mGlu4, mGlu6, mGlu7, mGlu8) (non-patent documents 5 to 7). Among these, mGlu2 and mGlu3 receptors belonging to Group II are coupled to Gi / Go proteins and suppress adenylate cyclase activity, and activation of mGlu2 and mGlu3 receptors by agonists is forskolin. Stimulus-induced cAMP accumulation is suppressed (Non-Patent Documents 1, 8, and 9). In the central nervous system, many expressions of mGlu2 and mGlu3 receptors have been observed in the cerebral cortex, olfactory bulb, striatum, nucleus accumbens, thalamus, hippocampus, amygdala, etc. (Non-Patent Documents 10 to 14). These sites are involved in brain functions such as emotion, cognition, motivation, and reward, suggesting an association with mGlu2 and mGlu3 receptor anxiety disorders, schizophrenia, depression, and drug dependence (Non-Patent Documents 15 to 19).

  From the analysis using a receptor-deficient mouse, it is considered that the mGlu2 receptor is mainly involved in the antipsychotic-like action of the mGlu2 / 3 receptor agonist (Non-patent Documents 20 to 22). Furthermore, the existence of an active regulatory site (allosteric binding site) different from the binding site (orthosteric binding site) of glutamate, an endogenous ligand, was reported, and a selective mGlu2 receptor positive allosteric modulator (PAM) was created (non- Patent Documents 23 and 24). These selective mGlu2 receptor PAMs show antipsychotic-like effects and cognitive dysfunction-improving effects in various animal models as well as mGlu2 / 3 receptors, suggesting the possibility as therapeutic drugs for schizophrenia ( Non-patent documents 25 to 32). In addition, since mGlu2 receptor PAM has been found to have anxiolytic effects on various animal models, it has also been suggested as a therapeutic agent for anxiety disorders (Non-Patent Documents 25, 28, 33, and 34).

  Recently, compounds having an mGlu2 receptor positive allosteric modulator activity have been reported (Non-patent Documents 35 to 37). However, these documents do not disclose or suggest any compounds having the dihydroimidazooxazole skeleton of the compound of the present invention.

Science, 258 (5082), 597-603, 1992. Psychopharmacology (Berl), 179 (1), 4-29, 2005. Nature, 349 (6312), 760-765, 1991. Science, 252 (5010), 1318-1321, 1991. Neuropharmacology, 34 (1), 1-26, 1995 Annu Rev Pharmacol Toxicol., 37, 205-237, 1997. Neuropharmacology, 38 (10), 1431-1476, 1999. Neuron, 8 (1), 169-179, 1992. J Neurosci, 13 (4), 1372-1378, 1993. Neurosci Lett., 202 (3), 197-200, 1996. Neuroscience, 71 (4), 949-976, 1996. Neurosci Res., 30 (1), 65-82, 1998. J Comp Neurol., 505 (6), 682-700, 2007. Brain Res., 1197, 47-62, 2008. Current Drug Targets-CNS & Neurological Disorders, 1, 215-225, 2002. Nat. Rev. Drug Discov., 4 (2), 131-144, 2005. Eur J Pharmacol., 639 (1-3), 59-66, 2010. Neuropharmacology. 2011 Jun 21. [Epub ahead of print] PMID: 21704048. Neuropharmacology, 60 (7-8), 1017-1041, 2011. Eur J Pharmacol., 397 (1), R1-2, 2000. Psychopharmacology (Berl), 196 (3), 431-440, 2008. J Pharmacol Exp. Ther., 326 (1), 209-217, 2008. J Med Chem., 46 (15), 3189-3192, 2003. Mol Pharmacol., 64 (4), 798-810, 2003. Psychopharmacology (Berl), 179 (1), 271-283, 2005. Bioorg Med Chem Lett., 15 (18), 4068-4072, 2005. J Pharmacol Exp Ther., 315 (3), 1181-1187, 2005. J Pharmacol Exp Ther., 318 (1), 173-185, 2006. Mol Pharmacol., 72 (2), 477-484, 2007. Psychopharmacology (Berl), 192 (4), 511-519, 2007. Neuroscience, 168 (1), 209-218, 2010. ACS Med Chem Lett., 1 (8), 406-410, 2010. J Pharmacol Exp Ther., 336 (1), 165-177, 2011. Neuropharmacology, 62, 322-331, 2012. Expert Opin. Ther. Patents, 19 (9), 1259-1275, 2009. Current Medicinal Chemistry, 18 (1), 47-68, 2011. ACS Chem. Neurosci., 2 (8), 382-393, 2011.

  The object of the present invention is to find a novel compound having a positive allosteric modulator action on the mGlu2 receptor, and to achieve schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (lack of attention) / Hyperactivity disorder), to provide drugs for the prevention or treatment of drug dependence, convulsions, tremors and sleep disorders.

As a result of intensive studies, the present inventors have found a novel dihydroimidazoxazole derivative having an mGlu2 receptor positive allosteric modulator action, and completed the present invention.
That is, the present invention
(1) Formula (IA)

[In the formula (IA),
R ¹ represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), Optionally substituted with 1-3 groups selected from the group consisting of 4- to 8-membered cyclic amino, hydroxy, and C _1-6 alkoxy.), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, amino (wherein the amino is one or two groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, and C _1-6 alkanoyl) Optionally substituted)) 4-8 membered cyclic amino, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, hetero aryl (the aryl, and heteroaryl C _1-6 alkyl, halo C _1-6 A . Kill, and the C _3-8 optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl), or shows the carboxy;
R ² represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), 4- to 8-membered cyclic amino (the 4- to 8-membered cyclic amino may be substituted with 1 to 3 halogen atoms), imino, hydroxy, C _1-6 alkoxy, aryl, C _3-8 cyclo Optionally substituted with 1 to 3 groups selected from the group consisting of alkyl and carboxy)), halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl , Carbamoyl (the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, or heteroaryl (the aryl and heteroaryl are halogen atoms, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _3-8 cycloalkyl Carboxymethyl, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (said amino may be substituted by one or two C _1-6 alkyl.), Or 4-8 membered cyclic amino (said 4- to 8-membered cyclic amino may be substituted with 1 to 3 groups selected from the group consisting of 1 C _1-6 alkyl.), Pyridonyl (the pyridonyl is _May be substituted with one C _1-6 alkyl.), Tri C _1-6 alkylsilyl, arylcarbonyl, arylsulfonyl, C _3-8 cycloalkyl, C _2-6 alkenyl (the C _2-6 alkenyl). May be substituted with C _1-6 alkoxy), or C _3-8 cycloalkylcarbonyl;
R ³ is aryl, heteroaryl, or C _3-8 cycloalkyl (the aryl, heteroaryl, and C _3-8 cycloalkyl are halogen atoms, C _1-8 alkyl (the C _1-8 alkyl is cyano, Optionally substituted with 1 to 3 groups selected from the group consisting of hydroxy and aryl), halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is a halogen atom, _Optionally substituted with 1 to 5 groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and aryl.), C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, aryloxy, C _1-6 alkanoyl, aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 Sik With 1-3 substituents selected from the group consisting of alkyloxy and C _1-6 alkanoyl which may be substituted.), Heteroaryl (said heteroaryl halogen atom, C _1-6 alkyl, halo C _1-6 Optionally substituted with 1 to 3 groups selected from the group consisting of alkyl, C _1-6 alkoxy, and halo C _1-6 alkoxy.) 4-8 membered cyclic amino, pyridonyl (wherein pyridonyl is 1 may be substituted with pieces of C _1-6 alkyl.), cyclic ethers 4-8 membered cyclic ether (said 4-8 membered is optionally substituted with 1 to 3 C _1-6 alkyl. ), C _5-8 bicycloalkyl (the C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), adamantyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, and 1 to selected from the group consisting of arylcarbonyl May be substituted with 3 groups), quinolinonyl (which may be substituted with 1 C _1-6 alkyl), or indanyl (wherein indanyl is 1-3 C _1-6). Optionally substituted with alkyl);
R ⁴ represents a hydrogen atom or C _1-6 alkyl]
A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD comprising a dihydroimidazooxazole derivative represented by the formula: / HD (deficiency of attention / hyperactivity disorder), drug dependence, convulsions, tremor and medicine for the prevention or treatment of diseases selected from the group consisting of sleep disorders,
(2) In the above formula (IA),
Schizophrenia, Alzheimer's disease, cognitive dysfunction characterized by containing as an active ingredient the dihydroimidazooxazole derivative according to (1), wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, A medicament for the prevention or treatment of a disease selected from the group consisting of dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders,
(3) In the above formula (IA),
R ¹ is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of hydroxy and C _1-6 alkoxy) ), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl is substituted with 1 or 2 C _1-6 alkyl). Or a heteroaryl, which is substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and C _3-8 cycloalkyl. Good).
R ² is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is imino, hydroxy, C _1-6 alkoxy, aryl, and C _3-8 cycloalkyl). 1 to 3 groups)), halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl, aryl, or heteroaryl ( The aryl and heteroaryl are a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the amino is 1 Or may be substituted with 2 C _1-6 alkyls), or 4-8 membered cyclic amino (the 4-8 membered cyclic amino may be substituted with 1 C _1-6 alkyl). 1-3) selected from the group consisting of Substituted.), Pyridonyl (the pyridonyl may be substituted with one C _1-6 alkyl.), Tri C _1-6 alkyl silyl, C _3-8 cycloalkyl or C _3-8 Cycloalkylcarbonyl;
R ³ is aryl or heteroaryl (the aryl and heteroaryl are halogen atoms, C _1-8 alkyl (the C _1-8 alkyl is selected from the group consisting of cyano, hydroxy, and aryl). ), Halo C _1-6 alkyl, C _3-8 cycloalkyl (wherein the C _3-8 cycloalkyl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and Optionally substituted with 1 to 5 groups selected from the group consisting of aryl), C _1-6 alkoxy, halo C _1-6 alkoxy, aryl C _1-6 alkoxy, aryloxy, aryl (the aryl is May be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy), heteroaryl (the heteroaryl Is C _1-6 alkyl, and And optionally substituted with 1 to 3 groups selected from the group consisting of halo C _1-6 alkyl.) 4-8 membered cyclic amino, pyridonyl (wherein the pyridonyl is one C _1-6 alkyl). 4-8 membered cyclic ether (the 4-8 membered cyclic ether may be substituted with 1 to 3 C _1-6 alkyl), C _5-8 bicycloalkyl (The C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms.), 1 to 3 groups selected from the group consisting of adamantyl and arylcarbonyl. Or a dihydroimidazooxazole derivative or a pharmaceutically acceptable salt thereof according to (1) or (2), which is indanyl (the indanyl may be substituted with 1 to 3 C _1-6 alkyls). Is characterized by containing as an active ingredient Of a disease selected from the group consisting of Alzheimer's disease, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention-deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Preventive or therapeutic drugs,
(4) In the above formula (IA),
R ¹ is a halogen atom, cyano, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl is substituted with two C _1-6 alkyls) Or the dihydroimidazooxazole derivative according to any one of (1) to (3), which is a heteroaryl, or a pharmaceutically acceptable salt thereof as an active ingredient Selected from the group consisting of: schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Drugs for the prevention or treatment of diseases,
(5) In the above formula (IA),
R ¹ is cyano or carbamoyl, (1) to (4) dihydroimidazoxazole derivative according to any one of the above, or a pharmaceutically acceptable salt thereof as an active ingredient Disease selected from the group consisting of ataxia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Medicine for the prevention or treatment of
(6) In the above formula (IA),
R ² is a halogen atom, C _1-6 alkyl (the C _1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkoxy, aryl, and C _3-8 cycloalkyl) ), Halo C _1-6 alkyl, heteroaryl (the heteroaryl may be substituted with 1 to 3 C _1-6 alkoxy groups), or C _3-8 cycloalkyl. (1) to (5) comprising the dihydroimidazoxazole derivative according to any one of the above, or a pharmaceutically acceptable salt thereof as an active ingredient, schizophrenia, Alzheimer's disease, cognitive impairment, A medicament for the prevention or treatment of a disease selected from the group consisting of dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders,
(7) In the above formula (IA),
The dihydroimidazooxazole derivative or the pharmaceutically acceptable derivative thereof according to any one of (1) to (6), wherein R ² is C _1-6 alkyl, halo C _1-6 alkyl, or C _3-8 cycloalkyl. , Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (deficit of attention / hyperactivity disorder), drug dependence A medicament for preventing or treating a disease selected from the group consisting of convulsions, tremors and sleep disorders,
(8) In the above formula (IA),
R ³ is aryl (the aryl is a halogen atom, C _1-8 alkyl (the C _1-8 alkyl may be substituted with 1 to 3 aryls), haloC _1-6 alkyl, C _{3 -8} cycloalkyl (wherein the C _3-8 cycloalkyl may be substituted with 1 to 5 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and aryl). ), Halo C _1-6 alkoxy, aryl (wherein the aryl is 1 to 3 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy) 4-8 membered cyclic ether (the 4-8 membered cyclic ether may be substituted with 1 to 3 C _1-6 alkyl), C _5-8 bicycloalkyl (The C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), adamant 1 to 3 groups selected from the group consisting of til and arylcarbonyl, heteroaryl (wherein the heteroaryl is a halogen atom, C _1-8 alkyl, and aryl (the aryl is a halogen) Substituted with 1 to 3 groups selected from the group consisting of atoms, C _1-6 alkyl, and halo C _1-6 alkyl. Or a dihydroimidazooxazole derivative according to any one of (1) to (7), which is indanyl (the indanyl may be substituted with 1 to 3 C _1-6 alkyls). Or a pharmaceutically acceptable salt thereof as an active ingredient, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity) Sexual disorders), drugs Dependent, convulsions, prophylactic or therapeutic medicament for a disease selected from the group consisting of tremor, and sleep disorders,
(9) The above formula (IA) is converted to the following formula (IIA)

(1) to (8), wherein the dihydroimidazooxazole derivative or a pharmaceutically acceptable salt thereof according to any one of the above is contained as an active ingredient, schizophrenia, Alzheimer's disease, cognitive function A medicament for preventing or treating a disease selected from the group consisting of disorder, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorder,
(10) Formula (I)

[In the formula (I),
R ¹ represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), Optionally substituted with 1-3 groups selected from the group consisting of 4- to 8-membered cyclic amino, hydroxy, and C _1-6 alkoxy.), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, amino (wherein the amino is one or two groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, and C _1-6 alkanoyl) Optionally substituted)) 4-8 membered cyclic amino, C _1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, or Heteroaryl (the aryl and heteroaryl are C _1-6 alkyl, haloC _{1- Which} may be substituted with 1 to 3 groups selected from the group consisting of ₆ alkyl and C _3-8 cycloalkyl);
R ² represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), Optionally substituted with 1 to 3 groups selected from the group consisting of 4- to 8-membered cyclic amino, imino, hydroxy, C _1-6 alkoxy, and aryl.), Halo C _1-6 alkyl, C _{1 -6} alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, or heteroaryl (the aryl, And heteroaryl is a halogen atom, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the amino is 1 or with two C _1-6 alkyl May be conversion.) Or cyclic amino having 4 to 8-membered cyclic amino (said 4-8 membered 1 selected from the group consisting of one to the C _1-6 alkyl may be substituted.) 3 may be substituted with 3 groups), pyridonyl (which may be substituted with 1 C _1-6 alkyl), or tri-C _1-6 alkylsilyl;
R ³ is aryl, heteroaryl, or C _3-8 cycloalkyl (the aryl, heteroaryl, and C _3-8 cycloalkyl are each a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _{3 -8} cycloalkyl (said C _3-8 cycloalkyl C _1-6 alkyl, and may be substituted with 1 or 2 groups selected from the group consisting of halo C _1-6 alkyl.), C _{1- 6} alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, aryloxy, C _1-6 alkanoyl, aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _It may be substituted with 1 to 3 groups selected from the group consisting of _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy and C _1-6 alkanoyl. ), Heteroaryl (the heteroaryl is Androgenic atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, and with 1 to 3 substituents selected from the group consisting of halo C _1-6 alkoxy may be substituted.), 4 to 8-membered cyclic amino and pyridonyl (which may be substituted with 1 C _1-6 alkyl) may be substituted with 1 to 3 groups selected from the group consisting of Or quinolinonyl (wherein the quinolinonyl may be substituted with one C _1-6 alkyl)]
A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD comprising a dihydroimidazooxazole derivative represented by the formula: / HD (deficiency of attention / hyperactivity disorder), drug dependence, convulsions, tremor and medicine for the prevention or treatment of diseases selected from the group consisting of sleep disorders,
(11) In the above formula (I),
R ¹ is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of hydroxy and C _1-6 alkoxy) ), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl is substituted with 1 or 2 C _1-6 alkyl). Or a heteroaryl, which is substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and C _3-8 cycloalkyl. Good).
R ² is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is 1-3 groups selected from the group consisting of imino, hydroxy, C _1-6 alkoxy, and aryl) ), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl, aryl, or heteroaryl (the aryl and heteroaryl are A halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the amino is one or two C _{1- 6} alkyl may be substituted.), or cyclic amino cyclic amino (said 4-8 membered 4-8 membered selected from the group consisting of which may be substituted with one C _1-6 alkyl.) 1 to 3 groups may be substituted. ), Pyridonyl (which may be substituted with one C _1-6 alkyl), or tri-C _1-6 alkylsilyl;
R ³ is aryl or heteroaryl (the aryl and heteroaryl are a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is C _1-6 alkyl, and 1 or 2 groups selected from the group consisting of halo C _1-6 alkyl may be substituted.), C _1-6 alkoxy, halo C _1-6 alkoxy, aryl C _{1- 6} alkoxy, aryloxy, aryl (said aryl is optionally substituted by a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and 1-3 substituents selected from the group consisting of halo C _1-6 alkoxy or.), heteroaryl (said heteroaryl, C _1-6 alkyl, and 1-3 substituents selected from the group consisting of halo C _1-6 alkyl may be substituted.), 4-8 Member cyclic amino, and pyridonyl (the pyridonyl is Dihydro imidazooxazole derivative according to may be substituted.) Is (10) with 1 to 3 groups selected from one C _1-6 group consisting may be substituted.) Alkyl, or Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder) characterized by containing a pharmaceutically acceptable salt as an active ingredient ), A drug for preventing or treating a disease selected from the group consisting of drug dependence, convulsions, tremors and sleep disorders,
(12) In the above formula (I),
R ¹ is a halogen atom, cyano, halo C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with two C _1-6 alkyl). Or a dihydroimidazooxazole derivative according to (10) or (11), or a pharmaceutically acceptable salt thereof as an active ingredient, which is a heteroaryl, or schizophrenia, Alzheimer's disease, cognitive function A medicament for preventing or treating a disease selected from the group consisting of disorder, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorder,
(13) In the above formula (I),
R ^1, wherein cyano, or carbamoyl (10) to (12) dihydro-imidazo oxazole derivative according to any one, or that it contains a pharmaceutically acceptable salt thereof as an active ingredient, integration Disease selected from the group consisting of ataxia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Medicine for the prevention or treatment of
(14) In the above formula (I),
R ² is a halogen atom, C _1-6 alkyl (the C _1-6 alkyl may be substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkoxy and aryl), (10) to (13) according to any one of (10) to (13), which is haloC _1-6 alkyl or heteroaryl, which is optionally substituted with 1 to 3 C _1-6 alkoxy. Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD characterized by containing a dihydroimidazooxazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient Deficiency / hyperactivity disorder), drug dependence, convulsions, tremors and drugs for the prevention or treatment of diseases selected from the group consisting of sleep disorders,
(15) In the above formula (I),
The dihydroimidazooxazole derivative or the pharmaceutically acceptable salt thereof according to any one of (10) to (14), wherein R ² is C _1-6 alkyl or haloC _1-6 alkyl. Containing schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep A medicament for the prevention or treatment of a disease selected from the group consisting of disorders,
(16) In the above formula (I),
R ³ is aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is C _1-6 alkyl, and halo C 1 or 2 groups selected from the group consisting of _1-6 alkyl may be substituted.), Halo C _1-6 alkoxy, aryl (wherein the aryl is a halogen atom, C _1-6 alkyl, halo C _{1- 6} alkyl, and optionally substituted by 1 to 3 groups selected from the group consisting of haloC _1-6 alkoxy), and heteroaryl (the heteroaryl is C _1-6 alkyl, and haloC _{1 (It} may be substituted with 1 to 3 groups selected from the group consisting of _-6 alkyl. It may be substituted with 1 to 3 groups selected from the group consisting of). 15) The dihydroimidazooxazole derivative according to any one of the above, or a medicine thereof Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), characterized by containing a top acceptable salt as an active ingredient, A medicament for the prevention or treatment of a disease selected from the group consisting of drug dependence, convulsions, tremor and sleep disorders,
(17) The above formula (I) is converted to the following formula (II)

