WO2011002067A1 - Heterocyclic compound and use thereof - Google Patents

Heterocyclic compound and use thereof Download PDF

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WO2011002067A1
WO2011002067A1 PCT/JP2010/061280 JP2010061280W WO2011002067A1 WO 2011002067 A1 WO2011002067 A1 WO 2011002067A1 JP 2010061280 W JP2010061280 W JP 2010061280W WO 2011002067 A1 WO2011002067 A1 WO 2011002067A1
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ring
group
substituted
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compound
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French (fr)
Japanese (ja)
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淳 寺内
竜樹 小池
栄治 本多
実 中村
雄一 梶田
保孝 帆足
幸恵 森本
辰彦 藤本
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武田薬品工業株式会社
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Publication of WO2011002067A1 publication Critical patent/WO2011002067A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to a heterocyclic compound having an excellent inhibitory effect on amyloid ⁇ production and useful as a preventive or therapeutic agent for mild cognitive impairment, Alzheimer's disease and the like.
  • Alzheimer's disease and mild cognitive impairment account for the majority of dementia, and the number of patients has increased significantly with the arrival of an aging society.
  • drugs such as acetylcholinesterase inhibitors as therapeutic drugs, and drugs that stop or delay the progression of the disease state or have a preventive effect are desired.
  • a ⁇ amyloid ⁇
  • a ⁇ is produced from a precursor protein, a single-transmembrane protein amyloid precursor (APP), processed by a degrading enzyme called secretase, and A ⁇ 40 consisting of 40 amino acids and A ⁇ 42 consisting of 42 amino acids are mainly used. Is a molecular species. Among them, A ⁇ 42 is likely to aggregate and is considered to play an important role in senile plaque formation or neuronal cell death (Non-patent Document 1). On the other hand, it is known that secretase as a cleaving enzyme includes ⁇ -secretase that cleaves the amino terminus and ⁇ -secretase that cleaves the carboxy terminus.
  • Non-patent Document 2 A curative treatment for Alzheimer's disease that inhibits these secretases and suppresses the production and secretion of A ⁇ has been studied (Non-patent Document 1).
  • ⁇ -secretase is responsible not only for APP processing but also for essential functions such as activation of the Notch receptor, which plays an important role in cell differentiation, by transmembrane cleavage.
  • a drug that specifically inhibits only the production of A ⁇ is expected (Non-patent Document 3).
  • Non-patent Document 4 Sulfonamide derivatives and the like are known as drugs that inhibit ⁇ -secretase.
  • drugs that do not affect the Notch signal and modulate ⁇ -secretase activity drugs that do not affect the Notch signal and modulate ⁇ -secretase activity.
  • NSAIDs Non-patent Document 4
  • imidazole derivatives Non-patent Document 4, Patent Documents 1 and 2)
  • cinamide derivatives Patent Documents 3 and 4) 5, 6, 7
  • piperazine derivatives Patent Document 8
  • Patent Document 9 piperidine derivatives
  • arylazole derivatives Patent Document 10
  • Patent Documents 11 to 22 disclose various heterocyclic compounds.
  • the present invention relates to a heterocyclic compound having an amyloid ⁇ production inhibitory action, which has a chemical structure different from that of known compounds (including the above-mentioned compounds), and prevention of diseases such as mild cognitive impairment and Alzheimer's disease including the heterocyclic compound.
  • the purpose is to provide therapeutic drugs.
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 and R 3 are the same or different and Hydrogen atom, Halogen atoms, Hydroxy, An optionally substituted C 1-6 alkyl group, An optionally substituted C 1-6 alkoxy group, An optionally substituted C 1-6 alkylthio group, An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group
  • n is 1 or 2
  • R 1 is a methyl group having an optionally substituted amino group, and a partial structural formula of the formula (I):
  • a benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring; Or a salt thereof according to the above [1]; [5] R 1 is a C 1-6 alkyl group; R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group; n is 1 or 2; Y is —CO—, —CORa 1 —, —CON (Rb 1 ) —, or —CON (Rb 1 ) Ra 1 —.
  • Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
  • Rb 1 represents a hydrogen atom);
  • Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
  • Ring B is a benzene ring;
  • Ring D may be substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (when two or more substituents are present) May be bonded to each other to form a crosslinked structure);
  • Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen
  • R 1 is a C 1-6 alkyl group
  • One of R 2 and R 3 is a hydrogen atom, the other is a hydrogen atom or a C 1-6 alkoxy group
  • n is 1 or 2
  • Y is a C 1-6 alkylene group or —Ra 1 CON (Rb 1 ) —
  • Ra 1 is a C 1-6 alkylene group
  • Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom
  • Ring A is a pyrazole ring, an oxazole ring or
  • the compound of the present invention or a prodrug thereof has excellent amyloid ⁇ production inhibitory activity, it is possible to safely prevent or prevent all amyloid ⁇ production-related diseases such as mild cognitive impairment and Alzheimer's disease. Useful as a therapeutic agent.
  • Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
  • C 1-6 alkyl (group) examples include linear or branched C 1-6 alkyl (group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. Tert-butyl, pentyl, hexyl and the like.
  • C 1-6 alkoxy (group) examples include linear or branched C 1-6 alkoxy (group), for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Examples include butoxy and tert-butoxy.
  • C 1-6 alkylthio (group) examples include linear or branched C 1-6 alkylthio (group), such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like. Is mentioned.
  • C 1-6 alkylsulfonyl (group) examples include linear or branched C 1-6 alkylsulfonyl (group), for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butyl Examples include sulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
  • C 1-6 alkylsulfinyl (group) examples include linear or branched C 1-6 alkylsulfinyl (group), such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butyl And sulfinyl, pentylsulfinyl, hexylsulfinyl and the like.
  • C 1-6 alkylene (group) examples include linear C 1-6 alkylene (group) such as methylene, ethylene, propylene, butylene, pentylene, hexylene and the like.
  • substituent group A 1 to 3 substituents selected from the following substituent group (hereinafter abbreviated as substituent group A), etc. Is mentioned. When two or more substituents are present, the substituents may be the same or different.
  • Substituent group A (1) a halogen atom, (2) Nitro, (3) Cyano, (4) (a) a halogen atom, (B) a 3- to 8-membered heterocyclic group (eg, morpholinyl, pyridyl), (C) hydroxy, (D) C 1-6 alkyl-carbonyl (eg, acetyl), and (e) C 1-6 alkoxy (eg, methoxy) C 1-6 alkyl optionally having 1 to 5 substituents selected from (5) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) optionally having 1 to 5 halogen atoms, (6) C 6-14 aryl (eg, phenyl, naphthyl, etc.) optionally having C 1-6 alkyl optionally having 1 to 3 halogen atoms, (7) hydroxy
  • the “substituent” include 1 to 3 substituents selected from the above substituent group A (excluding the substituent group (4) of substituent group A). When two or more substituents are present, the substituents may be the same or different.
  • Ring A “5-membered aromatic optionally further having an optionally substituted C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • Examples of the “heterocycle” include a 5-membered aromatic heterocycle (group) having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • oxadiazolyl eg, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl
  • triazolyl eg, 1H-1,2,3-triazolyl, 2H-1, 2,3-triazolyl, 1H-1,2,4-triazolyl
  • the ring A is a optionally substituted C 1-6 alkyl group other than R 1, further 1 or 2 may be present.
  • the ring constituent atom may have one or two nitrogen atoms in addition to the carbon atom and may be further substituted”
  • the 6-membered aromatic ring (group) optionally having 1 or 2 nitrogen atoms include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
  • “may be further substituted” means that the ring B may further have 1 or 2 substituents other than R 2 and R 3 .
  • Heterocycle of “optionally substituted heterocycle” of ring D and “optionally substituted heterocycle having one or two oxo groups” is, for example, monocyclic A non-aromatic heterocyclic ring is shown.
  • “may be further substituted” means that the ring D may further have a substituent other than one or two oxo groups.
  • the “monocyclic non-aromatic heterocycle” refers to, for example, a 6- or 7-membered non-aromatic heterocycle having two nitrogen atoms in addition to carbon atoms as ring-constituting atoms.
  • Examples of the “monocyclic non-aromatic heterocyclic ring” include, for example, “monocyclic 4-7 member having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” of the following ring E Among those exemplified as “non-aromatic heterocycle (group)”, those having 6 or 7 members having two nitrogen atoms can be mentioned.
  • Non-rogen atom, oxygen atom and sulfur of ring E “optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom”
  • Monitoring 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from atoms means a monocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • a 4- to 7-membered aromatic heterocycle or a monocyclic 4- to 7-membered non-aromatic heterocycle is represented.
  • Examples of the “monocyclic 4 to 7-membered aromatic heterocycle (group) having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” include furyl, thienyl, pyridyl, pyridazinyl. , Pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl and the like.
  • Examples of the “monocyclic 4 to 7-membered non-aromatic heterocycle (group) having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” include azetidinyl, oxetanyl, thietanyl, Pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, oxepanyl, thiepanyl, oxocanyl, thiocanyl, diazepanyl (eg, 1,4-diazepanyl), dioxanyl, dihydropyrazolyl, hexahydropyrimidyl , Tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyridyl, dihydr
  • “Nitrogen atom, oxygen atom and sulfur” of ring E “optionally substituted 9-membered or 10-membered condensed heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom”
  • a 9-membered or 10-membered fused heterocyclic ring having 1 to 3 heteroatoms selected from atoms A 9- or 10-membered fused non-aromatic heterocycle in which a 5- or 6-membered monocyclic non-aromatic heterocycle and a benzene ring are condensed;
  • a 9- or 10-membered fused aromatic heterocycle in which a 5- or 6-membered monocyclic aromatic heterocycle and a benzene ring are condensed; and a 5- or 6-membered monocyclic aromatic heterocycle and a 6-membered monocyclic 9- or 10-membered fused heterocycles fused with an aromatic heterocycle;
  • the “5- or 6-membered monocyclic aromatic heterocycle” is a monocyclic 4 to 7 having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom of the above ring E.
  • the “6-membered monocyclic aromatic heterocycle” is a monocyclic 4- to 7-membered aromatic having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom of the ring E.
  • 6-membered ones can be mentioned.
  • Examples of the “3- to 7-membered saturated carbocycle (group)” of the “optionally substituted 3- to 7-membered saturated carbocycle” of ring E include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the “9 to 13-membered condensed carbocycle” of the “optionally substituted 9 to 13-membered fused carbocycle” of ring E is a 5- to 7-membered saturated carbocycle and one or two 6 to 6- A 9- to 13-membered condensed carbocycle in which a 10-membered monocyclic aromatic carbocycle (eg, benzene) is condensed is shown.
  • the “5- to 7-membered saturated carbocycle” is exemplified by the “3- to 7-membered saturated carbocycle (group)” in the “optionally substituted 3- to 7-membered saturated carbocycle” of the above ring E. Among those, 5 to 7 members (eg, 5 members) are listed.
  • Examples of the “6- to 10-membered monocyclic aromatic carbocycle (group)” include benzene and naphthalene.
  • Examples of the “9 to 13-membered condensed carbocycle (group)” of the ring E include indenyl, tetralinyl, fluorenyl, 9,10-dihydroanthracenyl and the like.
  • the “13 to 15-membered spiro heterocycle (group)” of the “optionally substituted 13 to 15-membered spiro heterocycle” of ring E includes, in addition to carbon atoms, oxygen atoms, sulfur atoms, and nitrogen atoms. Examples thereof include 13 to 15-membered spiroheterocycle having 1 to 3 heteroatoms selected, and examples thereof include spiro [1,3-dihydroisobenzofuran-1,4′-piperidine and the like.
  • Ring B “6-membered aromatic ring which may have 1 or 2 nitrogen atoms other than carbon atoms as a ring-constituting atom, and may be further substituted” Ring D “optionally substituted heterocycle”, “An optionally substituted heterocycle having 1 or 2 oxo groups", as well as an “optionally substituted benzene ring” in ring E; “Optionally substituted naphthalene ring”, “Optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom”, “Optionally substituted 9-membered or 10-membered fused heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms”, “Optionally substituted 3- to 7-membered saturated carbocyclic ring” and “optionally substituted 9- to 13-membered fused carbocyclic ring”, “Optionally substituted 13-15 membered spiro heterocycle
  • the substituents may be the same or different.
  • the substituents may be bonded to each other to form a crosslinked structure.
  • ring D in which substituents are bonded to form a crosslinked structure 2,6-diazabicyclo [3.2.2] nonan-3-one, 3,9-diazabicyclo [4.2.1] Nonan-4-one, 3,6-diazabicyclo [3.2.1] octane-7-one, 8-oxa-3,10-diazabicyclo [4.3.1] decan-4-one, 3,9- And diazabicyclo [3.3.1] nonane-2,4-dione, 3,9-diazabicyclo [3.3.1] nonane.
  • substituent group B 1 to 3 substituents may be mentioned. When two or more substituents are present, the substituents may be the same or different.
  • Substituent group B (1) a halogen atom, (2) Nitro, (3) Cyano, (4) (a) a halogen atom, (B) a 3- to 8-membered heterocyclic group (eg, morpholinyl, pyridyl), (C) hydroxy, and (d) C 1-6 alkyl-carbonyl (eg, acetyl) C 1-6 alkyl optionally having 1 to 5 substituents selected from (5) C 2-6 alkenyl optionally having 1 to 3 halogen atoms (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), (6) C 2-6 alkynyl (eg, ethynyl, propargyl, butynyl, hexynyl, etc.) optionally having 1 to 3 halogen atoms, (7) C 3-8 cycloalkyl (eg, cyclopropy
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • R 1 is preferably a hydrogen atom and a C 1-6 alkyl group, more preferably a hydrogen atom, methyl, ethyl, propyl, isopropyl and the like.
  • Another preferred embodiment of R 1 includes a C 1-6 alkyl group.
  • R 2 and R 3 are the same or different and Hydrogen atom, Halogen atoms, Hydroxy, An optionally substituted C 1-6 alkyl group, An optionally substituted C 1-6 alkoxy group, An optionally substituted C 1-6 alkylthio group, An optionally substituted C 1-6 alkylsulfonyl group or an optionally substituted C 1-6 alkylsulfinyl group is shown.
  • R 2 and R 3 (1) a hydrogen atom, (2) a halogen atom, (3) hydroxy, (4) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom), (5) a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom (eg, fluorine atom), and (b) a phenyl group, (6) a C 1-6 alkylthio group, (7) C 1-6 alkylsulfinyl group and the like can be mentioned.
  • R 2 and R 3 are more preferably hydrogen atom, chlorine atom, fluorine atom, hydroxy, methyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, benzyloxy , Hydroxy, methylthio, methylsulfinyl and the like.
  • R 2 and R 3 It is the same or different and is a hydrogen atom, a halogen atom or a C 1-6 alkoxy group.
  • One is a hydrogen atom and the other is a hydrogen atom or a C 1-6 alkoxy group.
  • n 1 or 2. n is preferably 1.
  • Y As still another preferred embodiment of Y, -CO-, -Ra 1- , -CORa 1- , -CON (Rb 1 )-, -CON (Rb 1 ) Ra 1- , -Ra 1 CON (Rb 1 )- Etc.
  • Y As yet another preferred embodiment of Y, -CO-, -CORa 1- , -CON (Rb 1 )-, -CON (Rb 1 ) Ra 1- , Etc.
  • Y As yet another preferred embodiment of Y, -CON (Rb 1 ) Ra 1- Etc.
  • Ra 1 and Ra 2 in Y represent the same or different and optionally substituted C 1-6 alkylene, and preferably the same or different, 1 or 2 substituents selected from the substituent group A And C 1-6 alkylene which may be substituted with a group.
  • (1) cyano (2) (a) halogen atom (eg, fluorine atom), (B) a 3- to 8-membered heterocyclic group, (C) hydroxy, (D) C 1-6 alkyl-carbonyl (e) C 1-6 alkoxy (eg, methoxy) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl) optionally having 1 to 5 substituents selected from (3) C 3-8 cycloalkyl optionally having 1 to 5 halogen atoms (eg, cyclopropyl) (4) C 6-14 aryl optionally having 1 to 3 halogen atoms and optionally having C 1-6 alkyl (e
  • Ra 1 and Ra 2 in Y are more preferably methylene, methylmethylene, dimethylmethylene, ethylmethylene, methylene, cyanomethylene, methoxycarbonylmethylene, hydroxymethylmethylene, ethylene, phenylethylene, hydroxyethylene, propylene, and the like. It is done. Further, the substituents may be bonded to form a ring.
  • Ra 1 and Ra 2 in Y Same or different, (1) optionally substituted with hydroxy C 1-6 alkyl group, and (2) is selected from a cyano group (eg, 1 or 2) which may be substituted with a substituent C 1- 6 alkylene group (when two or more (eg, 2) of the substituents are present, the substituents may be bonded to form a ring (eg, cyclopropane)) Is mentioned.
  • a cyano group eg, 1 or 2
  • a substituent C 1- 6 alkylene group when two or more (eg, 2) of the substituents are present, the substituents may be bonded to form a ring (eg, cyclopropane)) Is mentioned.
  • Ra 1 and Ra 2 in Y It is the same or different and is a C 1-6 alkylene group.
  • Rb 1 and Rb 2 in Y are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, preferably the same or different, a hydrogen atom or substituent group A (provided that A C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from (excluding the substituent of (4) in substituent group A).
  • Rb 1 and Rb 2 are more preferably the same or different, Hydrogen atom, (1) halogen atom (fluorine atom), (2) cyano, (3) Di-C 1-6 alkylamino (eg, dimethylamino), and (4) C 3-8 cycloalkyl (eg, cyclopropyl) C 1-6 alkyl (eg, methyl, ethyl, isobutyl) and the like, which may have 1 to 3 substituents selected from, particularly preferably a hydrogen atom, methyl, ethyl, isobutyl, cyclopropyl Methyl, 2-cyanoethyl, 2- (dimethylamino) ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and the like.
  • Rb 1 and Rb 2 in Y Hydrogen atom, And a C 1-6 alkyl group substituted with a halogen atom.
  • Yet another preferred embodiment of Rb 1 and Rb 2 in Y is a hydrogen atom or the like.
  • Ring A may further have an optionally substituted C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 5-membered aromatic group Indicates a heterocycle.
  • ring A preferably A 5-membered aromatic heterocycle which may further have a C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Ring A is more preferably an oxazole ring or a triazole ring (eg, 1,2,3-triazole, 1,2,4), each of which may further have a C 1-6 alkyl group (eg, methyl).
  • -Triazole pyrazole ring, oxadiazole ring, isoxazole ring, thiazole ring, thiophene ring, imidazole ring and the like.
  • Ring A may further have an optionally substituted C 1-6 alkyl group.
  • Each moiety may further have a C 1-6 alkyl group (eg, methyl), Oxazolyl (eg, 1,3-oxazol-5-yl), Triazolyl (eg, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 4H-1, 2,4-triazol-3-yl), Pyrazolyl (eg, 1H-pyrazol-4-yl), Oxadiazolyl (eg, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl), Isoxazolyl (eg, isoxazol-4-yl), Thiazolyl (eg, thiazol-5-yl), Thienyl (eg, 2-thienyl), Such as imidazolyl. ]
  • ring A preferably An oxazole ring which may further have an optionally substituted C 1-6 alkyl group, A 1,2,3-triazole ring optionally further having an optionally substituted C 1-6 alkyl group, A 1,2,4-triazole ring which may further have an optionally substituted C 1-6 alkyl group, And a pyrazole ring which may further have an optionally substituted C 1-6 alkyl group.
  • Ring A may further have an optionally substituted C 1-6 alkyl group.
  • Ring A is more preferably an oxazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring and the like.
  • Oxazolyl eg, 1,3-oxazol-5-yl
  • 1,2,3-triazolyl eg, 1H-1,2,3-triazol-1-yl
  • 1,2,4-triazolyl eg, 1H-1,2,4-triazol-1-yl
  • Pyrazolyl eg, 1H-pyrazol-4-yl
  • ring A includes an oxadiazole ring, a triazole ring, an isoxazole ring, a thiazole ring, a thiophene ring, and the like.
  • Oxadiazolyl eg, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl
  • triazolyl eg 2H-1,2,3-triazol-4-yl, 4H-1,2,4-triazol-3-yl
  • Isoxazolyl eg, isoxazol-4-yl
  • Thiazolyl eg, thiazol-5-yl
  • Thienyl eg, 2-thienyl
  • Still another preferred embodiment of ring A includes a pyrazole ring, an oxazole ring, a triazole ring, and the like.
  • Part is Pyrazolyl (eg, 1H-pyrazol-4-yl), Oxazolyl (eg, 1,3-oxazol-5-yl), Triazolyl (eg, 1H-1,2,4-triazol-1-yl) Etc. ] Of these, an oxazole ring is preferable.
  • Ring B represents a 6-membered aromatic ring which may have 1 or 2 nitrogen atoms in addition to carbon atoms as a ring-constituting atom, and may be further substituted.
  • the ring B preferably includes a benzene ring, a pyridine ring, a pyrimidine ring (that is, corresponding to phenyl, pyridyl, pyrimidinyl) and the like. Of these, a benzene ring is preferred.
  • Ring D represents an optionally substituted heterocyclic ring.
  • the “heterocycle” of the “optionally substituted heterocycle” is preferably a monocyclic non-aromatic heterocycle, and more preferably has two nitrogen atoms in addition to carbon atoms as ring-constituting atoms. Examples include 6- or 7-membered non-aromatic heterocycles. More preferred are piperazinyl, 1,4-diazepanyl and the like.
  • Examples of the “substituent” of the “optionally substituted heterocycle” of Ring D include 1 to 3 substituents selected from Substituent Group B. When two or more substituents are present, the substituents may be bonded to form a crosslinked structure.
  • the “optionally substituted heterocycle” in ring D includes a monocyclic non-aromatic heterocycle (eg, 2,6-diazabicyclo [3.2.2]) that may have a bridge structure.
  • a monocyclic non-aromatic heterocycle eg, 2,6-diazabicyclo [3.2.2]
  • substituents preferably (1) oxo, (2) (a) a halogen atom, (B) a 3- to 8-membered heterocyclic group, (C) hydroxy, and (d) C 1-6 alkyl - 1-5 may have a substituent group C 1-6 alkyl selected from carbonyl (e.g., methyl, ethyl), (3) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl), (4) mono-C 1-6 alkyl-carbamoyl (eg, ethylcarbamoyl), and (5) di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl) 1 to 3 substituents selected from: More preferable examples of the substituent include methyl, ethyl, hydroxymethyl, ethylcarbamoyl, diethylcarbamoyl, oxo, methoxycarbon
  • the ring D includes a heterocyclic ring which has one or two oxo groups and may be further substituted.
  • a heterocyclic ring for example, piperazinyl, 1,4-diazepanyl
  • Specific examples include oxopiperazinyl, 7-oxo-1,4-diazepanyl and the like.
  • ring D (1) an oxo group, (2) a C 1-6 alkyl group, and (3) a heterocyclic ring which may be substituted with 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl groups (two or more of the substituents) When present, the substituents may be bonded to each other to form a crosslinked structure) Is mentioned.
