WO2013062079A1 - Dérivé de dihydroimidazooxazole - Google Patents

Dérivé de dihydroimidazooxazole Download PDF

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WO2013062079A1
WO2013062079A1 PCT/JP2012/077697 JP2012077697W WO2013062079A1 WO 2013062079 A1 WO2013062079 A1 WO 2013062079A1 JP 2012077697 W JP2012077697 W JP 2012077697W WO 2013062079 A1 WO2013062079 A1 WO 2013062079A1
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alkyl
substituted
aryl
halo
alkoxy
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Japanese (ja)
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洋樹 浦部
梨絵 下野
智子 民田
信隆 服部
一成 坂上
洋平 松田
明登 安原
誠治 増田
一豪 小西
年男 中村
修資 山本
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大正製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic 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
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present invention provides a novel compound having positive allosteric modulator action on metabotropic glutamate receptor subtype 2 (mGlu2 receptor) or a pharmaceutically acceptable salt thereof, and schizophrenia comprising them as an active ingredient, Prevention of a disease selected from the group consisting of Alzheimer's disease, cognitive impairment, dementia, anxiety disorder, depression, AD / HD (lack of attention / hyperactivity disorder), drug dependence, convulsions, tremors and sleep disorders It relates to a therapeutic drug.
  • mGlu2 receptor metabotropic glutamate receptor subtype 2
  • Glutamate receptors are broadly classified into ionotropic glutamate receptors and metabotropic glutamate receptors (mGlu receptors) (Non-patent Documents 1 and 2). Among them, the mGlu receptor was identified as a GPCR-type glutamate receptor coupled to a G protein, but receptor cDNAs were successively cloned in the early 1990's (Non-patent Documents 3 and 4). At present, the existence of eight subtypes (mGlu1 to mGlu8) has been reported, and these are divided into three groups (group I: mGlu1, mGlu5; group II) according to differences in receptor structure, pharmacological properties and signal transduction.
  • group I mGlu1, mGlu5; group II
  • mGlu2, mGlu3; Group III: mGlu4, mGlu6, mGlu7, mGlu8) (non-patent documents 5 to 7).
  • mGlu2 and mGlu3 receptors belonging to group II are coupled to Gi / Go protein and repressively modulate adenylate cyclase activity, and activation of mGlu2 and mGlu3 receptors by agonists is forskolin It suppresses stimulation-induced cAMP accumulation (Non-patent Documents 1, 8, 9).
  • mGlu2 and mGlu3 receptors are often expressed 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 that mGlu2 and mGlu3 receptors are related to mental disorders such as anxiety disorder, schizophrenia, depression and drug addiction (Non-Patent Documents 15 to 19).
  • mGlu2 receptors are mainly involved in the antipsychotic action of mGlu2 / 3 receptor agonists (non-patent documents 20 to 22). Furthermore, the presence of an active regulatory site (allosteric binding site) different from the binding site (orthosteric binding site) of the endogenous ligand glutamate was reported, and a selective mGlu2 receptor positive allosteric modulator (PAM) was created (non- Patent documents 23, 24).
  • PAM mGlu2 receptor positive allosteric modulator
  • These selective mGlu2 receptor PAMs like mGlu2 / 3 receptors, have antipsychotic and cognitive impairment ameliorating effects in various animal models, suggesting their potential as a drug for treating schizophrenia ( Non-patent documents 25-32).
  • mGlu2 receptor PAM has been shown to have anti-anxiety effects in various animal models, which suggests its potential as a therapeutic agent for anxiety disorder (Non-patent Documents 25, 28, 33, 34).
  • Non-patent Documents 35 to 37 compounds having mGlu2 receptor positive allosteric modulator activity have been reported.
  • these documents do not disclose or suggest at all a compound having a dihydroimidazo oxazole skeleton of the compound of the present invention.
  • the object of the present invention is to find novel compounds having positive allosteric modulator action on mGlu2 receptor, and to treat schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (Hyperkinetic disorder), drug dependence, convulsions, tremor, and providing a medicine for preventing or treating sleep disorder and the like.
  • schizophrenia Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, AD / HD (Hyperkinetic disorder), drug dependence, convulsions, tremor, and providing a medicine for preventing or treating sleep disorder and the like.
  • R 1 is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is amino (the amino may be substituted with one or two C 1-6 alkyl)), 4-8 membered cyclic amino, hydroxy, and C 1-6 with 1 to 3 groups selected from the group consisting of alkoxy may be substituted.), 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 4) 8-membered cyclic amino,
  • aryl (the aryl, and heteroaryl C 1-6 alkyl, halo C 1-6 A . Kill, and the C 3-8 may be substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl), or shows the carboxy;
  • R 2 is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is amino (the amino may be substituted with one or two C 1-6 alkyl)), 4- to 8-membered cyclic amino (The 4- to 8-membered cyclic amino may be substituted with 1 to 3 halogen atoms), imino, hydroxy, C 1-6 alkoxy, aryl, C 3-8 cyclo Alkyl, and optionally substituted with 1 to 3 groups selected from the group consisting of carboxy), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl ,
  • R 2 is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is selected from the group consisting of imino, hydroxy, C 1-6 alkoxy, aryl, and C 3-8 cycloalkyl (Optionally substituted with 1 to 3 groups), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl, carbamoyl, aryl or heteroaryl ( the aryl, and heteroaryl halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, aryl C 1-6 alkoxy, C 1-6 alkylsulfonyl, amino (said amino is 1 Or 2 C 1-6 alkyl) or 4- to 8-membered cyclic amino (wherein the 4- to 8-membered cyclic amino may be substituted by one C
  • R 1 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, carbamoyl (the carbamoyl is substituted with two C 1-6 alkyls Dihydroimidazo oxazole derivative according to any one of (1) to (3) which is heteroaryl), or a pharmaceutically acceptable salt thereof, (5)
  • R 2 is substituted with
  • halo C 1-6 alkyl, heteroaryl the heteroaryl may be substituted with 1 to 3 C 1-6 alkoxy groups
  • C 3-8 cycloalkyl The dihydroimidazo oxazole derivative according to any one of (1) to (5), or a pharmaceutically acceptable salt thereof, (7)
  • R 2 is C 1-6 alkyl, halo C 1-6 alkyl, or C 3-8 cycloalkyl, or a pharmaceutically acceptable thereof Salt
  • R 3 is aryl (the aryl is a halogen atom, C 1-8 alkyl (the C 1-8 alkyl may be substituted with 1 to 3 aryl)), halo C 1-6 alkyl, C 3 -8 cycloalkyl (the C 3-8 cycloalkyl may be substituted with 1 to 5 groups selected from the
  • Heteroaryl (the said 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.), 4-8 membered cyclic amino, and pyridonyl (the pyridonyl is one C 1-6 may also be. which is substituted with alkyl) may be substituted with 1 to 3 substituents selected from the group consisting of.) Or quinolinyl (the quinolinyl may be substituted with one C 1-6 alkyl).