(10) to (16), wherein the dihydroimidazooxazole derivative according to any one of the above or a pharmaceutically acceptable salt thereof is contained as an active ingredient, schizophrenia, Alzheimer's disease, cognitive function A medicament for preventing or treating a disease selected from the group consisting of disorder, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorder,
(18) Schizophrenia characterized by containing, as an active ingredient, any one or a mixture of two or more selected from the following compound group described in (1) above and a pharmaceutically acceptable salt thereof: Prevention of a disease selected from the group consisting of: Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Or a therapeutic drug,
(2S) -2-[(4-tert-butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile,
(2S) -2-{[(2'-Fluorobiphenyl-4-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- Carboxamide,
(2S) -5-Ethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carbonitrile,
(2S) -5-Ethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-cyclopropyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1- b] [1,3] oxazole-6-carboxamide,
(2S) -5-propyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-Butyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1, 3] oxazole-6-carboxamide,
5-methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide;
2-{[3-Chloro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-Methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carbonitrile,
2-{[3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5- (2-Fluoroethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ 2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-cyclopropyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ 2,1-b] [1,3] oxazole-6-carbonitrile,
(2S) -5-ethyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-methyl-2-{[4- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2, 1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-Methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- 6-carbonitrile,
(2S) -5-methyl-2-{[4- (1-methylcyclobutyl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-propyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- 6-carboxamide,
(2S) -2-{[4- (7,7-Difluorobicyclo [4.1.0] hept-1-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -2-{[4- (3,3-Difluoro-1-methylcyclobutyl) phenoxy] methyl} -5-propyl-2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carboxamide,
(2S) -2-{[4- (3,3-Difluoro-1-methylcyclobutyl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carbonitrile,
It is.

  It has been clarified that the novel dihydroimidazooxazole derivative of the present invention acts on the activity-regulating site of the mGlu2 receptor to enhance receptor stimulation by a physiological ligand (glutamic acid).

  The terms used in the present specification have the following meanings.

  “Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

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

“C _1-8 alkyl” means a linear or branched alkyl group having 1 to 8 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, 2,4,4-trimethylpentan-2-yl and the like. .

"Halo C _1-6 alkyl" indicates a 1-5 identical or different said alkyl group "halogen atom" is substituted into "C _1-6 alkyl" of the, monofluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2-fluoro-2-propyl, 1,1,1-trifluoromethyl-2-methyl-2-propyl, 3-fluoropropyl, 3,3 -Groups such as -difluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluoro-2-methylbutan-2-yl and the like can be mentioned.

“C _3-8 cycloalkyl” means a cyclic cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

“C _1-6 alkoxy” means a linear or branched alkoxy group having 1 to 6 carbon atoms, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy and the like.

"Halo C _1-6 alkoxy" represents a one to five alkoxy group "halogen atom" is substituted into "C _1-6 alkoxy" of the mono fluoromethoxy, difluoromethoxy, such as a trifluoromethoxy The group can be mentioned.

“C _3-8 cycloalkyloxy” means a group in which the above “C _3-8 cycloalkyl” and an oxygen atom are bonded to each other. Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy And cyclooctyloxy group.

“C _3-8 cycloalkylcarbonyl” means a group in which the above “C _3-8 cycloalkyl” is bonded to carbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl. And cyclooctylcarbonyl group.

“C _1-6 alkylsulfonyl” means a sulfonyl group substituted with the above “C _1-6 alkyl”, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutyl Examples include sulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl and the like.

“C _1-6 alkanoyl” means a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc. The group can be mentioned.

“C _2-6 alkenyl” means a linear or branched alkenyl group having 2 to 6 carbon atoms, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 1-methyl- Examples include 2-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 4-pentenyl and the like.

  “Aryl” is a monocyclic to bicyclic aromatic carbocycle, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like.

  “Heteroaryl” is an aromatic group having 2 to 9 carbon atoms and having at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and includes furyl, pyrrolyl, Examples include thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, indolyl, benzofuranyl and the like.

“4- to 8-membered cyclic amino” means a 4- to 8-membered saturated or partially saturated group containing one nitrogen atom in the ring and optionally containing one or more nitrogen atoms, oxygen atoms or sulfur atoms. A heterocycle, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-1-yl, 1, Examples include 4-oxazepan-4-yl, azocan-1-yl and the like.

“Aryl C _1-6 alkoxy” refers to an alkoxy group in which 1 to 3 identical or different “aryl” is substituted on the above “C _1-6 alkoxy”, and includes benzyloxy, 1-phenylethyloxy , 2-phenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1-naphthylmethyloxy, diphenylmethyloxy, triphenylmethyloxy and the like be able to.

“Tri-C _1-6 alkylsilyl” refers to a silyl group in which “silyl” is substituted with three identical or different “C _1-6 alkyls”, such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, etc. Can be mentioned.

“Aryloxy” means a group in which the above “aryl” is bonded to an oxygen atom, and examples thereof include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.

“Arylsulfonyl” means a sulfonyl group substituted with the above “aryl”, and examples thereof include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.

The “4- to 8-membered cyclic ether” is a 4- to 8-membered cyclic ether group containing one oxygen atom in the ring, and examples thereof include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

“C _5-8 bicycloalkyl” means a cyclic bicycloalkyl group having 5 to 8 carbon atoms, bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, bicyclo [4]. .1.0] heptyl, bicyclo [2.2.1] heptyl, and bicyclo [5.1.0] heptyl groups.

“C _1-6 alkoxycarbonyl” refers to a group in which the above “C _1-6 alkoxy” and carbonyl are bonded, and includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, iso Examples include butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, n-hexyloxycarbonyl and the like.

“Arylcarbonyl” means a group in which the above “aryl” and carbonyl are bonded, and examples thereof include phenylcarbonyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.

Preferable R ¹ in the above formula (IA) of the present invention is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is hydroxy and C _1-6 alkoxy). 1 to 3 groups may be substituted.), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (1 or 2 of the carbamoyl) the C _1-6 alkyl may be substituted.), or heteroaryl (1 said heteroaryl selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and C _3-8 cycloalkyl May be substituted with ~ 3 groups),
More preferable R ¹ is a halogen atom, cyano, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl is two C _1-6 alkyls). Or a heteroaryl,
More preferred R ¹ is a halogen atom, cyano, trifluoromethyl, carbamoyl,
Particularly preferred R ¹ is cyano or carbamoyl.

Preferred R ² in the above formula (IA) of the present invention is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is imino, hydroxy, C _1-6 alkoxy, aryl, and C 1 _Optionally substituted with 1 to 3 groups selected from the group consisting of _3-8 cycloalkyl), halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkyl Sulfonyl, carbamoyl, aryl, or heteroaryl (the aryl and heteroaryl are halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _{1- 6} alkylsulfonyl, amino (the amino may be substituted with 1 or 2 C _1-6 alkyl), or 4-8 membered cyclic amino (the 4-8 membered cyclic amino is 1 C It is substituted with _1-6 alkyl . With 1-3 substituents selected from the group consisting of) may be substituted.), Pyridonyl (the pyridonyl may be substituted with one C _1-6 alkyl.), Tri C _1-6 Alkylsilyl, C _3-8 cycloalkyl or C _3-8 cycloalkylcarbonyl;
R ² is more preferably a halogen atom, C _1-6 alkyl (the C _1-6 alkyl is 1 to 3 groups selected from the group consisting of C _1-6 alkoxy, aryl, and C _3-8 cycloalkyl). ), HaloC _1-6 alkyl, heteroaryl (the heteroaryl may be substituted with 1 to 3 C _1-6 alkoxy groups), or C _3-8 cycloalkyl. And
More preferred R ² is C _1-6 alkyl, haloC _1-6 alkyl, or C _3-8 cycloalkyl.

Preferred R ³ in the above formula (IA) of the present invention is aryl or heteroaryl (the aryl and heteroaryl are halogen atoms, C _1-8 alkyl (the C _1-8 alkyl is cyano, hydroxy, and aryl). 1 to 3 groups selected from the group consisting of: halo C _1-6 alkyl, C _3-8 cycloalkyl (wherein C _3-8 cycloalkyl is a halogen atom, C _1-6 Optionally substituted with 1 to 5 groups selected from the group consisting of alkyl, halo C _1-6 alkyl, and aryl.), C _1-6 alkoxy, halo C _1-6 alkoxy, aryl C _1-6 Alkoxy, aryloxy, aryl (the aryl may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy) Good), heteroaryl Said heteroaryl, C _1-6 alkyl, and 1-3 substituents selected from the group consisting of halo C _1-6 alkyl may be substituted.), 4-8-membered cyclic amino, pyridonyl (the Pyridonyl may be substituted with 1 to 3 C groups selected from the group consisting of 1 C _1-6 alkyl.) 4 to 8 membered cyclic ether 8-membered cyclic ethers may be substituted with 1 to 3 C _1-6 alkyls), C _5-8 bicycloalkyl (the C _5-8 bicycloalkyl is substituted with 1 to 3 halogen atoms) May be substituted with 1 to 3 groups selected from the group consisting of adamantyl and arylcarbonyl. Or indanyl (which may be substituted with 1 to 3 C _1-6 alkyls),
More preferred R ³ is aryl (wherein the aryl is a halogen atom, C _1-8 alkyl (the C _1-8 alkyl may be substituted with 1 to 3 aryls), haloC _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl may be substituted with 1 to 5 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and aryl). Halo, C _1-6 alkoxy, aryl (wherein the aryl is selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy). A 4- to 8-membered cyclic ether (the 4- to 8-membered cyclic ether may be substituted with 1 to 3 C _1-6 alkyls), C _5-8. Bicycloalkyl (The C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms. ), Adamantyl, and arylcarbonyl may be substituted with 1 to 3 groups selected from the group consisting of arylcarbonyl), heteroaryl (the heteroaryl is a halogen atom, alkyl, and aryl (the aryl is a halogen atom, _Optionally substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkyl, and haloC _1-6 alkyl.), Or indanyl (wherein indanyl is 1-3 C _1-6 alkyl) And may be substituted with
More preferred R ³ is aryl (wherein the aryl is a halogen atom, C _1-8 alkyl (the C _1-8 alkyl may be substituted with 1 to 3 aryls), haloC _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl may be substituted with 1 to 5 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, and haloC _1-6 alkyl). ), Halo C _1-6 alkoxy, aryl (the aryl may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, and halo C _1-6 alkyl). , C _5-8 bicycloalkyl (the C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), and 1 to 3 groups selected from the group consisting of adamantyl. It is good.)

Preferred R ⁴ in the above formula (IA) of the present invention is a hydrogen atom or methyl,
More preferred R ⁴ is a hydrogen atom.

  A preferred steric structure in the above formula (IA) of the present invention is the following formula (IIA):

The preferred configuration is (2S).

Preferable R ¹ in the above formula (I) of the present invention is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is hydroxy and C _1-6 alkoxy). 1 to 3 groups may be substituted.), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (1 or 2 of the carbamoyl) the C _1-6 alkyl may be substituted.), or heteroaryl (1 said heteroaryl selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and C _3-8 cycloalkyl May be substituted with ~ 3 groups),
R ¹ is more preferably a halogen atom, cyano, halo C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with two C _1-6 alkyls). Or heteroaryl,
More preferred R ¹ is a halogen atom, cyano, trifluoromethyl, carbamoyl,
Particularly preferred R ¹ is cyano or carbamoyl.

Preferred R ² in the above formula (I) of the present invention is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl consists of imino, hydroxy, C _1-6 alkoxy, and aryl). Optionally substituted with 1 to 3 groups selected from the group)), halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl, aryl, or Heteroaryl (the aryl and heteroaryl are a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the The amino may be substituted with 1 or 2 C _1-6 alkyl.), Or 4-8 membered cyclic amino (wherein the 4-8 membered cyclic amino is substituted with 1 C _1-6 alkyl) Selected from the group consisting of: 1), pyridonyl (which may be substituted with 1 C _1-6 alkyl), or tri-C _1-6 alkylsilyl;
R ² is more preferably a halogen atom, C _1-6 alkyl (the C _1-6 alkyl is 1 to 3 groups selected from the group consisting of C _1-6 alkoxy, aryl, and C _3-8 cycloalkyl). ), HaloC _1-6 alkyl, heteroaryl (the heteroaryl may be substituted with 1 to 3 C _1-6 alkoxy groups), or C _3-8 cycloalkyl. And
More desirable R ² is C _1-6 alkyl or haloC _1-6 alkyl.

Preferred R ³ in the above formula (I) of the present invention is aryl or heteroaryl (the aryl and heteroaryl are a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl) (the C _3-8 cycloalkyl C _1-6 alkyl, and may be substituted with 1 or 2 groups selected from the group consisting of halo C _1-6 alkyl.), C _1-6 alkoxy, halo C _1-6 alkoxy, aryl C _1-6 alkoxy, aryloxy, aryl (wherein the aryl is selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy) with 1-3 groups may be substituted.), heteroaryl (said heteroaryl is substituted by C _1-6 alkyl, and 1-3 substituents selected from the group consisting of halo C _1-6 alkyl 4-8 member cyclic ring Mino, or pyridonyl (which may be substituted with 1 to 3 groups selected from the group consisting of 1 C _1-6 alkyl).
More preferably, R ³ is aryl (wherein the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl (wherein the C _3-8 cycloalkyl is C _1-6 alkyl, and Optionally substituted with one or two groups selected from the group consisting of haloC _1-6 alkyl.), HaloC _1-6 alkoxy, aryl (wherein the aryl is a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, and 1 to 3 groups selected from the group consisting of haloC _1-6 alkoxy, and heteroaryl (wherein the heteroaryl is C _1-6 alkyl and halo) And may be substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkyl).
More preferred R ³ is aryl (wherein the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is C _1-6 alkyl, and Optionally substituted with 1 to 5 groups selected from the group consisting of haloC _1-6 alkyl.), HaloC _1-6 alkoxy, and aryl (wherein the aryl is a halogen atom, C _1-6 alkyl, and It may be substituted with 1 to 3 groups selected from the group consisting of haloC _1-6 alkyl. It may be substituted with 1 to 3 groups selected from the group consisting of).

  A preferred steric structure in the above formula (I) of the present invention is the following formula (II):

The preferred configuration is (2S).

