JP2015006994A - Dihydroimidazooxazole derivative - Google Patents

Dihydroimidazooxazole derivative Download PDF

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JP2015006994A
JP2015006994A JP2011237606A JP2011237606A JP2015006994A JP 2015006994 A JP2015006994 A JP 2015006994A JP 2011237606 A JP2011237606 A JP 2011237606A JP 2011237606 A JP2011237606 A JP 2011237606A JP 2015006994 A JP2015006994 A JP 2015006994A
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alkyl
substituted
halo
aryl
alkoxy
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洋樹 浦部
Hiroki Urabe
洋樹 浦部
梨絵 西川
Rie Nishikawa
梨絵 西川
智子 民田
Tomoko Tamida
智子 民田
信隆 服部
Nobutaka Hattori
信隆 服部
一成 坂上
Kazunari Sakagami
一成 坂上
松田 洋平
Yohei Matsuda
洋平 松田
明登 安原
Akito Yasuhara
明登 安原
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大正製薬株式会社
Taisho Pharmaceutical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02Silicon compounds
    • C07F7/08Compounds having one or more C—Si linkages
    • C07F7/10Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical for prophylaxis or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders, depression, AD/HD (attention-deficit/hyperactivity disorder), drug dependence, convulsion, tremor, and sleep disorder.SOLUTION: There is provided a novel dihydroimidazooxazole derivative represented by general formula (I) and having an action of a positive allosteric modulator with respect to metabotropic glutamate receptor subtype 2 (mGlu2 receptor), or a pharmaceutically acceptable salt of the derivative.

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 (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), pyridone (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, pyridone (which may be substituted with 1 to 3 groups selected from the group consisting of 1 C 1-6 alkyl). Or quinolinone (which may be substituted with one C 1-6 alkyl)
Show]
A dihydroimidazooxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
(2) 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. ), Pyridone (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 A member of cyclic amino or pyridone (one pyridone In the C 1-6 alkyl may be substituted.) Optionally substituted with 1 to 3 substituents selected from the group consisting of.),
The dihydroimidazooxazole derivative according to (1), or a pharmaceutically acceptable salt thereof.
(3) 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 (1) or (2), which is heteroaryl, or a pharmaceutically acceptable salt thereof.
(4) Schizophrenia, Alzheimer's disease, comprising as an active ingredient the dihydroimidazooxazole derivative according to any one of (1) to (3) or 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 .

  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.

"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, Mention may be made of groups such as trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2-fluoro-2-propyl, 1,1,1-trifluoromethyl-2-methyl-2-propyl and the like.

“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 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.

R 1 in the present invention is preferably a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (wherein the C 1-6 alkyl is a group 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 1 or 2 C 1-6 alkyl) Or a heteroaryl (wherein the heteroaryl is 1 to 3 groups selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl, and C 3-8 cycloalkyl). R 1 is more preferably a halogen atom, cyano, halo C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl is two C 1-6 alkyl substituted Or a heteroaryl.

R 2 in the present invention is preferably a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (wherein the C 1-6 alkyl is selected from the group consisting of imino, hydroxy, C 1-6 alkoxy, and aryl). May be substituted with three 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 is 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 (wherein the amino is 1 or 2 the C 1-6 alkyl may be substituted.), or from 4 to 8 membered cyclic amino (cyclic amino of the 4-8 membered is optionally substituted with one C 1-6 alkyl.) 1-3 selected from the group consisting of Group), pyridone (which may be substituted with one C 1-6 alkyl), or tri-C 1-6 alkylsilyl.

R 3 in the present invention is preferably aryl or heteroaryl (the aryl and heteroaryl are each a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl (the C 3-8 Cycloalkyl may be substituted with 1 or 2 groups selected from the group consisting of C 1-6 alkyl, and 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 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) substituted.), 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- to 8-membered cyclic amino or pyri Don (which may be substituted with 1 to 3 groups selected from the group consisting of 1 pyridone may be substituted with 1 C 1-6 alkyl)),
It is.

  “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 in an amount of 0.001 to 500 mg once a day or divided into 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 (II) chloride, aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.

  The compound of the present invention 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.

Process 6: It can manufacture by Mitsunobu reaction of this invention compound shown by Formula (I), the compound represented by Formula (11), and the compound represented by 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.

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, “Reveleris NH” is Gravel's Reveleris® Amino Silica Cartridge, and “Reveleris” is Grace's Reveleris® Silica Cartridge.
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.
Each instrument data described in the production examples and examples was measured with the following measuring instruments.