  • a heterocyclic ring optionally substituted with 1 to 3 substituents selected from (1) a C 1-6 alkyl group and (2) a C 1-6 alkoxy-carbonyl group (two or more of the substituents) When present, the substituents may be bonded to each other to form a crosslinked structure) Is mentioned.
  • Still another preferred embodiment of ring D includes a heterocyclic ring having one oxo group.
  • Yet another preferred embodiment of ring D is a heterocyclic ring.
  • Ring E is i) an optionally substituted benzene ring, ii) an optionally substituted naphthalene ring, iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms; v) an optionally substituted 3- to 7-membered saturated carbocyclic ring, vi) an optionally substituted 9-13 membered fused carbocycle, or vii) an optionally substituted 13-15 membered spiro heterocycle.
  • ring E preferably i) a benzene ring optionally substituted with 1 to 3 substituents selected from substituent group B; ii) a naphthalene ring optionally substituted with 1 to 3 substituents selected from substituent group B; iii) substituted with 1 to 3 substituents selected from Substituent Group B having 1 to 3 (eg, 1 or 2) heteroatoms selected from nitrogen, oxygen and sulfur atoms A monocyclic 4 to 7 membered heterocycle which may be iv) 9-membered or 10-membered optionally substituted by 1 to 3 substituents selected from Substituent Group B having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms A fused heterocycle of v) a 3- to 7-membered saturated carbocyclic ring which may be substituted with 1 to 3 substituents selected from Substituent Group B; vi) a 9- to 13-membered fused carbocycle optionally substituted with 1 to 3 substituent
  • a halogen atom eg, chlorine atom, fluorine atom
  • Nitro (3) hydroxy
  • (4) (a) a halogen atom (eg, fluorine atom), (B) a 3- to 8-membered heterocyclic group, (C) hydroxy, (D) C 1-6 alkyl-carbonyl, and (e) C 1-6 alkoxy (eg, methoxy) C 1-6 alkyl (eg, methyl, isopropyl, tert-butyl) optionally having 1 to 5 substituents selected from (5) (a) a halogen atom (eg, chlorine atom, fluorine atom), (B) cyano, (C) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (D) C 6-14 aryl optionally having 1 to 3 substituents selected from C 1-6 alkoxy (eg, phenyl) (6) (a) a halogen atom (eg, chlorine atom, flu
  • a halogen atom (2) a C 1-6 alkyl group substituted with a halogen atom, 1 to 3 substituents selected from (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a phenyl group substituted with a C 1-6 alkyl group substituted with a halogen atom.
  • substituents selected from (3) a C 1-6 alkoxy group substituted with a halogen atom
  • a phenyl group substituted with a C 1-6 alkyl group substituted with a halogen atom examples thereof include a benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, pyrrolidine ring or pyrazole ring which may be substituted.
  • Still another preferred embodiment of the ring E includes a benzene ring in which the ring E is substituted with 1 to 3 halogen atoms. Still another preferred embodiment of ring E includes a benzene ring substituted with 1 to 3 C 1-6 alkyl groups substituted with a halogen atom.
  • R 1a is a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2a and R 3a are the same or different, Hydrogen atom, Halogen atoms, Hydroxy, An optionally substituted C 1-6 alkyl group, An optionally substituted C 1-6 alkoxy group, An optionally substituted C 1-6 alkylthio group, An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group
  • n a is 1 or 2
  • Ring A a may further have an optionally substituted C 1-6 alkyl group.
  • Part is 1,3-oxazol-5-yl which may further have an optionally substituted C 1-6 alkyl group, 1H-1,2,3-triazol-1-yl which may further have an optionally substituted C 1-6 alkyl group, Further have a substituent which do may be C 1-6 alkyl groups further may have IH-1,2,4-triazol-1-yl, or optionally substituted C 1-6 alkyl group, 1H-pyrazol-4-yl (that is, in the above formula (Ia), the partial structural formula:
  • Ring Ba may have 1 or 2 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and may be further substituted 6-membered aromatic ring
  • Ring Da is an optionally substituted heterocycle
  • Ring E a is i) an optionally substituted benzene ring, ii) an optionally substituted naphthalene ring, iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms; v) an optionally substituted 3- to 7-membered saturated carbocycle, or vi) an optionally substituted 9- to 13-membered fused carb
  • R 1b is a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2b and R 3b are the same or different and Hydrogen atom, Halogen atoms, Hydroxy, An optionally substituted C 1-6 alkyl group, An optionally substituted C 1-6 alkoxy group, An optionally substituted C 1-6 alkylthio group, An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group
  • n b is 1 or 2
  • Y b is Join hands, -Ra 1- , -Ra 1 CO-, -Ra 1 CON (Rb 1 )-, -Ra 1 CON (Rb 1 ) Ra 2- , -Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-, -Ra 1 CON (Rb 1 ) Ra 2 O-, -Ra 1 O-, -CO-, -CO-CO-
  • Y b is Join hands, -Ra 1- , -Ra 1 CO-, -Ra 1 CON (Rb 1 )-, -Ra 1 CON (Rb 1 ) Ra 2- , -Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-, —Ra 1 CON (Rb 1 ) Ra 2 O—, or —Ra 1 O—
  • Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene
  • Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group); Is preferred.
  • R 1 is a C 1-6 alkyl group
  • R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group
  • n is 1 or 2
  • Y is, -CO -, - Ra 1 - , - CORa 1 -, - CON (Rb 1) -, - CON (Rb 1) Ra 1 - or -Ra 1 CON (Rb 1) -
  • Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring)
  • Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom
  • Ring A is a pyrazole ring, an oxazole
  • a benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring; The compound of the present invention.
  • Y is —CO—, C 1-6 alkylene, —CONH—, —CONHRa 1 —
  • Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group
  • Y is —Ra 1 CON (Rb 1 ) — Wherein Ra 1 is a C 1-6 alkylene group; Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom) And the compounds of the present invention.
  • Examples of the compound of the present invention include one in which R 2 and R 3 are one of a hydrogen atom or a halogen atom and the other is a hydrogen atom or a C 1-6 alkoxy group.
  • R 1 is a C 1-6 alkyl group
  • R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group
  • n is 1 or 2
  • Y is —CO—, —CORa 1 —, —CON (Rb 1 ) —, or —CON (Rb 1 ) Ra 1 —.
  • Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
  • Rb 1 represents a hydrogen atom);
  • Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
  • Ring B is a benzene ring;
  • Ring D may be substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (when two or more substituents are present) May be bonded to each other to form a crosslinked structure);
  • Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen
  • a benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring; The compound of the present invention.
  • Y is —CO—, —CONH—, —CONHRa 1 —
  • Ra 1 is a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group
  • the compounds of the present invention are preferred.
  • Examples of the compound of the present invention include one in which R 2 and R 3 are one of a hydrogen atom or a halogen atom and the other is a hydrogen atom or a C 1-6 alkoxy group.
  • R 1 is a C 1-6 alkyl group;
  • One of R 2 and R 3 is a hydrogen atom, the other is a hydrogen atom or a C 1-6 alkoxy group; n is 1 or 2;
  • Y is a C 1-6 alkylene group or —Ra 1 CON (Rb 1 ) —
  • Ra 1 is a C 1-6 alkylene group;
  • Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
  • Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
  • Ring B is a benzene ring;
  • Ring D is a heterocycle having one oxo group;
  • the compound of the present invention is a C 1-6 alkyl group;
  • One of R 2 and R 3 is a hydrogen atom
  • R 1 is a C 1-6 alkyl group;
  • One of R 2 and R 3 is a hydrogen atom and the other is a C 1-6 alkoxy group; n is 1;
  • Y is —CON (Rb 1 ) Ra 1 — (Ra 1 is a C 1-6 alkylene group which may be substituted with a C 1-6 alkyl group which may be substituted with a hydroxy group; Rb 1 is a hydrogen atom);
  • Ring A is an oxazole ring;
  • Ring B is a benzene ring;
  • Ring D is a heterocycle;
  • the compound of the present invention is a C 1-6 alkyl group;
  • One of R 2 and R 3 is a hydrogen atom and the other is a C 1-6 alkoxy group;
  • n is 1;
  • Y is —
  • R 1 is a hydrogen atom or a C 1-6 alkyl group (preferably a hydrogen atom, methyl, ethyl, propyl, isopropyl);
  • R 2 and R 3 are the same or different, (1) a hydrogen atom, (2) a halogen atom, (3) hydroxy, (4) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom), (5) a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom (eg, fluorine atom), and (b) a phenyl group, (6) C 1-6 alkylthio group, or (7) C 1-6 alkylsulfinyl group (preferably a hydrogen atom, a chlorine atom, a fluorine atom, hydroxy, methyl, trifluoromethyl, methoxy, ethoxy, propoxy,
  • Ra 1 and Ra 2 methylene, methylmethylene, dimethylmethylene, ethylmethylene, methylene, cyanomethylene, methoxycarbonylmethylene, hydroxymethylmethylene, ethylene, phenylethylene, hydroxy
  • Rb 1 and Rb 2 are the same or different, Hydrogen atom, (1) halogen atom (fluorine atom), (2) cyano, (3) di-C 1-6 alkylamino (eg, dimethylamino), and (4) C 3-8 cycloalkyl (eg, cyclopropyl).
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from (eg, methyl, ethyl, isobutyl) (Preferably a hydrogen atom, methyl, ethyl, isobutyl, cyclopropylmethyl, 2-cyanoethyl, 2- (dimethylamino) ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl); Ring A may further have a C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (preferably, Oxazole ring, triazole ring (eg, 1,2,3-triazole, 1,2,4-triazole), pyrazole ring, oxadiazole ring, isoxazole ring, thiazole ring, thiophene ring, imidazole ring); Ring B is a benzene ring, a pyridine ring
  • the compounds described in the examples are particularly preferred.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids.
  • metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the compound of the present invention and its starting compound can be produced by a method known per se, for example, by the method shown in the following scheme [Production methods A and B (reaction 01 to reaction 04)].
  • room temperature usually indicates 0 to 30 ° C.
  • each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified.
  • the compound in the formula includes a case where a salt is formed. Examples of such a salt include the same salts as those of the compound of the present invention.
  • the compound obtained in each step can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be easily purified.
  • a commercially available product can be used as it is.
  • the corresponding precursor also has the same substituent.
  • the raw material compound has an amino, carboxy, hydroxy, or heterocyclic group, these groups may be protected with a protecting group generally used in peptide chemistry or the like. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • P 1 to P 3 represent a protecting group for a nitrogen atom of amine or amide, a protecting group for a hydroxy group, or a hydrogen atom, and those known per se can be used.
  • P 1 to P 3 are preferably tert-butyl carbamate group, benzyl carbamate group, benzyl group, methyl group, ethyl group and the like.
  • P 1 to P 3 itself can be a substituent of the compound (1), and examples thereof include a tert-butyl carbamate group, a benzyl carbamate group, a benzyl group, a methyl group, and an ethyl group.
  • L 1 to L 7 each represent a leaving group such as a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethane) Sulfonyloxy, etc.), C 6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), C 1-6 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like are used.
  • a halogen atom eg, chlorine atom, bromine atom, iodine atom
  • C 1-6 alkylsulfonyloxy eg, methanesulfonyloxy, e
  • L 1 to L 7 also contain a substituent that can be converted into a leaving group, and the substituent can be converted into the leaving group by a reaction known per se in a desired step.
  • L 1 to L 7 are methylthio groups, they are converted to methanesulfonyl groups by an oxidation reaction.
  • R 5 to R 10 , R 12 and R 13 each represents a C 1-6 alkyl group which may have a substituent, or a hydrogen atom, and R 11 has a substituent.
  • an optionally substituted C 1-6 alkyl group or an optionally substituted C 6-10 aryl group is optionally substituted.
  • Each step described below can be performed without solvent or by dissolving or suspending in an appropriate solvent, and two or more solvents may be mixed and used in an appropriate ratio.
  • two or more solvents may be mixed and used in an appropriate ratio.
  • the following solvents are used.
  • Ethers such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol: Aromatic hydrocarbons such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane: Saturated hydrocarbons such as benzene, chlorobenzene, toluene, xylene: Amides such as cyclohexane and hexane: Halogenated hydrocarbons such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide: Nitriles such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane: Sulfoxides such as acetonitrile and propionitrile: Aromatic organic bases such as dimethyl sulfoxide: Acid anhydrides such as
  • Inorganic bases Basic salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide: Organic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate: Triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [ Metal alkoxides such as 4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene: Alkali metal hydr
  • Inorganic acids Organic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid: Lewis acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid: Boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.
  • the compound of the present invention can be produced by condensing compound (2) and compound (3) in the presence of a metal catalyst according to Step A-1.
  • a metal catalyst metal complexes having various ligands are used.
  • palladium compounds eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) chloride.
  • Triphenylphosphine nickel (0), bis (triethylphosphine) nickel (II) chloride, bis (triphenylphosphine) nickel (II) chloride, etc.]
  • rhodium compounds Example: tris (triphenylphosphine) rhodium chloride (III ), Etc.] cobalt compounds, copper compounds [e.g., copper oxide, copper iodide (I), copper sulfate, copper chloride (II), etc.], platinum compounds and the like. Of these, palladium compounds and copper compounds are preferred.
  • Compound (3) is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (2).
  • the metal catalyst is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (2).
  • This reaction is preferably performed in the presence of a base.
  • the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like.
  • the base is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (2).
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 50 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • the compound of the present invention can also be produced by condensing compound (2) and compound (3) according to Step A-1.
  • Compound (3) is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 5 mol, per 1 mol of compound (2).
  • the reaction can be carried out in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides. And organic lithiums.
  • the base is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (2).
  • This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is usually 0 to 250 ° C., preferably 0 to 200 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (2) and compound (3) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Compound (2) can be produced by condensing compound (4) and compound (5a) according to Step B-1.
  • the reaction may be performed according to the same method as in step A-1.
  • Compound (2) can also be produced by condensing compound (4) and compound (5b) according to Step B-1.
  • R 4 represents a boron atom portion, a tri-C 1-6 alkylstannyl group, a hydrogen atom, or the like of an organic boronic acid or organic boronic acid ester.
  • the organic boronic acid or organic boronic acid ester for example dihydroxyboranyl group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group are preferable, the tri C 1-
  • the 6- alkylstannyl group is preferably a tributylstannyl group.
  • the condensation reaction is carried out by reacting compound (4) with compound (5b) in the presence of a metal catalyst.
  • a metal catalyst include palladium compounds [eg, palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, dichlorobis (triethylphosphine) palladium (0), Tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate and 1,1′-bis (diphenylphosphino) ferrocene complex, etc.] are preferred.
  • the reaction is usually performed in the presence of a base.
  • Examples of the base include inorganic bases and basic salts.
  • Compound (5b) is used in an amount of about 0.1-10 mol, preferably about 0.8-2.0 mol, per 1 mol of compound (4).
  • the metal catalyst is used in an amount of about 0.000001 to 5.0 mol, preferably about 0.0001 to 1.0 mol, per 1 mol of compound (4).
  • the base is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (4).
  • the reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas. This reaction is advantageously performed using a solvent inert to the reaction.
  • Such a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent for example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, water Or a mixed solvent thereof.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 5 min to 100 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 0 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Compound (2a) can be produced according to Step B-6 by subjecting compound (6) to a condensation reaction with 1-[(isocyanomethyl) sulfonyl] -4-methylbenzene in the presence of a base.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides and the like.
  • the base is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (6).
  • 1-[(Isocyanomethyl) sulfonyl] -4-methylbenzene is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (6).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent inert for example, solvents, such as alcohol, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, etc.
  • solvents such as alcohol, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, etc.
  • a mixed solvent thereof is preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (2a) can also be produced by subjecting compound (8) and compound (9) to a condensation reaction in the presence of an oxidizing agent and an acid according to Step B-7.
  • an oxidizing agent include organic peracids such as perbenzoic acid, m-chloroperbenzoic acid (MCPBA), and peracetic acid such as perchloric acid such as lithium perchlorate, silver perchlorate, and tetrabutylammonium perchlorate.
  • Acid salts such as iodobenzene diacetate, sodium periodate, Dess-Martin periodinane, periodate such as o-iodooxybenzoic acid (IBX), manganic acid such as manganese dioxide, potassium permanganate, such as lead tetraacetate
  • Leads such as, for example, chromate such as pyridinium chlorochromate, pyridinium dichromate, inorganic nitrogen compounds such as acyl nitrate, dinitrogen tetroxide, such as halogen, N-bromosuccinimide (NBS), N-chloro Halogen compounds such as succinimide (NCS), sulfuryl chloride, Examples include chloramine T, oxygen, hydrogen peroxide, and the like.
  • the oxidizing agent is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (8).
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 10 mol, per 1 mol of compound (8).
  • the compound (9) include C 1-6 alkyl nitriles such as acetonitrile and propionitrile.
  • Compound (9) is used in an amount of about 0.8 mol or more per 1 mol of compound (8) and can also be used as a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds. Etc. are preferable.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-48 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 100 ° C.
  • Compound (2a) can also be produced by subjecting compound (10) and compound (11) to a condensation reaction in the presence of an acid according to Step B-8.
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.001 to 10 mol, preferably about 0.1 to 2.0 mol, per 1 mol of compound (10).
  • the compound (11) include ortho acid esters such as trimethyl orthoacetate, triethyl orthopropionate and trimethyl orthoformate.
  • Compound (11) is used in an amount of about 0.8 mol or more per 1 mol of compound (10), and can also be used as a solvent. This reaction is advantageously performed using a solvent inert to the reaction.
  • solvents such as alcohol, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, etc.
  • a mixed solvent thereof is preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 1 hr-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (2a) is produced according to a method known per se, for example, the method described in Bioorganic & Medicinal Chemistry Letters, Vol. 13, p. 2059 (2003), or a method analogous thereto. You can also.
  • Compound (8) can be produced from compound (4) according to step B-2, from compound (6) according to step B-4, or from compound (7) according to step B-3.
  • Compound (10) can be produced from compound (8) according to Step B-5.
  • Step B-2 includes, for example, a method of subjecting compound (4) and tributyl (ethoxyvinyl) -tin to the same reaction as the method of producing compound (2) from compound (4) and compound (5b), etc.
  • Step B-4 includes, for example, a method of adding a Grignard reagent represented by R 5 CH 2 MgBr to an aldehyde group, and then subjecting it to an oxidation reaction.
  • Step B-3 includes, for example, And a method in which a carboxyl group is converted to wine levamide and then subjected to a reaction with a Grignard reagent represented by R 5 CH 2 MgBr.
  • Step B-5 includes, for example, an action of a halogenating agent on a ketone. And an ⁇ -haloketone, followed by a reaction with an aminating agent.
  • Compound (2b) can be produced by condensing compound (13) and compound (14) according to Step B-10, followed by condensation reaction with ortho acid esters.
  • Examples of the compound (14) include alkylimide thioates such as methyl ethaneimide thioate hydroiodide, methyl propanimide thioate hydrochloride, etc., and methods known per se, such as Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion Medicinal Chemistry (Indian Journal of Chemistry, Section Organic: Chemistry, Including Medicinal Chemistry), Volume 21, page 272 (1982), etc. Can do.
  • Compound (14) is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 5 mol, per 1 mol of compound (13).
  • ortho acid esters examples include trimethyl orthoacetate, triethyl orthopropionate, trimethyl orthoformate and the like. Ortho acid esters are used in an amount of about 0.8 mol or more per 1 mol of compound (13), and can also be used as a solvent.
  • the solvent in the condensation reaction between the compound (13) and the compound (14) is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogens Solvents such as fluorinated hydrocarbons, nitriles, sulfoxides or a mixed solvent thereof are preferred.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 100 ° C.
  • the solvent in the condensation reaction with the ortho acid ester is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles , Sulfoxides, aromatic organic bases, organic bases, or a mixed solvent thereof.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-200 hr, preferably 10 min-48 hr.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 150 ° C.
  • Compound (13) can be produced by reacting compound (12) with nitrous acid in the presence of an acid, followed by a reduction reaction according to Step B-9.
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.01 mol or more per 1 mol of compound (12), and can also be used as a solvent.
  • the nitrites include nitrites such as sodium nitrite and potassium nitrite, and nitrites such as isoamyl nitrite.
  • Nitrous acid is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 5 mol, per 1 mol of compound (12).
  • the reducing agent include reducing agents such as tin chloride.
  • the reducing agent is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 10 mol, per 1 mol of compound (12).
  • the solvent in the reaction with nitrous acid is not particularly limited as long as the reaction proceeds.
  • a solvent such as inorganic acids, organic acids, alcohols, ethers, amides, nitriles, sulfoxides or a mixed solvent thereof. Etc. are preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 80 ° C.
  • the solvent in the reduction reaction is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 80 ° C.
  • Compound (2c) can be produced by condensing compound (12) and compound (17) according to Step B-12.
  • Compound (12) is used in an amount of about 0.1 to 10 mol, preferably about 0.2 to 5 mol, per 1 mol of compound (17).
  • the solvent is not particularly limited as long as the reaction proceeds.
  • inorganic acids, organic acids, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, Solvents such as sulfoxides, aromatic organic bases and organic bases, or mixed solvents thereof are preferred.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 80 ° C.
  • Compound (17) can be produced by condensing compound (15) and compound (16) in the presence of an acid according to Step B-11.
  • the acid include inorganic acids, organic acids, Lewis acids and the like.
  • the acid is used in an amount of about 0.01 mol or more per 1 mol of compound (16), and can also be used as a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • inorganic acids, organic acids, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, Solvents such as sulfoxides or mixed solvents thereof are preferred.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 80 ° C.
  • Compound (2) is a method known per se, for example, European Journal of Organic Chemistry, Vol. 13, p. 2970 (2006), Synthetic Communications, Vol. 36, p. 2927 (2006). ), Journal of Organic Chemistry, 44, 4160 (1979), Journal of the Chemical Society, 4251 (1954), WO 2008/77649, etc. It can also be produced according to the method described in 1. or a method analogous thereto.
  • R 2 or R 3 groups are halogen atoms
  • a C 1-6 alkyl oxide is allowed to act on those halogen atoms according to a method known per se or a method analogous thereto
  • R Examples include the case where one or two of the two groups or R 3 groups are converted into a C 1-6 alkyloxy group.
  • Compound (3a) can be produced according to Step C-1 by introducing compound (18) to compound (20a) and then removing the protecting group of compound (20a). Removal of the protecting group, a method known per se, for example, Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) according the like to the method described in Just do it. Even when compound (18) is unprotected (when P 1 is a hydrogen atom), it can be led to compound (3a) according to Step C-1. In that case, removal of the protecting group can be omitted.
  • Compound (3b) is obtained by removing Step C-2 and the protecting group from Compound (18)
  • Compound (3c) is obtained by removing Step C-3 and the protecting group from Compound (18)
  • Compound (20e) is obtained by Compound (18).
  • step C-4 and removal of the protecting group compound (3d) is obtained from compound (20e) by removal of step C-5 and the protecting group
  • compound (3e) is converted from compound (18) to step C-6 and the protecting group.