Examples of preferred compounds in the compounds of the present invention include
(2S) -2-[(4-tert-butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile,
(2S) -2-{[(2'-Fluorobiphenyl-4-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- Carboxamide,
(2S) -5-Ethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carbonitrile,
(2S) -5-Ethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-cyclopropyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1- b] [1,3] oxazole-6-carboxamide,
(2S) -5-propyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-Butyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1, 3] oxazole-6-carboxamide,
5-methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide;
2-{[3-Chloro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-Methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carbonitrile,
2-{[3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5- (2-Fluoroethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ 2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-cyclopropyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ 2,1-b] [1,3] oxazole-6-carbonitrile,
(2S) -5-ethyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-methyl-2-{[4- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2, 1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-Methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- 6-carbonitrile,
(2S) -5-methyl-2-{[4- (1-methylcyclobutyl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-propyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- 6-carboxamide,
(2S) -2-{[4- (7,7-Difluorobicyclo [4.1.0] hept-1-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -2-{[4- (3,3-Difluoro-1-methylcyclobutyl) phenoxy] methyl} -5-propyl-2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carboxamide,
(2S) -2-{[4- (3,3-Difluoro-1-methylcyclobutyl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carbonitrile,
Or a pharmaceutically acceptable salt thereof.

  “Pharmaceutically acceptable salt” refers to salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, formic acid, trifluoroacetic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, Maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid , Salts with organic acids such as galactaric acid and naphthalene-2-sulfonic acid, salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion and aluminum ion , Ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcycline Hexylamine, 2-aminoethanol, salts with amines such as benzathine.

  In addition, the compound of this invention can exist also as various solvates. Moreover, it may be a hydrate from the viewpoint of applicability as a medicine.

  The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.

  The compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents into a pharmaceutical formulation. As said carrier, excipient and diluent, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup And various oils such as methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil and soybean oil.

  In addition, additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients, or diluents, and tablets are prepared by conventional formulation techniques. , Pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches and the like. The compound of the present invention can be orally or parenterally administered to an adult patient at a dose of 0.001 to 2000 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

  The compounds of the present invention also include compounds in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.

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

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

Examples of the “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or alkaline earth metal carbonate; Sodium hydrogen carbonate, potassium hydrogen carbonate or other alkali metal or alkaline earth Metal bicarbonate; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3 0.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; quaternary ammonium salts such as tetra-n-butylammonium fluoride and benzyltrimethylammonium hydroxide; pyridine, imidazole, 2,6 -Basic heterocyclic compounds such as lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and the like. Lewis acids such as organic acids, zinc chloride (II), aluminum chloride (III), titanium chloride (IV), boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.

  The compound of the present invention represented by the formula (I) can be produced by the method of the following scheme 1.

In the formula, R ¹ , R ² and R ³ are as defined above. X ¹ represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom or an organic sulfonyloxy group (such as a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group).
Step 1: The compound of the present invention represented by the formula (I) can be produced by reacting a compound represented by the formula (1) with a compound represented by the formula (2) in the presence of a base in an inert solvent. Here, as the compounds represented by formula (1) and formula (2), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis techniques known to those skilled in the art are used. Can do.

  The compound of the present invention represented by the formula (I) can also be produced by the method of the following scheme 2.

In the formula, R ¹ , R ² , R ³ and X ¹ are as defined above. Y ¹ represents a hydrogen atom or a halogen atom.
Step 2: The compound of the present invention represented by formula (I) can be produced by reacting a compound represented by formula (3) with a compound represented by formula (4) in the presence of alkyllithium in an inert solvent. Here, as the compounds represented by the formulas (3) and (4), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis methods known to those skilled in the art are used. Can do.

  The compound of the present invention represented by the formula (I) can also be produced by the method of the following scheme 3.

In the formula, R ¹ , R ² , R ³ , X ¹ and Y ¹ are as defined above.

  Step 3: The compound of the present invention represented by the formula (I) can be produced from the compound represented by the formula (5) and the compound represented by the formula (6) by the same method as in the step 2 in Scheme 2. Here, as the compounds represented by the formulas (5) and (6), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis methods known to those skilled in the art are used. Can do.

The compound of the present invention represented by the formula (I) can also be produced by the method of the following scheme 4.

In the formula, R ¹ , R ² , R ³ and X ¹ are as defined above. M represents a metal atom or a metal atom group used in the coupling reaction, and examples of the compound represented by the formula (8) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, tin A reactive agent etc. are mentioned.
Step 4: The compound of the present invention represented by the formula (I) is compounded with the compound represented by the formula (7) in an inert solvent in the presence or absence of a base using a palladium catalyst and optionally a ligand. It can manufacture by the coupling reaction of the compound represented by Formula (8). Here, examples of the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, {Comprehensive Organic Transformations Second Edition {Comprehensive Organic Transformations Second Edition] 1999, John Willie and Sons (John Wiley & Sons, INC.)} Or the like, a method based thereon, or a combination of these with conventional methods. Here, the palladium catalyst is, for example, palladium (II) acetate, palladium (II) chloride, palladium (II) bis (triphenylphosphine) acetate, palladium (II) bis (triphenylphosphine) chloride, tris (dibenzylideneacetone). ) Dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), allyl palladium chloride (II), bis (acetonitrile) palladium chloride (II), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium chloride (II), and the like. Examples of ligands include triphenylphosphine, 2,2-bis (diphenylphosphino ) -1,1-binaphthyl (BINAP), 2- (di-tert-butylphosphino) biphenyl, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos) and the like. . Here, as the compounds represented by formula (7) and formula (8), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis techniques known to those skilled in the art are used. Can do.

  The compound of the present invention represented by the formula (I) can also be produced by the method of the following scheme 5.

In the formula, R ¹ , R ² , R ³ and X ¹ are as defined above.

  Step 5: The compound of the present invention represented by the formula (I) can be produced by reacting a compound represented by the formula (9) and a compound represented by the formula (10) in the presence of a base in an inert solvent. Here, as the compounds represented by formula (9) and formula (10), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis techniques known to those skilled in the art are used. Can do.

  The compound of the present invention represented by the formula (I) can also be produced by the method of the following scheme 6.

In the formula, R ¹ , R ² and R ³ are as defined above.

Step 6: The compound of the present invention represented by the formula (I) can be produced by Mitsunobu reaction between the compound represented by the formula (11) and the compound represented by the formula (12). Mitsunobu reaction is, for example, a method using an organophosphorus compound such as triphenylphosphine or tributylphosphine and an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate, or cyanomethyltributylphospho Examples include a method using a phosphorus ylide reagent such as orchid (see Chem. Rev. 2009. 109, 2551-2651). Here, as the compounds represented by formula (11) and formula (12), commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis methods known to those skilled in the art are used. Can do.
Among the compounds of the present invention represented by the formula (I), a compound represented by the following formula (I-II) can be produced by the method of the following scheme 7.

In the formula, R ¹ , R ² , R ³ , X ¹ and M are as defined above. Ar ¹ is aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy and C _1-6 alkanoyl) Or a heteroaryl (the heteroaryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy) And 1 to 3 groups selected from the group consisting of halo C _1-6 alkoxy may be substituted.
Step 7: A compound represented by the formula (I-II) can be produced from a compound represented by the formula (13) and a compound represented by the formula (14) by the same method as in Step 4 in Scheme 4. Here, as the compounds represented by formula (13) and formula (14), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis methods known to those skilled in the art are used. Can do.
Among the compounds of the present invention represented by the formula (I), a compound represented by the following formula (I-II) can also be produced by the method of the following scheme 8.

In the formula, R ¹ , R ² , R ³ , X ¹ , M, and Ar ¹ are as defined above.
Step 8: The compound represented by the formula (I-II) can be produced from the compound represented by the formula (15) and the compound represented by the formula (16) by the same method as in the step 4 in Scheme 4. Here, as the compounds represented by formula (15) and formula (16), commercially available compounds, known compounds or compounds synthesized from known compounds using various organic synthesis techniques known to those skilled in the art are used. Can do.
Among the compounds of the present invention represented by the formula (I), a compound represented by the following formula (I-III) can be produced by the method of the following scheme 9.

In the formula, R ² and R ³ are as defined above.
Step 9: The compound represented by the formula (I-III) can be produced by hydrolysis reaction of the compound represented by the formula (17) in the presence of a base in an inert solvent. Here, as the compound represented by the formula (17), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used.
The compound represented by the formula (11) can be produced by the method of the following scheme 10.

In the formula, R ¹ , R ² and X ¹ are as defined above, and R ⁵ is a hydroxyl-protecting group such as tert-butyldimethylsilyl group, p-methoxybenzyl group, 2-tetrahydropyranyl group or trityl group. (See Theodora W. Green, Peter GM Wuts, “Protecting Groups in Organic Synthesis (see Green's Protective Groups in Organic Synthesis, Forth Edition)”; see Wiley Interscience).
Step 10: The compound represented by formula (19) can be produced from the compound represented by formula (18) and the compound represented by formula (2) by the same method as in step 1 in scheme 1. Here, as the compound represented by the formula (18), a commercially available compound, a known compound, or a compound synthesized using various organic synthesis techniques known to those skilled in the art can be used.
Step 11: The compound represented by the formula (11) is prepared according to Theodora W. et al. Green, Peter G. et al. M.M. It can be produced from the compound represented by the formula (19) by a deprotection reaction described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
The compound of the present invention represented by the formula (IA) can be produced by the method of the following scheme 11.

In the formula, R ¹ , R ² , R ³ , R ⁴ and X ¹ are as defined above.
Step 12: The compound of the present invention represented by the formula (IA) is produced from the compound represented by the formula (20) and the compound represented by the formula (2) by the same method as in Step 1 in Scheme 1. be able to. Here, as the compound represented by the formula (20), a commercially available compound, a known compound, or a compound synthesized using various organic synthesis methods known to those skilled in the art can be used.

EXAMPLES Hereinafter, although a manufacture example, an Example, and a test example are given and this invention is demonstrated further in detail, these do not limit this invention, You may change in the range which does not deviate from the scope of the present invention.
In the production examples and examples, “SNAP Cartridge KP-NH” when purified using column chromatography is Biotage's SNAP Cartridge KP-NH, and “SNAP Cartridge HP-Sil” is Biotage's SNAP Cartridge HP- Sil, "Revelelis NH" means Grace's Reveleris (registered trademark) Amino Silica Cartridge, "Revelelis" means Grace's Reveleris (registered trademark) Silica Cartridge, YMC-DispoPakAT NHp and YMC-DispoPakAT NHp NH2.
When purifying using preparative thin layer chromatography (PTLC), Merck silica gel 60F ₂₅₄ , 20 cm × 20 cm was used. When purification was performed using preparative thin layer chromatography (PTLC) NH, NH ₂ silica gel 60F ₂₅₄ , 20 cm × 20 cm, manufactured by Wako Pure Chemical Industries, Ltd. was used.
The microwave reactor used in the following preparation examples and examples is Initiator (Biotage AB) or Emrys Optimizer (personal chemistry).
Each instrument data described in the production examples and examples was measured with the following measuring instruments.

MS spectrum: LCMS-2010EV (Shimadzu Corporation), LCMS-IT-TOF (Shimadzu Corporation), micromass Platform LC or micromass GCT, Agilent 2900 and Agilent 6150
NMR spectrum: JEOL JNM-ECA600 (600 MHz), JEOL JNM-ECA500 (500 MHz), Varian UNITYNOVA300 (300 MHz), Varian GEMINI 2000/200 (200 MHz)
The compound name in a manufacture example and an Example was named by ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).

Abbreviations used in the examples are shown below.
MS (mass spectrometry), ESI (electrospray ionization), APCI (atmospheric pressure chemical ionization), NMR (nuclear magnetic resonance spectroscopy), H (proton), J (coupling constant), DMSO-d6 (dimethyl deuteride) Sulfoxide), br. S (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), ddd (double doublet), dt (double triplet), td (triple doublet), m (multiplet), v / v (capacity / capacity), v / v / v (capacity / capacity / capacity).

In the following production examples and examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson preparative HPLC system
Column: Waters Sunfire (registered trademark) prep C18 OBD, 5.0 μm, φ30 × 50 mm
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile flow rate: 40 mL / min, detection method: UV 254 nm
Condition A
Gradient: 0 minutes (A liquid / B liquid = 90/10), 11 minutes (A liquid / B liquid = 20/80), 12-13.5 minutes (A liquid / B liquid = 5/95)
Condition B
Gradient: 0 minutes (A liquid / B liquid = 80/20), 10 minutes (A liquid / B liquid = 5/95), 11-13.5 minutes (A liquid / B liquid = 1/99)
In the following Examples 42 to 47 and Example 62, the racemate was analyzed using the following conditions.
Measuring machine: Agilent 1100
Column: CHIRALPAK AD-3 (Daicel, 4.6 mm x 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: ethanol only

In the following production examples and examples, in the case of a compound having a basic functional group, a salt may be formed using various acids under various reaction conditions known to those skilled in the art.

  Production Example 1: Preparation of 5,6-dibromo-2-{[(4-methoxybenzyl) oxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (intermediate 1) Composition

(2S) -2-{[(4-Methoxybenzyl) oxy] methyl} oxirane (10.9 g), 2,4,5-tribromo-1H-imidazole (14.3 g) and cesium carbonate (18.4 g) in dimethyl sulfoxide ( (300 mL) The suspension was stirred at 130 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90 / 10-50 / 50; v / v) to obtain the title compound (intermediate 1: 4.73 g, pale yellow oil). .

  Production Example 2: 6-bromo-2-{[(4-methoxybenzyl) oxy] methyl} -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3 ] Synthesis of Oxazole (Intermediate 7)

5,6-Dibromo-2-{[(4-methoxybenzyl) oxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (intermediate) obtained in Production Example 1 1: 1.0 g), 3-pyridylboronic acid (323 mg), tetrakistriphenylphosphine palladium (0) (276 mg) and cesium carbonate (2.34 g) in toluene / ethanol / water (3/3/2; v / (v / v, 10 mL) The suspension was stirred at 100 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 15/85 to chloroform / methanol = 97/3; v / v) to obtain a yellow amorphous. The resulting yellow amorphous was purified by column chromatography (Reveleris NH, mobile phase: hexane / ethyl acetate = 80 / 20-30 / 70; v / v) to give the title compound (Intermediate 7: 672 mg, colorless amorphous) Got.

  Production Example 3: 2-{[(4-Methoxybenzyl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (intermediate) 8) Synthesis

6-Bromo-2-{[(4-methoxybenzyl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [2, obtained using the same method as in Production Example 1 1,3] oxazole (intermediate 2: 500 mg), zinc (22 mg), zinc cyanide (333 mg), 1,1'-bis (diphenylphosphino) ferrocene (314 mg) and tris (dibenzylideneacetone) ) A suspension of dipalladium (0) (259 mg) in dimethylacetamide (20 mL) was stirred at 100 ° C. for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and the mixture was filtered through Celite (registered trademark), and the organic layer and the aqueous layer were separated. The aqueous layer was extracted once with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 80/20 to 20/80; v / v) to obtain the title compound (Intermediate 8: 124 mg, brown oil).

  Production Example 4: Preparation of [6-bromo-5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate 9) Composition

6-Bromo-2-{[(4-methoxybenzyl) oxy] methyl} -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [obtained in Production Example 2 To 1,3] oxazole (Intermediate 7: 54 mg) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 50 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice cooling, water and chloroform / methanol (9/1; v / v) were added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform / methanol (9/1; v / v). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 97/3 to 87/13; v / v) to obtain the title compound (intermediate 9: 26 mg, colorless solid).

  Production Example 5: Synthesis of [5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate 11)

[6-Bromo-5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate) obtained in Production Example 4 9:22 mg) in methanol (2 mL) was added 10% palladium carbon (22 mg), and the mixture was stirred at room temperature for 50 minutes in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give the title compound (Intermediate 11: 28 mg, colorless solid).

  Production Example 6: 4-Methylbenzenesulfonic acid [5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methyl (intermediate 12 ) Synthesis

[5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (Intermediate 11: 200 mg) obtained in Production Example 5 ) In chloroform (10 mL) at 0 ° C., triethylamine (0.256 mL), trimethylamine hydrochloride (44 mg) and p-toluenesulfonyl chloride (263 mg) were added, and the mixture was stirred at the same temperature for 5 minutes. And stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, ethyl acetate was added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge HP-Sil, mobile phase: chloroform / methanol = 97/3 to 95/5; v / v) to give the title compound (Intermediate 12: 229 mg, pale yellow solid) Obtained.

  Production Example 7: 4-Methylbenzenesulfonic acid [6-cyano-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methyl (intermediate 13) Composition

2- (Hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (intermediate) obtained using the same method as in Production Example 4. Body 10: 108 mg) in a chloroform (5 mL) suspension at 0 ° C. was added triethylamine (0.168 mL), trimethylamine hydrochloride (29 mg), p-toluenesulfonyl chloride (172 mg), and the same temperature for 5 minutes. After stirring, the mixture was stirred for 2.5 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, ethyl acetate was added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 97/3 to 95/5; v / v) to obtain the title compound (Intermediate 13: 209 mg, colorless solid).

Production Example 8: 4-Methylbenzenesulfonic acid (6-carbamoyl-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl) methyl (intermediate 14) Composition

  4-methylbenzenesulfonic acid (6-cyano-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl) methyl (intermediate) obtained in Production Example 7 13: 1.0 g) in dimethyl sulfoxide (15 mL) was ice-cooled, and potassium carbonate (829 mg) and aqueous hydrogen peroxide (about 35%, 2.9 mL) were added. After stirring at 40 ° C. for 1 hour, ice water was added, and the precipitated solid was collected by filtration and washed with water and diethyl ether. The solid was dried under reduced pressure to give the title compound (Intermediate 14: 747 mg).

Production Example 9: 2-{[(5-Bromopyridin-2-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbo Synthesis of nitrile (intermediate 15)

  2- (hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (intermediate 10) obtained by the same method as in Production Example 4. : 200 mg) in N, N-dimethylformamide (5.5 mL) was added 5-bromo-2-fluoropyridine (255 mg), and sodium hydride (about 60%, 58 mg) was added under ice cooling. After stirring at the same temperature for 15 minutes, the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with chloroform, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 100/0 to 90/10; v / v) to give the title compound (Intermediate 15: 284 mg). Obtained.