Microwave reactor: Initiator (Biotage AB) or Emrys Optimizer (personal chemistry)
MS spectrum: LCMS-2010EV (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 TritionLC
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)
Flow rate: 40 mL / min, detection method: UV 254 nm
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 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: (2S) -5,6-Dibromo-2-{[(4-methoxybenzyl) oxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (intermediate) Synthesis of body 1)

(2S) -2-{[4- (Methoxy) phenoxy] 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: (2S) -6-bromo-2-{[(4-methoxybenzyl) oxy] methyl} -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] Synthesis of [1,3] oxazole (Intermediate 7)

(2S) -5,6-Dibromo-2-{[(4-methoxybenzyl) oxy] methyl} -2,3-dihydroimidazo [2,1-b] [1,3] obtained in Production Example 1 Oxazole (intermediate 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 yellow amorphous ethyl acetate solution was concentrated under reduced pressure. The residue was purified by column chromatography (Reveleris NH, mobile phase: hexane / ethyl acetate = 80 / 20-30 / 70; v / v) to obtain the title compound (Intermediate 7: 672 mg, colorless amorphous).

  Production Example 3: (2S) -2-{[(4-methoxybenzyl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbo Synthesis of nitrile (intermediate 8)

(2S) -6-Bromo-2-{[(4-methoxybenzyl) oxy] methyl} -5-methyl-2,3-dihydroimidazo [2,1] obtained using the same method as in Production Example 1 -b] [1,3] oxazole (intermediate 2: 500 mg), zinc (22 mg), zinc cyanide (333 mg), 1,1'-bis (diphenylphosphino) ferrocene (314 mg) and tris A suspension of (dibenzylideneacetone) 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: [(2S) -6-bromo-5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate) Synthesis of body 9)

(2S) -6-Bromo-2-{[(4-methoxybenzyl) oxy] methyl} -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1] obtained in Production Example 2 -b] [1,3] oxazole (Intermediate 7: 54 mg) was added with 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: Preparation of [(2S) -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate 11) Composition

[(2S) -6-Bromo-5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] obtained in Production Example 4 To a methanol (2 mL) solution of methanol (intermediate 9:22 mg) 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 [(2S) -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methyl Synthesis of (Intermediate 12)

[(2S) -5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (intermediate) obtained in Production Example 5 11: 200 mg) in chloroform (10 mL) was added triethylamine (0.256 mL), trimethylamine hydrochloride (44 mg) and p-toluenesulfonyl chloride (263 mg) at 0 ° C. and stirred at the same temperature for 5 minutes. Then, the mixture was stirred for 1.5 hours while raising the temperature 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 (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 [(2S) -6-cyano-5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methyl (intermediate) Synthesis of body 13)

(2S) -2- (Hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6- obtained by the same method as in Production Example 4 Triethylamine (0.168 mL), trimethylamine hydrochloride (29 mg), and p-toluenesulfonyl chloride (172 mg) were added to a suspension of carbonitrile (intermediate 10: 108 mg) in chloroform (5 mL) at 0 ° C. After stirring for 5 minutes at the temperature, 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).

  Tables 1-1 to 1-2 show the structural formulas, compound names, and instrument data of intermediates shown in Production Examples 1 to 7 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 7 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 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: (2S) -2-[(3-Fluorophenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole ( Synthesis of Compound 65) [(2S) -5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl obtained in Production Example 5 ] 3-fluorophenol (0.014 mL), diisopropyl azodicarboxylate (1.9 M toluene solution, 0.136 mL) and triphenylphosphine in a suspension of methanol (intermediate 11: 28 mg) in 1,4-dioxane (1 mL) (68 mg) was added and stirred 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: (2S) -2-[(biphenyl-4-yloxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole Synthesis of (Compound 93) 4-Methylbenzenesulfonic acid obtained in Production Example 6 [(2S) -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1, 3] Add 4-phenylphenol (35 mg) and cesium carbonate (123 mg) to a solution of oxazol-2-yl] methyl (intermediate 12:72 mg) in acetonitrile (1.5 mL) and stir at 80 ° C. for 2 hours. did. 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 yellow solid ethyl acetate solution was 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 the title compound (Compound 44: 91 mg, colorless solid).