  • Removal of the group or compound (3) can be prepared from compound (18) by step C-7 and removal of the protecting group. Removal of the protecting group may be carried out by the same method as the method for producing compound (3a) from compound (20a). Even when P 1-2 is a hydrogen atom, compound (3a) is produced from compound (18). A method similar to the method may be used.
  • Compound (20a) can be produced by reacting compound (18) and alkylating agent (19a) in the presence of a base according to Step C-1.
  • the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like.
  • the base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (18).
  • sodium iodide, potassium iodide or the like may be added. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably ⁇ 10 to 150 ° C.
  • Compound (20b) can be produced by reacting compound (18) with carboxylic acid (19b), a salt thereof or a reactive derivative thereof according to Step C-2.
  • the reactive derivative of the carboxylic acid include acid halides such as acid chlorides and acid bromides, acid amides such as pyrazole, imidazole and benzotriazole, acid anhydrides such as acetic anhydride, propionic anhydride and butyric anhydride, Acid azide, diethoxyphosphate, diphenoxyphosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide , Esters with 1-hydroxybenzotriazole, esters with 6-chloro-1-hydroxybenzotriazole, esters with 1-hydroxy-1H-2-pyridone, 2-pyridylthioester, 2-benzothia Like activity thi
  • the carboxylic acid or a salt thereof may be directly reacted with the compound (18) in the presence of a suitable condensing agent.
  • a suitable condensing agent for example, N, N′-disubstituted carbodiimides such as N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride, N, N′— Azolides such as carbonyldiimidazole, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, 2-chloromethylpyridinium iodide, 2-fluoro-1-methyl And 2-halogenopyridinium salts such as pyridinium iodide.
  • the reaction is considered to proceed through a reactive derivative of carboxylic acid.
  • the carboxylic acid, salt thereof or reactive derivative thereof is generally used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (18).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases Or a solvent mixture thereof is preferred.
  • the reaction can be performed in the presence of a deoxidizing agent for the purpose of removing them from the reaction system.
  • a deoxidizing agent include basic salts and organic bases.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 72 hr, preferably 30 min to 24 hr.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 70 ° C.
  • Compound (20c) can be produced by reacting compound (18) with isocyanate (19c) according to Step C-3. It can also be produced by reacting compound (19d) with a reactive derivative of compound (18).
  • the reactive derivative include carboxamide with imidazole and the like.
  • the compound (19d) may be directly reacted with the compound (18) in the presence of a suitable condensing agent.
  • the condensing agent include phosgenes such as phosgene and triphosgene, and azolides such as N, N′-carbonyldiimidazole. When these condensing agents are used, the reaction is considered to proceed via a reactive derivative of compound (18).
  • the isocyanate (19c) or compound (19d) is generally used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (18) or a reactive derivative thereof.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases Or a solvent mixture thereof is preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 24 hr, preferably 30 min to 4 hr.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 70 ° C.
  • R ⁇ 12 > group is a hydrogen atom in a compound (20c)
  • it can also attach to alkylation reaction if desired.
  • the alkylating agent include compounds represented by L 6 -R 12 .
  • the alkylation reaction may be performed by the same method as in Step C-1.
  • Compound (20d) can be produced by reacting compound (18) and alkylating agent (19e) in the presence of a base according to Step C-4.
  • the alkylation reaction may be performed by the same method as in Step C-1.
  • Compound (20f) can be produced by condensing compound (20e) and compound (19f) according to Step C-5.
  • the condensation reaction may be performed by the same method as in Step C-2.
  • R ⁇ 13 > group is a hydrogen atom in a compound (20f), it can also be further attached
  • the alkylating agent include compounds represented by L 7 -R 13 .
  • the alkylation reaction may be performed by the same method as in Step C-1.
  • Compound (20 g) can be produced by condensing compound (18) and compound (19 g) according to Step C-6.
  • the condensation reaction may be performed by a method similar to the method for producing the compound of the present invention from the compound (2) and the compound (3).
  • Compound (20h) is produced from compound (18) by carrying out known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, etc., alone or in combination of two or more thereof, in Step C-7. Can do. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations (ORGANIC ⁇ ⁇ FUNCTIONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PRESS, INC.) Comprehensive Organic Transformation (Comprehensive Organic Transformations) VCH Publishers Inc. 1989, etc. may be used.
  • Compounds (3a-e), (18), (19a-g), and (20a-h) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • the compound of the present invention can also be produced by subjecting compound (2) to a series of reaction steps of Step D-1, deprotection, and Step D-2.
  • the compound of the present invention can also be produced by subjecting compound (23) to a series of reaction steps of Step D-3, Deprotection, Step D-5, and Step D-7.
  • R 14 represents a substituent such as a halogen, a carboxyl group, an aldehyde group, an amino group, or a C 1-6 alkylcarbonyl group.
  • Compound (21) can also be produced from compound (24) according to step D-4, and compound (26) from compound (3) according to step D-6.
  • the reaction steps exemplified in Steps D-1 to D-7 are the reaction steps exemplified in Step A-1, Steps B-1 to B-12, and Steps C-1 to C-7, etc. This can be done by combining two or more.
  • the compound of the present invention can be produced as a configurational isomer or stereoisomer alone or as a mixture thereof.
  • These isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) And the like can be obtained individually.
  • the compound of the present invention may have a stereoisomer depending on the type of substituent, and not only this isomer alone but also a mixture thereof is also included in the present invention.
  • a known hydrolysis reaction, deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, substituent exchange reaction, condensation reaction may be performed as desired.
  • the compounds of the present invention can also be produced by performing each of these alone or in combination of two or more thereof. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations, 2nd edition, ACADEMIC PRESS, INC., 1989. Comprehensive Organic Transformations VCH Publishers Inc. may be performed according to the method described in 1989 and the like.
  • the compound of the present invention can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractional distillation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • the compound of the present invention When the compound of the present invention is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, a method known per se Alternatively, it can be converted to a free form or other desired salt by a method equivalent thereto.
  • the compound of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, any one of the isomers and a mixture are also included in the compound of the present invention.
  • an optical isomer exists in the compound of the present invention, an optical isomer separated from a racemate is also encompassed in the compound of the present invention.
  • the compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a mixture of crystal forms. Crystals can be produced by crystallization by applying a crystallization method known per se.
  • the compound of the present invention may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non-hydrate etc.), and both are included in the compound of the present invention.
  • a prodrug of the compound of the present invention is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidizes, reduces, hydrolyzes, etc. and changes to the compound of the present invention A compound that undergoes hydrolysis or the like due to a compound, gastric acid or the like and changes to the compound of the present invention.
  • a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.); compounds of the present invention Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated,
  • the prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Drug Development, Volume 7 (Molecular Design), pp. 163-198 (Hirokawa Shoten). May be.
  • the compound of the present invention or a prodrug thereof has excellent amyloid ⁇ production inhibitory activity and has toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.) It is also useful as a pharmaceutical because it is low and has excellent stability and pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.).
  • the compound of the present invention or a prodrug thereof has an action of inhibiting amyloid ⁇ production on mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It can be used as a prophylactic / therapeutic agent for diseases that may be related to the production of amyloid ⁇ .
  • Diseases that may be related to amyloid ⁇ production include, for example, neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Parkinson's disease), memory disorders (eg, senile dementia, mild cognition) Disorders (MCI), amnesia, etc.), ischemic central nervous disorders (eg, brain amyloid angiopathy (CAA), etc.), Down's syndrome and the like.
  • the compound of the present invention or a prodrug thereof is preferably useful as an agent for inhibiting or treating amyloid ⁇ production, mild cognitive impairment or Alzheimer's disease.
  • the medicament containing the compound of the present invention or a prodrug thereof can be used alone or in accordance with a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia, etc.)
  • a pharmaceutical preparation eg, a method described in the Japanese Pharmacopoeia, etc.
  • tablets including sugar-coated tablets, film-coated tablets, etc.
  • powders including sugar-coated tablets, film-coated tablets, etc.
  • powders granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained release ( For example, sublingual tablets, microcapsules, etc.), patches, orally disintegrating tablets, orally disintegrating films, etc., orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) can do.
  • the content of the compound of the present invention or a prodrug thereof in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament.
  • the dose of the compound of the present invention or a prodrug thereof varies depending on the administration subject, administration route, disease, symptom and the like.
  • the prodrug is about 0.001 to about 100 mg / kg body weight, preferably about 0.005 to about 50 mg / kg body weight, more preferably about 0.01 to about 2 mg / kg body weight.
  • the pharmacologically acceptable carrier examples include various organic or inorganic carrier substances that are conventionally used as pharmaceutical materials.
  • excipients examples include excipients, lubricants, binders and disintegrants in solid preparations, or solvents in liquid preparations.
  • Solubilizers suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate;
  • hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention or a prodrug thereof When the compound of the present invention or a prodrug thereof is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or a therapeutic method usually used for those diseases.
  • the combination agent of the present invention the combined use of the compound of the present invention or a prodrug thereof and a concomitant drug is referred to as “the combination agent of the present invention”.
  • concomitant drugs include acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, etc.), amyloid ⁇ protein production, secretion, accumulation, aggregation and / or deposition inhibitors, ⁇ secretase inhibitors, amyloid ⁇ protein aggregation inhibitors , Amyloid ⁇ vaccine, amyloid ⁇ antibody, amyloid ⁇ -degrading enzyme, etc., brain function activator (eg, idebenone, memantine, vinpocetine, etc.), abnormal behavior associated with progression of dementia, therapeutic agent for epilepsy (eg, sedative, Anti-anxiety agents, etc.), Alzheimer's disease progression inhibitors, etc.
  • acetylcholinesterase inhibitors eg, donepezil, rivastigmine, galantamine, etc.
  • amyloid ⁇ protein production secretion, accumulation, aggregation and / or deposition inhibitors
  • apoptosis inhibitors include neuronal differentiation / regeneration promoters, anti-Parkinson drugs (eg, L-dopa, deprenyl, carbidopa + levodopa, pergolide, ropinirole, cabergoline, Pramipexole, entacapron, lazabemide)
  • anti-Parkinson drugs eg, L-dopa, deprenyl, carbidopa + levodopa, pergolide, ropinirole, cabergoline, Pramipexole, entacapron, lazabemide
  • Atrophic lateral sclerosis drug eg, riluzole, etc.
  • antidepressant eg, fluoxetine, sertraline, paroxetine, venlafaxine, nefazodone, reboxetine, mirtazapine, imipramine hydrochloride, duloxetine, es
  • Hypnotics Non-GABA hypnotics such as eprivaserin, prubanserin, diphenhydramine, trazodone, doxepin, ramelteon, etc., hypersomnia, schizophrenia (eg, olanzapine, risperidone, quetiapine, iloperidone, etc.), anti-obesity Non-steroidal anti-inflammatory drugs (eg, indomethacin, ibuprofen, acetylsalicylic acid, diclofenac, naproxen, piroxicam, etc.), COX-2 inhibitors (eg, celecoxib, rofecoxib, etc.), cerebral circulation metabolism improving drugs (eg, nicergoline, ibudilast) , Ifenprodil, etc.), disease-modifying anti-rheumatic drugs (DMARDs), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), steroid drugs
  • the compound of the present invention or a prodrug thereof By combining the compound of the present invention or a prodrug thereof and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or a prodrug thereof, or a concomitant drug is administered alone.
  • Concomitant drugs can be selected according to the patient's symptoms (mild, severe, etc.)
  • the treatment period By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the treatment period can be set longer.
  • the concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof the therapeutic effect can be sustained.
  • excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or a prodrug thereof, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se.
  • a pharmacologically acceptable carrier for example, tablets (including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.) It can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) as a patch, orally disintegrating tablet, orally disintegrating film and the like.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients and lubricants in solid preparations. , Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the timing of administration of the compound of the present invention or a prodrug thereof and the concomitant drug is not limited, and the compound of the present invention or prodrug thereof or a pharmaceutical composition thereof, and the concomitant drug or pharmaceutical composition thereof May be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention or a prodrug thereof and a concomitant drug, (2) Co-administration of two preparations obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug by the same administration route, (3) Administration of the two compounds obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug with a time difference in the same administration route, (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug at different administration routes (eg, the compound of
  • the compounding ratio of the compound of the present invention or a prodrug thereof and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention or a prodrug thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 0.1% by weight based on the whole preparation. 50% by weight, more preferably about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. Further, when the compound of the present invention or a prodrug thereof and a concomitant drug are formulated separately, the same content may be used.
  • NMR Nuclear magnetic resonance spectrum
  • s singlet d: doublet t: triplet q: quartet quint: quintet dd: double doublet (double doublet) td: triple doublet (triple doublet) dt: double triplet (double triplet) m: multiplet br: broad brs: broad singlet J: Coupling constant
  • THF Tetrahydrofuran MeOH: Methanol
  • DMF N, N-dimethylformamide
  • DMSO Dimethyl sulfoxide
  • MS Liquid chromatography-mass spectrometry spectrum
  • ESI Electrospray ionization method [M + H] + : Molecular ion peak
  • TFA Trifluoroacetic acid
  • M Molar concentration
  • N Normal concentration
  • NH silica gel As the basic silica gel for the column (NH silica gel), basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silysia Chemical Ltd. or Purite-Pack manufactured by MORITEX was used. NMR spectra were measured with a Bruker AVANCE-300 or Varian VNMRS-400 spectrometer using tetramethylsilane as an internal or external reference, chemical shifts expressed as ⁇ values, and coupling constants expressed in Hz. The numerical value shown in parentheses in the mixed solvent is the volume mixing ratio of each solvent. Further,% in the solution represents the number of grams in 100 mL of the solution. Room temperature usually means a temperature of about 10 ° C to 30 ° C.
  • Measuring instrument Waters MUX on-board 4-ch LC / MS System column: CAPCELL PAK C18 UG-120, S-3 ⁇ m, 1.5x35mm (Shiseido)
  • Injection volume 2 ⁇ L
  • flow rate 0.5 mL / min
  • detection method UV 220 nm Ionization method: ESI 5.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified by NH silica gel column chromatography (hexane only to ethyl acetate only) and then purified by preparative HPLC. The fraction collected was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (52 mg, 17%).
  • the reaction mixture was diluted with ethyl acetate and washed with saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) and then purified by preparative HPLC.
  • the fraction collected was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless amorphous solid (23 mg, 18%).
  • the obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (150 mg, 84% (2 steps)).
  • the obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (146 mg, 76% (2 steps)).
  • the solvent was distilled off under reduced pressure, and 1/3 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (170 ⁇ L, 1.0 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (87 ⁇ L, 0.50 mmol) was added, and the mixture was stirred at room temperature for 3 hours.
  • the reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 21 4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethyl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] Piperazine-1-carboxamide
  • the reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound as a pale yellow solid (45 mg, 59%).
  • Example 32 4- ⁇ 4- [2- (1-Methylethyl) -1,3-oxazol-5-yl] phenyl ⁇ -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
  • Example 38 4- [3-Fluoro-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
  • the reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (86 mg, 45% (2 steps)).
  • Example 44 4- [3- (Methylsulfanyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine -1-carboxamide
  • Example 47 4- [3- (Methylsulfinyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine -1-carboxamide
  • the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was suspended in methanol, 4N hydrochloric acid ethyl acetate solution was added, and the mixture was stirred at room temperature for 3 hr.
  • the solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (190 ⁇ L, 1.1 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (62 ⁇ L, 0.36 mmol) was added, and the mixture was stirred at room temperature for 14 hours.
  • the reaction solution was diluted with water and extracted with ethyl acetate.
  • the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
  • the solvent was distilled off under reduced pressure, and 1/4 of the obtained residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (200 ⁇ L, 1.2 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (88 ⁇ L, 0.50 mmol) was added, and the mixture was stirred at room temperature for 14 hours.
  • the reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the solvent was distilled off under reduced pressure, and 1/3 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (150 ⁇ L, 0.85 mmol) and 3,4-dichlorobenzyl isocyanate (54 ⁇ L, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (99 mg, 69% (2 steps)).
  • the obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (140 mg, 76%).
  • the obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained solid was washed with hexane to give the title compound as a pale yellow amorphous solid (120 mg, 64%).
  • the obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a colorless solid (143 mg, 78%). This was recrystallized from EtOH-IPE to give the title compound as a colorless solid (84.2 mg).
  • Example 70 (2- ⁇ 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl ⁇ -2-oxoethyl) -1H-pyrrolo [2, 3-b] pyridine
  • Example 72 (2- ⁇ 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl ⁇ -2-oxoethyl) -5- (trifluoromethyl ) -1H-pyrrolo [2,3-b] pyridine
  • Triethylamine (0.13 mL, 0.92 mmol) was added to a solution of bis (trichloromethyl) carbonate (87 mg, 0.29 mmol) in THF (5 mL) under ice cooling, and the mixture was stirred for 15 minutes under ice cooling.
  • THF triethylamine
  • 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.20 g, 0.73 mmol) in THF (3 mL) solution was added under ice cooling.
  • Example 100 1- (3,4-Dichlorobenzyl) -6,6-dimethyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-2-one
  • the fraction collected was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound as white crystals (80 mg, 17%).
  • Example 101 [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -4- (3,4,5-trifluorobenzyl) -1,4-diazepan-5-one
  • Example 104 4- (3,4-dichlorobenzyl) -1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -3-methyl-1,4- Diazepan-5-one
  • Example 106 4- (3,4-Dichlorobenzyl) -1- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-diazepan-5-one
  • Example 107 4-Benzyl-1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-methyl-1,4-diazepan-5-one
  • Examples 108 4-Benzyl-1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-methyl-1,4-diazepan-5-one
  • This oil (0.24 g), 1- (4-bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.30 g, 1.1 mmol), DavePhos (0.039 g, 0.10 mmol) , Pd 2 (dba) 3 (0.046 g, 0.050 mmol), sodium tert-butoxide (0.14 g, 1.5 mmol) and toluene (5 mL) were stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure.
  • Example 109 4- (3,4-dichlorobenzyl) -1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -6,6-dimethyl-1, 4-diazepan-5-one
  • Example 110 4- [4-Methoxy-2-methyl-5- (1-methylethyl) benzyl] -1- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-diazepan-5 -on
  • Example 111 4-[(6-Chloro-5-fluoro-1H-benzimidazol-2-yl) methyl] -1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-5-one
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 119 to 1828 The compounds described in Tables 1 to 13 (Examples 119 to 188) were obtained in the same manner as Example 118.
  • Example 190 to Example 236 the compounds described in Tables 14 to 22 (Example 190 to Example 236) were obtained.
  • Example 237 In the same manner as in Example 237, the compounds described in Tables 23 to 96 (Example 238 to Example 667) were obtained.
  • Example 668 4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
  • the obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (130 mg, 69% (2 steps)).
  • Example 669 4- [2-Fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
  • the obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (130 mg, 64% (2 steps)).
  • Example 672 4- [3-Fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
  • Example 673 4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) -3-propoxyphenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
  • Example 675 4- [3- (1-Methylethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl ] Piperazine-1-carboxamide
  • Example 676 4- [4- (2-Methyl-1,3-oxazol-5-yl) -3- (2,2,2-trifluoroethoxy) phenyl] -N-[(1S) -1-naphthalene-1- Ylethyl] piperazine-1-carboxamide

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Abstract

Disclosed are a heterocyclic derivative which has excellent amyloid ß production inhibitory activity, and a use of the heterocyclic derivative. Specifically disclosed is a compound represented by formula (I) or a salt thereof. (In the formula, the symbols are as defined in the description.)

Description

複素環化合物およびその用途Heterocyclic compounds and uses thereof
　本発明は、優れたアミロイドβ産生抑制作用を有し、軽度認知障害、アルツハイマー病などの予防または治療薬等として有用な複素環化合物に関する。 The present invention relates to a heterocyclic compound having an excellent inhibitory effect on amyloid β production and useful as a preventive or therapeutic agent for mild cognitive impairment, Alzheimer's disease and the like.
（発明の背景）
　アルツハイマー病や軽度認知障害は、認知症の大半を占めており、高齢化社会の到来と共に大幅に患者数が増加している。治療薬としては、アセチルコリンエステラーゼ阻害薬などの症状改善薬があるのみで、病態の進行を止める、または遅らせるあるいは予防効果のある薬物が望まれている。
　アルツハイマー病の発症原因としてアミロイドβ（Ａβ）と呼ばれる、約４０個のアミノ酸からなるペプチドの蓄積による老人斑の形成や神経細胞死が考えられている。Ａβは、前駆タンパク質である１回膜貫通型蛋白アミロイド前駆体（ＡＰＰ）よりセクレターゼと呼ばれる分解酵素によるプロセッシングを受けて産生され、４０個のアミノ酸からなるＡβ４０と４２個のアミノ酸からなるＡβ４２が主な分子種である。中でもＡβ４２は、凝集しやすく、老人斑形成あるいは神経細胞死に重要な役割を果たしていると考えられている（非特許文献１）。
　一方、切り出し酵素であるセクレターゼには、アミノ末端を切り出すβセクレターゼとカルボキシ末端を切り出すγセクレターゼが存在することが知られている。γセクレターゼは、プレセニリン（ＰＳ）と３種のコファクタータンパク質（ニカストリン：ＮＣＴ、ＡＰＨ－１、ＰＥＮ－２）などから構成されている（非特許文献２）。これらセクレターゼを阻害し、Ａβの産生・分泌を抑制するアルツハイマー病の根治治療薬が検討されてきている（非特許文献１）。しかしながら、γセクレターゼは、ＡＰＰのプロッセッシングのみならず、細胞分化に重要な役割を担うＮｏｔｃｈ受容体の膜内切断による活性化などの必須の機能を担っており、このような必須機能に影響を及ぼさずＡβの産生のみを特異的に阻害する薬物が期待されている（非特許文献３）。
　γセクレターゼを阻害する薬物としては、スルホンアミド誘導体などが知られている（非特許文献４）。Ｎｏｔｃｈシグナルに影響を及ぼさず、γセクレターゼ活性を調節する薬物としてはＮＳＡＩＤｓ系薬物（非特許文献４）やイミダゾール誘導体（非特許文献４、特許文献１、２）、シンナミド誘導体（特許文献３、４、５、６、７）、ピペラジン誘導体（特許文献８）、ピペリジン誘導体（特許文献９）およびアリールアゾール誘導体（特許文献１０）が知られている。
　また、特許文献１１～２２には、各種の複素環化合物が開示されている。 (Background of the Invention)
Alzheimer's disease and mild cognitive impairment account for the majority of dementia, and the number of patients has increased significantly with the arrival of an aging society. There are only symptom-improving drugs such as acetylcholinesterase inhibitors as therapeutic drugs, and drugs that stop or delay the progression of the disease state or have a preventive effect are desired.
As a cause of the onset of Alzheimer's disease, the formation of senile plaques and neuronal cell death due to accumulation of a peptide consisting of about 40 amino acids called amyloid β (Aβ) is considered. Aβ is produced from a precursor protein, a single-transmembrane protein amyloid precursor (APP), processed by a degrading enzyme called secretase, and Aβ40 consisting of 40 amino acids and Aβ42 consisting of 42 amino acids are mainly used. Is a molecular species. Among them, Aβ42 is likely to aggregate and is considered to play an important role in senile plaque formation or neuronal cell death (Non-patent Document 1).