Production Example 10: Synthesis of 2,5-dibromo-1H-imidazole-4-carbonitrile (intermediate 16)

  1H-imidazole-4-carbonitrile (39.5 g) was dissolved in 0.4 M aqueous sodium hydroxide solution (790 mL) and cooled on ice. Bromine (53 mL) was added dropwise and stirred at room temperature for 46 hours. After ice cooling again, the solid was collected by filtration. After washing with ice water and drying, the title compound (Intermediate 16: 107.19 g) was obtained.

Production Example 11: 4-Methylbenzenesulfonic acid [(2S) -6-carbamoyl-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methyl (intermediate) Synthesis of body 18)

(A) tert-butyl (dimethyl) [(2S) -oxiran-2-ylmethoxy] silane (7.5 g) in ethanol (100 mL) with sodium acetate (6.5 g) and 2,5-dibromo-1H-imidazole -4-carbonitrile (intermediate 16: 12.0 g) was added, and the mixture was stirred at 60 ° C. for 2 days. The solvent was distilled off under reduced pressure, the residue was suspended in chloroform (100 mL), and the insoluble material was removed by filtration. Water was added to the filtrate and extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (100 mL), ice-cooled, and sodium hydride (about 60%, 2.1 g) was added. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to stop the reaction. Water was added and the mixture was extracted with ethyl acetate / toluene (= 5: 1), and then the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 80 / 20-60 / 40) and (2S ) -5-Bromo-2-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (5 .49 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 3 H), 0.08 (s, 3 H), 0.82 (s, 9 H), 3.83 (dd, J = 12.0, 2.9 Hz, 1 H) , 4.02-4.08 (m, 1 H), 4.13-4.22 (m, 2 H), 5.31-5.41 (m, 1 H)
(B) (2S) -5-bromo-2-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 -A solution of carbonitrile (5.48 g) in tetrahydrofuran (51 mL) was cooled to -78 ° C, and n-butyllithium (2.64 M hexane solution, 7.0 mL) was added. After stirring at the same temperature for 1 hour, methyl iodide (1.9 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at 0 ° C. for 30 minutes. Saturated aqueous ammonium chloride solution was added to stop the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge KP-NH, mobile phase: hexane / ethyl acetate = 60/40), and (2S) -2-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-Methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (3.0 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 3 H), 0.08 (s, 3 H), 0.82 (s, 9 H), 2.31 (s, 3 H), 3.84 (dd, J = 11.8, 3.1 Hz, 1 H), 3.96-4.03 (m, 1 H), 4.05-4.15 (m, 2 H), 5.24-5.34 (m, 1 H)
(C) (2S) -2-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 -(+/-)-Camphor-10-sulfonic acid (1.2 g) was added to a solution of carbonitrile (3.0 g) in chloroform / methanol (1: 1, 100 mL) and stirred overnight at room temperature. After ice cooling, a solution of triethylamine (3.6 mL) in chloroform (30 mL) was added, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (YMC-DispoPakAT NH2, mobile phase: chloroform / methanol = 100/0 to 90/10). The obtained solid was washed with stirring in hexane / ethyl acetate (= 1/2), and the solid was collected by filtration and dried to give (2S) -2- (hydroxymethyl) -5-methyl-2,3-dihydroimidazo. [2,1-b] [1,3] oxazole-6-carbonitrile (1.06 g) was obtained. When the optical purity of this compound was measured by HPLC analysis under the following conditions, it was 99% ee or higher.
HPLC analysis column: CHIRALPAK AD-3 (Daicel, 4.6 mm × 150 mm)
Flow rate: 1 mL / min
Mobile phase: hexane / ethanol = 50/50
Retention time for this compound: 2.2 min (Racemic retention times: 2.0 min and 2.2 min)
(D) (2S) -2- (hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (500 mg) in chloroform (11 mL) The suspension was ice-cooled, triethylamine (0.78 mL), trimethylamine hydrochloride (80 mg) and p-toluenesulfonyl chloride (798 mg) were added, and the mixture was stirred for 1.5 hr. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: chloroform / ethyl acetate = 100/0 to 30/70) to give 4-methylbenzenesulfone. The acid [(2S) -6-cyano-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methyl (intermediate 17: 918 mg) was obtained.

  (E) Using the same method as in Production Example 8, 4-methylbenzenesulfonic acid [(2S) -6-cyano-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3 ] Oxazol-2-yl] methyl (Intermediate 17: 907 mg) gave the title compound (Intermediate 18: 691 mg).

Production Example 12: Synthesis of 4- [1- (trifluoromethyl) cyclopropyl] phenol (intermediate 23)

(A) 1-bromo-4- [1- (trifluoromethyl) cyclopropyl] benzene (4.72 g), bis (pinacolato) diboron (5.4 g), potassium acetate (5.2 g), tris (dibenzylidene) A suspension of 1,4-dioxane (36 mL) in acetone) dipalladium (0) (326 mg) and 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropylbiphenyl (340 mg) at 100 ° C. Stir for 3 hours. The mixture was allowed to cool, diluted with ethyl acetate, insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 92/8), and 4,4,5,5-tetramethyl-2- {4- [1- (tri Fluoromethyl) cyclopropyl] phenyl} -1,3,2-dioxaborolane (5.03 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.01-1.05 (m, 2 H), 1.34 (s, 12 H), 1.34-1.36 (m, 2 H), 7.40-7.51 (m, 2 H), 7.74-7.82 (m, 2 H)
(B) 4,4,5,5-tetramethyl-2- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,3,2-dioxaborolane (2.5 g) in acetone (30 mL) The solution was ice-cooled, and a solution of potassium peroxymonosulfate (7.4 g) in water (30 mL) was added dropwise, followed by stirring at room temperature for 1.5 hours. After adding water and extracting with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (Intermediate 23: 880 mg).

Production Example 13: 3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenol (intermediate 25)

(A) A solution of 1- (2-fluoro-4-methoxyphenyl) ethanone (1.00 g) in tetrahydrofuran (15 mL) was ice-cooled, (trifluoromethyl) trimethylsilane (1.27 g) and tetrabutylammonium fluoride Hydrate (16 mg) was added and stirred at room temperature overnight. Ethyl acetate and 1M hydrochloric acid were added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. After liquid separation, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 80/20), 1,1,1 -Trifluoro-2- (2-fluoro-4-methoxyphenyl) propan-2-ol (1.10 g) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.78-1.87 (m, 3 H), 3.81 (s, 3 H), 6.54-6.78 (m, 2 H), 7.46 (t, J = 9.0 Hz, 1 H)
(B) A solution of 1,1,1-trifluoro-2- (2-fluoro-4-methoxyphenyl) propan-2-ol (600 mg) in chloroform (10 mL) was ice-cooled, and titanium (IV) chloride was added. After that, the mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. The reaction solution was transferred to ice water little by little and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 90/10) to give 1- (2-chloro-1,1,1- Trifluoropropan-2-yl) -2-fluoro-4-methoxybenzene (210 mg) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 2.19-2.28 (m, 3 H), 3.84 (s, 3 H), 6.64-6.82 (m, 2 H), 7.66 (t, J = 9.2 Hz, 1 H)
(C) A solution of 1- (2-chloro-1,1,1-trifluoropropan-2-yl) -2-fluoro-4-methoxybenzene (207 mg) in hexane (2.0 mL) was added to trimethylaluminum (1. (08 M hexane solution, 1.7 mL) was added, and the mixture was heated to reflux at 85 ° C. for 2 hours. After cooling with ice, a small amount of 1M hydrochloric acid was added to stop the reaction. Water was added to the reaction mixture, and the mixture was extracted with hexane / ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100 / 0-80 / 20) to give 2-fluoro-4 -Methoxy-1- (1,1,1-trifluoro-2-methylpropan-2-yl) benzene (170 mg) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.57-1.65 (m, 6 H), 3.80 (s, 3 H), 6.54-6.76 (m, 2 H), 7.25-7.37 (m, 1 H)
(D) A solution of 2-fluoro-4-methoxy-1- (1,1,1-trifluoro-2-methylpropan-2-yl) benzene (169 mg) in chloroform (2.0 mL) was ice-cooled. Boron bromide (0.07 mL) was added. After stirring at room temperature for 1.5 hours, the mixture was cooled with ice and water was added. After extraction with chloroform, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 70/30) to obtain the title compound (Intermediate 25: 131 mg).

Production Example 14 Synthesis of 3,3,4,4,4-pentafluoro-2- (4-methoxyphenyl) butan-2-ol (Intermediate 27)

  A solution of 2,2,3,3,3-pentafluoro-1- (4-methoxyphenyl) propan-1-one (5.31 g) in diethyl ether was ice-cooled and methylmagnesium bromide (3M diethyl ether solution, 8 4 mL) and stirred at room temperature for 4.5 hours. After cooling with ice, methylmagnesium bromide (8.4 mL) was added, and the mixture was stirred overnight at room temperature. After further stirring at 35 ° C. for 1 hour, 1M hydrochloric acid was added to stop the reaction. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 70/30) to give the title compound (Intermediate 27: 5.67 g) was obtained.

Production Example 15: Synthesis of 4- [2,2-difluoro-1- (trifluoromethyl) cyclopropyl] phenol (intermediate 29)

  (A) To a solution of 1-methoxy-4- (3,3,3-trifluoroprop-1-en-2-yl) benzene (500 mg) in acetonitrile (5.0 mL) was added sodium iodide (815 mg) and (tri Fluoromethyl) trimethylsilane (1.76 g) was added and stirred in a sealed tube at 110 ° C. for 7.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 90/10). 1- [2,2-difluoro-1- (trifluoromethyl) cyclopropyl] -4-methoxybenzene (506 mg) was obtained.

  (B) A chloroform (1.0 mL) solution of 1- [2,2-difluoro-1- (trifluoromethyl) cyclopropyl] -4-methoxybenzene (100 mg) was ice-cooled, and boron tribromide (0. 06 mL), and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. After cooling with ice, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100/0 to 70/30) to obtain the title compound (Intermediate 29: 64 mg).

Production Example 16: Synthesis of 4- (1-phenylcyclopropyl) phenol (intermediate 33)

(A) Diethyl zinc (1.1 M toluene solution, 9.9 mL) was added to a chloroform (5.0 mL) solution of 1-methoxy-4- (1-phenylethenyl) benzene (456 mg), and the mixture was stirred at room temperature for 10 minutes. did. Diiodomethane (5.81 g) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 100 / 0-80 / 20) to obtain 1-methoxy-4- (1-phenylcyclopropyl) benzene (479 mg).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23-1.27 (m, 4 H), 3.77 (s, 3 H), 6.79-6.83 (m, 2 H), 7.12-7.25 (m, 7 H)
(B) A solution of 1-methoxy-4- (1-phenylcyclopropyl) benzene (479 mg) in chloroform (5.0 mL) was ice-cooled, boron tribromide (0.3 mL) was added, and 1 ° C. was added at the same temperature. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, hexane / ethyl acetate = 100/0 to 70/30) to obtain the title compound (Intermediate 33: 398 mg).

Production Example 17: Synthesis of 1-chloro-4- (3,3-difluoro-1-methylcyclobutyl) benzene (intermediate 34)

(A) A tetrahydrofuran (26 mL) solution of 1- (4-chlorophenyl) -3,3-difluorocyclobutanecarboxylic acid (1.58 g) was ice-cooled, and borane-tetrahydrofuran complex (1.06 M tetrahydrofuran solution, 12 mL) was added dropwise. The mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 3 days. After ice cooling, methanol (12 mL) was added and stirred for 10 minutes. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 100/0 to 90/10), and [1- (4-chlorophenyl) -3,3- Difluorocyclobutyl] methanol (1.48 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.74-2.98 (m, 4 H), 3.70-3.77 (m, 2 H), 7.08-7.17 (m, 2 H), 7.31-7.40 (m, 2 H )
(B) A solution of [1- (4-chlorophenyl) -3,3-difluorocyclobutyl] methanol (1.48 g) in ethyl acetate (42 mL) was ice-cooled, triethylamine (1.3 mL) and methanesulfonyl chloride (640 μL). ) And stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (12.7 mL), ice-cooled, and lithium triethylborohydride (1.7 M tetrahydrofuran solution, 18.7 mL) was added dropwise. The mixture was stirred at the same temperature for 20 minutes and at room temperature overnight, then ice-cooled and 1M hydrochloric acid was added. After extraction with diethyl ether, the organic layer was washed with 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (Revelelis, hexane / ethyl acetate = 100/0 to 80/20). Hexane was added to the crude product, the resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform and washed successively with 1M hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 34: 1.25 g).

  Tables 1-1 to 1-6 show the structural formulas, compound names, and instrument data of the intermediates shown in Production Examples 1 to 17 and intermediates synthesized by the same method. The number described in the column of the production example in the table indicates which production example among the production examples 1 to 17 was synthesized by the same method.

Example 1: (2S) -5-bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 2) and Synthesis of (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 3)
(2S) -2-{[4- (tert-butyl) phenoxy] methyl} oxirane (1.37 g), 2,4-dibromo-1H-imidazole (1.00 g) and cesium carbonate (2.16 g) in dimethyl sulfoxide (30 mL) The suspension was stirred at 130 ° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70/30 to 20/80; v / v) to give the title compound (Compound 2: 118 mg, colorless solid) and the title compound (Compound 3 : 356 mg, colorless solid).

Example 2: (2S) -2-[(4-tert-butylphenoxy) methyl] -6-chloro-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 8) and (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -5-chloro-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 9) Synthesis (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (1) obtained in Example 1 Compound 3: 400 mg) in tetrahydrofuran (4 mL) was added n-butyllithium (2.6 M hexane solution, 0.438 mL) at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. Hexachloroethane (539 mg) was added to the reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 1 hour, and then stirred for 1.5 hours while raising the temperature to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, ethyl acetate was added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90/10 to 70/30; v / v) to give the title compound (Compound 8: 152 mg, colorless solid) and the title compound (Compound 9 : 63 mg, yellow solid).

Example 3: (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole ( Synthesis of Compound 1) (2S) -5,6-Dibromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2] obtained using the same procedure as in Example 1 , 1-b] [1,3] oxazole (compound 54: 400 mg) in tetrahydrofuran (4 mL) was added n-butyllithium (2.6 M hexane solution, 0.358 mL) at −78 ° C. Stir for hours. To the reaction solution was added iodomethane (0.064 mL) at −78 ° C., and the mixture was stirred at the same temperature for 1 hour, and then stirred for 4 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, ethyl acetate was added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90/10 to 65/35; v / v) to obtain the title compound (Compound 1: 235 mg, pale yellow solid).

Example 4: (2S) -2-[(4-tert-Butylphenoxy) methyl] -5-phenyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 6) Synthesis (2S) -5-Bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (1) obtained in Example 1 Compound 2: 77 mg), phenylboronic acid (27 mg), tetrakistriphenylphosphine palladium (0) (25 mg) and cesium carbonate (86 mg) in toluene / ethanol / water (3/3/2; v / v / v, 1 mL) The suspension was stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70 / 30-50 / 50; v / v) to obtain the title compound (Compound 6: 64 mg, colorless solid).

Example 5: (2S) -2-[(4-tert-Butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile Synthesis of (Compound 11) (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-] obtained in Example 3 b] [1,3] oxazole (compound 1:38 mg), zinc (3 mg), zinc cyanide (12 mg), 1,1'-bis (diphenylphosphino) ferrocene (6 mg) and tris (di A suspension of benzylideneacetone) dipalladium (0) (10 mg) in dimethylacetamide (1 mL) was stirred at 95 ° C. for 28 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70 / 30-50 / 50; v / v) to obtain the title compound (Compound 11: 3 mg, pale yellow solid).

Example 6: (2S) -2-[(4-tert-Butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 4) Synthesis (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,1 obtained in Example 3 3] 10% Palladium carbon (10 mg) was added to a solution of oxazole (Compound 1: 50 mg) in methanol (2 mL), and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge KP-NH, mobile phase: hexane / ethyl acetate = 65 / 35-5 / 95; v / v) to give the title compound (Compound 4: 15 mg, brown solid) It was.

Example 7: (2S) -2-[(4-tert-Butylphenoxy) methyl] -5-chloro-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 23) Synthesis (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -5-chloro-2,3-dihydroimidazo [2,1-b] [1, obtained in Example 2 3] To a solution of oxazole (Compound 9: 36 mg) in tetrahydrofuran (1 mL) was added n-butyllithium (2.6 M hexane solution, 0.036 mL) at -78 ° C, and the mixture was stirred at the same temperature for 2 hours, and then warmed to room temperature. Stir for 2.5 hours while warming. A saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, ethyl acetate was added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: hexane / ethyl acetate = 50/50; v / v) to obtain the title compound (Compound 23: 15 mg, colorless solid). .