  • R 1 is substituted with a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (wherein the C 1-6 alkyl is hydroxy, and 1 to 3 groups selected from the group consisting of C 1-6 alkoxy) ), Halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl, carbamoyl (wherein the carbamoyl is substituted with one or two C 1-6 alkyl; Or heteroaryl (wherein the heteroaryl 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).
  • R 2 represents 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) , Halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl, carbamoyl, aryl or heteroaryl (the aryl and heteroaryl are halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, aryl C 1-6 alkoxy, C 1-6 alkylsulfonyl, amino (said amino is one or two C 1- 6 ) or 4 to 8 membered cyclic amino (wherein the 4 to 8 membered cyclic amino may be substituted by one C 1-6 alkyl).
  • R 3 is aryl or heteroaryl (wherein 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 is C 1-6 alkyl, and may be substituted by 1 or 2 groups selected from the group consisting of halo C 1-6 alkyl), C 1-6 alkoxy, halo C 1-6 alkoxy, aryl C 1- 6 alkoxy, aryloxy, aryl (wherein the aryl is substituted with 1 to 3 groups selected from the group consisting of halogen atoms, C 1-6 alkyl, halo C 1-6 alkyl, and halo C 1-6 alkoxy) or.), heteroaryl (s
  • R 1 is a halogen atom, cyano, haloC 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 dihydroimidazo oxazole derivative according to (10) or (11) which is heteroaryl, or a pharmaceutically acceptable salt thereof, (13)
  • R 2 is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with 1 to 3 groups selected from the group consisting of C 1-6 alkoxy and aryl), (10) to (13) described in any one of halo
  • a dihydroimidazo oxazole derivative, or a pharmaceutically acceptable salt thereof (15) In the above formula (I), The dihydroimidazo oxazole derivative according to any one of (10) to (14), wherein R 2 is C 1-6 alkyl, or haloC 1-6 alkyl, or a pharmaceutically acceptable salt thereof, (16) In the above formula (I), R 3 is aryl (the aryl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is C 1-6 alkyl, and halo C It may be substituted by one or two groups selected from the group consisting of 1-6 alkyl), halo C 1-6 alkoxy, aryl (the aryl is a halogen atom, C 1-6 alkyl, halo C 1- 6 alkyl, and may be substituted with 1 to 3 groups selected from the group consisting of halo C
  • the dihydroimidazo oxazole derivative according to any one, or a doctor Above acceptable salts has the following formula (II) The dihydroimidazo oxazole derivative according to any one of (10) to (16), or a pharmaceutically acceptable salt thereof, (18) A pharmaceutical composition comprising the dihydroimidazo oxazole derivative according to any one of the above (1) to (17), or a pharmaceutically acceptable salt thereof as an active ingredient, (19) Schizophrenia, Alzheimer's disease characterized by comprising the dihydroimidazo oxazole derivative according to any one of the above (1) to (17), or a pharmaceutically acceptable salt thereof as an active ingredient
  • a disease selected from the group consisting of: cognitive impairment, dementia, anxiety disorder, depression, AD / HD (lack of attention / hyperactivity disorder), drug dependence, convulsions, tremor and sleep disorder Medicine, It is.
  • novel dihydroimidazo oxazole derivative of the present invention has been found to act on the active regulatory site of mGlu2 receptor to enhance receptor stimulation by a physiological ligand (glutamic acid).
  • halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl represents a linear or branched alkyl group having 1 to 6 carbon atoms, and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Groups such as butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and the like can be mentioned.
  • C 1-8 alkyl represents a linear or branched alkyl group having 1 to 8 carbon atoms, and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Groups such as butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, 2,4,4-trimethylpentan-2-yl and the like can be mentioned .
  • Halo C 1-6 alkyl refers to an alkyl group in which 1 to 5 identical or different the aforementioned “halogen atoms” are substituted to the above “C 1-6 alkyl”, and monofluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2-fluoro-2-propyl, 1,1,1-trifluoromethyl-2-methyl-2-propyl, 3-fluoropropyl, 3,3 And groups such as -difluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluoro-2-methylbutan-2-yl and the like.
  • C 3-8 cycloalkyl means a cyclic cycloalkyl group having 3 to 8 carbon atoms, and examples 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, and methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Groups such as butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy and the like can be mentioned.
  • Halo C 1-6 alkoxy refers to an alkoxy group in which 1 to 5 “halogen atom” is substituted to the above “C 1-6 alkoxy”, such as monofluoromethoxy, difluoromethoxy and trifluoromethoxy Groups can be mentioned.
  • C 3-8 cycloalkyloxy means a group in which an oxygen atom is bonded to the aforementioned “C 3-8 cycloalkyl”, and cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy And cyclooctyloxy groups.
  • C 3-8 cycloalkyl carbonyl means a group in which a carbonyl is bonded to the above “C 3-8 cycloalkyl”, and cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentyl carbonyl, cyclohexyl carbonyl, cycloheptyl carbonyl And cyclooctylcarbonyl group can be mentioned.
  • C 1-6 alkylsulfonyl means a sulfonyl group substituted by the above “C 1-6 alkyl”, and methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutyl Groups such as sulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl and the like can be mentioned.
  • 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 Groups can be mentioned.
  • C 2-6 alkenyl means a linear or branched alkenyl group having 2 to 6 carbon atoms, and vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 1-methyl- Groups such as 2-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 4-pentenyl and the like can be mentioned.
  • aryl is a monocyclic to bicyclic aromatic carbocyclic ring, and groups such as phenyl, 1-naphthyl and 2-naphthyl can be mentioned.
  • Heteroaryl is a C 2-9 aromatic group consisting of one or two rings having at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom, furyl and pyrrolyl, Thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, indolyl, benzofuranyl and the like.
  • 4-8 membered cyclic amino refers to a 4-8 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.