On the other hand, it is known that secretase as a cleaving enzyme includes β-secretase that cleaves the amino terminus and γ-secretase that cleaves the carboxy terminus. γ-secretase is composed of presenilin (PS) and three cofactor proteins (nicastrin: NCT, APH-1, PEN-2) and the like (Non-patent Document 2). A curative treatment for Alzheimer's disease that inhibits these secretases and suppresses the production and secretion of Aβ has been studied (Non-patent Document 1). However, γ-secretase is responsible not only for APP processing but also for essential functions such as activation of the Notch receptor, which plays an important role in cell differentiation, by transmembrane cleavage. A drug that specifically inhibits only the production of Aβ is expected (Non-patent Document 3).
Sulfonamide derivatives and the like are known as drugs that inhibit γ-secretase (Non-patent Document 4). As drugs that do not affect the Notch signal and modulate γ-secretase activity, NSAIDs (Non-patent Document 4), imidazole derivatives (Non-patent Document 4, Patent Documents 1 and 2), cinamide derivatives (Patent Documents 3 and 4) 5, 6, 7), piperazine derivatives (Patent Document 8), piperidine derivatives (Patent Document 9) and arylazole derivatives (Patent Document 10) are known.
Patent Documents 11 to 22 disclose various heterocyclic compounds.
国際公開第２００８／９７５３８号パンフレットInternational Publication No. 2008/97538 Pamphlet 国際公開第２００８／１３７１３９号パンフレットInternational Publication No. 2008/137139 Pamphlet 国際公開第２００７／１３５９７０号パンフレットInternational Publication No. 2007/135970 Pamphlet 国際公開第２００７／６０８１０号パンフレットInternational Publication No. 2007/60810 Pamphlet 国際公開第２００７／６０８２１号パンフレットInternational Publication No. 2007/60821 Pamphlet 国際公開第２００７／１０２５８０号パンフレットInternational Publication No. 2007/102580 Pamphlet 国際公開第２００５／１１５９９０号パンフレットInternational Publication No. 2005/115990 Pamphlet 国際公開第２００８／９９２１０号パンフレットInternational Publication No. 2008/99210 Pamphlet 国際公開第２００８／１００４１２号パンフレットInternational Publication No. 2008/100412 Pamphlet 国際公開第２００８／１３７１０２号パンフレットInternational Publication No. 2008/137102 Pamphlet 国際公開第２００５／０８２８９２号パンフレットInternational Publication No. 2005/082892 Pamphlet 国際公開第２００８／０９９８０４号パンフレットInternational Publication No. 2008/099804 Pamphlet 国際公開第２００５／０１２２９３号パンフレットInternational Publication No. 2005/012293 Pamphlet 国際公開第２００７／０９７９３７号パンフレットInternational Publication No. 2007/097937 Pamphlet 国際公開第２００５／０５６０１５号パンフレットInternational Publication No. 2005/056015 Pamphlet 国際公開第２００７／０１６４９６号パンフレットInternational Publication No. 2007/016496 Pamphlet 国際公開第２００５／０４０１３６号パンフレットInternational Publication No. 2005/040136 Pamphlet 国際公開第２００７／０９７９３７号パンフレットInternational Publication No. 2007/097937 Pamphlet 国際公開第２００９／０２０５３４号パンフレットInternational Publication No. 2009/020534 Pamphlet 国際公開第２００６／０３４４４０号パンフレットInternational Publication No. 2006/034440 Pamphlet 国際公開第２００６／０８８８４０号パンフレットInternational Publication No. 2006/088840 Pamphlet 国際公開第２００４／１１０３５０号パンフレットInternational Publication No. 2004/110350 Pamphlet
　優れたアミロイドβ産生抑制活性を有し、軽度認知障害、アルツハイマー病などの予防または治療薬等として有用であり、かつ、薬効、低毒性、安定性、体内動態等の点で優れた性質を有する化合物の開発が望まれている。
　本発明は、公知化合物（前記の化合物を含む）とは化学構造が異なる、アミロイドβ産生抑制作用を有する複素環化合物、および当該複素環化合物を含む軽度認知障害、アルツハイマー病等の疾患の予防または治療薬を提供することを目的とする。 Has excellent amyloid β production inhibitory activity, is useful as a prophylactic or therapeutic agent for mild cognitive impairment, Alzheimer's disease, etc., and has excellent properties in terms of drug efficacy, low toxicity, stability, pharmacokinetics, etc. Development of compounds is desired.
The present invention relates to a heterocyclic compound having an amyloid β production inhibitory action, which has a chemical structure different from that of known compounds (including the above-mentioned compounds), and prevention of diseases such as mild cognitive impairment and Alzheimer's disease including the heterocyclic compound. The purpose is to provide therapeutic drugs.
　本発明者らは、上記課題を解決するために鋭意研究した結果、以下の式（Ｉ）で表される化合物またはその塩が、優れたアミロイドβ産生抑制活性を有することを見出し、さらなる研究により、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the following formula (I) or a salt thereof has an excellent amyloid β production inhibitory activity, and has been further studied. The present invention has been completed.
　すなわち、本発明は、
［１］式（Ｉ）： That is, the present invention
[1] Formula (I):
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
［式中、
Ｒ１は、水素原子または置換されていてもよいＣ１－６アルキル基；
Ｒ２およびＲ３は、同一または異なって、
水素原子、
ハロゲン原子、
ヒドロキシ、
置換されていてもよいＣ１－６アルキル基、
置換されていてもよいＣ１－６アルコキシ基、
置換されていてもよいＣ１－６アルキルチオ基、
置換されていてもよいＣ１－６アルキルスルホニル基、または
置換されていてもよいＣ１－６アルキルスルフィニル基；
ｎは、１または２；
Ｙは、
結合手、
－Ｒａ１－、
－Ｒａ１ＣＯ－、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、
－Ｒａ１Ｏ－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
－ＣＯＮ（Ｒｂ１）ＳＯ２－
　　　（式中、Ｒａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレン基；
　　　Ｒｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）；
環Ａは、酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい、５員芳香族複素環；
環Ｂは、環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環；
環Ｄは、置換されていてもよい複素環；
環Ｅは、
ｉ）置換されていてもよいベンゼン環、
ｉｉ）置換されていてもよいナフタレン環、
ｉｉｉ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環、
ｉｖ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環、
ｖ）置換されていてもよい３～７員飽和炭素環、
ｖｉ）置換されていてもよい９～１３員の縮合炭素環、または
ｖｉｉ）置換されていてもよい１３～１５員のスピロ複素環；
を示す］で表される化合物
［但し、以下の化合物を除く。
（１）式（Ｉ）の部分構造式 [Where:
R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
R 2 and R 3 are the same or different and
Hydrogen atom,
Halogen atoms,
Hydroxy,
An optionally substituted C 1-6 alkyl group,
An optionally substituted C 1-6 alkoxy group,
An optionally substituted C 1-6 alkylthio group,
An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group;
n is 1 or 2;
Y is
Join hands,
-Ra 1- ,
-Ra 1 CO-,
-Ra 1 CON (Rb 1 )-,
-Ra 1 CON (Rb 1 ) Ra 2- ,
-Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-,
-Ra 1 CON (Rb 1 ) Ra 2 O-,
-Ra 1 O-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
—CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
Wherein Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene groups;
Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group);
Ring A may further have an optionally substituted C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 5-membered aromatic group Heterocycle;
Ring B may have 1 or 2 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and may be further substituted 6-membered aromatic ring;
Ring D is an optionally substituted heterocycle;
Ring E is
i) an optionally substituted benzene ring,
ii) an optionally substituted naphthalene ring,
iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms;
v) an optionally substituted 3- to 7-membered saturated carbocyclic ring,
vi) an optionally substituted 9-13 membered fused carbocycle, or vii) an optionally substituted 13-15 membered spiro heterocycle;
] [Excluding the following compounds].
(1) Partial structural formula of formula (I)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
が、 But,
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
である、式（Ｉ）で表される化合物、
（２）Ｒ１が置換されていてもよいアミノ基を有するメチル基であり、かつ式（Ｉ）の部分構造式： A compound of formula (I),
(2) R 1 is a methyl group having an optionally substituted amino group, and a partial structural formula of the formula (I):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
が、 But,
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
である、式（Ｉ）で表される化合物、
（３）以下の式： A compound of formula (I),
(3) The following formula:
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
（式中、環ＥＸは、置換されていてもよい２，３－ジヒドロ－１－ベンゾフラン環または置換されていてもよいクロマン環を示す）で表される化合物、
（４）以下の式： (Wherein ring E X is substituted represents an chroman ring be also be 2,3-dihydro-1-benzofuran ring or a substituted optionally) a compound represented by,
(4) The following formula:
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
（式中、Ｒｙ１は、水素原子またはＣ１－６アルキル基；Ｒｙ２は、水素原子または置換されていてもよいメチル基を示す）で表される化合物、
（５）（３Ｒ）－Ｎ－（３－クロロ－４－ヒドロキシフェニル）－１－（２－｛４－［４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－イル｝－２－オキソエチル）ピロリジン－３－カルボキサミド、
（６）１－｛［４－クロロ－５－メチル－３－（トリフルオロメチル）－１Ｈ－ピラゾール－１－イル］アセチル｝－４－［４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン、
（７）１－シクロブチル－４－（｛４－［４－（３－メチル－１，２，４－オキサジアゾール－５－イル）フェニル］ピペラジン－１－イル｝アセチル）ピペラジン、
（８）（２Ｒ，５Ｓ）－４－［３－メトキシ－４－（１，３－オキサゾール－５－イル）フェニル］－２，５－ジメチル－Ｎ－［４－（トリフルオロメチル）ピリジン－３－イル］ピペラジン－１－カルボキサミド、
（９）（２Ｒ，５Ｓ）－４－［３－メトキシ－４－（１Ｈ－１，２，４－トリアゾール－１－イル）フェニル］－２，５－ジメチル－Ｎ－［４－（トリフルオロメチル）ピリジン－３－イル］ピペラジン－１－カルボキサミド、
（１０）（３Ｒ）－Ｎ－（３－クロロ－４－ヒドロキシフェニル）－１－（２－オキソ－２－｛４－［４－（１Ｈ－１，２，３－トリアゾール－１－イル）フェニル］ピペラジン－１－イル｝エチル）ピロリジン－３－カルボキサミド、
（１１）３－［３－（３－メチルブチル）－１，２，４－オキサジアゾール－５－イル］－６－（４－｛［２－（トリフルオロメチル）フェニル］カルボニル｝ピペラジン－１－イル）ピリダジン、
（１２）３－（３－プロピル－１，２，４－オキサジアゾール－５－イル）－６－（４－｛［２－（トリフルオロメチル）フェニル］カルボニル｝ピペラジン－１－イル）ピリダジン、
（１３）１－シクロペンチル－４－｛５－［３－（１－メチルエチル）－１，２，４－オキサジアゾール－５－イル］ピリジン－２－イル｝ピペラジン－２－オン、
（１４）（２Ｓ）－１－［１－（４－クロロベンジル）ピペリジン－４－イル］－４－［３－クロロ－５－（１，３－オキサゾール－５－イル）ピリジン－２－イル］－２－エチルピペラジン、
（１５）Ｎ－｛［（５Ｓ）－３－（３－フルオロ－４－｛４－［３－フルオロ－４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－イル｝フェニル）－２－オキソ－１，３－オキサゾリジン－５－イル］メチル｝アセトアミド、および
（１６）Ｎ－｛［（５Ｓ）－３－（３－フルオロ－４－｛４－［２－フルオロ－４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－イル｝フェニル）－２－オキソ－１，３－オキサゾリジン－５－イル］メチル｝アセトアミド］またはその塩；
［２］（１）Ｙが、
結合手、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
－ＣＯＮ（Ｒｂ１）ＳＯ２－
　　　（式中、Ｒａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレン基；
　　　Ｒｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）であり、
（２）環Ａが、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいオキサゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，３－トリアゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，４－トリアゾール環、または
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいピラゾール環
である、上記［１］記載の化合物またはその塩；
［３］環Ｄが、１個または２個のオキソ基を有する、さらに置換されていてもよい複素環である、上記［１］記載の化合物またはその塩；
［４］Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基；
ｎが、１または２；
Ｙが、－ＣＯ－、－Ｒａ１－、－ＣＯＲａ１－、－ＣＯＮ（Ｒｂ１）－、－ＣＯＮ（Ｒｂ１）Ｒａ１－または－Ｒａ１ＣＯＮ（Ｒｂ１）－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上存在する場合には、該置換基同士が結合して環を形成してもよい）；
　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）；
環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
環Ｂが、ベンゼン環；
環Ｄが、オキソ基、Ｃ１－６アルキル基およびＣ１－６アルコキシ－カルボニル基から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）；
環Ｅが、それぞれ（１）ハロゲン原子、（２）ハロゲン原子で置換されたＣ１－６アルキル基、（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環；
である上記［１］記載の化合物またはその塩；
［５］Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基；
ｎが、１または２；
Ｙが、－ＣＯ－、－ＣＯＲａ１－、－ＣＯＮ（Ｒｂ１）－、または－ＣＯＮ（Ｒｂ１）Ｒａ１－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上存在する場合には、該置換基同士が結合して環を形成してもよい）；
　　　Ｒｂ１は、水素原子を示す）；
環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
環Ｂが、ベンゼン環；
環Ｄが、Ｃ１－６アルキル基およびＣ１－６アルコキシ－カルボニル基から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）；
環Ｅが、それぞれ（１）ハロゲン原子、（２）ハロゲン原子で置換されたＣ１－６アルキル基、（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環；
である上記［１］記載の化合物またはその塩；
［６］Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３の、一方が水素原子、他方が水素原子またはＣ１－６アルコキシ基；
ｎが、１または２；
Ｙが、Ｃ１－６アルキレン基または－Ｒａ１ＣＯＮ（Ｒｂ１）－
　　　（式中、Ｒａ１は、Ｃ１－６アルキレン基；
　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）；
環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
環Ｂが、ベンゼン環；
環Ｄが、1個のオキソ基を有する複素環；
環Ｅが、１～３個のハロゲン原子で置換されたベンゼン環；
である上記［１］記載の化合物またはその塩；
［７］Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３の一方が水素原子、他方がＣ１－６アルコキシ基；
ｎが、１；
Ｙが、－ＣＯＮ（Ｒｂ１）Ｒａ１－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基で置換されていてもよい、Ｃ１－６アルキレン基；
　　　Ｒｂ１は、水素原子）；
環Ａが、オキサゾール環；
環Ｂが、ベンゼン環；
環Ｄが、複素環；
環Ｅが、ハロゲン原子で置換された１～３個のＣ１－６アルキル基で置換された、ベンゼン環；
である上記［１］記載の化合物またはその塩；
［８］４－［３－メトキシ－４－（２－メチル－１，３－オキサゾール－５－イル）フェニル］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピペラジン－１－カルボキサミド（実施例９０に記載の化合物）またはその塩；
［９］Ｎ－｛２－ヒドロキシ－２－メチル－１－［４－（トリフルオロメチル）フェニル］プロピル｝－４－［３－メトキシ－４－（２－メチル－１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－カルボキサミド（実施例６９３に記載の化合物）またはその塩；
［１０］上記［１］記載の化合物またはその塩のプロドラッグ；
［１１］上記［１］記載の化合物またはその塩、あるいはそのプロドラッグを含有する医薬；
［１２］アミロイドβ産生抑制薬である上記［１１］記載の医薬；
［１３］軽度認知障害またはアルツハイマー病の予防または治療薬である上記［１１］記載の医薬；
［１４］哺乳動物に対して、上記［１］記載の化合物またはその塩、あるいはそのプロドラッグを有効量投与することを特徴とする、アミロイドβ産生抑制方法；
［１５］哺乳動物に対して、上記［１］記載の化合物またはその塩、あるいはそのプロドラッグを有効量投与することを特徴とする、軽度認知障害またはアルツハイマー病の予防または治療方法；
［１６］アミロイドβ産生抑制薬を製造するための、上記［１］記載の化合物またはその塩、あるいはそのプロドラッグの使用；
［１７］軽度認知障害またはアルツハイマー病の予防または治療薬を製造するための、上記［１］記載の化合物またはその塩、あるいはそのプロドラッグの使用；
［１８］アミロイドβ産生抑制のための、上記［１］記載の化合物またはその塩、あるいはそのプロドラッグ；
［１９］軽度認知障害またはアルツハイマー病の予防または治療のための、上記［１］記載の化合物またはその塩、あるいはそのプロドラッグ；
等に関する。
　本明細書中、上記式（Ｉ）で表される化合物またはその塩を、「本発明化合物」と称する場合がある。 (Wherein Ry 1 represents a hydrogen atom or a C 1-6 alkyl group; Ry 2 represents a hydrogen atom or an optionally substituted methyl group),
(5) (3R) -N- (3-Chloro-4-hydroxyphenyl) -1- (2- {4- [4- (1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) pyrrolidine-3-carboxamide,
(6) 1-{[4-Chloro-5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl} -4- [4- (1,3-oxazol-5-yl) Phenyl] piperazine,
(7) 1-cyclobutyl-4-({4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazin-1-yl} acetyl) piperazine,
(8) (2R, 5S) -4- [3-methoxy-4- (1,3-oxazol-5-yl) phenyl] -2,5-dimethyl-N- [4- (trifluoromethyl) pyridine- 3-yl] piperazine-1-carboxamide,
(9) (2R, 5S) -4- [3-Methoxy-4- (1H-1,2,4-triazol-1-yl) phenyl] -2,5-dimethyl-N- [4- (trifluoro Methyl) pyridin-3-yl] piperazine-1-carboxamide,
(10) (3R) -N- (3-Chloro-4-hydroxyphenyl) -1- (2-oxo-2- {4- [4- (1H-1,2,3-triazol-1-yl) Phenyl] piperazin-1-yl} ethyl) pyrrolidine-3-carboxamide,
(11) 3- [3- (3-Methylbutyl) -1,2,4-oxadiazol-5-yl] -6- (4-{[2- (trifluoromethyl) phenyl] carbonyl} piperazine-1 -Il) pyridazine,
(12) 3- (3-Propyl-1,2,4-oxadiazol-5-yl) -6- (4-{[2- (trifluoromethyl) phenyl] carbonyl} piperazin-1-yl) pyridazine ,
(13) 1-cyclopentyl-4- {5- [3- (1-methylethyl) -1,2,4-oxadiazol-5-yl] pyridin-2-yl} piperazin-2-one,
(14) (2S) -1- [1- (4-Chlorobenzyl) piperidin-4-yl] -4- [3-chloro-5- (1,3-oxazol-5-yl) pyridin-2-yl ] -2-ethylpiperazine,
(15) N-{[(5S) -3- (3-Fluoro-4- {4- [3-fluoro-4- (1,3-oxazol-5-yl) phenyl] piperazin-1-yl} phenyl ) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide, and (16) N-{[(5S) -3- (3-fluoro-4- {4- [2-fluoro-4 -(1,3-oxazol-5-yl) phenyl] piperazin-1-yl} phenyl) -2-oxo-1,3-oxazolidine-5-yl] methyl} acetamido] or a salt thereof;
[2] (1) Y is
Join hands,
-Ra 1 CON (Rb 1 )-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
—CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
Wherein Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene groups;
Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group),
(2) Ring A is
An oxazole ring which may further have an optionally substituted C 1-6 alkyl group,
A 1,2,3-triazole ring optionally further having an optionally substituted C 1-6 alkyl group,
It may have an optionally substituted C 1-6 alkyl group may further have a 1,2,4-triazole ring, or a C 1-6 alkyl group which may be substituted further The compound or a salt thereof according to the above [1], which is a pyrazole ring;
[3] The compound or a salt thereof according to the above [1], wherein ring D is a heterocyclic ring which has one or two oxo groups and may be further substituted;
[4] R 1 is a C 1-6 alkyl group;
R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group;
n is 1 or 2;
Y is, -CO -, - Ra 1 - , - CORa 1 -, - CON (Rb 1) -, - CON (Rb 1) Ra 1 - or -Ra 1 CON (Rb 1) -
(In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
Ring B is a benzene ring;
Ring D is a heterocycle optionally substituted with 1 to 3 substituents selected from an oxo group, a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (two or more such substituents When present, the substituents may be bonded to form a crosslinked structure);
Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a halogen atom. A benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring;
Or a salt thereof according to the above [1];
[5] R 1 is a C 1-6 alkyl group;
R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group;
n is 1 or 2;
Y is —CO—, —CORa 1 —, —CON (Rb 1 ) —, or —CON (Rb 1 ) Ra 1 —.
(In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
Rb 1 represents a hydrogen atom);
Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
Ring B is a benzene ring;
Ring D may be substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (when two or more substituents are present) May be bonded to each other to form a crosslinked structure);
Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a halogen atom. A benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring;
Or a salt thereof according to the above [1];
[6] R 1 is a C 1-6 alkyl group;
One of R 2 and R 3 is a hydrogen atom, the other is a hydrogen atom or a C 1-6 alkoxy group;
n is 1 or 2;
Y is a C 1-6 alkylene group or —Ra 1 CON (Rb 1 ) —
Wherein Ra 1 is a C 1-6 alkylene group;
Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
Ring B is a benzene ring;
Ring D is a heterocycle having one oxo group;
A benzene ring in which ring E is substituted with 1 to 3 halogen atoms;
Or a salt thereof according to the above [1];
[7] R 1 is a C 1-6 alkyl group;
One of R 2 and R 3 is a hydrogen atom and the other is a C 1-6 alkoxy group;
n is 1;
Y is —CON (Rb 1 ) Ra 1 —
Wherein Ra 1 is a C 1-6 alkylene group which may be substituted with a C 1-6 alkyl group which may be substituted with a hydroxy group;
Rb 1 is a hydrogen atom);
Ring A is an oxazole ring;
Ring B is a benzene ring;
Ring D is a heterocycle;
A benzene ring in which ring E is substituted with 1 to 3 C 1-6 alkyl groups substituted with a halogen atom;
Or a salt thereof according to the above [1];
[8] 4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- [4- (trifluoromethyl) benzyl] piperazine-1-carboxamide (Examples) 90) or a salt thereof;
[9] N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazole-5 -Yl) phenyl] piperazine-1-carboxamide (compound described in Example 693) or a salt thereof;
[10] A prodrug of the compound of the above-mentioned [1] or a salt thereof;
[11] A medicament containing the compound according to [1] above or a salt thereof, or a prodrug thereof;
[12] The medicament according to [11] above, which is an amyloid β production inhibitor;
[13] The medicament according to [11] above, which is a prophylactic or therapeutic drug for mild cognitive impairment or Alzheimer's disease;
[14] A method for inhibiting amyloid β production, comprising administering an effective amount of the compound according to [1] above or a salt thereof, or a prodrug thereof to a mammal;
[15] A method for preventing or treating mild cognitive impairment or Alzheimer's disease, which comprises administering an effective amount of the compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof to a mammal;
[16] Use of the compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for producing an amyloid β production inhibitor;
[17] Use of the compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for producing a preventive or therapeutic agent for mild cognitive impairment or Alzheimer's disease;
[18] The compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for suppressing amyloid β production;
[19] The compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for the prevention or treatment of mild cognitive impairment or Alzheimer's disease;
Etc.