Example 8: (2S) -2-[(4-tert-Butylphenoxy) methyl] -5- (trimethylsilyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 12 (2) (2S) -5,6-dibromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [] obtained using the same procedure as in Example 1 To a solution of 2,1-b] [1,3] oxazole (Compound 54: 300 mg) in tetrahydrofuran (3 mL) was added n-butyllithium (2.6 M hexane solution, 0.282 mL) at −78 ° C. Stir for 30 minutes. Trimethylsilyl chloride (0.093 ml) was added at −78 ° C., stirred at the same temperature for 30 minutes, and then stirred for 20 minutes while raising the temperature to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, ethyl acetate was added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 95 / 5-80 / 20; v / v) and (2S) -6-bromo-2-[(4-tert-butylphenoxy ) Methyl] -5- (trimethylsilyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (143 mg, colorless amorphous) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.34 (s, 9 H), 1.30 (s, 9 H), 4.09-4.30 (m, 4 H), 5.44-5.50 (m, 1 H), 6.82-6.87 (m, 2 H), 7.30-7.34 (m, 2 H); ESI / APCI MS m / z 423 [M + H] +
(B) The obtained (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -5- (trimethylsilyl) -2,3-dihydroimidazo [2,1-b] [1, 3] To a solution of oxazole (143 mg) in tetrahydrofuran (1.5 ml) was added n-butyllithium (2.6 M hexane solution, 0.130 mL) at -78 ° C, and the mixture was stirred at the same temperature for 2 hours, and then iodomethane (0.023 ml) And stirred for 3 hours while raising the temperature to 0 ° C. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 80 / 20-50 / 50; v / v) to obtain a pale yellow amorphous (35 mg). To a solution of the obtained pale yellow amorphous (35 mg) in methanol (1 mL) was added potassium carbonate (13 mg), and the mixture was stirred at room temperature for 95 minutes. Water and ethyl acetate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate NH, mobile phase: hexane / ethyl acetate = 33/67; v / v) to obtain a colorless amorphous. This colorless amorphous was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: hexane / ethyl acetate = 50/50; v / v) to give the title compound (Compound 12: 16 mg, colorless solid). Obtained.

Example 9: 2-[(3-Fluorophenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 65) Synthesis [5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate 11:28) obtained in Production Example 5 mg) in 1,4-dioxane (1 mL) suspension was added 3-fluorophenol (0.014 mL), diisopropyl azodicarboxylate (1.9 M toluene solution, 0.136 mL) and triphenylphosphine (68 mg) Stir at room temperature for 20 hours. Water and chloroform were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: hexane / ethyl acetate = 30/70; v / v) to obtain the title compound (Compound 65: 12 mg, colorless solid). .

Example 10: 2-[(biphenyl-4-yloxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 93) Synthesis of 4-methylbenzenesulfonic acid [5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] obtained in Production Example 6 4-phenylphenol (35 mg) and cesium carbonate (123 mg) were added to a solution of methyl (intermediate 12: 72 mg) in acetonitrile (1.5 mL), and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge HP-Sil, mobile phase: hexane / ethyl acetate = 50/50 to 85/15 to chloroform / methanol = 95/5 to 90/10; v / v) to give the title compound (Compound 93: 35 mg, colorless solid) was obtained.

Example 11: (2S) -2-[(4-Chlorophenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (compound 124) Synthesis To a solution of diisopropylamine (1.12 g) in tetrahydrofuran (20 mL) was added n-butyllithium (2.6 M hexane solution, 4.3 mL) at −78 ° C., and the mixture was stirred for 30 minutes while raising the temperature to 0 ° C. (2S) -2-[(4-chlorophenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [2] [2S] -2-[(4-chlorophenoxy) methyl] obtained using the same procedure as in Example 5 at −78 ° C. 1,3] Oxazole-6-carbonitrile (Compound 144: 2.04 g) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added iodomethane (5.25 g) at −78 ° C., and the mixture was stirred at the same temperature for 1 hour, and then stirred for 3.5 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture at 0 ° C., ethyl acetate was added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted once with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70 / 30-30 / 70; v / v) to obtain the title compound (Compound 124: 1.21 g, pale yellow solid).

Example 12: (2S) -2-[(biphenyl-4-yloxy) methyl] -5- [6- (propan-2-yloxy) pyridin-3-yl] -2,3-dihydroimidazo [2,1 -b] [1,3] Oxazole (Compound 108) Synthesis (2S) -2-[(4-Chlorophenoxy) methyl] -5- [6- (6) obtained using the same procedure as in Example 4. Propan-2-yloxy) pyridin-3-yl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 101: 100 mg), phenylboronic acid (41 mg), (1 , 3-Bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride (18 mg) and potassium carbonate (107 mg) in toluene / ethanol / water (3/3/2; (v / v / v, 1.0 mL) The suspension was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90 / 10-0 / 100; v / v) to obtain the title compound (Compound 108: 48 mg, colorless solid).

Example 13: (2S) -2-[(biphenyl-4-yloxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile ( Synthesis of Compound 125) (2S) -2-[(4-Chlorophenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] obtained in Example 11 Oxazole-6-carbonitrile (compound 124: 150 mg), phenylboronic acid (82 mg), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride (35 mg) and potassium carbonate (215 mg) in toluene / ethanol / water (3/3/2; v / v / v, 2.9 mL) were stirred at 100 ° C. for 1 hour in a nitrogen atmosphere. Phenylboronic acid (107 mg), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride (140 mg) were added, and the mixture was stirred for 1 hour. The mixture was allowed to cool to room temperature, filtered through Celite (registered trademark), water and ethyl acetate were added to the filtrate, and then the organic layer and the aqueous layer were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70/30 to 10/90; v / v) to obtain the title compound (Compound 125: 80 mg, colorless solid).

Example 14: (2S) -2-{[(2'-chlorobiphenyl-4-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] Synthesis of Oxazole-6-carbonitrile (Compound 160) (a) (2S) -2-[(4-Chlorophenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2] obtained in Example 11 , 1-b] [1,3] oxazole-6-carbonitrile (compound 124: 600 mg), bis (pinacolato) diboron (631 mg), tris (dibenzylideneacetone) dipalladium (0) (95 mg), A suspension of 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (197 mg) and potassium acetate (609 mg) in 1,4-dioxane (12 mL) at 110 ° C under nitrogen atmosphere Stir for 21 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90 / 10-40 / 60; v / v) and (2S) -5-methyl-2-{[4- (4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile ( 445 mg, pale brown amorphous).
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.34 (s, 12 H), 2.34 (s, 3 H), 4.17-4.36 (m, 4 H), 5.56-5.62 (m, 1 H), 6.86-6.89 (m, 2 H), 7.74-7.78 (m, 2 H); ESI / APCI MS m / z 382 [M + H] +
(B) The obtained (2S) -5-methyl-2-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl} -2 , 3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (150 mg), 2-bromochlorobenzene (90 mg), tetrakistriphenylphosphine palladium (0) (45 mg) and A suspension of cesium carbonate (384 mg) in toluene / ethanol / water (3/3/2; v / v / v, 3 mL) was stirred at 100 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90 / 10-30 / 70; v / v) to give a pale yellow oil. The pale yellow oil was recrystallized (hexane / ethyl acetate) to obtain the title compound (Compound 160: 73 mg, colorless solid).

Example 15: (2S) -5-methyl-2-{[(4'-methylbiphenyl-4-yl) oxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] Synthesis of Oxazole-6-carboxamide (Compound 136) (2S) -5-Methyl-2-{[(4'-methylbiphenyl-4-yl) oxy] methyl obtained using the same procedure as in Example 13 } -2,3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 133: 57 mg) in methanol (8 mL) suspension in 1M sodium hydroxide aqueous solution (8 mL) was added, and the mixture was stirred at 100 ° C. for 3.5 days. The reaction mixture was allowed to cool to room temperature, neutralized with 1M hydrochloric acid, water and chloroform / methanol (9/1; v / v) were added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform / methanol (9/1; v / v). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: chloroform / methanol = 90/10; v / v) to obtain the title compound (Compound 136: 18 mg, colorless solid).

Example 16: (2S) -2-[(4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (Compound 39) Synthesis (2S) -2-[(4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] obtained using the same procedure as in Example 5 To a suspension of oxazole-6-carbonitrile (compound 7: 291 mg) in methanol (4 mL) was added 1M aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at 85 ° C. for 4.5 hours. The reaction mixture was allowed to cool to room temperature, neutralized with 1M hydrochloric acid, water and chloroform / methanol (9/1; v / v) were added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform / methanol (9/1; v / v). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue and stirred for 16 hours, and then the precipitate was collected by filtration and dried to give the title compound (Compound 39: 175 mg, colorless solid).

Example 17: (2S) -2-[(4-tert-Butylphenoxy) methyl] -5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide ( Synthesis of Compound 139) (a) n-Butyllithium (2.6 M hexane solution, 0.39 mL) was added to a solution of diisopropylamine (102 mg) in tetrahydrofuran (2 mL) at −78 ° C., and the temperature was raised to 0 ° C. Stir for minutes. (2S) -2-[(4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] was obtained on the reaction mixture at −78 ° C. using the same procedure as in Example 5. ] A solution of [1,3] oxazole-6-carbonitrile (Compound 7: 200 mg) in tetrahydrofuran (2 mL) was added and stirred at the same temperature for 30 minutes. To the reaction mixture was added iodoethane (525 mg) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes, and then stirred for 2 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, ethyl acetate was added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted once with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 80 / 20-40 / 60; v / v) and (2S) -2-[(4-tert-butylphenoxy) methyl]- 5-Ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (45 mg, yellow oil) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.24-1.33 (m, 12 H), 2.72 (q, J = 7.4 Hz, 2 H), 4.17-4.22 (m, 1 H), 4.25-4.30 (m, 3 H), 5.53-5.59 (m, 1 H), 6.80-6.84 (m, 2 H), 7.29-7.34 (m, 2 H); ESI MS m / z 326 [M + H] +
(B) The obtained (2S) -2-[(4-tert-butylphenoxy) methyl] -5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- The title compound (Compound 139) was obtained using carbonitrile in the same manner as in Example 16.

Example 18: (2S) -5-butyl-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide ( Synthesis of Compound 140) (a) (2S) -5-Butyl-2-[(4-tert-butylphenoxy) methyl] was performed in the same manner as in Example 17 (a) using iodobutane instead of iodoethane. -2,3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.96 (t, J = 7.4 Hz, 3 H), 1.30 (s, 9 H), 1.37-1.44 (m, 2 H), 1.58-1.65 (m, 2 H ), 2.66-2.71 (m, 2 H), 4.16-4.20 (m, 1 H), 4.23-4.32 (m, 3 H), 5.53-5.59 (m, 1 H), 6.80-6.83 (m, 2 H ), 7.30-7.34 (m, 2 H); ESI MS m / z 354 [M + H] +
(B) The obtained (2S) -5-butyl-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- The title compound (Compound 140) was obtained using carbonitrile in the same manner as in Example 16.

Example 19: (2S) -2-[(4-tert-Butylphenoxy) methyl] -N, N-dimethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- Synthesis of Carboxamide (Compound 45) After adding dimethyl sulfoxide (3 mL) to potassium hydroxide (103 mg) and stirring at room temperature for 15 minutes, (2S) -2-[(4-tert) obtained in Example 16 was obtained. -Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound 39: 75 mg) and iodomethane (0.030 mL) were added, and the mixture was stirred at room temperature for 18.5 hours Stir. Water and chloroform were added to the reaction mixture, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: ethyl acetate / methanol = 90/10; v / v) to give a colorless oil. This colorless oil was recrystallized (hexane / diethyl ether) to give the title compound (Compound 45: 8 mg, colorless solid).

Example 20: (2S) -2-[(biphenyl-4-yloxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound 116) Synthesis of (2S) -2-[(4-chlorophenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] obtained using the same method as in Example 16 [1,3] Oxazole-6-carboxamide (Compound 106: 13 mg), phenylboronic acid (7 mg), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) chloride A suspension of palladium (II) (3 mg) and potassium carbonate (17 mg) in toluene / ethanol / water (3/3/2; v / v / v, 1 mL) at 100 ° C for 2 hours under nitrogen atmosphere Stir. Further, phenylboronic acid (7 mg) and (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride (3 mg) were added and stirred at 100 ° C. for 1 hour. did. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: chloroform / methanol = 90/10; v / v) to obtain the title compound (Compound 116: 4 mg, colorless solid).

Example 21: 1-{(2S) -2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-5-yl} ethanone Synthesis of (Compound 50) (2S) -5-Bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1 obtained in Example 1 , 3] oxazole (compound 2: 100 mg), tributyl (1-ethoxyvinyl) tin (103 mg), tetrakistriphenylphosphine palladium (0) (33 mg) and cesium fluoride (43 mg) N, N- A suspension of dimethylformamide (1 mL) was stirred at 120 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was ice-cooled, 1M hydrochloric acid (1 mL) was added, and the mixture was stirred at 0 ° C. for 1 hr, and then stirred for 12 hr while warming to room temperature. Water, saturated brine and ethyl acetate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70/30 to 20/80; v / v) to give a colorless oil. This colorless oil was recrystallized (hexane / diethyl ether) to give the title compound (Compound 50: 16 mg, colorless solid).

Example 22: (2S) -2-[(4-tert-Butylphenoxy) methyl] -6- (methylsulfonyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 42) Synthesis of (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3 obtained in Example 1 ] Oxazole (compound 3: 150 mg), sodium methanesulfinate (52 mg), L-proline (9.8 mg), copper (I) iodide (8.1 mg), sodium hydroxide (3.4 mg) dimethyl sulfoxide (1.5 mg) mL) The suspension was stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted once with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: hexane / ethyl acetate = 50/50; v / v) to obtain the title compound (Compound 42: 7 mg, colorless solid). .

Example 23: (2S) -2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbaldehyde (Compound 37) (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole obtained in Example 1 N-Butyllithium (2.6 M hexane solution, 5.48 mL) was added to a solution of (Compound 3: 5.00 g) in tetrahydrofuran (100 mL) at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. N, N-dimethylformamide (3.12 g) was added at −78 ° C., stirred at the same temperature for 30 minutes, and then stirred for 13 hours while warming to room temperature. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture at room temperature, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: ethyl acetate) to give a yellow solid. Ethyl acetate / diethyl ether (2 mL / 11 mL) was added to the yellow solid and stirred for 16 hours. The precipitate was collected by filtration and dried to give the title compound (Compound 37: 483 mg, colorless solid).

Example 24: {(2S) -2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-6-yl} methanol (compound 41) Synthesis of (2S) -2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 obtained in Example 23 -To a solution of carbaldehyde (Compound 37: 183 mg) in ethanol (2 mL) was added sodium borohydride (23 mg) at 0 ° C, and the mixture was stirred at the same temperature for 50 min. Water, saturated brine and ethyl acetate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 97/3 to 93/7; v / v) to obtain the title compound (Compound 41: 54 mg, colorless solid).

Example 25: (2S) -2-[(4-tert-Butylphenoxy) methyl] -6- (methoxymethyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 55) Synthesis of {(2S) -2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- obtained in Example 24 To a suspension of 6-yl} methanol (Compound 41: 154 mg) and sodium carbonate (270 mg) in chloroform (2 mL) was added thionyl chloride (0.041 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1.5 hours. . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Sodium methoxide (8 mg) was added to a methanol (2 mL) solution of the residue at room temperature, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: ethyl acetate) to obtain the title compound (Compound 55: 9 mg, pale yellow solid).

Example 26: (2S) -2-[(4-tert-Butylphenoxy) methyl] -6-ethenyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 44) Synthesis (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (1) obtained in Example 1 Compound 3: 200 mg), tributylvinyltin (0.182 mL), and a suspension of tetrakistriphenylphosphine palladium (0) (132 mg) in toluene (2 mL) were stirred at 100 ° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris NH, mobile phase: hexane / ethyl acetate = 80/20 to 70/30; v / v) to obtain a yellow solid. The obtained yellow solid was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 80 / 20-50 / 50; v / v) to obtain the title compound (Compound 44: 91 mg, colorless solid). It was.

Example 27: (2S) -2-[(4-tert-Butylphenoxy) methyl] -6-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 48) Synthesis (2S) -2-[(4-tert-Butylphenoxy) methyl] -6-ethenyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole obtained in Example 26 ( Compound 44: 43 mg) in a methanol (1 mL) solution was added 10% palladium carbon (20 mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 80/20 to 70/30; v / v) to obtain the title compound (Compound 48: 33 mg, colorless solid).

Example 28: (2S) -2-[(4-tert-Butylphenoxy) methyl] -6-ethenyl-5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole ( Synthesis of Compound 56) (a) n-Butyllithium (2.6 M hexane solution, 3.54 mL) was added to a solution of diisopropylamine (953 mg) in tetrahydrofuran (20 mL) at -78 ° C, and the temperature was raised to 0 ° C. Stir for minutes. The (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [2S] -6-bromo-2-[(4-tert-butylphenoxy) methyl] obtained in Example 1 was added to the reaction mixture at −78 ° C. 1,3] Oxazole (Compound 3: 2.7 g) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added iodoethane (2.94 g) at −78 ° C., and the mixture was stirred at the same temperature for 5 minutes, and then stirred for 15 minutes while warming to 0 ° C. and overnight while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, ethyl acetate was added, and then the organic layer and the aqueous layer were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90/10 to 70/30; v / v) and (2S) -6-bromo-2-[(4-tert-butylphenoxy ) Methyl] -5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (2.4 g, yellow solid) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.14-1.19 (m, 3 H), 1.30 (s, 9 H), 2.51-2.56 (m, 2 H), 4.09-4.14 (m, 1 H), 4.20 -4.30 (m, 3 H), 5.45-5.50 (m, 1 H), 6.81-6.86 (m, 2 H), 7.30-7.33 (m, 2 H)
(B) The obtained (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] The title compound (Compound 56) was obtained using oxazole in the same manner as in Example 26.

Example 29: (2S) -2-[(4-tert-butylphenoxy) methyl] -5,6-diethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 62 )) The (2S) -2-[(4-tert-butylphenoxy) methyl] -6-ethenyl-5-ethyl-2,3-dihydroimidazo [2,1-b] [2,1] obtained in Example 28 1,3] Oxazole (Compound 56) was used in the same manner as in Example 27 to obtain the title compound (Compound 62).