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: (2S) -5-methyl-2-[({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) methyl] -2,3-dihydroimidazo [2,1 -b] [1,3] Oxazole-6-carbonitrile (Compound 171) (2S) -2- (hydroxymethyl) -5-methyl-2, obtained using the same method as in Production Example 4. 3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (intermediate 10: 20 mg), 2-bromo-5- (4-trifluoromethylphenyl) pyridine (34 mg) , A suspension of palladium acetate (3 mg), [1,1'-binaphthalene] -2-yldi-tert-butylphosphine (5 mg) and cesium carbonate (109 mg) in toluene (1 mL) under a nitrogen atmosphere The mixture was stirred at 110 ° C. for 5 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 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: (2S) -2-[(4-cyclopropylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole Synthesis of (Compound 96) 4-Methylbenzenesulfonic acid [(2S) -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,2] obtained in Production Example 6 3] A mixture of 4-cyclopropylphenol and 4-ethenylphenol (44 mg) and cesium carbonate (193 mg) were added to a solution of oxazol-2-yl] methyl (intermediate 12: 110 mg) in acetonitrile (2.0 mL). In addition, the mixture was stirred at 85 ° C. for 2 hours. 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 (2S) -2- Obtained [(4-ethenylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (12 mg, colorless solid) .
(2S) -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: (2S) -2-[(4-Ethylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole ( Synthesis of Compound 100) (2S) -2-[(4-Ethenylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1- b] To a solution of [1,3] oxazole (12 mg) in methanol (0.5 mL) was added 10% palladium carbon (5 mg), 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: (2S) -6-Bromo-5-methyl-2-{[4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl} -2,3- Synthesis of dihydroimidazo [2,1-b] [1,3] oxazole (compound 173) (a) (2S)-(+)-glycidyl tosylate (2.48 g) and 2,5-dibromo-4-methylimidazole ( To a solution of 1.00 g) in N, N-dimethylformamide (20 mL) was added cesium carbonate (3.34 g), and the mixture was stirred with heating at 50 ° C. for 2 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, 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-[(2S) -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 resulting 2,4-dibromo-5-methyl-1-[(2S) -oxiran-2-ylmethyl] -1H-imidazole (795 mg) and 4- (2,2,2-trifluoro- Sodium hydride (162 mg) was added to a solution of 1,1-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 obtained in Production Example 7 [(2S) -6-cyano-5-methyl-2,3-dihydroimidazo To a solution of [2,1-b] [1,3] oxazol-2-yl] methyl (intermediate 13: 130 mg) in acetonitrile (2.6 mL), 4- (1,1,1-trifluoro-2-methyl Propan-2-yl) phenol (88 mg) and cesium carbonate (254 mg) were added, and the mixture was stirred at 80 ° C. for 3.5 hr. 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).

  Tables 2-1 to 2-21 show the structural formulas, compound names, and instrument data of the compounds shown in Examples 1 to 37 and the compounds synthesized by the same method. The number described in the column of the example in the table indicates that the compound was synthesized by the same method as in any of the above Examples 1 to 37.

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 . The confluent cells were washed twice with PBS (−), detached with a cell scraper, and centrifuged at 4 ° C., 1000 rpm for 5 minutes to collect the cells. The obtained precipitate was suspended in 20 mM HEPES buffer (pH 7.4), the suspension was homogenized with a 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 EC50 value of each compound was calculated by a regression curve using a nonlinear least square method.

All of the compounds of the present invention acted on the mGlu2 receptor to enhance the receptor response. Among them, Table 3 shows compounds having EC 50 values of less than 10 μM and EC 50 values thereof.

  Further, when the specific binding amount obtained in the presence of 1 mM glutamic acid was taken as 100%, the maximum response Emax value obtained by coexisting with 3 μM glutamic acid and each Example compound was calculated.

  As another analysis method, the compound concentration at which a specific binding amount of 50% was obtained in the presence of 3 μM glutamic acid and the compounds of the respective examples was calculated. For example, compounds 80, 139, 156, 159, 160, 166, 173, 177, 180, 181 have 35 nM, 21 nM, 20 nM, 0.90 nM, 2.1 nM, 20 nM, 3.4 nM, 25 nM, 3.6 nM, respectively. 131 nM.

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 . The confluent cells were washed twice with PBS (−), detached with a cell scraper, and centrifuged at 4 ° C., 1000 rpm for 5 minutes to collect the cells. The obtained precipitate was suspended in 20 mM HEPES buffer (pH 7.4), the suspension was homogenized with a 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.

  Further, when the specific binding amount obtained in the presence of 1 mM glutamic acid was taken as 100%, the maximum response Emax value obtained by coexisting with 1 μM glutamic acid and each Example compound was calculated.

  As another analysis method, the compound concentration at which a specific binding amount of 50% was obtained in the presence of 1 μM glutamic acid and each compound of each example was calculated. For example, the compounds 80, 139, 159 and 160 were 94 nM, 48 nM, 3.1 nM and 5.5 nM, respectively.

  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 (4)

  1. 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), pyridone (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, pyridone (which may be substituted with 1 to 3 groups selected from the group consisting of 1 C 1-6 alkyl). Or quinolinone (which may be substituted with one C 1-6 alkyl)
    Show]
    A dihydroimidazooxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
  2. 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. ), Pyridone (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 A member of cyclic amino or pyridone (one pyridone In the C 1-6 alkyl may be substituted.) Optionally substituted with 1 to 3 substituents selected from the group consisting of.),
    The dihydroimidazooxazole derivative according to claim 1, or a pharmaceutically acceptable salt thereof.
  3. 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 heteroaryl, or a dihydroimidazooxazole derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  4. A schizophrenia, Alzheimer's disease, cognitive dysfunction, cognition, comprising as an active ingredient the dihydroimidazooxazole derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. A medicament for the prevention or treatment of a disease selected from the group consisting of symptom, anxiety disorder, depression, AD / HD (attention deficit / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorder.
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