In the present specification, the compound represented by the above formula (I) or a salt thereof may be referred to as “the compound of the present invention”.
　本発明化合物またはそのプロドラッグは、優れたアミロイドβ産生抑制活性を有するため、総てのアミロイドβの産生に関連する可能性のある疾患、例えば、軽度認知障害、アルツハイマー病等の安全な予防または治療薬として有用である。 Since the compound of the present invention or a prodrug thereof has excellent amyloid β production inhibitory activity, it is possible to safely prevent or prevent all amyloid β production-related diseases such as mild cognitive impairment and Alzheimer's disease. Useful as a therapeutic agent.
（発明の詳細な説明）
　以下、本発明において用いられる、式（Ｉ）中の各記号の定義について詳述する。 (Detailed description of the invention)
Hereinafter, the definition of each symbol in formula (I) used in the present invention will be described in detail.
　「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 “Halogen atom” includes fluorine atom, chlorine atom, bromine atom and iodine atom.
　「Ｃ１－６アルキル（基）」としては、直鎖状又は分岐鎖状のＣ１－６アルキル（基）が挙げられ、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等が挙げられる。 Examples of the “C 1-6 alkyl (group)” include linear or branched C 1-6 alkyl (group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. Tert-butyl, pentyl, hexyl and the like.
　「Ｃ１－６アルコキシ（基）」としては、直鎖状又は分岐鎖状のＣ１－６アルコキシ（基）が挙げられ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等が挙げられる。 Examples of the “C 1-6 alkoxy (group)” include linear or branched C 1-6 alkoxy (group), for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Examples include butoxy and tert-butoxy.
　「Ｃ１－６アルキルチオ（基）」としては、直鎖状又は分岐鎖状のＣ１－６アルキルチオ（基）が挙げられ、例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、ペンチルチオ、ヘキシルチオ等が挙げられる。 Examples of the “C 1-6 alkylthio (group)” include linear or branched C 1-6 alkylthio (group), such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like. Is mentioned.
　「Ｃ１－６アルキルスルホニル（基）」としては、直鎖状又は分岐鎖状のＣ１－６アルキルスルホニル（基）が挙げられ、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニル等が挙げられる。 Examples of the “C 1-6 alkylsulfonyl (group)” include linear or branched C 1-6 alkylsulfonyl (group), for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butyl Examples include sulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
　「Ｃ１－６アルキルスルフィニル（基）」としては、直鎖状又は分岐鎖状のＣ１－６アルキルスルフィニル（基）が挙げられ、例えば、メチルスルフィニル、エチルスルフィニル、プロピルスルフィニル、イソプロピルスルフィニル、ブチルスルフィニル、ペンチルスルフィニル、ヘキシルスルフィニル等が挙げられる。 Examples of the “C 1-6 alkylsulfinyl (group)” include linear or branched C 1-6 alkylsulfinyl (group), such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butyl And sulfinyl, pentylsulfinyl, hexylsulfinyl and the like.
　「Ｃ１－６アルキレン（基）」としては、直鎖状のＣ１－６アルキレン（基）が挙げられ、例えば、メチレン、エチレン、プロピレン、ブチレン、ペンチレン、ヘキシレン等が挙げられる。 Examples of the “C 1-6 alkylene (group)” include linear C 1-6 alkylene (group) such as methylene, ethylene, propylene, butylene, pentylene, hexylene and the like.
　「置換されていてもよいＣ１－６アルキレン（基）」の「置換基」としては、下記置換基群（以下、置換基群Ａと略記する）から選ばれる１～３個の置換基等が挙げられる。該置換基が２個以上存在する場合には、該置換基は同じ種類のものであっても異なる種類のものであってもよい。 As the “substituent” of “optionally substituted C 1-6 alkylene (group)”, 1 to 3 substituents selected from the following substituent group (hereinafter abbreviated as substituent group A), etc. Is mentioned. When two or more substituents are present, the substituents may be the same or different.
置換基群Ａ：
（１）ハロゲン原子、
（２）ニトロ、
（３）シアノ、
（４）（ａ）ハロゲン原子、
　　　（ｂ）３～８員の複素環基（例、モルホリニル、ピリジル）、
　　　（ｃ）ヒドロキシ、
　　　（ｄ）Ｃ１－６アルキル－カルボニル（例、アセチル）、および
　　　（ｅ）Ｃ１－６アルコキシ（例、メトキシ）
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル、
（５）１～５個のハロゲン原子を有していてもよいＣ３－８シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等）、
（６）１～３個のハロゲン原子を有していてもよいＣ１－６アルキルを有していてもよいＣ６－１４アリール（例、フェニル、ナフチル等）、
（７）ヒドロキシ、
（８）（ａ）ハロゲン原子、および
　　　（ｂ）Ｃ３－８シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等）
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ、
（９）Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ）を有していてもよいＣ６－１４アリールオキシ（例、フェニルオキシ、ナフチルオキシ等）、
（１０）メルカプト、
（１１）１～３個のハロゲン原子を有していてもよいＣ１－６アルキルチオ、
（１２）Ｃ６－１４アリールチオ（例、フェニルチオ、ナフチルチオ等）、
（１３）アミノ、
（１４）モノ－Ｃ１－６アルキルアミノ（例、メチルアミノ、エチルアミノ等）、
（１５）モノ－Ｃ６－１４アリールアミノ（例、フェニルアミノ、ナフチルアミノ等）、
（１６）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ、ジエチルアミノ等）、
（１７）ジ－Ｃ６－１４アリールアミノ（例、ジフェニルアミノ等）、
（１８）（Ｃ１－６アルキル）－（Ｃ１－６アルキル－カルボニル）アミノ（例、アセチル（メチル）アミノ）、
（１９）ホルミル、
（２０）Ｃ１－６アルキル－カルボニル（例、アセチル、プロピオニル等）、
（２１）Ｃ６－１４アリール－カルボニル（例、ベンゾイル、ナフトイル等）、
（２２）カルボキシ、
（２３）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、
（２４）Ｃ６－１４アリールオキシ－カルボニル（例、フェノキシカルボニル等）、
（２５）カルバモイル、
（２６）チオカルバモイル、
（２７）モノ－Ｃ１－６アルキル－カルバモイル（例、メチルカルバモイル、エチルカルバモイル等）、
（２８）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル、ジエチルカルバモイル、エチルメチルカルバモイル等）、
（２９）Ｃ６－１４アリール－カルバモイル（例、フェニルカルバモイル、ナフチルカルバモイル等）、
（３０）Ｃ１－６アルキルスルホニル、
（３１）Ｃ６－１４アリールスルホニル（例、フェニルスルホニル、ナフチルスルホニル等）、
（３２）アミノスルホニル、
（３３）Ｃ１－６アルキルスルフィニル、
（３４）Ｃ６－１４アリールスルフィニル（例、フェニルスルフィニル、ナフチルスルフィニル等）、
（３５）ホルミルアミノ、
（３６）カルバモイルアミノ、
（３７）Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ等）、
（３８）Ｃ６－１４アリール－カルボニルアミノ（例、ベンゾイルアミノ、ナフトイルアミノ等）、
（３９）Ｃ１－６アルコキシ－カルボニルアミノ（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ、ｔｅｒｔ－ブトキシカルボニルアミノ等）、
（４０）Ｃ１－６アルキルスルホニルアミノ（例、メチルスルホニルアミノ、エチルスルホニルアミノ等）、
（４１）Ｃ６－１４アリールスルホニルアミノ（例、フェニルスルホニルアミノ、ナフチルスルホニルアミノ等）、
（４２）Ｃ１－６アルキル－カルボニルオキシ（例、アセトキシ、プロピオニルオキシ等）、
（４３）Ｃ６－１４アリール－カルボニルオキシ（例、ベンゾイルオキシ、ナフチルカルボニルオキシ等）、
（４４）Ｃ１－６アルコキシ－カルボニルオキシ（例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ等）、
（４５）モノ－Ｃ１－６アルキル－カルバモイルオキシ（例、メチルカルバモイルオキシ、エチルカルバモイルオキシ等）、
（４６）ジ－Ｃ１－６アルキル－カルバモイルオキシ（例、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ等）、
（４７）Ｃ６－１４アリール－カルバモイルオキシ（例、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシ等）、
（４８）（ａ）オキソ、
　　　　（ｂ）１～３個のハロゲン原子を有していてもよいＣ１－６アルキル－カルボニル（例、アセチル）、
　　　　（ｃ）Ｃ１－６アルコキシ－カルボニル（例、ｔｅｒｔ－ブトキシカルボニル）、
　　　　（ｄ）Ｃ１－６アルキル、および
　　　　（ｅ）Ｃ６－１４アリール（例、フェニル）
から選ばれる１～５個の置換を有していてもよい、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１～３種のヘテロ原子を、１～５個含む３～１４員（単環、２環または３環式）複素環基
［例、芳香族複素環基（例、ピロリル、フリル、チエニル、ピラゾリル、イミダゾリル、イソオキサゾリル、イソチアゾリル、チアゾリル、トリアゾリル、オキサジアゾリル、チアジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、イソインドリル、インドリル、ベンゾ［ｂ］フラニル、ベンゾ［ｃ］フラニル、ベンゾ［ｂ］チエニル、ベンゾ［ｃ］チエニル、インダゾリル、ベンゾイミダゾリル、１，２－ベンゾイソオキサゾリル、ベンゾオキサゾリル、１，２－ベンゾイソチアゾリル、ベンゾチアゾリル、イソキノリル、キノリル、シンノリニル、フタラジニル、キナゾリニル、キノキサリニル、ピラゾロ［１，５－ａ］ピリジル、イミダゾ［１，２－ａ］ピリジル等）；
非芳香族複素環基（例、オキサゾリジニル、イミダゾリニル、アジリジニル、アゼチジニル、ピロリジニル、ピペリジニル、アゼパニル、アゾカニル、ピペラジニル、ジアゼパニル、ジアゾカニル、４－モルホリニル、４－チオモルホリニル、２－アザスピロ［４．５］デカン－２－イル等）；
前記の芳香族複素環基の一部が水素化された複素環基（例、インドリニル、ジヒドロキノリル、ジヒドロキノキサリニル、ジヒドロオキサゾリル等）；
前記の非芳香族複素環基の一部が脱水素化された複素環基（例、ジヒドロフリル等）］、
（４９）Ｃ６－１４アリール－カルボニル（例、ベンゾイル）を有していてもよい３～１４員複素環－オキシ（例、ピペリジン－４－イルオキシ、ピリジン－２－イルオキシ、１－ベンゾイル－ピペリジン－４－イルオキシ）、
（５０）Ｃ１－６アルキル－カルボニル（例、アセチル）を有していてもよい３～１４員複素環－アミノ（例、４－ピペリジルアミノ）、
（５１）Ｃ１－３アルキレンジオキシ（例、メチレンジオキシ、エチレンジオキシ等）、
（５２）オキソ、および
（５３）１個のＣ１－６アルコキシ－カルボニル（例、ｔｅｒｔ－ブトキシカルボニル）を有していてもよいヒドラジノ。 Substituent group A:
(1) a halogen atom,
(2) Nitro,
(3) Cyano,
(4) (a) a halogen atom,
(B) a 3- to 8-membered heterocyclic group (eg, morpholinyl, pyridyl),
(C) hydroxy,
(D) C 1-6 alkyl-carbonyl (eg, acetyl), and (e) C 1-6 alkoxy (eg, methoxy)
C 1-6 alkyl optionally having 1 to 5 substituents selected from
(5) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) optionally having 1 to 5 halogen atoms,
(6) C 6-14 aryl (eg, phenyl, naphthyl, etc.) optionally having C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(7) hydroxy,
(8) (a) a halogen atom, and (b) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.)
C 1-6 alkoxy optionally having 1 to 3 substituents selected from
(9) C 6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.) optionally having C 1-6 alkyl-carbonylamino (eg, acetylamino),
(10) Mercapto,
(11) C 1-6 alkylthio optionally having 1 to 3 halogen atoms,
(12) C 6-14 arylthio (eg, phenylthio, naphthylthio, etc.),
(13) amino,
(14) mono-C 1-6 alkylamino (eg, methylamino, ethylamino, etc.),
(15) Mono-C 6-14 arylamino (eg, phenylamino, naphthylamino, etc.)
(16) di-C 1-6 alkylamino (eg, dimethylamino, diethylamino, etc.),
(17) di-C 6-14 arylamino (eg, diphenylamino),
(18) (C 1-6 alkyl)-(C 1-6 alkyl-carbonyl) amino (eg, acetyl (methyl) amino),
(19) Formyl,
(20) C 1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.),
(21) C 6-14 aryl-carbonyl (eg, benzoyl, naphthoyl, etc.),
(22) carboxy,
(23) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.),
(24) C 6-14 aryloxy-carbonyl (eg, phenoxycarbonyl etc.),
(25) Carbamoyl,
(26) thiocarbamoyl,
(27) mono-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.),
(28) Di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.),
(29) C 6-14 aryl-carbamoyl (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.),
(30) C 1-6 alkylsulfonyl,
(31) C 6-14 arylsulfonyl (eg, phenylsulfonyl, naphthylsulfonyl, etc.),
(32) aminosulfonyl,
(33) C 1-6 alkylsulfinyl,
(34) C 6-14 arylsulfinyl (eg, phenylsulfinyl, naphthylsulfinyl, etc.),
(35) formylamino,
(36) Carbamoylamino,
(37) C 1-6 alkyl-carbonylamino (eg, acetylamino etc.),
(38) C 6-14 aryl-carbonylamino (eg, benzoylamino, naphthoylamino, etc.),
(39) C 1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino, etc.),
(40) C 1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.),
(41) C 6-14 arylsulfonylamino (eg, phenylsulfonylamino, naphthylsulfonylamino, etc.),
(42) C 1-6 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.),
(43) C 6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.),
(44) C 1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.),
(45) Mono-C 1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.),
(46) di-C 1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.),
(47) C 6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.),
(48) (a) Oxo,
(B) C 1-6 alkyl-carbonyl (eg acetyl) optionally having 1 to 3 halogen atoms,
(C) C 1-6 alkoxy-carbonyl (eg, tert-butoxycarbonyl),
(D) C 1-6 alkyl, and (e) C 6-14 aryl (eg, phenyl)
3 to 14 members having 1 to 5 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom, which may have 1 to 5 substituents selected from (Monocyclic, bicyclic or tricyclic) heterocyclic group [eg, aromatic heterocyclic group (eg, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl , Pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, indolyl, benzo [b] furanyl, benzo [c] furanyl, benzo [b] thienyl, benzo [c] thienyl, indazolyl, benzimidazolyl, 1,2-benzisoxazolyl, benzo Oxazolyl, 1,2-benzisothiazolyl, benzothiazo Le, isoquinolyl, quinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, etc.);
Non-aromatic heterocyclic groups (eg, oxazolidinyl, imidazolinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, diazepanyl, diazocanyl, 4-morpholinyl, 4-thiomorpholinyl, 2-azaspiro [4.5] decan-2 -Ile etc.);
A heterocyclic group in which a part of the aromatic heterocyclic group is hydrogenated (eg, indolinyl, dihydroquinolyl, dihydroquinoxalinyl, dihydrooxazolyl, etc.);
A heterocyclic group in which a part of the non-aromatic heterocyclic group is dehydrogenated (eg, dihydrofuryl, etc.)],
(49) 3-14 membered heterocyclic-oxy optionally having C 6-14 aryl-carbonyl (eg, benzoyl) (eg, piperidin-4-yloxy, pyridin-2-yloxy, 1-benzoyl-piperidine) -4-yloxy),
(50) a 3 to 14-membered heterocyclic-amino (eg, 4-piperidylamino) optionally having C 1-6 alkyl-carbonyl (eg, acetyl),
(51) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.),
(52) Oxo, and (53) Hydazino optionally having one C 1-6 alkoxy-carbonyl (eg, tert-butoxycarbonyl).
　「置換されていてもよいＣ１－６アルキル（基）」、
「置換されていてもよいＣ１－６アルコキシ（基）」、
「置換されていてもよいＣ１－６アルキルチオ（基）」、
「置換されていてもよいＣ１－６アルキルスルホニル（基）」、
「置換されていてもよいＣ１－６アルキルスルフィニル（基）」、
「置換されていてもよいアミノ基を有するメチル（基）」、および
「置換されていてもよいメチル（基）」
の「置換基」としては、上記置換基群Ａ（但し、置換基群Ａの（４）の置換基を除く）から選ばれる１～３個の置換基等が挙げられる。該置換基が２個以上存在する場合には、該置換基は同じ種類のものであっても異なる種類のものであってもよい。 “Optionally substituted C 1-6 alkyl (group)”,
“Optionally substituted C 1-6 alkoxy (group)”,
“Optionally substituted C 1-6 alkylthio (group)”,
“Optionally substituted C 1-6 alkylsulfonyl (group)”,
“Optionally substituted C 1-6 alkylsulfinyl (group)”,
“Methyl (group) having an amino group which may be substituted”, and “Methyl (group) which may be substituted”
Examples of the “substituent” include 1 to 3 substituents selected from the above substituent group A (excluding the substituent group (4) of substituent group A). When two or more substituents are present, the substituents may be the same or different.
　環Ａの「酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい、５員芳香族複素環」の「酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、５員芳香族複素環（基）」としては、例えば、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル（例、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル）、チアジアゾリル、トリアゾリル（例、１Ｈ－１，２，３－トリアゾリル、２Ｈ－１，２，３－トリアゾリル、１Ｈ－１，２，４－トリアゾリル）等が挙げられる。ここで「置換されていてもよいＣ１－６アルキル基をさらに有していてもよい」とは、環Ａが、Ｒ１以外に置換されていてもよいＣ１－６アルキル基を、さらに１または２個有していてもよいことを示す。 Ring A “5-membered aromatic optionally further having an optionally substituted C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom Examples of the “heterocycle” include a 5-membered aromatic heterocycle (group) having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. , Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl, triazolyl (eg, 1H-1,2,3-triazolyl, 2H-1, 2,3-triazolyl, 1H-1,2,4-triazolyl) and the like. Here, "may further have an optionally substituted C 1-6 alkyl group", the ring A is a optionally substituted C 1-6 alkyl group other than R 1, further 1 or 2 may be present.
　環Ｂの「環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環」の「環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、６員芳香環（基）」としては、フェニル、ピリジル、ピリダジニル、ピリミジニル、ピラジニルが挙げられる。ここで、「さらに置換されていてもよい」とは、環Ｂが、Ｒ２およびＲ３以外の１または２個の置換基を、さらに有していてもよいことを示す。 In addition to the carbon atom as the ring constituent atom of the ring B, “the ring constituent atom may have one or two nitrogen atoms in addition to the carbon atom and may be further substituted” Examples of the 6-membered aromatic ring (group) optionally having 1 or 2 nitrogen atoms include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Here, “may be further substituted” means that the ring B may further have 1 or 2 substituents other than R 2 and R 3 .
　環Ｄの「さらに置換されていてもよい複素環」および「１個または２個のオキソ基を有する、さらに置換されていてもよい複素環」の「複素環」とは、例えば、単環式非芳香族複素環を示す。ここで「さらに置換されていてもよい」とは、環Ｄが、１または２個のオキソ基以外の置換基を、さらに有していてもよいことを示す。
　該「単環式非芳香族複素環」とは、例えば、環構成原子として炭素原子以外に窒素原子を２個有する、６または７員の非芳香族複素環等を示す。該「単環式非芳香族複素環」としては、例えば、下記の環Ｅの「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員非芳香族複素環（基）」で例示されたもののうち、窒素原子を２個有する６または７員のものが挙げられる。 “Heterocycle” of “optionally substituted heterocycle” of ring D and “optionally substituted heterocycle having one or two oxo groups” is, for example, monocyclic A non-aromatic heterocyclic ring is shown. Here, “may be further substituted” means that the ring D may further have a substituent other than one or two oxo groups.
The “monocyclic non-aromatic heterocycle” refers to, for example, a 6- or 7-membered non-aromatic heterocycle having two nitrogen atoms in addition to carbon atoms as ring-constituting atoms. Examples of the “monocyclic non-aromatic heterocyclic ring” include, for example, “monocyclic 4-7 member having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” of the following ring E Among those exemplified as “non-aromatic heterocycle (group)”, those having 6 or 7 members having two nitrogen atoms can be mentioned.
　環Ｅの「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環」の「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員複素環」とは、窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員芳香族複素環または単環式４～７員非芳香族複素環を示す。
　該「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員芳香族複素環（基）」としては、例えば、フリル、チエニル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、トリアジニル等が挙げられる。
　該「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員非芳香族複素環（基）」としては、例えば、アゼチジニル、オキセタニル、チエタニル、ピロリジニル、テトラヒドロフリル、チオラニル、ピペリジニル、テトラヒドロピラニル、チアニル、モルホリニル、チオモルホリニル、ピペラジニル、アゼパニル、オキセパニル、チエパニル、オキソカニル、チオカニル、ジアゼパニル（例、１，４－ジアゼパニル）、ジオキサニル、ジヒドロピラゾリル、ヘキサヒドロピリミジニル、テトラヒドロピリミジニル、ジヒドロピリミジニル、テトラヒドロピリジル、ジヒドロピリジル、テトラヒドロイミダゾリル等が挙げられる。 “Nitrogen atom, oxygen atom and sulfur” of ring E “optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” "Monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from atoms" means a monocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms. A 4- to 7-membered aromatic heterocycle or a monocyclic 4- to 7-membered non-aromatic heterocycle is represented.
Examples of the “monocyclic 4 to 7-membered aromatic heterocycle (group) having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” include furyl, thienyl, pyridyl, pyridazinyl. , Pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl and the like.
Examples of the “monocyclic 4 to 7-membered non-aromatic heterocycle (group) having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” include azetidinyl, oxetanyl, thietanyl, Pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, oxepanyl, thiepanyl, oxocanyl, thiocanyl, diazepanyl (eg, 1,4-diazepanyl), dioxanyl, dihydropyrazolyl, hexahydropyrimidyl , Tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyridyl, dihydropyridyl, tetrahydroimidazolyl and the like.