Example 30: 5-methyl-2-[({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) methyl] -2,3-dihydroimidazo [2,1-b] [ Synthesis of 1,3] oxazole-6-carbonitrile (Compound 171) 2- (Hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1] obtained in the same manner as in Production Example 4. -b] [1,3] oxazole-6-carbonitrile (intermediate 10: 20 mg), 2-bromo-5- (4-trifluoromethylphenyl) pyridine (34 mg), palladium acetate (3 mg), A suspension of [1,1′-binaphthalene] -2-yldi-tert-butylphosphine (5 mg) and cesium carbonate (109 mg) in toluene (1 mL) was stirred at 110 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90/10 to 70/30; v / v) to give a colorless oil. The colorless oil was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: hexane / ethyl acetate = 50/50; v / v) to give the title compound (Compound 171: 5 mg, colorless oil) )

Example 31: (2S) -2-[(4-tert-butylphenoxy) methyl] -6-chloro-5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [ 1,3] Synthesis of Oxazole (Compound 76) (2S) -2-[(4-tert-Butylphenoxy) methyl] -5- (pyridin-3-yl) obtained using the same method as in Example 4 ) -2,3-Dihydroimidazo [2,1-b] [1,3] oxazole (Compound 13: 16 mg) in chloroform (1 mL) was ice-cooled and N-chlorosuccinimide (7 mg) And stirred at the same temperature for 40 minutes and at 60 ° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: ethyl acetate) to obtain the title compound (Compound 76: 8 mg, colorless solid).

Example 32: 2-[(4-Cyclopropylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 96) Synthesis of 4-methylbenzenesulfonic acid [5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] obtained in Production Example 6 To a solution of methyl (intermediate 12: 110 mg) in acetonitrile (2.0 mL) was added a mixture of 4-cyclopropylphenol and 4-ethenylphenol (44 mg) and cesium carbonate (193 mg), and then at 85 ° C for 2 hours. Stir. The reaction mixture was allowed to cool to room temperature, water and chloroform were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform, and the organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 100/0 to 90/10; v / v) to give the title compound (Compound 96: 35 mg, colorless solid) and 2-[(4- Ethenylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (12 mg, colorless solid) was obtained.
2-[(4-Ethenylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole
1H NMR (600 MHz, CHLOROFORM-d) δppm 4.31-4.45 (m, 3 H), 4.51-4.56 (m, 1 H), 5.14-5.18 (m, 1 H), 5.59-5.67 (m, 2 H) , 6.62-6.69 (m, 1 H), 6.84-6.90 (m, 2 H), 6.99-7.03 (m, 1 H), 7.28-7.33 (m, 1 H), 7.33-7.38 (m, 2 H) , 7.68-7.73 (m, 1 H), 8.47-8.50 (m, 1 H), 8.68-8.72 (m, 1 H); ESI / APCI MS m / z 320 [M + H] +

Example 33: 2-[(4-Ethylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 100) Synthesis 2-[(4-Ethenylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole obtained in Example 32 10% Palladium carbon (5 mg) was added to a solution of (12 mg) in methanol (0.5 mL), and the mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with ethanol / ethyl acetate to give the title compound (Compound 100: 12 mg, pale pink solid).

Example 34: 5-{(2S) -2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-5-yl} pyridine Synthesis of -2 (1H) -one (Compound 38) (2S) -5- [6- (Benzyloxy) pyridin-3-yl] -2-[( 4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 33: 110 mg) was added trifluoroacetic acid (1.0 mL) and 40-45 ° C. For 45 minutes. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8. Water and chloroform were added, and the organic layer and the aqueous layer were separated. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 100/0 to 90/10; v / v) to obtain the title compound (Compound 38: 7 mg, colorless solid).

Example 35: 6-Bromo-5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole (Compound 173) (a) (2S)-(+)-Glycidyl tosylate (2.48 g) and 2,5-dibromo-4-methylimidazole (1.00 g) To a N, N-dimethylformamide (20 mL) solution was added cesium carbonate (3.34 g), and the mixture was stirred with heating at 50 ° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (Reveleris NH, mobile phase: chloroform / methanol = 100/0 to 50/50; v / v) and column chromatography (Reveleris, mobile phase: chloroform / methanol = 100/0 to 50/50; v / v) to give 2,4-dibromo-5-methyl-1- (oxiran-2-ylmethyl) -1H-imidazole (976 mg, colorless oil).
1H NMR (200 MHz, CHLOROFORM-d) δppm 2.18 (s, 3 H), 2.57-2.66 (m, 1 H), 2.80-2.87 (m, 1 H), 3.17-3.29 (m, 1 H), 4.07 -4.28 (m, 2 H); ESI / APCI MS m / z 295 [M + H] +
(B) The obtained 2,4-dibromo-5-methyl-1- (oxiran-2-ylmethyl) -1H-imidazole (795 mg) and 4- (2,2,2-trifluoro-1,1- Sodium hydride (162 mg) was added to a solution of (dimethylethyl) phenol (576 mg) in N, N-dimethylformamide (8.0 mL) under ice cooling, and the mixture was stirred at 70 ° C. for 3.5 hours. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added under ice cooling, and the organic layer and aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris NH, mobile phase: chloroform / methanol = 90 / 10-50 / 50; v / v) to obtain the title compound (Compound 173: 752 mg, colorless solid).

Example 36: 5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] Synthesis of Oxazole-6-carbonitrile (Compound 180) 4-Methylbenzenesulfonic acid [6-cyano-5-methyl-2,3-dihydroimidazo [2,1] obtained in Production Example 7 -b] [1,3] oxazol-2-yl] methyl (Intermediate 13: 130 mg) in acetonitrile (2.6 mL) in 4- (1,1,1-trifluoro-2-methylpropane-2- Yl) phenol (88 mg) and cesium carbonate (254 mg) were added, and the mixture was stirred at 80 ° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and then the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 50 / 50-40 / 60; v / v) and preparative HPLC to give the title compound (Compound 180: 79 mg, colorless amorphous) It was.

Example 37: 5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b Synthesis of] [1,3] oxazole-6-carboxamide (Compound 181) 5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropane-2) obtained in Example -Yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (compound 180: 55 mg) in 1,4-dioxane (1 mL) A 2M aqueous sodium hydroxide solution (1 mL) was added to the suspension, and the mixture was stirred at 100 ° C. for 2.5 days. The reaction mixture was allowed to cool to room temperature, neutralized with 1M aqueous hydrochloric acid solution, water and chloroform / methanol (9/1; v / v) were added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform / methanol (9/1; v / v). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: chloroform / methanol = 100/0 to 95/5; v / v) to obtain the title compound (compound 181: 29 mg, colorless solid).

Example 38: 2-{[4- (2-hydroxypropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 -Synthesis of carbonitrile (compound 210)
A solution of 2-[(4-acetylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (20 mg) in tetrahydrofuran (1 mL) was added. The mixture was cooled in a dry ice / acetone bath, and methylmagnesium bromide (about 3M tetrahydrofuran solution, 0.045 mL) was added dropwise. After stirring at the same temperature for 30 minutes, under ice-cooling for 40 minutes, at room temperature for 2.5 hours, and at 50 ° C. for 1 hour, methylmagnesium bromide (0.045 mL) was further added and stirred for 3 hours. The mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (preparative TLC plate, mobile phase: chloroform / methanol = 90/10; v / v) and preparative HPLC to give the title compound (compound 210: 8 mg, colorless solid) Got.

Example 39: 5-methyl-2-({[5- (trifluoromethyl) pyrimidin-2-yl] oxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole Synthesis of -6-carbonitrile (compound 217)
2- (Hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (50 mg) and 2-chloro-5- (trifluoromethyl) A solution of pyridine (62 mg) in DMF (1.0 mL) was ice-cooled, sodium hydride (about 60%, 14 mg) was added, and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, water was added, and the mixture was extracted with chloroform. After the organic layer was concentrated under reduced pressure, the residue was purified by preparative HPLC to obtain the title compound (Compound 217: 80 mg, colorless solid).

Example 40: (2S) -5-ethyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3- Synthesis of dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound 253)
(2S) -5-ethyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carbonitrile (246 mg) in dimethyl sulfoxide (1.2 mL) was added potassium carbonate (171 mg). After cooling with ice, hydrogen peroxide (about 35%, 0.6 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. Further, aqueous hydrogen peroxide (1.2 mL) was added, and the mixture was stirred overnight at room temperature. After cooling with ice, an aqueous sodium thiosulfate solution was added to stop the reaction. Water was added to the reaction mixture, and the mixture was extracted with chloroform. After the organic layer was concentrated under reduced pressure, the residue was purified by preparative HPLC to obtain the title compound (Compound 253: 135 mg, colorless solid).

Example 41: (2S) -5- (2-Fluoroethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3 -Synthesis of dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 239) (a) Synthesized using the same method as Example 48 described later (2S) -5- Bromo-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] A solution of oxazole-6-carbonitrile (compound 250: 126 mg) in tetrahydrofuran (2.5 mL) was cooled to −78 ° C., n-butyllithium (2.64 M hexane solution, 144 μL) was added, and the same temperature was maintained for 30 minutes. Stir. Ethylene oxide (1.4 M toluene solution, 627 μL) was added and stirred at the same temperature for 30 minutes. After stirring for 2 hours while gradually raising the temperature, a saturated aqueous solution of ammonium chloride was added. After adding water and extracting with chloroform, the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC and (2S) -5- (2-hydroxyethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] Methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (11 mg) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.51-1.56 (m, 6 H), 2.92 (t, J = 5.6 Hz, 2 H), 3.92 (t, J = 5.6 Hz, 2 H), 4.22- 4.44 (m, 5 H), 5.50-5.60 (m, 0 H), 6.79-6.93 (m, 2 H), 7.34-7.48 (m, 2 H)
(B) (2S) -5- (2-hydroxyethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3- To a solution of dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (11 mg) in chloroform (226 μL) was added N, N-diethylaminosulfur trifluoride (4.2 μL) and stirred for 5 hours. did. The reaction solution was purified by preparative HPLC to obtain the title compound (Compound 239: 2.8 mg, colorless amorphous).

Example 42: 5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b Optical resolution of] [1,3] oxazole-6-carboxamide 5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) obtained in Example 37 Phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (Compound 181: 480 mg) was subjected to the racemic analysis conditions described above (Rt1 = 5.2 min, Rt2 = The compound 240 (Rt1 = 5.2 min, 247 mg) having a short relative retention time and the compound 238 (Rt2 = 6.1 min, 241 mg) having a long relative retention time were separated using a semi-preparative column based on 6.1 min). Obtained.

Example 43: 5-methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- Synthesis and optical resolution of 6-carboxamide (a) 4-methylbenzenesulfonic acid (6-carbamoyl-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] obtained in Production Example 8 ] Oxazol-2-yl) methyl (intermediate 14, 342 mg) and 4- [1- (trifluoromethyl) cyclopropyl] phenol (intermediate 23, 197 mg) obtained in Preparation Example 12 in acetonitrile (6.8 mL) ) Cesium carbonate (634 mg) was added to the solution and stirred at 80 ° C. for 3 hours. After allowing to cool, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 5-methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [ 1,3] Oxazole-6-carboxamide (202 mg, colorless solid) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.94-1.03 (m, 2 H), 1.28-1.37 (m, 2 H), 2.52 (s, 3 H), 4.14 (dd, J = 9.7, 6.4 Hz , 1 H), 4.20-4.34 (m, 3 H), 5.14 (br. S., 1 H), 5.49-5.61 (m, 1 H), 6.82-6.92 (m, 2 H), 7.39 (d, (J = 8.7 Hz, 2 H)
(B) 5-methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 -Carboxamide (400 mg) was resolved using a semi-preparative column based on the aforementioned racemic analysis conditions (Rt1 = 5.5 min, Rt2 = 6.3 min), and compound 241 (Rt1 = 5.5 min) having a short relative retention time 139 mg).

Example 44: 2-{[3-chloro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carboxamide optical resolution 2-{[3-chloro-4- (1,1,1-trifluoro) obtained using the same method as in Example 15 -2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound 235: 40 mg) as described above Was separated using a semi-preparative column based on the racemic analysis conditions (Rt1 = 4.6 min, Rt2 = 5.9 min) to obtain Compound 242 (Rt1 = 4.6 min, 18 mg) having a short relative retention time.

Example 45: 2-{[3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carboxamide optical resolution 2-{[3-fluoro-4- (1,1,1-trifluoro) obtained using the same method as in Example 15 -2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound 234: 40 mg) as described above Was separated using a semi-preparative column based on the racemic analysis conditions (Rt1 = 4.3 min, Rt2 = 5.1 min) to obtain Compound 244 (Rt1 = 4.3 min, 22 mg) having a short relative retention time.

Example 46: 2-{[4- (2-cyanopropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 -Carboxamide Synthesis and Optical Resolution (a) Cesium carbonate (201 mg) was added to a solution of intermediate 14 (109 mg) and 2- (4-hydroxyphenyl) -2-methylpropanenitrile (75 mg) in acetonitrile (2.2 mL). , And stirred at 80 ° C. for 3 hours. After allowing to cool, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-{[4- (2-cyanopropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1 , 3] Oxazole-6-carboxamide (colorless solid) was obtained.

  (B) 2-{[4- (2-cyanopropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] obtained by the method of (a) [1,3] Oxazole-6-carboxamide (109 mg) was resolved using a semi-preparative column based on the aforementioned racemic analysis conditions (Rt1 = 4.8 min, Rt2 = 7.0 min), and the relative retention time was short. Compound 245 (Rt1 = 4.8 min, 9 mg) was obtained.

Example 47: 2-{[(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] Synthesis and optical resolution of [1,3] oxazole-6-carboxamide (a) Intermediate 14 (113 mg) and 1,1-dimethyl-2,3-dihydro-1H-inden-5-ol (63 mg) of acetonitrile Cesium carbonate (210 mg) was added to the (2.3 mL) solution, and the mixture was stirred at 80 ° C. for 5 hours. After allowing to cool, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and 2-{[(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (77 mg, colorless solid) was obtained.

  (B) 2-{[(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl) oxy] methyl} -5-methyl-2, obtained using the method of (a), Semi-preparative column of 3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (73 mg) based on the aforementioned racemic analysis conditions (Rt1 = 3.5 min, Rt2 = 4.2 min) To obtain Compound 246 (Rt1 = 3.5 min, 36 mg) having a short relative retention time.

Example 48: ((2S) -5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ Synthesis of 2,1-b] [1,3] oxazole-6-carbonitrile (Compound 243) (a) 4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenol (6 .73 g) was dissolved in water (16.8 mL), sodium hydroxide (1.45 g) and (2R) -2- (chloromethyl) oxirane (5.2 mL) were added, and the mixture was stirred at 70 ° C. for 13 hours. After cooling, water was added to the reaction solution, followed by extraction with chloroform, and then the organic layer was concentrated under reduced pressure.The residue was subjected to column chromatography (YMC-NH, mobile phase: hexane / ethyl acetate = 100/0 to 85/15; v / v) and purified (2S) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} oxirane (5.03 g, colorless oil) A product was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.75 (dd, J = 5.0, 2.9 Hz, 1 H), 2.90 (t, J = 4.5 Hz, 1 H), 3.28-3.39 (m, 1 H), 3.96 (dd, J = 10.9, 5.6 Hz, 1 H), 4.21 (dd, J = 10.9, 3.1 Hz, 1 H), 6.84-6.93 (m, 2 H), 7.40 (d, J = 8.7 Hz, 2 H)
(B) (2S) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} oxirane (5.03 g) and 2-bromo-5-methyl Sodium acetate (3.17 g) was added to an ethanol solution of -1H-imidazole-4-carbonitrile (4.31 g), and the mixture was stirred at 90 ° C. for 5 hours. After allowing to cool, the solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with chloroform. After the organic layer was concentrated under reduced pressure, the obtained residue was dissolved in N, N-dimethylformamide (52 mL), sodium hydride (about 60%, 0.96 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Stir. The mixture was ice-cooled again, and a saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. Water was added to the reaction solution, followed by extraction with ethyl acetate / toluene (5: 1), and then the organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography (SNAP Cartridge KP-NH, mobile phase: hexane / ethyl acetate = 80 / 20-20 / 80; v / v, and Reveleris, mobile phase: chloroform / ethyl acetate = 80 / 20-60 / 40 V / v). A part of the crude product was purified by preparative HPLC to obtain the title compound (Compound 243: 233 mg, colorless amorphous).

Example 49: (2S) -5-cyclopropyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3 Synthesis of 2-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 252) (2S) -5-Bromo-2- obtained using the same procedure as Example 48 {[3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] To a solution of oxazole-6-carbonitrile (Compound 249: 795 mg) in tetrahydrofuran (12 mL) was added cyclopropylzinc bromide (0.5 M tetrahydrofuran solution, 5.3 mL) and tetrakistriphenylphosphine palladium (0) (205 mg). The mixture was stirred at 100 ° C. for 1 hour under wave irradiation. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: chloroform / ethyl acetate = 85 / 15-60 / 40; v / v) and preparative HPLC. A compound (Compound 252: 305 mg, colorless amorphous) was obtained.

Example 50: (2S) -2-[(4-tert-butyl-3-fluorophenoxy) methyl] -5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole- Synthesis of 6-carbonitrile (Compound 257) (2S) -5-Bromo-2-[(4-tert-butyl-3-fluorophenoxy) methyl] -2 obtained using the same method as in Example 48 , 3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 256: 415 mg) in tetrahydrofuran (4.2 mL) was cooled to −78 ° C. and cooled to n-butyllithium ( 2.69 M hexane solution, 0.39 mL) was added dropwise. After stirring at the same temperature for 30 minutes, ethyl iodide (819 mg) was added, and the mixture was stirred at the same temperature for 1 hour and further at 0 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 90 / 10-50 / 50; v / v) to give the title compound (Compound 257 99 mg) and (2S) -2-[(4-tert-butyl-3-fluorophenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 259: 30 mg) was obtained.