  • the “aryl C 1-6 alkoxy” is an alkoxy group in which 1 to 3 identical or different the above “aryl” is substituted to the above “C 1-6 alkoxy”, and benzyloxy, 1-phenylethyloxy And groups such as 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 three identical or different the aforementioned “C 1-6 alkyl” are substituted on “silyl”, such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like Groups can be mentioned.
  • aryloxy refers to a group in which an oxygen atom is bonded to the aforementioned “aryl”, and groups such as phenoxy, 1-naphthoxy, 2-naphthoxy and the like can be mentioned.
  • arylsulfonyl refers to a sulfonyl group substituted with the above “aryl”, and examples include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.
  • the “4- to 8-membered cyclic ether” is a 4- to 8-membered cyclic ether group containing one oxygen atom in the ring, and examples include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
  • C5-8 bicycloalkyl means a cyclic bicyclo alkyl group having 5 to 8 carbon atoms, and it is bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, bicyclo [4. .1.0] heptyl, bicyclo [2.2.1] heptyl, bicyclo [5.1.0] heptyl group can be mentioned.
  • C 1-6 alkoxycarbonyl represents a group in which the above “C 1-6 alkoxy” is bonded to carbonyl, and methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, iso Groups such as butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, n-hexyloxycarbonyl and the like can be mentioned.
  • arylcarbonyl refers to a group in which the above “aryl” is combined with carbonyl, and groups such as phenylcarbonyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like can be mentioned.
  • R 1 in the above formula (IA) of the present invention is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (wherein the C 1-6 alkyl is hydroxy, and C 1-6 alkoxy) (Optionally substituted by 1 to 3 groups), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl, carbamoyl (the carbamoyl is one or two) the C 1-6 alkyl may be substituted.), or heteroaryl (1 said heteroaryl selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl, and C 3-8 cycloalkyl To 3 groups which may be substituted), R 1 is more preferably a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl,
  • R 2 in the above formula (IA) of the present invention is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is imino, hydroxy, C 1-6 alkoxy, aryl, and C 3-8 cycloalkyl optionally substituted with 1 to 3 groups selected from the group consisting of 3-8 cycloalkyl), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl Sulfonyl, carbamoyl, aryl or heteroaryl (the aryl and heteroaryl are each 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 may be substituted with 1 or 2 C 1-6 alkyl), or 4- to 8-membered cyclic
  • R 2 is a halogen atom, C 1-6 alkyl (wherein the C 1-6 alkyl is a C 1-6 alkoxy, aryl, and 1 to 3 groups selected from the group consisting of C 3-8 cycloalkyl.
  • R 2 is C 1-6 alkyl, halo C 1-6 alkyl, or C 3-8 cycloalkyl.
  • R 3 in the above formula (IA) of the present invention is aryl or heteroaryl (the aryl and heteroaryl are each a halogen atom, C 1-8 alkyl (the C 1-8 alkyl is cyano, hydroxy and aryl may be substituted with 1 to 3 substituents selected from the group consisting of.), halo C 1-6 alkyl, C 3-8 cycloalkyl (said C 3-8 cycloalkyl is halogen atom, C 1-6 Alkyl, halo C 1-6 alkyl, and optionally substituted with 1 to 5 groups selected from the group consisting of aryl), C 1-6 alkoxy, halo C 1-6 alkoxy, aryl C 1-6 Alkoxy, aryloxy, aryl (wherein the aryl is substituted with 1 to 3 groups selected from the group consisting of halogen atoms, C 1-6 alkyl, halo C 1-6 alkyl, and halo C 1-6 alkoxy
  • R 3 is aryl (the aryl is a halogen atom, C 1-8 alkyl (the C 1-8 alkyl may be substituted with 1 to 3 aryl), halo C 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is substituted with 1 to 5 groups selected from the group consisting of halogen atoms, C 1-6 alkyl, halo C 1-6 alkyl, and aryl , Halo C 1-6 alkoxy, aryl (wherein the aryl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, and halo C 1-6 alkoxy selected from the group consisting of 1 to 3) Group may be substituted), 4-8-membered cyclic ether (The 4-8-membered cyclic ether may be substituted with 1
  • Halo C 1-6 alkoxy aryl (wherein the aryl may be substituted with 1 to 3 groups selected from the group consisting of halogen atoms, C 1-6 alkyl, and halo C 1-6 alkyl) , C 5-8 bicycloalkyl (wherein the C 5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), and substituted with 1 to 3 groups selected from the group consisting of adamantyl Is also good).
  • R 4 in the above formula (IA) of the present invention is a hydrogen atom or methyl, More preferable R 4 is a hydrogen atom.
  • the preferred steric structure in the above formula (IA) of the present invention is the following formula (IIA), The preferred configuration is (2S).
  • R 1 in the above formula (I) of the present invention is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (wherein the C 1-6 alkyl is hydroxy, and C 1-6 alkoxy) (Optionally substituted by 1 to 3 groups), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl, carbamoyl (the carbamoyl is one or two) the C 1-6 alkyl may be substituted.), or heteroaryl (1 said heteroaryl selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl, and C 3-8 cycloalkyl To 3 groups which may be substituted), More preferred R 1 is a halogen atom, cyano, haloC 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, carbamoyl (the carbamo
  • R 2 in the above formula (I) of the present invention is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is imino, hydroxy, C 1-6 alkoxy, and aryl Group may be substituted with 1 to 3 groups selected from the group), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkylsulfonyl, carbamoyl, aryl, or Heteroaryl (the aryl and heteroaryl are each 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 may be substituted with one or two C 1-6 alkyl), or 4-8 membered cyclic amino (wherein the 4-8 membered cyclic amino is substituted with one C
  • R 2 is C 1-6 alkyl or haloC 1-6 alkyl.
  • R 3 in the above formula (I) of the present invention is aryl or heteroaryl (wherein 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 C 1-6 alkyl, and may be substituted with 1 or 2 groups selected from the group consisting of halo C 1-6 alkyl.), C 1-6 alkoxy, halo C 1-6 alkoxy, aryl C 1-6 alkoxy, aryloxy, aryl (wherein the aryl is selected from the group consisting of a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, and halo C 1-6 alkoxy 1 may be substituted with three groups.), heteroaryl (said heteroaryl is substituted by C 1-6 alkyl, and 1-3 groups selected from the group consisting of halo C 1-6 alkyl ), 4-8
  • “Pharmaceutically acceptable salts” are 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, and salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion,
  • the compounds of the present invention may also exist as various solvates.