　環Ｅの「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環」の「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、９員または１０員の縮合複素環」としては、
５または６員の単環式非芳香族複素環とベンゼン環が縮合した、９または１０員の縮合非芳香族複素環；
５または６員の単環式芳香族複素環とベンゼン環が縮合した、９または１０員の縮合芳香族複素環；および
５または６員の単環式芳香族複素環と６員の単環式芳香族複素環が縮合した、９または１０員の縮合複素環；等を示す。
　該「５または６員の単環式非芳香族複素環」としては、上記環Ｅの「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員非芳香族複素環（基）」で例示されたもののうち、５または６員のものが挙げられる。
　該「５または６員の単環式芳香族複素環」としては、上記環Ｅの「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員芳香族複素環（基）」で例示されたもののうち、５または６員のものが挙げられる。
　該「６員の単環式芳香族複素環」としては、上記環Ｅの「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、単環式４～７員芳香族複素環（基）」で例示されたもののうち、６員のものが挙げられる。 “Nitrogen atom, oxygen atom and sulfur” of ring E “optionally substituted 9-membered or 10-membered condensed heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom” As a 9-membered or 10-membered fused heterocyclic ring having 1 to 3 heteroatoms selected from atoms ”
A 9- or 10-membered fused non-aromatic heterocycle in which a 5- or 6-membered monocyclic non-aromatic heterocycle and a benzene ring are condensed;
A 9- or 10-membered fused aromatic heterocycle in which a 5- or 6-membered monocyclic aromatic heterocycle and a benzene ring are condensed; and a 5- or 6-membered monocyclic aromatic heterocycle and a 6-membered monocyclic 9- or 10-membered fused heterocycles fused with an aromatic heterocycle;
The “5- or 6-membered monocyclic non-aromatic heterocyclic ring” is a monocyclic 4- to 4-cyclic monocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Among those exemplified as “7-membered non-aromatic heterocycle (group)”, 5-membered or 6-membered ones may be mentioned.
The “5- or 6-membered monocyclic aromatic heterocycle” is a monocyclic 4 to 7 having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom of the above ring E. Among those exemplified in the “membered aromatic heterocycle (group)”, those having 5 or 6 members may be mentioned.
The “6-membered monocyclic aromatic heterocycle” is a monocyclic 4- to 7-membered aromatic having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom of the ring E. Among those exemplified in “Group heterocycle (group)”, 6-membered ones can be mentioned.
　環Ｅの「置換されていてもよい３～７員飽和炭素環」の「３～７員飽和炭素環（基）」としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチルが挙げられる。 Examples of the “3- to 7-membered saturated carbocycle (group)” of the “optionally substituted 3- to 7-membered saturated carbocycle” of ring E include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
　環Ｅの「置換されていてもよい９～１３員の縮合炭素環」の「９～１３員の縮合炭素環」としては、５～７員の飽和炭素環と、１または２個の６～１０員単環式芳香族炭素環（例、ベンゼン）が縮合した、９～１３員の縮合炭素環等を示す。
　該「５～７員の飽和炭素環」としては、上記環Ｅの「置換されていてもよい３～７員飽和炭素環」の「３～７員飽和炭素環（基）」で例示されたもののうち、５～７員（例、５員）のものが挙げられる。
　該「６～１０員単環式芳香族炭素環（基）」としては、ベンゼン、ナフタレン等が挙げられる。
　該環Ｅの「９～１３員の縮合炭素環（基）」としては、インデニル、テトラリニル、フルオレニル、９，１０－ジヒドロアントラセニル等が挙げられる。 The “9 to 13-membered condensed carbocycle” of the “optionally substituted 9 to 13-membered fused carbocycle” of ring E is a 5- to 7-membered saturated carbocycle and one or two 6 to 6- A 9- to 13-membered condensed carbocycle in which a 10-membered monocyclic aromatic carbocycle (eg, benzene) is condensed is shown.
The “5- to 7-membered saturated carbocycle” is exemplified by the “3- to 7-membered saturated carbocycle (group)” in the “optionally substituted 3- to 7-membered saturated carbocycle” of the above ring E. Among those, 5 to 7 members (eg, 5 members) are listed.
Examples of the “6- to 10-membered monocyclic aromatic carbocycle (group)” include benzene and naphthalene.
Examples of the “9 to 13-membered condensed carbocycle (group)” of the ring E include indenyl, tetralinyl, fluorenyl, 9,10-dihydroanthracenyl and the like.
　環Ｅの「置換されていてもよい１３～１５員のスピロ複素環」の「１３～１５員のスピロ複素環（基）」としては、炭素原子以外に、酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、１３～１５員のスピロ複素環等を示し、例えば、スピロ［１，３－ジヒドロイソベンゾフラン－１，４’－ピペリジン等が挙げられる。 The “13 to 15-membered spiro heterocycle (group)” of the “optionally substituted 13 to 15-membered spiro heterocycle” of ring E includes, in addition to carbon atoms, oxygen atoms, sulfur atoms, and nitrogen atoms. Examples thereof include 13 to 15-membered spiroheterocycle having 1 to 3 heteroatoms selected, and examples thereof include spiro [1,3-dihydroisobenzofuran-1,4′-piperidine and the like.
　環Ｂの「環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環」、
環Ｄの「置換されていてもよい複素環」、
「１個または２個のオキソ基を有する、さらに置換されていてもよい複素環」、ならびに環Ｅの「置換されていてもよいベンゼン環」、
「置換されていてもよいナフタレン環」、
「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環」、
「窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環」、
「置換されていてもよい３～７員飽和炭素環」、および
「置換されていてもよい９～１３員の縮合炭素環」、
「置換されていてもよい１３～１５員のスピロ複素環」
の「置換基」としては、下記置換基群（以下、置換基群Ｂと略記する）等から選ばれる１～３個の置換基が挙げられる。
　該置換基が２個以上存在する場合には、該置換基は同じ種類のものであっても異なる種類のものであってもよい。
　また、環Ｄにおいて、該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい。ここで、置換基同士が結合して架橋構造を形成する環Ｄとしては、２，６－ジアザビシクロ［３．２．２］ノナン－３－オン、３，９－ジアザビシクロ［４．２．１］ノナン－４－オン、３，６－ジアザビシクロ［３．２．１］オクタン－７－オン、８－オキサ－３，１０－ジアザビシクロ［４．３．１］デカン－４－オン、３，９－ジアザビシクロ［３．３．１］ノナン－２，４－ジオン、３，９－ジアザビシクロ［３．３．１］ノナン等が挙げられる。 Ring B “6-membered aromatic ring which may have 1 or 2 nitrogen atoms other than carbon atoms as a ring-constituting atom, and may be further substituted”
Ring D “optionally substituted heterocycle”,
"An optionally substituted heterocycle having 1 or 2 oxo groups", as well as an "optionally substituted benzene ring" in ring E;
“Optionally substituted naphthalene ring”,
“Optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom”,
“Optionally substituted 9-membered or 10-membered fused heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms”,
“Optionally substituted 3- to 7-membered saturated carbocyclic ring” and “optionally substituted 9- to 13-membered fused carbocyclic ring”,
“Optionally substituted 13-15 membered spiro heterocycle”
Examples of the “substituent” include 1 to 3 substituents selected from the following substituent group (hereinafter abbreviated as substituent group B) and the like.
When two or more substituents are present, the substituents may be the same or different.
In the ring D, when two or more substituents are present, the substituents may be bonded to each other to form a crosslinked structure. Here, as ring D in which substituents are bonded to form a crosslinked structure, 2,6-diazabicyclo [3.2.2] nonan-3-one, 3,9-diazabicyclo [4.2.1] Nonan-4-one, 3,6-diazabicyclo [3.2.1] octane-7-one, 8-oxa-3,10-diazabicyclo [4.3.1] decan-4-one, 3,9- And diazabicyclo [3.3.1] nonane-2,4-dione, 3,9-diazabicyclo [3.3.1] nonane.
　また、本明細書中、「置換されていてもよい２，３－ジヒドロ－１－ベンゾフラン環」、「置換されていてもよいクロマン環」の「置換基」としては、置換基群Ｂから選ばれる１～３個の置換基が挙げられる。該置換基が２個以上存在する場合には、該置換基は同じ種類のものであっても異なる種類のものであってもよい。 In the present specification, the “substituent” of “optionally substituted 2,3-dihydro-1-benzofuran ring” and “optionally substituted chroman ring” is selected from substituent group B 1 to 3 substituents may be mentioned. When two or more substituents are present, the substituents may be the same or different.
置換基群Ｂ：
（１）ハロゲン原子、
（２）ニトロ、
（３）シアノ、
（４）（ａ）ハロゲン原子、
　　　（ｂ）３～８員の複素環基（例、モルホリニル、ピリジル）、
　　　（ｃ）ヒドロキシ、および
　　　（ｄ）Ｃ１－６アルキル－カルボニル（例、アセチル）
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル、
（５）１～３個のハロゲン原子を有していてもよいＣ２－６アルケニル（例、ビニル、アリル、イソプロペニル、ブテニル、イソブテニル、ｓｅｃ－ブテニル等）、
（６）１～３個のハロゲン原子を有していてもよいＣ２－６アルキニル（例、エチニル、プロパルギル、ブチニル、ヘキシニル等）、
（７）１～３個のハロゲン原子を有していてもよいＣ３－８シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等）、
（８）（ａ）ハロゲン原子、
　　　（ｂ）シアノ、
　　　（ｃ）１～３個のハロゲン原子を有していてもよいＣ１－６アルキル、および
　　　（ｄ）Ｃ１－６アルコキシ
から選ばれる１～３個の置換基を有していてもよいＣ６－１４アリール（例、フェニル、ナフチル等）、
（９）Ｃ７－１６アラルキル（例、ベンジル、フェネチル、ジフェニルメチル、１－ナフチルメチル、２－ナフチルメチル、２，２－ジフェニルエチル、３－フェニルプロピル、４－フェニルブチル、５－フェニルペンチル等）、
（１０）ヒドロキシ、
（１１）（ａ）ハロゲン原子、および
　　　　（ｂ）Ｃ３－８シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等）
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ、
（１２）Ｃ６－１４アリールオキシ（例、フェニルオキシ、ナフチルオキシ等）、
（１３）Ｃ７－１４アラルキルオキシ（例、ベンジルオキシ）、
（１４）メルカプト、
（１５）１～３個のハロゲン原子を有していてもよいＣ１－６アルキルチオ、
（１６）Ｃ６－１４アリールチオ（例、フェニルチオ、ナフチルチオ等）、
（１７）アミノ、
（１８）モノ－Ｃ１－６アルキルアミノ（例、メチルアミノ、エチルアミノ等）、
（１９）モノ－Ｃ６－１４アリールアミノ（例、フェニルアミノ、ナフチルアミノ等）、
（２０）（ａ）Ｃ１－６アルコキシ、および
　　　　（ｂ）Ｃ１－６アルキルを有していてもよい複素環基（例、イソオキサゾリル）から選ばれる１個の置換基を有していてもよいジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ、ジエチルアミノ、２－メトキシエチル（メチル）アミノ等）、
（２１）ジ－Ｃ６－１４アリールアミノ（例、ジフェニルアミノ等）、
（２２）ホルミル、
（２３）（ａ）シアノ、
　　　　（ｂ）ヒドロキシ、および
　　　　（ｃ）ハロゲン原子
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルキル－カルボニル（例、アセチル、プロピオニル、イソブチリル、ブチリル等）、
（２４）１個のヒドロキシを有していてもよいＣ３－６シクロアルキル－カルボニル（例、シクロプロピルカルボニル）、
（２５）（ａ）Ｃ１－６アルコキシ、
　　　　（ｂ）ハロゲン原子、
　　　　（ｃ）シアノ、および
　　　　（ｄ）Ｃ６－１４アリール（例、フェニル）
から選ばれる１～３個の置換基を有していてもよいＣ６－１４アリール－カルボニル（例、ベンゾイル、ナフトイル等）、
（２６）カルボキシ、
（２７）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、
（２８）Ｃ６－１４アリールオキシ－カルボニル（例、フェノキシカルボニル等）、
（２９）Ｃ７－１４アラルキルオキシ－カルボニル（例、ベンジルオキシカルボニル等）、
（３０）カルバモイル－カルボニル、
（３１）カルバモイル、
（３２）チオカルバモイル、
（３３）モノ－Ｃ１－６アルキル－カルバモイル（例、メチルカルバモイル、エチルカルバモイル等）、
（３４）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル、ジエチルカルバモイル、エチルメチルカルバモイル等）、
（３５）Ｃ３－６シクロアルキル－カルバモイル（例、シクロプロピルカルバモイル）、
（３６）Ｃ６－１４アリール－カルバモイル（例、フェニルカルバモイル、ナフチルカルバモイル等）、
（３７）Ｃ１－６アルキルスルホニル（例、メチルスルホニル、エチルスルホニル）、
（３８）Ｃ６－１４アリールスルホニル（例、フェニルスルホニル、ナフチルスルホニル等）、
（３９）Ｃ１－６アルキルスルフィニル、
（４０）Ｃ６－１４アリールスルフィニル（例、フェニルスルフィニル、ナフチルスルフィニル等）、
（４１）アミノスルホニル、
（４２）ホルミルアミノ、
（４３）Ｃ１－６アルキルで置換されていてもよい、Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ、Ｎ－（エチル）アセチルアミノ等）、
（４４）Ｃ６－１４アリール－カルボニルアミノ（例、ベンゾイルアミノ、ナフトイルアミノ等）、
（４５）Ｃ１－６アルコキシ－カルボニルアミノ（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ、ｔｅｒｔ－ブトキシカルボニルアミノ等）、
（４６）Ｃ１－６アルキルスルホニルアミノ（例、メチルスルホニルアミノ、エチルスルホニルアミノ等）、
（４７）Ｃ６－１４アリールスルホニルアミノ（例、フェニルスルホニルアミノ、ナフチルスルホニルアミノ等）、
（４８）Ｃ１－６アルキル－カルボニルオキシ（例、アセトキシ、プロピオニルオキシ等）、
（４９）Ｃ６－１４アリール－カルボニルオキシ（例、ベンゾイルオキシ、ナフチルカルボニルオキシ等）、
（５０）Ｃ１－６アルコキシ－カルボニルオキシ（例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ等）、
（５１）カルバモイルオキシ、
（５２）モノ－Ｃ１－６アルキル－カルバモイルオキシ（例、メチルカルバモイルオキシ、エチルカルバモイルオキシ等）、
（５３）ジ－Ｃ１－６アルキル－カルバモイルオキシ（例、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ等）、
（５４）Ｃ６－１４アリール－カルバモイルオキシ（例、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシ等）、
（５５）（ａ）１～３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　（ｂ）オキソ、
　　　　（ｃ）ハロゲン原子、および
　　　　（ｄ）Ｃ１－６アルコキシ－カルボニル（例、ｔｅｒｔ－ブトキシカルボニル）から選ばれる１～３個の置換基を有していてもよい、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１～３種のヘテロ原子を、１～５個含む３～１４員（単環、２環又は３環式）複素環基
［例、芳香族複素環基（例、ピロリル、フリル、チエニル、ピラゾリル、イミダゾリル、イソオキサゾリル、オキサゾリル、イソチアゾリル、チアゾリル、トリアゾリル、オキサジアゾリル、チアジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、イソインドリル、インドリル、ベンゾ［ｂ］フラニル、ベンゾ［ｃ］フラニル、ベンゾ［ｂ］チエニル、ベンゾ［ｃ］チエニル、インダゾリル、ベンゾイミダゾリル、１，２－ベンゾイソオキサゾリル、ベンゾオキサゾリル、１，２－ベンゾイソチアゾリル、ベンゾチアゾリル、イソキノリル、キノリル、シンノリニル、フタラジニル、キナゾリニル、キノキサリニル、ピラゾロ［１，５－ａ］ピリジル、イミダゾ［１，２－ａ］ピリジル等）；
非芳香族複素環基（例、オキサゾリジニル、イミダゾリニル、アジリジニル、アゼチジニル、ピロリジニル、ピペリジニル、アゼパニル、アゾカニル、ピペラジニル、ジアゼパニル、ジアゾカニル、４－モルホリニル、４－チオモルホリニル、１，１－ジオキシドチオモルホリン－４－イル等）；
前記の芳香族複素環基の一部が水素化された複素環基（例、インドリニル、ジヒドロキノリル、テトラヒドロピラジニル等）；
前記の非芳香族複素環基の一部が脱水素化された複素環基（例、ジヒドロフリル等）］、
（５６）１個のＣ１－６アルキル－カルボニル（例、アセチル）を有していてもよい５～１０員複素環－アミノ（該５～１０員複素環は、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１または２種のヘテロ原子を１～４個含む）（例、モルホリニルアミノ、４－ピペリジルアミノ）、
（５７）５～１０員複素環－カルボニル（例、２－フリルカルボニル、４－ピリジルカルボニル、Ｎ－オキシド－４－ピリジルカルボニル）、
（５８）Ｃ１－３アルキレンジオキシ（例、メチレンジオキシ、エチレンジオキシ等）、
（５９）オキソ、
（６０）Ｃ６－１４アリール－カルボニル（例、ベンゾイル）を有していてもよい３～１４員複素環－オキシ（例、ピペリジン－４－イルオキシ、１－ベンゾイル－ピペリジン－４－イルオキシ、ピリジン－２－イルオキシ）、
（６１）ジ－Ｃ１－６アルキルスルファモイル。 Substituent group B:
(1) a halogen atom,
(2) Nitro,
(3) Cyano,
(4) (a) a halogen atom,
(B) a 3- to 8-membered heterocyclic group (eg, morpholinyl, pyridyl),
(C) hydroxy, and (d) C 1-6 alkyl-carbonyl (eg, acetyl)
C 1-6 alkyl optionally having 1 to 5 substituents selected from
(5) C 2-6 alkenyl optionally having 1 to 3 halogen atoms (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.),
(6) C 2-6 alkynyl (eg, ethynyl, propargyl, butynyl, hexynyl, etc.) optionally having 1 to 3 halogen atoms,
(7) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) optionally having 1 to 3 halogen atoms,
(8) (a) a halogen atom,
(B) cyano,
(C) C 1-6 alkyl optionally having 1 to 3 halogen atoms, and (d) C 1-6 optionally having a substituent selected from C 1-6 alkoxy 6-14 aryl (eg, phenyl, naphthyl, etc.),
(9) C 7-16 aralkyl (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.) ),
(10) hydroxy,
(11) (a) a halogen atom, and (b) C 3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.)
C 1-6 alkoxy optionally having 1 to 3 substituents selected from
(12) C 6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.),
(13) C 7-14 aralkyloxy (eg, benzyloxy),
(14) Mercapto,
(15) C 1-6 alkylthio optionally having 1 to 3 halogen atoms,
(16) C 6-14 arylthio (eg, phenylthio, naphthylthio, etc.),
(17) amino,
(18) mono-C 1-6 alkylamino (eg, methylamino, ethylamino, etc.),
(19) Mono-C 6-14 arylamino (eg, phenylamino, naphthylamino, etc.)
(20) It may have one substituent selected from (a) C 1-6 alkoxy, and (b) a heterocyclic group (eg, isoxazolyl) optionally having C 1-6 alkyl. Good di-C 1-6 alkylamino (eg, dimethylamino, diethylamino, 2-methoxyethyl (methyl) amino, etc.),
(21) di-C 6-14 arylamino (eg, diphenylamino),
(22) Formyl,
(23) (a) cyano,
(B) hydroxy, and (c) C 1-6 alkyl-carbonyl (eg, acetyl, propionyl, isobutyryl, butyryl, etc.) optionally having 1 to 3 substituents selected from halogen atoms,
(24) C 3-6 cycloalkyl-carbonyl optionally having one hydroxy (eg, cyclopropylcarbonyl),
(25) (a) C 1-6 alkoxy,
(B) a halogen atom,
(C) cyano, and (d) C 6-14 aryl (eg, phenyl)
C 6-14 aryl-carbonyl (eg, benzoyl, naphthoyl, etc.) optionally having 1 to 3 substituents selected from
(26) carboxy,
(27) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.),
(28) C 6-14 aryloxy-carbonyl (eg, phenoxycarbonyl etc.),
(29) C 7-14 aralkyloxy-carbonyl (eg, benzyloxycarbonyl etc.),
(30) Carbamoyl-carbonyl,
(31) Carbamoyl,
(32) thiocarbamoyl,
(33) mono-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.),
(34) Di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.),
(35) C 3-6 cycloalkyl-carbamoyl (eg, cyclopropylcarbamoyl),
(36) C 6-14 aryl-carbamoyl (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.),
(37) C 1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl),
(38) C 6-14 arylsulfonyl (eg, phenylsulfonyl, naphthylsulfonyl, etc.),
(39) C 1-6 alkylsulfinyl,
(40) C 6-14 arylsulfinyl (eg, phenylsulfinyl, naphthylsulfinyl, etc.),
(41) aminosulfonyl,
(42) formylamino,
(43) C 1-6 alkyl-carbonylamino (eg, acetylamino, N- (ethyl) acetylamino, etc.) optionally substituted with C 1-6 alkyl,
(44) C 6-14 aryl-carbonylamino (eg, benzoylamino, naphthoylamino, etc.),
(45) C 1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino, etc.),
(46) C 1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.)
(47) C 6-14 arylsulfonylamino (eg, phenylsulfonylamino, naphthylsulfonylamino, etc.),
(48) C 1-6 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.),
(49) C 6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.),
(50) C 1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.),
(51) Carbamoyloxy,
(52) mono-C 1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.),
(53) Di-C 1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.),
(54) C 6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.),
(55) (a) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(B) oxo,
(C) a halogen atom, and (d) 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl (eg, tert-butoxycarbonyl) optionally having a nitrogen atom in addition to a carbon atom, 3- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic groups containing 1 to 5 heteroatoms selected from sulfur and oxygen atoms [eg, aromatic heterocyclic groups (eg, , Pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, indolyl, benzo [b] furanyl, benzo [c] furanyl , Benzo [b] thienyl, benzo [c] thienyl, indazolyl Benzimidazolyl, 1,2-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, benzothiazolyl, isoquinolyl, quinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrazolo [1,5-a] pyridyl, Imidazo [1,2-a] pyridyl etc.);
Non-aromatic heterocyclic groups (eg, oxazolidinyl, imidazolinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, diazepanyl, diazocanyl, 4-morpholinyl, 4-thiomorpholinyl, 1,1-dioxidethiomorpholine-4- Ill);
A heterocyclic group in which a part of the aromatic heterocyclic group is hydrogenated (eg, indolinyl, dihydroquinolyl, tetrahydropyrazinyl, etc.);
A heterocyclic group in which a part of the non-aromatic heterocyclic group is dehydrogenated (eg, dihydrofuryl, etc.)],
(56) 5- to 10-membered heterocycle-amino optionally having one C 1-6 alkyl-carbonyl (eg, acetyl) (the 5- to 10-membered heterocycle is a nitrogen atom in addition to a carbon atom, 1 to 4 heteroatoms selected from a sulfur atom and an oxygen atom) (eg, morpholinylamino, 4-piperidylamino),
(57) 5- to 10-membered heterocycle-carbonyl (eg, 2-furylcarbonyl, 4-pyridylcarbonyl, N-oxide-4-pyridylcarbonyl),
(58) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.),
(59) Oxo,
(60) 3-14 membered heterocyclic-oxy optionally having C 6-14 aryl-carbonyl (eg, benzoyl) (eg, piperidin-4-yloxy, 1-benzoyl-piperidin-4-yloxy, pyridine) -2-yloxy),
(61) Di-C 1-6 alkylsulfamoyl.
　以下、本発明化合物について説明する。 Hereinafter, the compound of the present invention will be described.