Example 51: (2S) -5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2 , 1-b] [1,3] Oxazole-6-carboxylic acid (Compound 264) To a solution of Compound 240 (50 mg) in trifluoroacetic acid / water (260 μL / 130 μL) was added sodium nitrite (32 mg) at room temperature. For 2 hours. Water was added to the reaction solution, followed by extraction with a 10% methanol / chloroform solution, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by preparative HPLC to give the title compound (Compound 264: 21 mg, colorless amorphous).

Example 52: (2S) -5-[(1E) -prop-1-en-1-yl] -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl ) Synthesis of Phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 269). Obtained using a method similar to Example 48 ( 2S) -5-Bromo-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carbonitrile (Compound 250: 136 mg) in 1,4-dioxane (2.7 mL) was added to cesium fluoride (144 mg), tris (dibenzylideneacetone) dipalladium (0) (29 mg). ), Tri-tert-butylphosphine (7.4 μL) and allyltributyltin (146 μL) were added, and the mixture was stirred at 100 ° C. overnight. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (Compound 269: 16 mg).

Example 53: (2S) -5- (trifluoromethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3- Synthesis of dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (compound 279) 2- (Fluorosulfonyl) acetic acid methyl ester (152 μL) and copper iodide (227 mg) were added, and the mixture was stirred at 160 ° C. for 45 minutes under microwave irradiation. After allowing to cool, the insoluble material was filtered off, and the filtrate was purified by preparative HPLC to give the title compound (Compound 279: 60 mg).

Example 54: (2S) -5- (3-hydroxypropyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3 Synthesis of 2-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 282) (a) Using a method similar to that in Example 4, from Compound 250 (207 mg) to (2S) -5-[(1E) -3-{[tert-butyl (dimethyl) silyl] oxy} prop-1-en-1-yl] -2-{[4- (1,1,1-trifluoro-2 -Methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (145 mg) was obtained.

  (B) (2S) -5-[(1E) -3-{[tert-butyl (dimethyl) silyl] oxy} prop-1-en-1-yl] -2-{[4- (1,1,1, 1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (145 mg) in methanol (2 .9 mL) solution was added palladium-activated carbon (29 mg) and stirred for 3 days under hydrogen atmosphere. LC / MS analysis confirmed the formation of a compound from which the tert-butyldimethylsilyl group had been removed at this point. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (Compound 282: 68 mg).

Example 55: (2S) -5-methyl-2-({[1- (propan-2-yl) -1H-indol-5-yl] oxy} methyl) -2,3-dihydroimidazo [2,1 -b] [1,3] Oxazole-6-carbonitrile (Compound 289) (a) Using a method similar to Example 10, using intermediate 17 (40 mg) to (2S) -2-[(1H -Indol-5-yloxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (13 mg) was obtained.

  (B) (2S) -2-[(1H-Indol-5-yloxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile Sodium hydride (about 60%, 4 mg) was added to a solution of (13 mg) in N, N-dimethylformamide (0.5 mL) and stirred for 5 minutes. 2-Iodopropane (8 mg) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the residue was subjected to column chromatography (SNAP cartridge HP-Sil, mobile phase: chloroform / methanol = 100/0 to 90/10; v / v). To give the title compound (Compound 289: 6 mg).

Example 56: (2S) -5- (3-chloropropyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3 Of 2-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 290) Thionyl chloride in pyridine (1.8 mL) solution of Compound 282 (92 mg) obtained in Example 54 (33 μL) was added and stirred for 5 hours. The reaction solution was purified by preparative HPLC to obtain the title compound (Compound 290: 16 mg).

Example 57: (2S) -5- (3,3-difluoropropyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2 , 3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 291) (a) Compound 1,282 (109 mg) in chloroform (1.1 mL) in 1,1, 1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (170 mg) was added and stirred for 1 hour. 1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (339 mg) was added, and the mixture was further stirred for 5 hours. After the reaction solution was ice-cooled, an aqueous sodium thiosulfate solution was added to stop the reaction. Water was added to the reaction solution, followed by extraction with chloroform, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was concentrated under reduced pressure, and (2S) -5- (3-oxopropyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (68 mg) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.56 (s, 6 H), 2.88-3.03 (m, 4 H), 4.24-4.38 (m, 4 H), 5.50-5.65 (m, 1 H), 6.81-6.92 (m, 2 H), 7.37-7.49 (m, 2 H), 9.82 (s, 1 H)
(B) (2S) -5- (3-oxopropyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3- To a solution of dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (68 mg) in chloroform (2.7 mL) was added N, N-diethylaminosulfur trifluoride (88 μL) and stirred for 2 hours. did. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (Compound 291, 20 mg).

Example 58: (2S) -5- (3-ethoxypropyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3 -Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 292)
Sodium hydride (about 60%, 15 mg) and ethyl iodide (41 μL) were added to a solution of compound 282 (105 mg) in N, N-dimethylformamide (2.1 mL), and the mixture was stirred for 4 hours. Sodium hydride (about 60%, 31 mg) and ethyl iodide (82 μL) were added and stirred overnight. After cooling with ice, a saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. Water was added to the reaction solution, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (Compound 292, 66 mg).

Example 59: (2S) -5- (cyclopropylcarbonyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3- Synthesis of dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 298) (a) A solution of Compound 250 (500 mg) in tetrahydrofuran (5.8 mL) was cooled to −78 ° C., n-Butyllithium (2.64 M hexane solution, 0.53 mL) was added and stirred for 1 hour. Cyclopropanecarboxaldehyde (174 μL) was added, and the mixture was stirred at −78 ° C. for 30 minutes and at 0 ° C. for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (SNAP Cartridge KP-NH, mobile phase: hexane / ethyl acetate = 20 / 80-0 / 100; v / v), (2S) − 5- [Cyclopropyl (hydroxy) methyl] -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2, 1-b] [1,3] oxazole-6-carbonitrile (366 mg) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.45-0.61 (m, 2 H), 0.65-0.78 (m, 2 H), 1.20-1.27 (m, 1 H), 1.55 (s, 6 H), 2.68-2.78 (m, 1 H), 4.18-4.24 (m, 1 H), 4.27-4.53 (m, 4 H), 5.54-5.65 (m, 1 H), 6.84-6.94 (m, 2 H), 7.40-7.46 (m, 2 H)
(B) (2S) -5- [cyclopropyl (hydroxy) methyl] -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2, A solution of 3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (30 mg) in chloroform (0.7 mL) was ice-cooled, and 1,1,1-triacetoxy-1, 1-Dihydro-1,2-benzoiodoxol-3- (1H) -one (45 mg) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain the title compound (Compound 298: 5.3 mg).

Example 60: 3-[(2S) -6-cyano-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydro Synthesis of imidazo [2,1-b] [1,3] oxazol-5-yl] propanoic acid (Compound 302) To a solution of Compound 282 (146 mg) in N, N-dimethylformamide (1.5 mL) pyridinium dichromate ( 268 mg) was added and stirred overnight. Chloroform and aqueous sodium hydroxide solution were added to the reaction solution and the phases were separated. Citric acid was added to the aqueous layer to adjust the pH to around 5, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (Compound 302: 66 mg).

Example 61: (2S) -5- (difluoromethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydro Synthesis of imidazo [2,1-b] [1,3] oxazole-6-carbonitrile (compound 225) (a) A solution of compound 250 (200 mg) in tetrahydrofuran (4 mL) was cooled to −78 ° C., and n-butyl Lithium (2.66 M hexane solution, 0.18 mL) was added and stirred for 10 minutes. N, N-dimethylformamide (102 mg) was added, and the mixture was stirred at 0 ° C. for 15 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Reveleris, mobile phase: hexane / ethyl acetate = 70 / 30-50 / 50; v / v). (2S) -5-formyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1 -b] [1,3] oxazole-6-carbonitrile (104 mg) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.56 (s, 6 H), 4.27-4.46 (m, 2 H), 4.52-4.67 (m, 2 H), 5.70-5.79 (m, 1 H), 6.82-6.90 (m, 2 H), 7.38-7.48 (m, 2 H), 9.79 (s, 1 H)
(B) (2S) -5-formyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2, 1-b] [1,3] oxazole-6-carbonitrile (210 mg) in chloroform (8.4 mL) was ice-cooled, bis (2-methoxyethyl) aminosulfur trifluoride (147 mg) was added, and the same temperature was added. For 30 minutes and at room temperature for 16.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography (Reveleris NH, mobile phase: hexane / ethyl acetate = 95/5 to 75/25; v / v, and Reveleris, mobile phase: hexane / ethyl acetate = 70/30 to 50/50; v / v. The product was purified in v) to obtain the title compound (Compound 225, 18 mg).

Example 62: (2S) -2-{[4- (7,7-difluorobicyclo [4.1.0] hept-1-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2, Synthesis of 1-b] [1,3] oxazole-6-carboxamide optically active compounds (compound 322 and compound 323) 4- (7,7-difluorobicyclo [4.1. 0] Hept-1-yl) phenol (intermediate 30:41 mg) was separated using a semi-preparative column based on the racemic analysis conditions (Rt1 = 2.1 min, Rt2 = 2.3 min). Using the respective isomers (isomers with a short retention time: 17 mg, isomers with a long retention time: 13 mg) and the intermediate 18 (27 mg, 20 mg) obtained in Production Example 11, the same method as in Example 10 The reaction was carried out. Compound 323 (16 mg) was obtained from phenol (Rt1 = 2.1 min) having a short retention time. In addition, Compound 322 (18 mg) was obtained from phenol (Rt2 = 2.3 min) having a long retention time.

Example 63: (2S) -5-[(dimethylamino) methyl] -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2, Synthesis of 3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 337) (2S) -5-formyl-2-{[ 4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (50 mg), dimethylamine (2M tetrahydrofuran solution, 0.132 mL), acetic acid (15 μL) in chloroform (0.3 mL) were stirred at room temperature for 1 hour. Triacetoxyborohydride (56 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. To the reaction solution was added 6M aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (preparative NH-TLC plate, mobile phase: hexane / ethyl acetate = 40/60; v / v, and preparative TLC plate, mobile phase. : Ethyl acetate only) to give the title compound (Compound 337: 14 mg).

Example 64: (2S) -2,5-dimethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo Synthesis of [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 348) (a) R-2-methylglycidyl-p-nosylate (5.0 g) and 2-bromo-5-methyl To a solution of −1H-imidazole-4-carbonitrile (3.4 g) in N, N-dimethylformamide (25 mL) was added potassium carbonate (3.3 g), and the mixture was stirred at 50 ° C. for 5.5 hours. After allowing to cool, the insoluble material was filtered off, water was added to the filtrate, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (Reveleris NH, mobile phase: hexane / ethyl acetate = 100/0 to 40/60; v / v) to give 2-bromo-5-methyl. -1-{[(2S) -2-methyloxiran-2-yl] methyl} -1H-imidazole-4-carbonitrile (1.93 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 3 H), 2.39 (d, J = 4.1 Hz, 1 H), 2.43 (s, 3 H), 2.66 (d, J = 4.1 Hz, 1 H), 4.03 (d, J = 15.3 Hz, 1 H), 4.23 (d, J = 15.3 Hz, 1 H)
(B) A solution of 4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenol (191 mg) in N, N-dimethylformamide (2 mL) was ice-cooled and sodium hydride (about 60 %, 35 mg) was added and stirred for 30 minutes. To the reaction solution, N, N-dimethylformamide of 2-bromo-5-methyl-1-{[(2S) -2-methyloxiran-2-yl] methyl} -1H-imidazole-4-carbonitrile (200 mg) ( 2 mL) solution was added and stirred at 50 ° C. for 4.5 hours. After ice cooling, a saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (Compound 348: 171 mg).

  Tables 2-1 to 2-59 show the structural formulas, compound names, and instrument data of the compounds shown in Examples 1 to 64 and compounds synthesized by the same method. The number described in the column of the example in the table indicates which compound was synthesized by the same method as in any of the above Examples 1 to 64.

Test Example 1 [ ³⁵ S] GTPγS binding test (1)
(Preparation of crude membrane fraction of CHO cells stably expressing rat metabotropic glutamate receptor (mGlu2))
Rat-type mGlu2 stably expressing CHO cells were mixed with Dulbecco's modified Eagle's medium containing 10% dialyzed fetal calf serum [1% proline, 50 units / mL penicillin, 50 μg / mL streptomycin, 1 mM sodium Pyruba.
te, 1 mM succinic acid, 2 mM L-glutamine (added when used)], and cultured at 37 ° C. under 5% CO ₂ . Confluent cells were washed twice with PBS (−), then detached with a cell scraper, and centrifuged at 4 ° C., 1,000 rpm for 5 minutes to collect the cells. The obtained precipitate was suspended in 20 mM HEPES buffer (pH 7.4), the suspension was homogenized with a homogenizer, and then centrifuged at 4 ° C., 48,000 × g for 20 minutes. Got sunk. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at −80 ° C.

([ ³⁵ S] GTPγS binding test)
The frozen membrane fraction prepared above was thawed before use, and a binding test buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , 8.4 μM GDP, 10 μg / mL saponin, 0.1% BSA) Diluted with
Example compounds were added to a membrane fraction of membrane protein 10 μg / assay and incubated at 30 ° C. for 20 minutes. Thereafter, glutamic acid (final concentration 3 μM) and [ ³⁵ S] GTPγS (final concentration 0.15 nM) were added, and incubation was performed at 30 ° C. for 1 hour. After incubation, the reaction solution was suction filtered onto a GF / C filter, and the GF / C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a scintillation cocktail was added to the filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.

In the above reaction, the amount of [ ³⁵ S] GTPγS binding obtained in the absence of glutamic acid is defined as the nonspecific binding amount, and the difference from the amount of [ ³⁵ S] GTPγS binding obtained in the presence of glutamic acid is defined as the specific binding amount. did. From the difference between 3 μM glutamic acid and the specific binding amount in the presence of each compound at various concentrations, the EC ₅₀ value of each compound was calculated by a regression curve using a nonlinear least square method.

Each Example compound acted on the rat mGlu2 receptor to enhance the receptor response. The EC ₅₀ values of the compounds of the present invention are exemplified in Table 3.

Test Example 2 [ ³⁵ S] GTPγS binding test (2)
(Preparation of crude membrane fraction of CHO cells stably expressing human metabotropic glutamate receptor (mGlu2))
Human-type mGlu2 stably expressing CHO cells were treated with Dulbecco's modified Eagle's medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 μg / mL streptomycin, 2 mM L-glutamine (when added), 400 μg / mL Hygromycin B (when used). Was added at the time of use)] at 37 ° C. under 5% CO ₂ . Confluent cells were washed twice with PBS (−), then detached with a cell scraper, and centrifuged at 4 ° C., 1,000 rpm for 5 minutes to collect the cells. The obtained precipitate was suspended in 20 mM HEPES buffer (pH 7.4), the suspension was homogenized with a homogenizer, and then centrifuged at 4 ° C., 48,000 × g for 20 minutes. Got sunk. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at −80 ° C.

([ ³⁵ S] GTPγS binding test)
The frozen membrane fraction prepared above was thawed before use, and a binding test buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , 8.4 μM GDP, 10 μg / mL saponin, 0.1% BSA) Diluted with Example compounds were added to a membrane fraction of membrane protein 10 μg / assay and incubated at 30 ° C. for 20 minutes. Thereafter, glutamic acid (final concentration 1 μM) and [ ³⁵ S] GTPγS (final concentration 0.15 nM) were added, and incubation was performed at 30 ° C. for 1 hour. After incubation, the reaction solution was suction filtered onto a GF / C filter, and the GF / C filter was washed with ice-cold 20 mM HEPES buffer (pH 7.4). After drying, a scintillation cocktail was added to the filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.

In the above reaction, the amount of [ ³⁵ S] GTPγS binding obtained in the absence of glutamic acid is defined as the nonspecific binding amount, and the difference from the amount of [ ³⁵ S] GTPγS binding obtained in the presence of glutamic acid is defined as the specific binding amount. did. From the difference between 1 μM glutamic acid and the specific binding amount in the presence of each compound at various concentrations, the EC ₅₀ value of each compound was calculated by a regression curve using a nonlinear least square method.

The EC ₅₀ values of the compounds of the present invention are exemplified in Table 4.

Test Example 3 Methamphetamine Induced Momentum Enhancement Test (Animal)
Seven-week-old male Wistar rats (Nippon Charles River Co., Ltd.) were used for the test. It was used for the test after preliminary breeding for 4 days or more in a breeding room in which temperature (23 ± 3 ° C.), humidity (50 ± 20%), and lighting (7:00 am-7: 00 pm) were controlled. Feed (MF: Oriental Yeast Co., Ltd.) and drinking water (sterilized water) were given freely. Animals that did not show gross abnormalities during the test were used.
This experiment was conducted with the approval of the Taisho Pharmaceutical Co., Ltd. Research Institute Animal Experimentation Ethics Committee.
(Method)
SCANET ((Yes) Merquest) was used as the momentum measuring device. A transparent acrylic box (45 × 28 × 30 cm) was used as a measurement cage.
On the day before the test, the animals were removed from the breeding room and acclimated to the laboratory. On the test day, the animals were individually placed in a measurement cage and acclimated for 60 minutes, followed by subcutaneous administration of methamphetamine (1 mg / kg), followed by 120 minutes of exercise. Data was analyzed using the total amount of exercise for 120 minutes.
Compound 231, Compound 243 and Compound 299 30 mg / kg were orally administered 60 minutes before administration of methamphetamine, and Compound 240 30 mg / kg was orally administered 120 minutes before administration of methamphetamine. The comparative control group was orally administered with a 0.5% methylcellulose solution. The administration volume was 2 mL / kg.
(result)
30 mg / kg of Compound 231, Compound 240, Compound 243 and Compound 299 significantly attenuated methamphetamine-induced hyperactivity.

  Treatment of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Or it becomes possible to provide a preventive agent.