  • 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 any ratio of these, racemates and the like.
  • the compounds of the present invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical formulation.
  • various oils such as methyl cellulose, polyvinyl pyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like.
  • additives such as commonly used fillers, binders, disintegrants, pH adjusters, solubilizers, etc. are mixed with the above-mentioned carriers, excipients or diluents as required, and tablets are prepared by conventional formulation techniques. They can be prepared as oral or parenteral medicines such as 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 as a single dose of 0.001 to 2000 mg once a day or divided into several times. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms and the like 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 in, for example, metabolism and pharmacokinetics studies, biological analysis as ligands of receptors, and the like.
  • the compound of the present invention and pharmaceutically acceptable salts thereof can be synthesized, for example, by the methods shown below, but the method of producing the compound of the present invention is not limited thereto.
  • inert solvent examples 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-methyl pyrrolidone and N, N-dimethyl acetamide;
  • base means, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Amides of alkali metals or alkaline earth metals such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • alkyllithiums such as butyllithium, sec-butyllithium, tert-butyllithium and methyllithium
  • Hydroxides of alkali metals or alkaline earth metals such as; carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate and cesium carbonate
  • alkali metals or alkaline earths such as sodium hydrogencarbonate and potassium hydrogencarbonate Metal bicarbonates
  • triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3 .0] amines such as non-5-ene (DBN), N, N-dimethylaniline, etc .
  • quaternary ammonium salts such as tetra-n
  • bases are appropriately selected according to various reaction conditions known to those skilled in the art.
  • the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and the like.
  • Organic acids zinc (II) chloride, aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate etc. 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.
  • 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 (methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group or the like).
  • Step 1 The compound of the present invention represented by the formula (I) can be produced by the reaction of the compound represented by the formula (1) with the compound represented by the formula (2) in the presence of a base in an inert solvent.
  • the compounds represented by the formulas (1) and (2) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • the compounds of the present invention represented by the formula (I) can also be produced by the method of the following scheme 2.
  • R 1 , R 2 , R 3 and X 1 are as defined above.
  • Y 1 represents a hydrogen atom or a halogen atom or the like.
  • Step 2 The compound of the present invention represented by the formula (I) can be produced by the reaction of a compound represented by the formula (3) with a compound represented by the formula (4) in the presence of an alkyllithium in an inert solvent.
  • compounds represented by the formulas (3) and (4) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • the compounds of the present invention represented by the formula (I) can also be produced by the method of the following scheme 3.
  • 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.
  • the compounds represented by the formulas (5) and (6) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • the compounds of the present invention represented by the formula (I) can also be produced by the method of the following scheme 4.
  • R 1 , R 2 , R 3 and X 1 are as defined above.
  • M represents a metal atom or metal group used in the coupling reaction, and as an example of a compound represented by the formula (8), a magnesium reagent, a zinc reagent, a boron reagent having boric acid or a boric acid ester bonded, tin Reactants and the like can be mentioned.
  • Step 4 The compound of the present invention represented by the formula (I) is treated with a compound represented by the formula (7) using a palladium catalyst and optionally a ligand in an inert solvent, in the presence or absence of a base It can manufacture by the coupling reaction of the compound represented by Formula (8).
  • examples of the coupling reaction include coupling reaction conditions known to those skilled in the art.
  • ⁇ Comprehensive Organic Transformations Second Edition ⁇ Comprehensive Organic Transformations Second Edition) 1999, John Willie and Sons (John)
  • the method can be carried out by the method described in Wiley & Sons, INC.) Etc., a method according thereto, or a combination of these with a conventional method.
  • the palladium catalyst includes, for example, palladium (II) acetate, palladium (II) chloride, palladium (II) bis (triphenylphosphine) acetate, palladium (II) bis (triphenylphosphine) palladium (II) chloride, tris (dibenzylideneacetone) ) Dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphinepalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride, allylpalladium chloride (II), bis (acetonitrile) palladium chloride (II), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium chloride (II), etc.
  • the ligands are, for example, 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.
  • the compounds represented by the formulas (7) and (8) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • the compounds of the present invention represented by the formula (I) can also be produced by the method of the following scheme 5.
  • 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 the reaction of a compound represented by the formula (9) with a compound represented by the formula (10) in the presence of a base in an inert solvent.
  • the compounds represented by the formulas (9) and (10) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • the compounds of the present invention represented by the formula (I) can also be produced by the method of the following scheme 6.
  • R 1 , R 2 and R 3 are as defined above.
  • the compound of the present invention represented by the formula (I) can be produced by the Mitsunobu reaction of the compound represented by the formula (11) and the compound represented by the formula (12).
  • the Mitsunobu reaction is carried out, for example, by a method using an organic phosphorus compound such as triphenylphosphine or tributylphosphine and an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or cyanomethyltributyl phospho
  • an organic phosphorus compound such as triphenylphosphine or tributylphosphine
  • an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or cyanomethyltributyl phospho
  • a phosphorus ylide reagent such as
  • compounds represented by the formulas (11) and (12) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • compounds represented by the following formula (I-II) can be produced by the method of the following scheme 7.
  • 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 may be substituted with 1 to 3 substituents selected from the group consisting of.), or heteroaryl (said heteroaryl halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy And optionally substituted with 1 to 3 groups selected from the group consisting of halo C 1-6 alkoxy.
  • Step 7 The compound represented by the formula (I-II) can be produced from the compound represented by the formula (13) and the compound represented by the formula (14) by the same method as in the step 4 in Scheme 4.
  • the compounds represented by the formulas (13) and (14) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • compounds represented by the following formula (I-II) can also be produced by the method of the following scheme 8.
  • 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.
  • the compounds represented by the formulas (15) and (16) may be commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis techniques known to those skilled in the art. Can.
  • compounds represented by the present invention represented by the formula (I) compounds represented by the following formula (I-III) can be produced by the method of the following scheme 9.
  • Step 9 The compound represented by the formula (I-III) can be produced by hydrolysis of the compound represented by the formula (17) in the presence of a base in an inert solvent.
  • a commercially available compound, a known compound, or a compound synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art can be used as the compound represented by the formula (17).
  • the compound shown by Formula (11) can be manufactured by the method of following Scheme 10.