　Ｒ１は、水素原子または置換されていてもよいＣ１－６アルキル基を示す。
　Ｒ１として好ましくは、水素原子およびＣ１－６アルキル基であり、より好ましくは、水素原子、メチル、エチル、プロピル、イソプロピル等が挙げられる。
　Ｒ１の別の好ましい態様としては、Ｃ１－６アルキル基が挙げられる。 R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
R 1 is preferably a hydrogen atom and a C 1-6 alkyl group, more preferably a hydrogen atom, methyl, ethyl, propyl, isopropyl and the like.
Another preferred embodiment of R 1 includes a C 1-6 alkyl group.
　Ｒ２およびＲ３は、同一または異なって、
水素原子、
ハロゲン原子、
ヒドロキシ、
置換されていてもよいＣ１－６アルキル基、
置換されていてもよいＣ１－６アルコキシ基、
置換されていてもよいＣ１－６アルキルチオ基、
置換されていてもよいＣ１－６アルキルスルホニル基、または
置換されていてもよいＣ１－６アルキルスルフィニル基を示す。
　Ｒ２およびＲ３として、好ましくは、
（１）水素原子、
（２）ハロゲン原子、
（３）ヒドロキシ、
（４）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよい、Ｃ１－６アルキル基、
（５）（ａ）ハロゲン原子（例、フッ素原子）、および
　　　（ｂ）フェニル基
からなる群から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基、
（６）Ｃ１－６アルキルチオ基、
（７）Ｃ１－６アルキルスルフィニル基等が挙げられる。
　Ｒ２およびＲ３として、更に好ましくは、水素原子、塩素原子、フッ素原子、ヒドロキシ、メチル、トリフルオロメチル、メトキシ、エトキシ、プロポキシ、イソプロポキシ、トリフルオロメトキシ、ジフルオロエトキシ、トリフルオロエトキシ、ベンジルオキシ、ヒドロキシ、メチルチオ、メチルスルフィニル等が挙げられる。
　Ｒ２およびＲ３の別の好ましい態様としては、
同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基である。
　Ｒ２およびＲ３の更に別の好ましい態様としては、
一方が水素原子、他方が水素原子またはＣ１－６アルコキシ基である。 R 2 and R 3 are the same or different and
Hydrogen atom,
Halogen atoms,
Hydroxy,
An optionally substituted C 1-6 alkyl group,
An optionally substituted C 1-6 alkoxy group,
An optionally substituted C 1-6 alkylthio group,
An optionally substituted C 1-6 alkylsulfonyl group or an optionally substituted C 1-6 alkylsulfinyl group is shown.
As R 2 and R 3 ,
(1) a hydrogen atom,
(2) a halogen atom,
(3) hydroxy,
(4) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom),
(5) a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom (eg, fluorine atom), and (b) a phenyl group,
(6) a C 1-6 alkylthio group,
(7) C 1-6 alkylsulfinyl group and the like can be mentioned.
R 2 and R 3 are more preferably hydrogen atom, chlorine atom, fluorine atom, hydroxy, methyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, benzyloxy , Hydroxy, methylthio, methylsulfinyl and the like.
As another preferred embodiment of R 2 and R 3 ,
It is the same or different and is a hydrogen atom, a halogen atom or a C 1-6 alkoxy group.
As still another preferred embodiment of R 2 and R 3 ,
One is a hydrogen atom and the other is a hydrogen atom or a C 1-6 alkoxy group.
　ｎは、１または２を示す。
　ｎとして好ましくは、１である。 n represents 1 or 2.
n is preferably 1.
　Ｙは、
結合手、
－Ｒａ１－、
－Ｒａ１ＣＯ－、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、
－Ｒａ１Ｏ－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
－ＣＯＮ（Ｒｂ１）ＳＯ２－を示す。 Y is
Join hands,
-Ra 1- ,
-Ra 1 CO-,
-Ra 1 CON (Rb 1 )-,
-Ra 1 CON (Rb 1 ) Ra 2- ,
-Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-,
-Ra 1 CON (Rb 1 ) Ra 2 O-,
-Ra 1 O-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
—CON (Rb 1 ) Ra 1 N (Rb 2 ) CO— or —CON (Rb 1 ) SO 2 — is shown.
　Ｙとして、好ましくは、
結合手、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、
－ＣＯＮ（Ｒｂ１）ＳＯ２－等が挙げられる。 Y is preferably
Join hands,
-Ra 1 CON (Rb 1 )-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
-CON (Rb 1 ) Ra 1 N (Rb 2 ) CO-,
-CON (Rb 1 ) SO 2- and the like.
　Ｙの別の好ましい態様としては、
－Ｒａ１－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、
－Ｒａ１ＣＯ－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－
等が挙げられる。 As another preferred embodiment of Y,
-Ra 1- ,
-Ra 1 CON (Rb 1 ) Ra 2- ,
-Ra 1 CON (Rb 1 ) Ra 2 O-,
-Ra 1 CO-,
-Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-
Etc.
　Ｙの更に別の好ましい態様としては、
－ＣＯ－、
－Ｒａ１－、
－ＣＯＲａ１－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－Ｒａ１ＣＯＮ（Ｒｂ１）－
等が挙げられる。
　Ｙのなお更に別の好ましい態様としては、
－ＣＯ－、
－ＣＯＲａ１－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
等が挙げられる。
　Ｙのなお更に別の好ましい態様としては、
Ｃ１－６アルキレン基、
－Ｒａ１ＣＯＮ（Ｒｂ１）－
等が挙げられる。
　Ｙのなお更に別の好ましい態様としては、
－ＣＯＮ（Ｒｂ１）Ｒａ１－
等が挙げられる。 As still another preferred embodiment of Y,
-CO-,
-Ra 1- ,
-CORa 1- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-Ra 1 CON (Rb 1 )-
Etc.
As yet another preferred embodiment of Y,
-CO-,
-CORa 1- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
Etc.
As yet another preferred embodiment of Y,
A C 1-6 alkylene group,
-Ra 1 CON (Rb 1 )-
Etc.
As yet another preferred embodiment of Y,
-CON (Rb 1 ) Ra 1-
Etc.
　前記ＹにおけるＲａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレンを示し、好ましくは、同一または異なって、置換基群Ａから選ばれる１または２個の置換基で置換されていてもよい、Ｃ１－６アルキレン等である。なかでも好ましくは、同一または異なって、
（１）シアノ
（２）（ａ）ハロゲン原子（例、フッ素原子）、
　　　（ｂ）３～８員の複素環基、
　　　（ｃ）ヒドロキシ、
　　　（ｄ）Ｃ１－６アルキル－カルボニル
　　　（ｅ）Ｃ１－６アルコキシ（例、メトキシ）
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル）、
（３）１～５個のハロゲン原子を有していてもよいＣ３－８シクロアルキル（例、シクロプロピル）
（４）１～３個のハロゲン原子を有していてもよいＣ１－６アルキルを有していてもよいＣ６－１４アリール（例、フェニル）
（５）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）、
（６）ヒドロキシ、および
（７）（ａ）ハロゲン原子、および
　　　（ｂ）Ｃ３－８シクロアルキル
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ（例、メトキシ）、
から選ばれる１または２個の置換基で置換されていてもよい、Ｃ１－６アルキレン（例、メチレン、エチレン、プロピレン）等が挙げられる。該置換基同士は結合して環（例、シクロプロパン、シクロペンタン）を形成してもよい。
　前記ＹにおけるＲａ１およびＲａ２として、更に好ましくは、メチレン、メチルメチレン、ジメチルメチレン、エチルメチレン、メチレン、シアノメチレン、メトキシカルボニルメチレン、ヒドロキシメチルメチレン、エチレン、フェニルエチレン、ヒドロキシエチレン、プロピレン等が挙げられる。
　さらに、該置換基同士が結合して環を形成してもよい。
　前記ＹにおけるＲａ１およびＲａ２の別の好ましい態様としては、
同一または異なって、
（１）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および
（２）シアノ基
から選択される（例、１または２個の）置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上（例、２個）存在する場合には、該置換基同士が結合して環（例、シクロプロパン）を形成してもよい）
が挙げられる。
　前記ＹにおけるＲａ１およびＲａ２の更に別の好ましい態様としては、
同一または異なって、Ｃ１－６アルキレン基である。
　前記ＹにおけるＲａ１およびＲａ２のなお更に別の好ましい態様としては、
ヒドロキシ基で置換されていてもよいＣ１－６アルキル基で置換されていてもよい、Ｃ１－６アルキレン基である。 Ra 1 and Ra 2 in Y represent the same or different and optionally substituted C 1-6 alkylene, and preferably the same or different, 1 or 2 substituents selected from the substituent group A And C 1-6 alkylene which may be substituted with a group. Among these, preferably the same or different,
(1) cyano (2) (a) halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy,
(D) C 1-6 alkyl-carbonyl (e) C 1-6 alkoxy (eg, methoxy)
C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl) optionally having 1 to 5 substituents selected from
(3) C 3-8 cycloalkyl optionally having 1 to 5 halogen atoms (eg, cyclopropyl)
(4) C 6-14 aryl optionally having 1 to 3 halogen atoms and optionally having C 1-6 alkyl (eg, phenyl)
(5) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(6) hydroxy, and (7) (a) a halogen atom, and (b) C 1-6 alkoxy optionally having 1 to 3 substituents selected from C 3-8 cycloalkyl (eg, Methoxy),
And C 1-6 alkylene (eg, methylene, ethylene, propylene) which may be substituted with 1 or 2 substituents selected from The substituents may be bonded to form a ring (eg, cyclopropane, cyclopentane).
Ra 1 and Ra 2 in Y are more preferably methylene, methylmethylene, dimethylmethylene, ethylmethylene, methylene, cyanomethylene, methoxycarbonylmethylene, hydroxymethylmethylene, ethylene, phenylethylene, hydroxyethylene, propylene, and the like. It is done.
Further, the substituents may be bonded to form a ring.
As another preferred embodiment of Ra 1 and Ra 2 in Y,
Same or different,
(1) optionally substituted with hydroxy C 1-6 alkyl group, and (2) is selected from a cyano group (eg, 1 or 2) which may be substituted with a substituent C 1- 6 alkylene group (when two or more (eg, 2) of the substituents are present, the substituents may be bonded to form a ring (eg, cyclopropane))
Is mentioned.
As another preferred embodiment of Ra 1 and Ra 2 in Y,
It is the same or different and is a C 1-6 alkylene group.
As still another preferred embodiment of Ra 1 and Ra 2 in Y,
A C 1-6 alkylene group which may be substituted with a C 1-6 alkyl group which may be substituted with a hydroxy group.
　前記ＹにおけるＲｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示し、好ましくは、同一または異なって、水素原子または置換基群Ａ（但し、置換基群Ａの（４）の置換基を除く）から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基等である。Ｒｂ１およびＲｂ２として、更に好ましくは、同一または異なって、
水素原子、
（１）ハロゲン原子（フッ素原子）、
（２）シアノ、
（３）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ）、および
（４）Ｃ３－８シクロアルキル（例、シクロプロピル）
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル、イソブチル）等であり、特に好ましくは、水素原子、メチル、エチル、イソブチル、シクロプロピルメチル、２－シアノエチル、２－（ジメチルアミノ）エチル、２，２－ジフルオロエチル、２，２，２－トリフルオロエチル等である。
　前記ＹにおけるＲｂ１およびＲｂ２の別の好ましい態様としては、
水素原子、
ハロゲン原子で置換されたＣ１－６アルキル基
等である。
　前記ＹにおけるＲｂ１およびＲｂ２の更に別の好ましい態様としては、水素原子等である。 Rb 1 and Rb 2 in Y are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, preferably the same or different, a hydrogen atom or substituent group A (provided that A C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from (excluding the substituent of (4) in substituent group A). Rb 1 and Rb 2 are more preferably the same or different,
Hydrogen atom,
(1) halogen atom (fluorine atom),
(2) cyano,
(3) Di-C 1-6 alkylamino (eg, dimethylamino), and (4) C 3-8 cycloalkyl (eg, cyclopropyl)
C 1-6 alkyl (eg, methyl, ethyl, isobutyl) and the like, which may have 1 to 3 substituents selected from, particularly preferably a hydrogen atom, methyl, ethyl, isobutyl, cyclopropyl Methyl, 2-cyanoethyl, 2- (dimethylamino) ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and the like.
As another preferred embodiment of Rb 1 and Rb 2 in Y,
Hydrogen atom,
And a C 1-6 alkyl group substituted with a halogen atom.
Yet another preferred embodiment of Rb 1 and Rb 2 in Y is a hydrogen atom or the like.
　環Ａは、酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい、５員芳香族複素環を示す。
　環Ａとして、好ましくは、
酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、Ｃ１－６アルキル基をさらに有していてもよい、５員芳香族複素環である。
　環Ａとして、より好ましくは、それぞれＣ１－６アルキル基（例、メチル）をさらに有していてもよい、オキサゾール環、トリアゾール環（例、１，２，３－トリアゾール、１，２，４－トリアゾール）、ピラゾール環、オキサジアゾール環、イソオキサゾール環、チアゾール環、チオフェン環、イミダゾール環等である。
［即ち、部分構造式： Ring A may further have an optionally substituted C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 5-membered aromatic group Indicates a heterocycle.
As ring A, preferably
A 5-membered aromatic heterocycle which may further have a C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
Ring A is more preferably an oxazole ring or a triazole ring (eg, 1,2,3-triazole, 1,2,4), each of which may further have a C 1-6 alkyl group (eg, methyl). -Triazole), pyrazole ring, oxadiazole ring, isoxazole ring, thiazole ring, thiophene ring, imidazole ring and the like.
[Ie, partial structural formula:
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
（式中、各記号は前記のとおりである。環Ａは、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい。）における、 In the formula, each symbol is as described above. Ring A may further have an optionally substituted C 1-6 alkyl group.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
部分が、それぞれＣ１－６アルキル基（例、メチル）をさらに有していてもよい、
オキサゾリル（例、１，３－オキサゾール－５－イル）、
トリアゾリル（例、１Ｈ－１，２，３－トリアゾール－１－イル、２Ｈ－１，２，３－トリアゾール－４－イル、１Ｈ－１，２，４－トリアゾール－１－イル、４Ｈ－１，２，４－トリアゾール－３－イル）、
ピラゾリル（例、１Ｈ－ピラゾール－４－イル）、
オキサジアゾリル（例、１，２，４－オキサジアゾール－３－イル、１，３，４－オキサジアゾール－２－イル、１，２，４－オキサジアゾール－５－イル）、
イソオキサゾリル（例、イソオキサゾール－４－イル）、
チアゾリル（例、チアゾール－５－イル）、
チエニル（例、２－チエニル）、
イミダゾリル等である。］ Each moiety may further have a C 1-6 alkyl group (eg, methyl),
Oxazolyl (eg, 1,3-oxazol-5-yl),
Triazolyl (eg, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 4H-1, 2,4-triazol-3-yl),
Pyrazolyl (eg, 1H-pyrazol-4-yl),
Oxadiazolyl (eg, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl),
Isoxazolyl (eg, isoxazol-4-yl),
Thiazolyl (eg, thiazol-5-yl),
Thienyl (eg, 2-thienyl),
Such as imidazolyl. ]
　環Ａとして、好ましくは、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいオキサゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，３－トリアゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，４－トリアゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいピラゾール環等が挙げられる。
［即ち、部分構造式： As ring A, preferably
An oxazole ring which may further have an optionally substituted C 1-6 alkyl group,
A 1,2,3-triazole ring optionally further having an optionally substituted C 1-6 alkyl group,
A 1,2,4-triazole ring which may further have an optionally substituted C 1-6 alkyl group,
And a pyrazole ring which may further have an optionally substituted C 1-6 alkyl group.
[Ie, partial structural formula:
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
（式中、各記号は前記のとおりである。環Ａは、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい。）における、 In the formula, each symbol is as described above. Ring A may further have an optionally substituted C 1-6 alkyl group.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
部分が、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいオキサゾリル（例、１，３－オキサゾール－５－イル）、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，３－トリアゾリル（例、１Ｈ－１，２，３－トリアゾール－１－イル）、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，４－トリアゾリル（例、１Ｈ－１，２，４－トリアゾール－１－イル）、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいピラゾリル（例、１Ｈ－ピラゾール－４－イル）
等である。］
　環Ａとして、さらに好ましくは、オキサゾール環、１，２，３－トリアゾール環、１，２，４－トリアゾール環、ピラゾール環等が挙げられる。
［即ち、前記 Part is
An oxazolyl (eg, 1,3-oxazol-5-yl) optionally further having an optionally substituted C 1-6 alkyl group,
1,2,3-triazolyl (eg, 1H-1,2,3-triazol-1-yl) optionally further having an optionally substituted C 1-6 alkyl group,
1,2,4-triazolyl (eg, 1H-1,2,4-triazol-1-yl) optionally further having an optionally substituted C 1-6 alkyl group,
Pyrazolyl (eg, 1H-pyrazol-4-yl) optionally further having an optionally substituted C 1-6 alkyl group
Etc. ]
Ring A is more preferably an oxazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring and the like.
[I.e. said
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
部分が、
オキサゾリル（例、１，３－オキサゾール－５－イル）、
１，２，３－トリアゾリル（例、１Ｈ－１，２，３－トリアゾール－１－イル）、
１，２，４－トリアゾリル（例、１Ｈ－１，２，４－トリアゾール－１－イル）、
ピラゾリル（例、１Ｈ－ピラゾール－４－イル）
等である。］ Part is
Oxazolyl (eg, 1,3-oxazol-5-yl),
1,2,3-triazolyl (eg, 1H-1,2,3-triazol-1-yl),
1,2,4-triazolyl (eg, 1H-1,2,4-triazol-1-yl),
Pyrazolyl (eg, 1H-pyrazol-4-yl)
Etc. ]
　環Ａの別の好適な態様としては、オキサジアゾール環、トリアゾール環、イソオキサゾール環、チアゾール環、チオフェン環等である。
［即ち、前記 Another preferred embodiment of ring A includes an oxadiazole ring, a triazole ring, an isoxazole ring, a thiazole ring, a thiophene ring, and the like.
[I.e. said
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
部分が、
オキサジアゾリル（例、１，２，４－オキサジアゾール－３－イル、１，３，４－オキサジアゾール－２－イル、１，２，４－オキサジアゾール－５－イル）、トリアゾリル（例、２Ｈ－１，２，３－トリアゾール－４－イル、４Ｈ－１，２，４－トリアゾール－３－イル）、
イソオキサゾリル（例、イソオキサゾール－４－イル）、
チアゾリル（例、チアゾール－５－イル）、
チエニル（例、２－チエニル）
等である。］ Part is
Oxadiazolyl (eg, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl), triazolyl (eg 2H-1,2,3-triazol-4-yl, 4H-1,2,4-triazol-3-yl),
Isoxazolyl (eg, isoxazol-4-yl),
Thiazolyl (eg, thiazol-5-yl),
Thienyl (eg, 2-thienyl)
Etc. ]
　環Ａの更に別の好適な態様としては、ピラゾール環、オキサゾール環、トリアゾール環等が挙げられる。
［即ち、前記 Still another preferred embodiment of ring A includes a pyrazole ring, an oxazole ring, a triazole ring, and the like.
[I.e. said
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
部分が、
ピラゾリル（例、１Ｈ－ピラゾール－４－イル）、
オキサゾリル（例、１，３－オキサゾール－５－イル）、
トリアゾリル（例、１Ｈ－１，２，４－トリアゾール－１－イル）
等である。］
　なかでも好ましくは、オキサゾール環である。 Part is
Pyrazolyl (eg, 1H-pyrazol-4-yl),
Oxazolyl (eg, 1,3-oxazol-5-yl),
Triazolyl (eg, 1H-1,2,4-triazol-1-yl)
Etc. ]
Of these, an oxazole ring is preferable.
　環Ｂは、環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環を示す。環Ｂとして、好ましくは、ベンゼン環、ピリジン環、ピリミジン環（即ち、フェニル、ピリジル、ピリミジニルに対応）等が挙げられる。なかでも好ましくはベンゼン環である。 Ring B represents a 6-membered aromatic ring which may have 1 or 2 nitrogen atoms in addition to carbon atoms as a ring-constituting atom, and may be further substituted. The ring B preferably includes a benzene ring, a pyridine ring, a pyrimidine ring (that is, corresponding to phenyl, pyridyl, pyrimidinyl) and the like. Of these, a benzene ring is preferred.
　環Ｄは、置換されていてもよい複素環を示す。
　該「置換されていてもよい複素環」の「複素環」として好ましくは、単環式非芳香族複素環であり、より好ましくは、環構成原子として炭素原子以外に窒素原子を２個有する、６または７員の非芳香族複素環等が挙げられる。更に好ましくは、ピペラジニル、１，４－ジアゼパニル等が挙げられる。
　環Ｄの「置換されていてもよい複素環」の「置換基」としては、置換基群Ｂから選択される１～３個の置換基が挙げられる。該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい。即ち、環Ｄにおける「置換されていてもよい複素環」には、架橋構造を有していてもよい単環式非芳香族複素環（例、２，６－ジアザビシクロ［３．２．２］ノナン－３－オン、３，９－ジアザビシクロ［４．２．１］ノナン－４－オン、３，６－ジアザビシクロ［３．２．１］オクタン－７－オン、８－オキサ－３，１０－ジアザビシクロ［４．３．１］デカン－４－オン、３，９－ジアザビシクロ［３．３．１］ノナン－２，４－ジオン、３，９－ジアザビシクロ［３．３．１］ノナン）が包含される。
　該置換基として、好ましくは、
（１）オキソ、
（２）（ａ）ハロゲン原子、
　　　（ｂ）３～８員の複素環基、
　　　（ｃ）ヒドロキシ、および
　　　（ｄ）Ｃ１－６アルキル－カルボニル
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル）、
（３）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）、
（４）モノ－Ｃ１－６アルキル－カルバモイル（例、エチルカルバモイル）、および
（５）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル、ジエチルカルバモイル）
から選択される１～３個の置換基が挙げられる。該置換基として、より好ましくは、メチル、エチル、ヒドロキシメチル、エチルカルバモイル、ジエチルカルバモイル、オキソ、メトキシカルボニル、ジメチルカルバモイル等が挙げられる。 Ring D represents an optionally substituted heterocyclic ring.
The “heterocycle” of the “optionally substituted heterocycle” is preferably a monocyclic non-aromatic heterocycle, and more preferably has two nitrogen atoms in addition to carbon atoms as ring-constituting atoms. Examples include 6- or 7-membered non-aromatic heterocycles. More preferred are piperazinyl, 1,4-diazepanyl and the like.
Examples of the “substituent” of the “optionally substituted heterocycle” of Ring D include 1 to 3 substituents selected from Substituent Group B. When two or more substituents are present, the substituents may be bonded to form a crosslinked structure. That is, the “optionally substituted heterocycle” in ring D includes a monocyclic non-aromatic heterocycle (eg, 2,6-diazabicyclo [3.2.2]) that may have a bridge structure. Nonan-3-one, 3,9-diazabicyclo [4.2.1] nonane-4-one, 3,6-diazabicyclo [3.2.1] octane-7-one, 8-oxa-3,10- Diazabicyclo [4.3.1] decan-4-one, 3,9-diazabicyclo [3.3.1] nonane-2,4-dione, 3,9-diazabicyclo [3.3.1] nonane) Is done.