Claims (18)

Formula (IA)

[In the formula (IA),
R ¹ represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), Optionally substituted with 1-3 groups selected from the group consisting of 4- to 8-membered cyclic amino, hydroxy, and C _1-6 alkoxy.), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, amino (wherein the amino is one or two groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, and C _1-6 alkanoyl) Optionally substituted)) 4-8 membered cyclic amino, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, hetero aryl (the aryl, and heteroaryl C _1-6 alkyl, halo C _1-6 A . Kill, and the C _3-8 optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl), or shows the carboxy;
R ² represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), 4- to 8-membered cyclic amino (the 4- to 8-membered cyclic amino may be substituted with 1 to 3 halogen atoms), imino, hydroxy, C _1-6 alkoxy, aryl, C _3-8 cyclo Optionally substituted with 1 to 3 groups selected from the group consisting of alkyl and carboxy)), halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl , Carbamoyl (the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, or heteroaryl (the aryl and heteroaryl are halogen atoms, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _3-8 cycloalkyl Carboxymethyl, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (said amino may be substituted by one or two C _1-6 alkyl.), Or 4-8 membered cyclic amino (said 4- to 8-membered cyclic amino may be substituted with 1 to 3 groups selected from the group consisting of 1 C _1-6 alkyl.), Pyridonyl (the pyridonyl is _May be substituted with one C _1-6 alkyl.), Tri C _1-6 alkylsilyl, arylcarbonyl, arylsulfonyl, C _3-8 cycloalkyl, C _2-6 alkenyl (the C _2-6 alkenyl). May be substituted with C _1-6 alkoxy), or C _3-8 cycloalkylcarbonyl;
R ³ is aryl, heteroaryl, or C _3-8 cycloalkyl (the aryl, heteroaryl, and C _3-8 cycloalkyl are halogen atoms, C _1-8 alkyl (the C _1-8 alkyl is cyano, Optionally substituted with 1 to 3 groups selected from the group consisting of hydroxy and aryl), halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is a halogen atom, _Optionally substituted with 1 to 5 groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and aryl.), C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, aryloxy, C _1-6 alkanoyl, aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 Sik With 1-3 substituents selected from the group consisting of alkyloxy and C _1-6 alkanoyl which may be substituted.), Heteroaryl (said heteroaryl halogen atom, C _1-6 alkyl, halo C _1-6 Optionally substituted with 1 to 3 groups selected from the group consisting of alkyl, C _1-6 alkoxy, and halo C _1-6 alkoxy.) 4-8 membered cyclic amino, pyridonyl (wherein pyridonyl is 1 may be substituted with pieces of C _1-6 alkyl.), cyclic ethers 4-8 membered cyclic ether (said 4-8 membered is optionally substituted with 1 to 3 C _1-6 alkyl. ), C _5-8 bicycloalkyl (the C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), adamantyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, and 1 to selected from the group consisting of arylcarbonyl May be substituted with 3 groups), quinolinonyl (which may be substituted with 1 C _1-6 alkyl), or indanyl (wherein indanyl is 1-3 C _1-6). Optionally substituted with alkyl);
R ⁴ represents a hydrogen atom or C _1-6 alkyl]
A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD comprising a dihydroimidazooxazole derivative represented by the formula: / HD medicine for prevention or treatment of diseases selected from the group consisting of HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. In the above formula (IA),
R ⁴ is a hydrogen atom, comprising the dihydroimidazoxazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, schizophrenia, Alzheimer's disease, cognitive impairment, A medicament for the prevention or treatment of a disease selected from the group consisting of dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. In the above formula (IA),
R ¹ is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of hydroxy and C _1-6 alkoxy) ), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl is substituted with 1 or 2 C _1-6 alkyl). Or a heteroaryl, which is substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and C _3-8 cycloalkyl. Good).
R ² is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is imino, hydroxy, C _1-6 alkoxy, aryl, and C _3-8 cycloalkyl). 1 to 3 groups)), halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl, aryl, or heteroaryl ( The aryl and heteroaryl are a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the amino is 1 Or may be substituted with 2 C _1-6 alkyls), or 4-8 membered cyclic amino (the 4-8 membered cyclic amino may be substituted with 1 C _1-6 alkyl). 1-3) selected from the group consisting of Substituted.), Pyridonyl (the pyridonyl may be substituted with one C _1-6 alkyl.), Tri C _1-6 alkyl silyl, C _3-8 cycloalkyl or C _3-8 Cycloalkylcarbonyl;
R ³ is aryl or heteroaryl (the aryl and heteroaryl are halogen atoms, C _1-8 alkyl (the C _1-8 alkyl is selected from the group consisting of cyano, hydroxy, and aryl). ), Halo C _1-6 alkyl, C _3-8 cycloalkyl (wherein the C _3-8 cycloalkyl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and Optionally substituted with 1 to 5 groups selected from the group consisting of aryl), C _1-6 alkoxy, halo C _1-6 alkoxy, aryl C _1-6 alkoxy, aryloxy, aryl (the aryl is May be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy), heteroaryl (the heteroaryl Is C _1-6 alkyl, and And optionally substituted with 1 to 3 groups selected from the group consisting of halo C _1-6 alkyl.) 4-8 membered cyclic amino, pyridonyl (wherein the pyridonyl is one C _1-6 alkyl). 4-8 membered cyclic ether (the 4-8 membered cyclic ether may be substituted with 1 to 3 C _1-6 alkyl), C _5-8 bicycloalkyl (The C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms.), 1 to 3 groups selected from the group consisting of adamantyl and arylcarbonyl. Or a dihydroimidazooxazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is indanyl (the indanyl may be substituted with 1 to 3 C _1-6 alkyls). Schizophrenia characterized by containing as an ingredient Prevention of a disease selected from the group consisting of: Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Or a therapeutic drug. In the above formula (IA),
R ¹ is a halogen atom, cyano, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl is substituted with two C _1-6 alkyls) Or a heteroaryl, the dihydroimidazooxazole derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient Disease selected from the group consisting of ataxia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders For the prevention or treatment of In the above formula (IA),
R ¹ is cyano or carbamoyl, containing the dihydroimidazooxazole derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient, schizophrenia Prevention of a disease selected from the group consisting of: Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Or a therapeutic drug. In the above formula (IA),
R ² is a halogen atom, C _1-6 alkyl (the C _1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkoxy, aryl, and C _3-8 cycloalkyl) ), Halo C _1-6 alkyl, heteroaryl (the heteroaryl may be substituted with 1 to 3 C _1-6 alkoxy groups), or C _3-8 cycloalkyl. A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, comprising the dihydroimidazoxazole derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. A medicament for the prevention or treatment of a disease selected from the group consisting of: anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. In the above formula (IA),
R ² is C _1-6 alkyl, halo C _1-6 alkyl, or C _3-8 cycloalkyl, or the dihydroimidazooxazole derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. Schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (deficit of attention / hyperactivity disorder), drug dependence, convulsions characterized by containing salt as an active ingredient A medicament for the prevention or treatment of a disease selected from the group consisting of tremor and sleep disorder. In the above formula (IA),
R ³ is aryl (the aryl is a halogen atom, C _1-8 alkyl (the C _1-8 alkyl may be substituted with 1 to 3 aryls), haloC _1-6 alkyl, C _{3 -8} cycloalkyl (wherein the C _3-8 cycloalkyl may be substituted with 1 to 5 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and aryl). ), Halo C _1-6 alkoxy, aryl (wherein the aryl is 1 to 3 groups selected from the group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and halo C _1-6 alkoxy) 4-8 membered cyclic ether (the 4-8 membered cyclic ether may be substituted with 1 to 3 C _1-6 alkyl), C _5-8 bicycloalkyl (The C _5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), adamant 1 to 3 groups selected from the group consisting of til and arylcarbonyl, heteroaryl (wherein the heteroaryl is a halogen atom, C _1-8 alkyl, and aryl (the aryl is a halogen) Substituted with 1 to 3 groups selected from the group consisting of atoms, C _1-6 alkyl, and halo C _1-6 alkyl. Or a dihydroimidazooxazole derivative according to any one of claims 1 to 7, or indanyl (the indanyl may be substituted with 1 to 3 C _1-6 alkyls), or Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder) characterized by containing a pharmaceutically acceptable salt as an active ingredient ), Drugs Exist, convulsions, prophylactic or therapeutic medicament for a disease selected from the group consisting of tremor, and sleeping disorders. The above formula (IA) is represented by the following formula (IIA)

A schizophrenia, Alzheimer's disease, cognitive dysfunction characterized by containing the dihydroimidazooxazole derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof as an active ingredient, A medicament for the prevention or treatment of a disease selected from the group consisting of dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. Formula (I)

[In the formula (I),
R ¹ represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), Optionally substituted with 1-3 groups selected from the group consisting of 4- to 8-membered cyclic amino, hydroxy, and C _1-6 alkoxy.), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, amino (wherein the amino is one or two groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, and C _1-6 alkanoyl) Optionally substituted)) 4-8 membered cyclic amino, C _1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, or Heteroaryl (the aryl and heteroaryl are C _1-6 alkyl, haloC _{1- Which} may be substituted with 1 to 3 groups selected from the group consisting of ₆ alkyl and C _3-8 cycloalkyl);
R ² represents a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (the C _1-6 alkyl is amino (the amino may be substituted with 1 or 2 C _1-6 alkyl)), Optionally substituted with 1 to 3 groups selected from the group consisting of 4- to 8-membered cyclic amino, imino, hydroxy, C _1-6 alkoxy, and aryl.), Halo C _1-6 alkyl, C _{1 -6} alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 C _1-6 alkyl), aryl, or heteroaryl (the aryl, And heteroaryl is a halogen atom, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the amino is 1 or with two C _1-6 alkyl May be conversion.) Or cyclic amino having 4 to 8-membered cyclic amino (said 4-8 membered 1 selected from the group consisting of one to the C _1-6 alkyl may be substituted.) 3 may be substituted with 3 groups), pyridonyl (which may be substituted with 1 C _1-6 alkyl), or tri-C _1-6 alkylsilyl;
R ³ is aryl, heteroaryl, or C _3-8 cycloalkyl (the aryl, heteroaryl, and C _3-8 cycloalkyl are each a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _{3 -8} cycloalkyl (said C _3-8 cycloalkyl C _1-6 alkyl, and may be substituted with 1 or 2 groups selected from the group consisting of halo C _1-6 alkyl.), C _{1- 6} alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, aryloxy, C _1-6 alkanoyl, aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _It may be substituted with 1 to 3 groups selected from the group consisting of _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _3-8 cycloalkyloxy and C _1-6 alkanoyl. ), Heteroaryl (the heteroaryl is Androgenic atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, and with 1 to 3 substituents selected from the group consisting of halo C _1-6 alkoxy may be substituted.), 4 to 8-membered cyclic amino and pyridonyl (which may be substituted with 1 C _1-6 alkyl) may be substituted with 1 to 3 groups selected from the group consisting of Or quinolinonyl (which may be substituted with one C _1-6 alkyl)
Show]
A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD comprising a dihydroimidazooxazole derivative represented by the formula: / HD medicine for prevention or treatment of diseases selected from the group consisting of HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. In the above formula (I),
R ¹ is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of hydroxy and C _1-6 alkoxy) ), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl is substituted with 1 or 2 C _1-6 alkyl). Or a heteroaryl, which is substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, and C _3-8 cycloalkyl. Good).
R ² is a hydrogen atom, a halogen atom, cyano, C _1-6 alkyl (wherein the C _1-6 alkyl is 1-3 groups selected from the group consisting of imino, hydroxy, C _1-6 alkoxy, and aryl) ), Halo C _1-6 alkyl, C _1-6 alkanoyl, C _2-6 alkenyl, C _1-6 alkylsulfonyl, carbamoyl, aryl, or heteroaryl (the aryl and heteroaryl are A halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy, aryl C _1-6 alkoxy, C _1-6 alkylsulfonyl, amino (the amino is one or two C _{1- 6} alkyl may be substituted.), or cyclic amino cyclic amino (said 4-8 membered 4-8 membered selected from the group consisting of which may be substituted with one C _1-6 alkyl.) 1 to 3 groups may be substituted. ), Pyridonyl (which may be substituted with one C _1-6 alkyl), or tri-C _1-6 alkylsilyl;
R ³ is aryl or heteroaryl (the aryl and heteroaryl are a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is C _1-6 alkyl, and 1 or 2 groups selected from the group consisting of halo C _1-6 alkyl may be substituted.), C _1-6 alkoxy, halo C _1-6 alkoxy, aryl C _{1- 6} alkoxy, aryloxy, aryl (said aryl is optionally substituted by a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, and 1-3 substituents selected from the group consisting of halo C _1-6 alkoxy or.), heteroaryl (said heteroaryl, C _1-6 alkyl, and 1-3 substituents selected from the group consisting of halo C _1-6 alkyl may be substituted.), 4-8 Member cyclic amino, and pyridonyl (the pyridonyl is The dihydroimidazooxazole derivative according to claim 10, which may be substituted with 1 to 3 groups selected from the group consisting of 1 C _1-6 alkyl. Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder) characterized by containing a pharmaceutically acceptable salt as an active ingredient ), A medicament for preventing or treating a disease selected from the group consisting of drug dependence, convulsions, tremors and sleep disorders. In the above formula (I),
R ¹ is a halogen atom, cyano, halo C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, carbamoyl (the carbamoyl may be substituted with two C _1-6 alkyl). Or schizophrenia, Alzheimer's disease, cognitive dysfunction, comprising as an active ingredient the dihydroimidazooxazole derivative according to claim 10 or 11, which is a heteroaryl, or a pharmaceutically acceptable salt thereof. A medicament for the prevention or treatment of a disease selected from the group consisting of dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. In the above formula (I),
R ¹ is cyano or carbamoyl, comprising the dihydroimidazoxazole derivative according to any one of claims 10 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient, schizophrenia Prevention of a disease selected from the group consisting of: Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders Or a therapeutic drug. In the above formula (I),
R ² is a halogen atom, C _1-6 alkyl (the C _1-6 alkyl may be substituted with 1 to 3 groups selected from the group consisting of C _1-6 alkoxy and aryl), halo C _1-6 alkyl, or heteroaryl (said heteroaryl is optionally substituted with 1-3 C _1-6 alkoxy.) dihydro imidazo according to any one of claims 10 to 13 which is Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (deficiency of attention / features) characterized by containing an oxazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient A drug for prevention or treatment of a disease selected from the group consisting of hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders. In the above formula (I),
R ² is, contain C _1-6 alkyl, or dihydro imidazooxazole derivative according to any one of claims 10 to 14 is halo C _1-6 alkyl, or a pharmaceutically acceptable salt thereof as an active ingredient From schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders A medicament for the prevention or treatment of a disease selected from the group consisting of: In the above formula (I),
R ³ is aryl (the aryl is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl (the C _3-8 cycloalkyl is C _1-6 alkyl, and halo C 1 or 2 groups selected from the group consisting of _1-6 alkyl may be substituted.), Halo C _1-6 alkoxy, aryl (wherein the aryl is a halogen atom, C _1-6 alkyl, halo C _{1- 6} alkyl, and optionally substituted by 1 to 3 groups selected from the group consisting of haloC _1-6 alkoxy), and heteroaryl (the heteroaryl is C _1-6 alkyl, and haloC _{1 And} may be substituted with 1 to 3 groups selected from the group consisting of _-6 alkyl), and may be substituted with 1 to 3 groups selected from the group consisting of. The dihydroimidazooxazole derivative according to any one of the above, or a medicament thereof Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (deficit of attention / hyperactivity disorder), drug characterized by containing an acceptable salt as an active ingredient A medicament for the prevention or treatment of a disease selected from the group consisting of dependence, convulsions, tremors and sleep disorders. The above formula (I) is represented by the following formula (II)

A schizophrenia, Alzheimer's disease, cognitive dysfunction characterized by comprising the dihydroimidazooxazole derivative according to any one of claims 10 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient. A medicament for the prevention or treatment of a disease selected from the group consisting of dementia, anxiety disorder, depression, AD / HD (attention / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders. A schizophrenia, Alzheimer's disease, comprising as an active ingredient any one or a mixture of two or more selected from the following compound group described in claim 1 and a pharmaceutically acceptable salt thereof: A drug for the prevention or treatment of a disease selected from the group consisting of cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorders .
(2S) -2-[(4-tert-butylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile,
(2S) -2-{[(2'-Fluorobiphenyl-4-yl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- Carboxamide,
(2S) -5-Ethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carbonitrile,
(2S) -5-Ethyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-cyclopropyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1- b] [1,3] oxazole-6-carboxamide,
(2S) -5-propyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-Butyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1, 3] oxazole-6-carboxamide,
5-methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide;
2-{[3-Chloro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5-Methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carbonitrile,
2-{[3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b ] [1,3] oxazole-6-carboxamide,
(2S) -5- (2-Fluoroethyl) -2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ 2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-cyclopropyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [ 2,1-b] [1,3] oxazole-6-carbonitrile,
(2S) -5-ethyl-2-{[3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-methyl-2-{[4- (3,3,4,4,4-pentafluoro-2-methylbutan-2-yl) phenoxy] methyl} -2,3-dihydroimidazo [2, 1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-Methyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- 6-carbonitrile,
(2S) -5-methyl-2-{[4- (1-methylcyclobutyl) phenoxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -5-propyl-2-({4- [1- (trifluoromethyl) cyclopropyl] phenoxy} methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- 6-carboxamide,
(2S) -2-{[4- (7,7-Difluorobicyclo [4.1.0] hept-1-yl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide,
(2S) -2-{[4- (3,3-Difluoro-1-methylcyclobutyl) phenoxy] methyl} -5-propyl-2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carboxamide,
(2S) -2-{[4- (3,3-Difluoro-1-methylcyclobutyl) phenoxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] Oxazole-6-carbonitrile.