  • R 1 , R 2 and X 1 are as defined above, and R 5 is a protecting group for hydroxyl group such as tert-butyldimethylsilyl group, p-methoxybenzyl group, 2-tetrahydropyranyl group and trityl group.
  • R 5 is a protecting group for hydroxyl group such as tert-butyldimethylsilyl group, p-methoxybenzyl group, 2-tetrahydropyranyl group and trityl group.
  • Step 10 The compound represented by the formula (19) can be produced from the compound represented by the formula (18) and the compound represented by the formula (2) by the same method as in the step 1 in Scheme 1.
  • Process 11 The compound shown by Formula (11) is Theodora W. Green, Peter G. M. It can be prepared from the compound represented by the formula (19) by the deprotection reaction described in Wuts, "Green's Protective Groups in Organic Synthesis, Forth Edition".
  • the compound of the present invention represented by the formula (IA) can be produced by the method of the following scheme 11.
  • Step 12 The compound of the present invention represented by the formula (IA) is produced from the compound represented by the formula (20) and the compound represented by the formula (2) by the same method as step 1 in Scheme 1 be able to.
  • the compound represented by the formula (20) a commercially available compound, a known compound, or a compound synthesized using various organic synthesis methods known to those skilled in the art can be used.
  • SNAP Cartridge KP-NH when purified using column chromatography refers to Biotage SNAP Cartridge KP-NH
  • SNAP Cartridge HP-Sil refers to Biotage SNAP Cartridge HP- Sil
  • Reveleris NH means Gracele's Reveleris® Amino Silica Cartridge
  • Reveleris means Grace's Reveleris® Silica Cartridge
  • YMC-DispoPakAT NH2 means YMC, YMC-DisopoPakAT It is NH2.
  • MS spectrum LCMS-2010 EV (Shimadzu Corporation), LCMS-IT-TOF (Shimadzu Corporation), micromass Platform LC or micromass GCT, Agilent 2900 and Agilent 6150 NMR spectrum: Nippon Denshi JNM-ECA600 (600 MHz), Nippon Denshi JNM-ECA 500 (500 MHz), Varian UNITYNOVA 300 (300 MHz), Varian GEMINI 2000/200 (200 MHz) The compound names in Preparation Examples and Examples were named according to ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).
  • MS mass spectrometry
  • ESI electrospray ionization
  • APCI atmospheric pressure chemical ionization
  • NMR nuclear magnetic resonance spectroscopy
  • H proton
  • J coupling constant
  • DMSO-d6 deuterated dimethyl dimethyl Sulfoxide
  • salts may be formed using various acids under various reaction conditions known to those skilled in the art.
  • 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, the organic layers were combined and concentrated under reduced pressure.
  • methyl iodide (1.9 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at 0 ° C. for 30 minutes.
  • the reaction was quenched by the addition of saturated aqueous ammonium chloride solution, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the optical purity of the compound of the present invention was measured by HPLC analysis under the following conditions, to be 99% ee or more.
  • Mobile phase: hexane / ethanol 50/50
  • Retention time of this compound 2.2 min (retention time of racemate: 2.0 min and 2.2 min)
  • the suspension was ice-cooled, triethylamine (0.78 mL), trimethylamine hydrochloride (80 mg) and p-toluenesulfonyl chloride (798 mg) were added and stirred for 1.5 hours.
  • 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 from Example 1) Compound 3: 400 mg of n-butyllithium (2.6 M solution in hexane, 0.438 mL) was added to a solution of 400 mg of tetrahydrofuran in tetrahydrofuran (4 mL),
  • 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 warming to 0 ° C.
  • To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, ethyl acetate was added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • 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 in the same manner as Example 1 , 1-b] [1,3] oxazole (compound 54: 400 mg) in tetrahydrofuran (4 mL) at -78 ° C, n-butyllithium (2.6 M hexane solution, 0.358 mL) was added, and 1 at the same temperature Stir for hours.
  • 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 (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.
  • 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 on carbon (10 mg) was added to a methanol (2 mL) solution of oxazole (compound 1: 50 mg), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere.
  • 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] [1,1 obtained in Example 2 3) n-Butyllithium (2.6 M solution in hexane, 0.036 mL) was added to a solution of 1 oxazole (compound 9: 36 mg) in tetrahydrofuran (1 mL), stirred at the same temperature for 2 hours, and then warmed to room temperature Stir for 2.5 hours while warming.
  • Trimethylsilyl chloride (0.093 ml) was added at -78.degree. C., and the mixture was stirred for 30 minutes at the same temperature, and then stirred for 20 minutes while warming to 0.degree.
  • saturated aqueous ammonium chloride solution at room temperature, 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 and concentrated under reduced pressure.
  • Example 9 2-[(3-fluorophenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 65) Synthesis [5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] methanol (Intermediate 11: 28) obtained in Preparation Example 5 3-Fluorophenol (0.014 mL), diisopropyl azodicarboxylate (1.9 M in toluene, 0.136 mL) and triphenylphosphine (68 mg) were added to a suspension of 1 mg of 1,4-dioxane (1 mL), Stir at room temperature for 20 hours.
  • Example 10 2-[(biphenyl-4-yloxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 93) Synthesis of 4-methylbenzenesulfonic acid [5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] obtained in Preparation Example 6 To a solution of methyl (intermediate 12: 72 mg) in acetonitrile (1.5 mL) was added 4-phenylphenol (35 mg) and cesium carbonate (123 mg), and the mixture was stirred at 80 ° C.
  • Example 12 (2S) -2-[(biphenyl-4-yloxy) methyl] -5- [6- (propan-2-yloxy) pyridin-3-yl] -2,3-dihydroimidazo [2,1 Synthesis of -b] [1,3] oxazole (Compound 108) (2S) -2-[(4-Chlorophenoxy) methyl] -5- [6- ((S) obtained by using the same method as 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
  • 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 a
  • reaction mixture was allowed to cool to room temperature, filtered through Celite®, and the filtrate was concentrated under reduced pressure.
  • 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.
  • 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 once with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 18 (2S) -5-butyl-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide
  • 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 dimethylsulfoxide (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.
  • Example 20 (2S) -2-[(biphenyl-4-yloxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound (2S) -2-[(4-Chlorophenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] obtained by the same procedure 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) under nitrogen atmosphere at 100 ° C for 2 hours It stirred.
  • 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) in N, N- The dimethylformamide (1 mL) suspension was stirred at 120 ° C.
  • reaction mixture was ice-cooled, 1 M hydrochloric acid (1 mL) was added, and the mixture was stirred at 0 ° C. for 1 hour, and then stirred for 12 hours 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, the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 22 (2S) -2-[(4-tert-butylphenoxy) methyl] -6- (methylsulfonyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound (2S) -6-Bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] obtained in Example 1 Sodium dimethylsulfinate (52 mg), L-proline (9.8 mg), copper (I) iodide (8.1 mg), sodium hydroxide (3.4 mg) in dimethyl sulfoxide (1.5 mg) The suspension was stirred at 100 ° C.
  • Example 23 (2S) -2-[(4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbaldehyde (Compound 37) Synthesis of (2S) -6-bromo-2-[(4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole obtained in Example 1 To a solution of (compound 3: 5.00 g) in tetrahydrofuran (100 mL) was added n-butyllithium (2.6 M hexane solution, 5.48 mL) at -78 ° C, and the mixture was stirred at the same temperature for 1 hour.
  • n-butyllithium 2.6 M hexane solution, 5.48 mL
  • N, N-dimethylformamide (3.12 g) was added at -78.degree. C. and stirred at the same temperature for 30 minutes, and then stirred for 13 hours while warming to room temperature.
  • saturated aqueous ammonium chloride solution and ethyl acetate was added to the reaction mixture at room temperature.
  • the organic layer and the aqueous layer were separated.
  • the aqueous layer was extracted twice 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: ethyl acetate) to give a yellow solid.
  • Example 24 ⁇ (2S) -2-[(4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-6-yl ⁇ methanol (Compound Synthesis of 41) (2S) -2-[(4-tert-Butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 obtained in Example 23 Sodium borohydride (23 mg) was added to a solution of carbaldehyde (compound 37: 183 mg) in ethanol (2 mL), and the mixture was stirred at the same temperature for 50 minutes.
  • 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 (obtained from Example 1) A suspension of compound 3: 200 mg), tributylvinyltin (0.182 mL) and tetrakistriphenylphosphine palladium (0) (132 mg) in toluene (2 mL) was stirred at 100 ° C.
  • 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 from Example 26) To a solution of compound 44: 43 mg) in methanol (1 mL) was added 10% palladium carbon (20 mg), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
  • Example 29 (2S) -2-[(4-tert-butylphenoxy) methyl] -5,6-diethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 62) Synthesis of (2S) -2-[(4-tert-butylphenoxy) methyl] -6-ethenyl-5-ethyl-2,3-dihydroimidazo [2,1-b] [2 obtained in Example 28. Using a procedure similar to Example 27 for 1,3] oxazole (Compound 56), the title compound (Compound 62) was obtained.
  • Example 30 5-methyl-2-[( ⁇ 5- [4- (trifluoromethyl) phenyl] pyridin-2-yl ⁇ oxy) methyl] -2,3-dihydroimidazo [2,1-b]
  • Synthesis of 1,3] oxazole-6-carbonitrile (Compound 171) 2- (hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1 obtained by using the same procedure as in Preparation Example 4 -b] [1,3] oxazole-6-carbonitrile (intermediate 10: 20 mg), 2-bromo-5- (4-trifluoromethylphenyl) pyridine (34 mg), palladium acetate (3 mg), A suspension of [1,1′-binaphthalene] -2-yldi-tert-butylphosphine (5 mg) and cesium carbonate (109 mg) in toluene (1 mL) was stirred at 110 ° C.
  • Example 32 2-[(4-Cyclopropylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 96) Synthesis of 4-methylbenzenesulfonic acid [5- (Pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazol-2-yl] obtained in Preparation Example 6 Add a mixture of 4-cyclopropylphenol and 4-ethenylphenol (44 mg) and cesium carbonate (193 mg) to a solution of methyl (intermediate 12: 110 mg) in acetonitrile (2.0 mL), and at 85 ° C for 2 hours It stirred.
  • Example 33 2-[(4-ethylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (Compound 100) Synthesis 2-[(4-Ethenylphenoxy) methyl] -5- (pyridin-3-yl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole obtained in Example 32 10% Palladium on carbon (5 mg) was added to a solution of (12 mg) in methanol (0.5 mL), and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), the filtrate was concentrated under reduced pressure, and 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-[(2S) obtained by using the same procedure as Example 4 Trifluoroacetic acid (1.0 mL) is added to 4-tert-butylphenoxy) methyl] -2,3-dihydroimidazo [2,1-b] [1,3] oxazole (compound 33: 110 mg) to 40 to 45 ° C.
  • Example 35 6-bromo-5-methyl-2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2]
  • Cesium carbonate (3.34 g) was added to a solution of N, N-dimethylformamide (20 mL), and the mixture was heated and stirred at 50 ° C. for 2 hours.
  • 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, the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 36 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-carbonitrile (Compound 180) 4-Methylbenzenesulfonic Acid Obtained in Preparation Example 7 [6-Cyano-5-methyl-2,3-dihydroimidazo [2, 1 4- (1,1,1-Trifluoro-2-methylpropane-2-l) in a solution of -b] [1,3] oxazol-2-yl] methyl (Intermediate 13: 130 mg) in acetonitrile (2.6 mL) (Phenolic acid) (88 mg) and cesium carbonate (254 mg) were added and stirred at 80 ° C.
  • 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 36 -Yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (compound 180: 55 mg) in 1,4-dioxane (1 mL) To the suspension was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 100 ° C.
  • Example 38 2- ⁇ [4- (2-hydroxypropan-2-yl) phenoxy] methyl ⁇ -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6 Of 2-carbonitrile (compound 210) 2-[(4-acetylphenoxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile ( A solution of 20 mg) in tetrahydrofuran (1 mL) was cooled in a dry ice / acetone bath, and methylmagnesium bromide (about 3 M solution in tetrahydrofuran, 0.045 mL) was added dropwise.
  • methylmagnesium bromide (0.045 mL) was further added, followed by stirring for 3 hours.
  • the temperature was raised to room temperature, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 39 5-methyl-2-( ⁇ [5- (trifluoromethyl) pyrimidin-2-yl] oxy ⁇ methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole Synthesis of -6-carbonitrile (compound 217) 2- (hydroxymethyl) -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (50 mg) and A solution of 2-chloro-5- (trifluoromethyl) pyridine (62 mg) in DMF (1.0 mL) was ice-cooled, sodium hydride (about 60%, 14 mg) was added, and the mixture was stirred for 1 hour.
  • Example 40 (2S) -5-ethyl-2- ⁇ [3-fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3- Synthesis of dihydroimidazo [2,1-b] [1,3] oxazole-6-carboxamide (compound 253) (2S) -5-ethyl-2- ⁇ [3-fluoro-4- (1,1,1-) Trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (246 mg) in dimethyl sulfoxide (1.
  • Example 41 (2S) -5- (2-fluoroethyl) -2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3 -Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 239) (a) Synthesized in the same manner as in Example 48 described later (2S) -5- Bromo-2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] [1,3] A solution of oxazole-6-carbonitrile (Compound 250: 126 mg) in tetrahydrofuran (2.5 mL) is cooled to ⁇ 78 ° C., n-butyllithium (2.64 M solution in hexane, 144 ⁇ L) is added, and 30 minutes at the same temperature It
  • Example 43 5-methyl-2-( ⁇ 4- [1- (trifluoromethyl) cyclopropyl] phenoxy ⁇ methyl) -2,3-dihydroimidazo [2,1-b] [1,3] oxazole- Synthesis and optical resolution of 6-carboxamide
  • Cesium carbonate (634 mg) was added to the solution and stirred at 80 ° C.
  • Example 46 2- ⁇ [4- (2-cyanopropan-2-yl) phenoxy] methyl ⁇ -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6
  • Cesium carbonate (201 mg) was added to a solution of intermediate 14 (109 mg) and 2- (4-hydroxyphenyl) -2-methylpropane nitrile (75 mg) in acetonitrile (2.2 mL) The mixture was stirred at 80 ° C. for 3 hours. After allowing to cool, insolubles were filtered off, and the filtrate was concentrated under reduced pressure.
  • Example 47 2- ⁇ [(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl) oxy] methyl ⁇ -5-methyl-2,3-dihydroimidazo [2,1-b Synthesis and Optical Resolution of [1,3] oxazole-6-carboxamide (a) Intermediate 14 (113 mg) and Acetonitrile of 1,1-Dimethyl-2,3-dihydro-1H-inden-5-ol (63 mg) Cesium carbonate (210 mg) was added to the solution (2.3 mL), and the mixture was stirred at 80 ° C. for 5 hours. After allowing to cool, insolubles were filtered off, and the filtrate was concentrated under reduced pressure.
  • Example 48 ((2S) -5-methyl-2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [ Synthesis of 2,1-b] [1,3] oxazole-6-carbonitrile (compound 243)
  • Example 50 (2S) -2-[(4-tert-Butyl-3-fluorophenoxy) methyl] -5-ethyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole- Synthesis of 6-carbonitrile (Compound 257) (2S) -5-bromo-2-[(4-tert-butyl-3-fluorophenoxy) methyl] -2 obtained using the same method as Example 48 A solution of 3,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 256: 415 mg) in tetrahydrofuran (4.2 mL) is cooled to ⁇ 78 ° C., n-butyl lithium 2.69 M hexane solution, 0.39 mL) was added dropwise.
  • Example 51 (2S) -5-methyl-2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2 , 1-b] [1,3] oxazole-6-carboxylic acid (Compound 264)
  • Sodium nitrite 32 mg was added to a solution of Compound 240 (50 mg) in trifluoroacetic acid / water (260 ⁇ L / 130 ⁇ L), The mixture was stirred for 2 hours. Water was added to the reaction solution, extraction was performed with a 10% methanol / chloroform solution, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by preparative HPLC to give the title compound (Compound 264: 21 mg, colorless amorphous).
  • Example 52 (2S) -5-[(1E) -prop-1-en-1-yl] -2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl] Synthesis of phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 269) Obtained using a method similar to Example 48 ( 2S) -5-bromo-2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] Cesium fluoride (144 mg) in a solution of [1,3] oxazole-6-carbonitrile (compound 250: 136 mg) in 1,4-dioxane (2.7 mL), tris (dibenzylideneacetone) dipalladium (0) (29 mg) ), Tri-tert-butylpho
  • Example 54 (2S) -5- (3-hydroxypropyl) -2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3 -Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 282) (a) Using the same method as Example 4, Compound 250 (207 mg) to (2S) -5-[(1E) -3- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ prop-1-en-1-yl] -2- ⁇ [4- (1,1,1-trifluoro-2) -Methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (145 mg) was obtained.
  • Example 55 (2S) -5-methyl-2-( ⁇ [1- (propan-2-yl) -1H-indol-5-yl] oxy ⁇ methyl) -2,3-dihydroimidazo [2, 1 Synthesis of -b] [1,3] oxazole-6-carbonitrile (Compound 289) (a) Using the same method as in Example 10, the intermediate 17 (40 mg) to (2S) -2-[(1H) -Indol-5-yloxy) methyl] -5-methyl-2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (13 mg) was obtained.
  • Example 56 (2S) -5- (3-chloropropyl) -2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3 -Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 290) Thionyl chloride in a solution of compound 282 (92 mg) obtained in Example 54 (92 mg) in pyridine (1.8 mL) (33 ⁇ L) was added and stirred for 5 hours. The reaction solution was purified by preparative HPLC to give the title compound (Compound 290: 16 mg).
  • 1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (339 mg) was added and stirred for another 5 hours. After ice-cooling the reaction solution, an aqueous solution of sodium thiosulfate was added to stop the reaction. Water was added to the reaction solution, extraction was performed with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution.
  • Example 58 (2S) -5- (3-Ethoxypropyl) -2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3 -Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 292)
  • Sodium hydride (about 60%, 15 mg) and ethyl iodide (41 ⁇ L) were added to a solution of compound 282 (105 mg) in N, N-dimethylformamide (2.1 mL) and stirred for 4 hours.
  • Sodium hydride (about 60%, 31 mg) and ethyl iodide (82 ⁇ L) were added and stirred overnight.
  • Example 60 3-[(2S) -6-cyano-2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydro Synthesis of imidazo [2,1-b] [1,3] oxazol-5-yl] propanoic acid (Compound 302) Pyridinium dichromate was added to a solution of Compound 282 (146 mg) in N, N-dimethylformamide (1.5 mL). 268 mg) was added and stirred overnight. Chloroform and an aqueous solution of sodium hydroxide were added to the reaction solution to separate it. The aqueous layer was adjusted to pH 5 by adding citric acid, and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (Compound 302: 66 mg).
  • Example 63 (2S) -5-[(Dimethylamino) methyl] -2- ⁇ [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2, Synthesis of 3-Dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile (Compound 337) (2S) -5-formyl-2- ⁇ [[obtained in Example 61 (a) 4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenoxy] methyl ⁇ -2,3-dihydroimidazo [2,1-b] [1,3] oxazole-6-carbonitrile A solution of (50 mg), dimethylamine (2 M solution in tetrahydrofuran, 0.132 mL), acetic acid (15 ⁇ L) in chloroform (0.3 mL) was stirred at room temperature for 1 hour.
  • N, N-dimethylformamide 200 mg of 2-bromo-5-methyl-1- ⁇ [(2S) -2-methyloxiran-2-yl] methyl ⁇ -1H-imidazole-4-carbonitrile (200 mg) 2 mL) solution was added and stirred at 50 ° C. for 4.5 hours. After ice cooling, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (compound 348: 171 mg).
  • Test Example 1 [ 35 S] GTP ⁇ S Binding Test (1) (Preparation of crude membrane fraction of rat metabotropic glutamate receptor (mGlu2) stable expression CHO cells) Rat-type mGlu2 stably expressing CHO cells was prepared using Dulbecco's modified Eagle medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 ⁇ g / mL streptomycin, 1 mM sodium Pyruva The cells were cultured at 37 ° C. under 5% CO 2 using te, 1 mM Succinic acid, 2 mM L-glutamine (added at the time of use).
  • the confluent cells were washed twice with PBS (-), then detached with a cell scraper and centrifuged at 1,000 rpm for 5 minutes at 4 ° C to recover the cells.
  • the resulting precipitate is suspended in 20 mM HEPES buffer (pH 7.4), homogenized with a homogenizer, and centrifuged again at 48,000 ⁇ g for 20 minutes at 4 ° C. I got sunk. Further, the obtained precipitate was washed twice by centrifugation and homogenized with the above buffer to obtain a crude membrane fraction.
  • the crude membrane fraction obtained was stored at -80.degree.
  • 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, scintillation cocktail was added to the filter and membrane bound radioactivity was measured with a liquid scintillation counter.
  • the amount of [ 35 S] GTP ⁇ S binding obtained in the absence of glutamate is the nonspecific binding amount
  • the difference between the amount of [ 35 S] GTP ⁇ S binding obtained in the presence of glutamate is the specific binding amount and did.
  • the EC 50 value of each example compound was calculated from the difference between the specific binding amount in the presence of each example compound at various concentrations and 3 ⁇ M glutamic acid by a regression curve using the non-linear least squares method.
  • the confluent cells were washed twice with PBS (-), then detached with a cell scraper and centrifuged at 1,000 rpm for 5 minutes at 4 ° C to recover the cells.
  • the resulting precipitate is suspended in 20 mM HEPES buffer (pH 7.4), homogenized with a homogenizer, and centrifuged again at 48,000 ⁇ g for 20 minutes at 4 ° C. I got sunk. Further, the obtained precipitate was washed twice by centrifugation and homogenized with the above buffer to obtain a crude membrane fraction.
  • the crude membrane fraction obtained was stored at -80.degree.
  • 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, scintillation cocktail was added to the filter and membrane bound radioactivity was measured with a liquid scintillation counter.
  • the amount of [ 35 S] GTP ⁇ S binding obtained in the absence of glutamate is the nonspecific binding amount
  • the difference between the amount of [ 35 S] GTP ⁇ S binding obtained in the presence of glutamate is the specific binding amount and did. From the difference between 1 ⁇ M glutamate and the specific binding amount in the presence of each example compound at various concentrations, the EC 50 value of each example compound was calculated from the regression curve using the non-linear least squares method.
  • Test Example 3 Methamphetamine-induced increase in exercise (animal) Seven-week-old male Wistar rats (Japan Charles River Co., Ltd.) were used for the test. After preliminary breeding for 4 days or more in a breeding room where temperature (23 ⁇ 3 ° C.), humidity (50 ⁇ 20%), and lighting (7:00 am-7: 00 pm) were controlled, it was used for the test. Feed (MF: Oriental Yeast Co., Ltd.) and drinking water (sterile water) were given ad libitum. Animals with no gross abnormalities were used during the study. The experiment was conducted with the approval of Taisho Pharmaceutical Co., Ltd. General Research Institute Animal Experiment Ethics Committee.
  • Compound 231, Compound 243, Compound 299 30 mg / kg was orally administered 60 minutes before methamphetamine administration, and Compound 240 30 mg / kg was orally administered 120 minutes before methamphetamine administration.
  • the control group was orally administered a 0.5% methylcellulose solution.
  • the dose volume was 2 mL / kg. (result) 30 mg / kg of Compound 231, Compound 240, Compound 243 and Compound 299 significantly attenuated methamphetamine-induced hyperactivity.

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Abstract

La présente invention concerne : un dérivé de dihydroimidazooxazole représenté par la formule générale (IA), ou un sel pharmaceutiquement acceptable de celui-ci, possédant une activité de modulateur allostérique positif sur le récepteur métabotropique de sous-type 2 du glutamate (récepteur mGlu2) ; et un produit pharmaceutique permettant de prévenir ou de traiter une maladie choisie parmi la schizophrénie, la maladie d'Alzheimer, les dysfonctionnements cognitifs, la démence, les troubles de l'anxiété, la dépression, le trouble déficitaire de l'attention avec hyperactivité (TDAH), la pharmacodépendance, les convulsions, les tremblements et les troubles de sommeil. Le produit pharmaceutique contient le dérivé de dihydroimidazooxazole, ou un sel pharmaceutiquement acceptable de celui-ci, en tant que principe actif. (Dans la formule, R1 représente un atome d'hydrogène ou un atome équivalent ; R2 représente un atome d'hydrogène ou un atome équivalent ; R3 représente un groupe aryle ou un groupe équivalent ; et R4 représente un atome d'hydrogène ou un atome équivalent.)
PCT/JP2012/077697 2011-10-28 2012-10-26 Dérivé de dihydroimidazooxazole WO2013062079A1 (fr)

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WO2017216507A1 (fr) 2016-06-16 2017-12-21 The University Of Warwick Composés
WO2019185875A1 (fr) 2018-03-30 2019-10-03 Syngenta Participations Ag Composés herbicides

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