As the substituent, preferably
(1) oxo,
(2) (a) a halogen atom,
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy, and (d) C 1-6 alkyl - 1-5 may have a substituent group C 1-6 alkyl selected from carbonyl (e.g., methyl, ethyl),
(3) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(4) mono-C 1-6 alkyl-carbamoyl (eg, ethylcarbamoyl), and (5) di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl)
1 to 3 substituents selected from: More preferable examples of the substituent include methyl, ethyl, hydroxymethyl, ethylcarbamoyl, diethylcarbamoyl, oxo, methoxycarbonyl, dimethylcarbamoyl and the like.
　環Ｄの一態様としては、環Ｄは、１個または２個のオキソ基を有する、さらに置換されていてもよい複素環が挙げられる。なかでも好ましくは、１個のオキソ基を有する、１個または２個のメチルで置換されていてもよい、複素環（例、ピペラジニル、１，４－ジアゼパニル）が挙げられる。具体的には、オキソピペラジニル、７－オキソ－１，４－ジアゼパニル等が挙げられる。
　環Ｄの別の好ましい態様としては、
（１）オキソ基、
（２）Ｃ１－６アルキル基、および
（３）Ｃ１－６アルコキシ－カルボニル基
から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）
が挙げられる。
　環Ｄの更に別の好ましい態様としては、
（１）Ｃ１－６アルキル基、および
（２）Ｃ１－６アルコキシ－カルボニル基
から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）
が挙げられる。
　環Ｄの更に別の好ましい態様としては、1個のオキソ基を有する複素環が挙げられる。
　環Ｄの更に別の好ましい態様としては、複素環である。 As one embodiment of the ring D, the ring D includes a heterocyclic ring which has one or two oxo groups and may be further substituted. Among them, preferred is a heterocyclic ring (for example, piperazinyl, 1,4-diazepanyl) which has one oxo group and may be substituted with one or two methyl groups. Specific examples include oxopiperazinyl, 7-oxo-1,4-diazepanyl and the like.
As another preferred embodiment of ring D,
(1) an oxo group,
(2) a C 1-6 alkyl group, and (3) a heterocyclic ring which may be substituted with 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl groups (two or more of the substituents) When present, the substituents may be bonded to each other to form a crosslinked structure)
Is mentioned.
As still another preferred embodiment of ring D,
A heterocyclic ring optionally substituted with 1 to 3 substituents selected from (1) a C 1-6 alkyl group and (2) a C 1-6 alkoxy-carbonyl group (two or more of the substituents) When present, the substituents may be bonded to each other to form a crosslinked structure)
Is mentioned.
Still another preferred embodiment of ring D includes a heterocyclic ring having one oxo group.
Yet another preferred embodiment of ring D is a heterocyclic ring.
　環Ｅは、
ｉ）置換されていてもよいベンゼン環、
ｉｉ）置換されていてもよいナフタレン環、
ｉｉｉ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環、
ｉｖ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環、
ｖ）置換されていてもよい３～７員飽和炭素環、
ｖｉ）置換されていてもよい９～１３員の縮合炭素環、または
ｖｉｉ）置換されていてもよい１３～１５員のスピロ複素環を示す。 Ring E is
i) an optionally substituted benzene ring,
ii) an optionally substituted naphthalene ring,
iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms;
v) an optionally substituted 3- to 7-membered saturated carbocyclic ring,
vi) an optionally substituted 9-13 membered fused carbocycle, or vii) an optionally substituted 13-15 membered spiro heterocycle.
　環Ｅとして、好ましくは、
ｉ）置換基群Ｂから選択される１～３個の置換基で置換されていてもよいベンゼン環；、
ｉｉ）置換基群Ｂから選択される１～３個の置換基で置換されていてもよいナフタレン環；
ｉｉｉ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個（例、１または２個）のヘテロ原子を有する、置換基群Ｂから選択される１～３個の置換基で置換されていてもよい単環式４～７員複素環；
ｉｖ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換基群Ｂから選択される１～３個の置換基で置換されていてもよい９員または１０員の縮合複素環；
ｖ）置換基群Ｂから選択される１～３個の置換基で置換されていてもよい３～７員飽和炭素環；
ｖｉ）置換基群Ｂから選択される１～３個の置換基で置換されていてもよい９～１３員の縮合炭素環；
ｖｉｉ）置換基群Ｂから選択される１～３個の置換基で置換されていてもよい１３～１５員のスピロ複素環；
等が挙げられる。 As ring E, preferably
i) a benzene ring optionally substituted with 1 to 3 substituents selected from substituent group B;
ii) a naphthalene ring optionally substituted with 1 to 3 substituents selected from substituent group B;
iii) substituted with 1 to 3 substituents selected from Substituent Group B having 1 to 3 (eg, 1 or 2) heteroatoms selected from nitrogen, oxygen and sulfur atoms A monocyclic 4 to 7 membered heterocycle which may be
iv) 9-membered or 10-membered optionally substituted by 1 to 3 substituents selected from Substituent Group B having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms A fused heterocycle of
v) a 3- to 7-membered saturated carbocyclic ring which may be substituted with 1 to 3 substituents selected from Substituent Group B;
vi) a 9- to 13-membered fused carbocycle optionally substituted with 1 to 3 substituents selected from Substituent Group B;
vii) 13 to 15-membered spiro heterocycle optionally substituted with 1 to 3 substituents selected from Substituent Group B;
Etc.
　環Ｅとして、より好ましくは、
ｉ）（１）ハロゲン原子（例、塩素原子、フッ素原子）、
　　（２）ニトロ、
　　（３）ヒドロキシ、
　　（４）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　（ｂ）３～８員の複素環基、
　　　　　（ｃ）ヒドロキシ、
　　　　　（ｄ）Ｃ１－６アルキル－カルボニル、および
　　　　　（ｅ）Ｃ１－６アルコキシ（例、メトキシ）
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル（例、メチル、イソプロピル、ｔｅｒｔ－ブチル）、
　　（５）（ａ）ハロゲン原子（例、塩素原子、フッ素原子）、
　　　　　（ｂ）シアノ、
　　　　　（ｃ）１～３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　（ｄ）Ｃ１－６アルコキシ
から選ばれる１～３個の置換基を有していてもよいＣ６－１４アリール（例、フェニル）
　　（６）（ａ）ハロゲン原子（例、フッ素原子）、および
　　　　　（ｂ）Ｃ３－８シクロアルキル（例、シクロプロピル）
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ（例、メトキシ）、
　　（７）Ｃ６－１４アリールオキシ（例、フェニルオキシ）、
　　（８）Ｃ１－６アルキルスルホニル（例、メチルスルホニル）
　　（９）アミノスルホニル
　　（１０）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ）、
　　（１１）Ｃ１－６アルキルで置換されていてもよい３～１４員複素環（例、オキサジアゾリル、ピラゾリル）、
　　（１２）Ｃ７－１６アラルキル（例、ベンジル）、
　　（１３）シアノ、
　　（１４）Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ）、
　　（１５）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）、
　　（１６）Ｃ３－８シクロアルキルで置換されていてもよいＣ１－６アルコキシ（例、シクロプロピルメトキシ）、
　　（１７）３～１４員複素環－オキシ（例、ピリジン－２－イルオキシ）、
　　（１８）ジ－Ｃ１－６アルキルスルファモイル（例、ジメチルスルファモイル）、
　　（１９）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル）、および
　　（２０）Ｃ１－６アルキル－カルボニル（例、アセチル）
から選択される１～３個の置換基で置換されていてもよいベンゼン環；
ｉｉ）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよいナフタレン環；
ｉｉｉ）（１）ハロゲン原子（例、塩素原子）、
　　　　（２）ヒドロキシ、
　　　　（３）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよい１～３個のＣ１－６アルキル（例、メチル）で置換されていてもよい、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１～３種のヘテロ原子を、１～５個（例、１～３個）含む３～１４員（単環、２環又は３環式）複素環基［例、芳香族複素環基（例、フリル、チエニル、ピラゾリル、ピリミジニル、ピリジル、オキサジアゾリル）；非芳香族複素環基（例、ピロリジニル、ピペリジニル］
　　　　（４）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　　　（ｂ）３～８員の複素環基（例、１，３－ベンゾジオキソール）、
　　　　　　　（ｃ）ヒドロキシ、および
　　　　　　　（ｄ）Ｃ１－６アルキル－カルボニル
　　　　から選ばれる１～５個（例、１～３個）の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル）、および
　　　　（５）（ａ）ハロゲン原子（例、塩素原子、フッ素原子）、
　　　　　　　（ｂ）シアノ、
　　　　　　　（ｃ）１～３個のハロゲン原子（例、フッ素原子）を有していてもよいＣ１－６アルキル（例、メチル）、および
　　　　　　　（ｄ）Ｃ１－６アルコキシ（例、メトキシ、エトキシ）
　　　　から選ばれる１～３個（例、１または２個）の置換基を有していてもよいＣ６－１４アリール（例、フェニル）、
　　　　（６）（ａ）ハロゲン原子（例、フッ素原子）、および
　　　　　　　（ｂ）Ｃ３－８シクロアルキル
　　　　から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ）（例、トリフルオロエトキシ）、
　　　　（７）１～３個のハロゲン原子を有していてもよいＣ３－８シクロアルキル（例、シクロプロピル）、
　　　　（８）オキソ
　　　　（９）シアノ、
　　　　（１０）Ｃ１－６アルキル－カルボニル（例、アセチル）、
　　　　（１１）Ｃ７－１６アラルキル（例、ベンジル、ジフェニルメチル、フェニルエチル、ベンゾジオキソリルメチル）、
　　　　（１２）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ）、
　　　　（１３）Ｃ１－６アルキルスルホニル（例、エチルスルホニル）、
　　　　（１４）Ｃ１－６アルキルで置換されていてもよい、Ｃ１－６アルキル－カルボニルアミノ（例、メチルカルボニルアミノ、Ｎ－（エチル）アセチルアミノ）、
　　　　（１５）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル）、および
　　　　（１６）カルバモイル、
から選択される１～４個の置換基で置換されていてもよい、
窒素原子、酸素原子および硫黄原子から選ばれる１～３個（例、１または２個）のヘテロ原子を有する、
単環式４～７員芳香族複素環（例、ピリジル、チエニル、ピラゾリル、フリル、ピラジニル、イミダゾリル、チアゾリル、チアジアゾリル、オキサジアゾリル（好ましくは、１，２，４－オキサジアゾリル）、オキサゾリル、ピラゾリル）、または
単環式４～７員非芳香族複素環（例、アゼチジニル、ピロリジニル、モルホリニル、テトラヒドロフラニル、アゼパニル、ピペリジニル、ピペラジニル、ジアゼパニル、ジヒドロイソオキサゾリル、チオモルホリニル）；
ｉｖ）（１）ハロゲン原子（例、塩素原子、フッ素原子、臭素原子）、
　　　（２）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　　（ｂ）３～８員の複素環基、
　　　　　　（ｃ）ヒドロキシ、および
　　　　　　（ｄ）Ｃ１－６アルキル－カルボニル、
　　　から選ばれる１～５個（例、１～３個）の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル、イソプロピル）、
　　　（３）オキソ、
　　　（４）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよい、Ｃ１－６アルコキシ（例、メトキシ、エトキシ）（例、ジフルオロメトキシ、トリフルオロメトキシ、トリフルオロエトキシ）、および
　　　（５）Ｃ７－１６アラルキル（例、ベンジル）
から選択される１～３個の置換基で置換されていてもよい、
窒素原子、酸素原子および硫黄原子から選ばれる１～３個（例、１または２個）のヘテロ原子（例、窒素原子、硫黄原子、酸素原子）を有する、
（１）５または６員（例、６員）の単環式非芳香族複素環とベンゼン環が縮合した、９または１０員の縮合非芳香族複素環（例、ジヒドロイソキノリル、ベンゾオキサゾリル、インドリニル、イソインドリル、１，２，３，４－テトラヒドロキノリル、１，２，３，４－テトラヒドロイソキノリル、２，３－ジヒドロベンゾフリル、３，４－ジヒドロ－１，４－ベンゾオキサジン）、
（２）５または６員（例、５員）の単環式芳香族複素環とベンゼン環が縮合した、９または１０員の縮合芳香族複素環（例、インドリル、ベンゾイミダゾリル、ベンゾピラゾリル、ベンゾチエニル、インダゾリル、１，２－ベンゾイソオキサゾリル、ベンゾトリアゾリル、ベンゾフリル）、または
（３）５または６員の単環式芳香族複素環と、６員の単環式芳香族複素環が縮合した、９または１０員の縮合芳香族複素環（例、１Ｈ－ピロロ［２，３－ｂ］ピリジル、イミダゾ［１，２－ａ］ピリジル、ピラゾロ［１，５ａ］ピリジル、１，４，５，６－テトラヒドロピラノ［２，３－ｃ］ピラゾリル）；
ｖ）（１）１～３個のハロゲン原子（例、塩素原子）で置換されていてもよい、Ｃ６－１４アリール（例、フェニル）、および
　　（２）Ｃ７－１４アラルキルオキシ（例、ベンジルオキシ）、
から選ばれる１～５個（例、１～３個）の置換基を有していてもよい、
３～７員（例、３～６員）飽和炭素環（例、シクロプロピル、シクロペンチル、シクロヘキシル）；
ｖｉ）１～３個のハロゲン原子（例、塩素原子）で置換されていてもよい、
５～７員（例、５員）の飽和炭素環と、１または２個の６～１０員の単環式芳香族炭素環（例、ベンゼン）が縮合した、９～１３員の縮合炭素環（例、インダニル、フルオレニル）；または
ｖｉｉ）１～３個（例、１個）のハロゲン原子（塩素原子）で置換されていてもよい１３～１５員のスピロ複素環（例、スピロ［１，３－ジヒドロイソベンゾフラン－１，４’－ピペリジン］）；
等が挙げられる。
　環Ｅの別の好ましい態様としては、それぞれ
（１）ハロゲン原子、
（２）ハロゲン原子で置換されたＣ１－６アルキル基、
（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および
（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基
から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環等が挙げられる。
　環Ｅの更に別の好ましい態様としては、環Ｅが、１～３個のハロゲン原子で置換されたベンゼン環が挙げられる。
　環Ｅの更に別の好ましい態様としては、ハロゲン原子で置換された１～３個のＣ１－６アルキル基で置換された、ベンゼン環が挙げられる。 More preferably, as ring E,
i) (1) a halogen atom (eg, chlorine atom, fluorine atom),
(2) Nitro,
(3) hydroxy,
(4) (a) a halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy,
(D) C 1-6 alkyl-carbonyl, and (e) C 1-6 alkoxy (eg, methoxy)
C 1-6 alkyl (eg, methyl, isopropyl, tert-butyl) optionally having 1 to 5 substituents selected from
(5) (a) a halogen atom (eg, chlorine atom, fluorine atom),
(B) cyano,
(C) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(D) C 6-14 aryl optionally having 1 to 3 substituents selected from C 1-6 alkoxy (eg, phenyl)
(6) (a) a halogen atom (eg, fluorine atom), and (b) a C 3-8 cycloalkyl (eg, cyclopropyl)
C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 substituents selected from
(7) C 6-14 aryloxy (eg, phenyloxy),
(8) C 1-6 alkylsulfonyl (eg, methylsulfonyl)
(9) aminosulfonyl (10) di-C 1-6 alkylamino (eg, dimethylamino),
(11) a 3 to 14-membered heterocyclic ring (eg, oxadiazolyl, pyrazolyl) optionally substituted with C 1-6 alkyl,
(12) C 7-16 aralkyl (eg, benzyl),
(13) Cyano,
(14) C 1-6 alkyl-carbonylamino (eg, acetylamino),
(15) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(16) C 1-6 alkoxy optionally substituted with C 3-8 cycloalkyl (eg, cyclopropylmethoxy),
(17) 3-14 membered heterocyclic-oxy (eg, pyridin-2-yloxy),
(18) di-C 1-6 alkylsulfamoyl (eg, dimethylsulfamoyl),
(19) Di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl), and (20) C 1-6 alkyl-carbonyl (eg, acetyl)
A benzene ring optionally substituted with 1 to 3 substituents selected from:
ii) a naphthalene ring optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom);
iii) (1) a halogen atom (eg, a chlorine atom),
(2) hydroxy,
(3) In addition to carbon atoms that may be substituted with 1 to 3 C 1-6 alkyls (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atoms) 3 to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing 1 to 5 (eg, 1 to 3) of 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms Groups [eg, aromatic heterocyclic groups (eg, furyl, thienyl, pyrazolyl, pyrimidinyl, pyridyl, oxadiazolyl); non-aromatic heterocyclic groups (eg, pyrrolidinyl, piperidinyl])
(4) (a) a halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group (eg, 1,3-benzodioxole),
C 1-6 alkyl (eg, methyl) optionally having 1 to 5 (eg, 1 to 3) substituents selected from (c) hydroxy, and (d) C 1-6 alkyl-carbonyl , Ethyl), and (5) (a) a halogen atom (eg, chlorine atom, fluorine atom),
(B) cyano,
(C) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom), and (d) C 1-6 alkoxy (eg, methoxy, ethoxy)
C 6-14 aryl (eg, phenyl) optionally having 1 to 3 (eg, 1 or 2) substituents selected from
(6) C 1-6 alkoxy (eg, optionally having 1 to 3 substituents selected from (a) a halogen atom (eg, fluorine atom), and (b) C 3-8 cycloalkyl Methoxy, ethoxy) (eg, trifluoroethoxy),
(7) C 3-8 cycloalkyl (eg, cyclopropyl) optionally having 1 to 3 halogen atoms,
(8) Oxo (9) Cyano,
(10) C 1-6 alkyl-carbonyl (eg, acetyl),
(11) C 7-16 aralkyl (eg, benzyl, diphenylmethyl, phenylethyl, benzodioxolylmethyl),
(12) Di-C 1-6 alkylamino (eg, dimethylamino),
(13) C 1-6 alkylsulfonyl (eg, ethylsulfonyl),
(14) C 1-6 alkyl-carbonylamino (eg, methylcarbonylamino, N- (ethyl) acetylamino) optionally substituted with C 1-6 alkyl,
(15) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl), and (16) carbamoyl,
May be substituted with 1 to 4 substituents selected from:
Having 1 to 3 (eg, 1 or 2) heteroatoms selected from nitrogen, oxygen and sulfur atoms,
A monocyclic 4-7 membered aromatic heterocycle (eg, pyridyl, thienyl, pyrazolyl, furyl, pyrazinyl, imidazolyl, thiazolyl, thiadiazolyl, preferably oxadiazolyl (preferably 1,2,4-oxadiazolyl), oxazolyl, pyrazolyl), or Monocyclic 4-7 membered non-aromatic heterocycle (eg, azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, azepanyl, piperidinyl, piperazinyl, diazepanyl, dihydroisoxazolyl, thiomorpholinyl);
iv) (1) halogen atom (eg, chlorine atom, fluorine atom, bromine atom),
(2) (a) a halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy, and (d) C 1-6 alkyl-carbonyl,
C 1-6 alkyl (eg, methyl, ethyl, isopropyl) optionally having 1 to 5 (eg, 1 to 3) substituents selected from
(3) oxo,
(4) C 1-6 alkoxy (eg, methoxy, ethoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) (eg, difluoromethoxy, trifluoromethoxy, trifluoroethoxy) And (5) C 7-16 aralkyl (eg, benzyl)
May be substituted with 1 to 3 substituents selected from:
Having 1 to 3 (eg, 1 or 2) heteroatoms (eg, nitrogen, sulfur, oxygen) selected from nitrogen, oxygen and sulfur atoms,
(1) A 9- or 10-membered condensed non-aromatic heterocyclic ring (eg, dihydroisoquinolyl, benzoxane) in which a 5- or 6-membered (eg, 6-membered) monocyclic non-aromatic heterocyclic ring and a benzene ring are condensed Zolyl, indolinyl, isoindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 2,3-dihydrobenzofuryl, 3,4-dihydro-1,4- Benzoxazine),
(2) A 9- or 10-membered condensed aromatic heterocycle in which a 5- or 6-membered (eg, 5-membered) monocyclic aromatic heterocycle and a benzene ring are condensed (eg, indolyl, benzimidazolyl, benzopyrazolyl, benzothienyl) , Indazolyl, 1,2-benzisoxazolyl, benzotriazolyl, benzofuryl), or (3) a 5- or 6-membered monocyclic aromatic heterocycle and a 6-membered monocyclic aromatic heterocycle Fused 9- or 10-membered fused aromatic heterocycles (eg, 1H-pyrrolo [2,3-b] pyridyl, imidazo [1,2-a] pyridyl, pyrazolo [1,5a] pyridyl, 1,4, 5,6-tetrahydropyrano [2,3-c] pyrazolyl);
v) (1) C 6-14 aryl (eg, phenyl) optionally substituted with 1 to 3 halogen atoms (eg, chlorine atom), and (2) C 7-14 aralkyloxy (eg, Benzyloxy),
Optionally having 1 to 5 (eg, 1 to 3) substituents selected from
3-7 membered (eg, 3-6 membered) saturated carbocycle (eg, cyclopropyl, cyclopentyl, cyclohexyl);
vi) optionally substituted by 1 to 3 halogen atoms (eg, chlorine atoms),
A 9 to 13-membered condensed carbocycle in which a 5- to 7-membered (eg, 5-membered) saturated carbocycle and one or two 6- to 10-membered monocyclic aromatic carbocycles (eg, benzene) are condensed (Eg, indanyl, fluorenyl); or vii) 13-15 membered spiro heterocycle (eg, spiro [1, 1) optionally substituted with 1 to 3 (eg, 1) halogen atom (chlorine atom) 3-dihydroisobenzofuran-1,4′-piperidine]);
Etc.
In another preferred embodiment of ring E, (1) a halogen atom,
(2) a C 1-6 alkyl group substituted with a halogen atom,
1 to 3 substituents selected from (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a phenyl group substituted with a C 1-6 alkyl group substituted with a halogen atom. Examples thereof include a benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, pyrrolidine ring or pyrazole ring which may be substituted.
Still another preferred embodiment of the ring E includes a benzene ring in which the ring E is substituted with 1 to 3 halogen atoms.
Still another preferred embodiment of ring E includes a benzene ring substituted with 1 to 3 C 1-6 alkyl groups substituted with a halogen atom.
　本発明化合物としては、以下のものが好ましく用いられる。
［化合物（Ｉａ）］
　式（Ｉａ）： The following compounds are preferably used as the compound of the present invention.
[Compound (Ia)]
Formula (Ia):
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　式中、
Ｒ１ａが、水素原子または置換されていてもよいＣ１－６アルキル基；
Ｒ２ａおよびＲ３ａが、同一または異なって、
水素原子、
ハロゲン原子、
ヒドロキシ、
置換されていてもよいＣ１－６アルキル基、
置換されていてもよいＣ１－６アルコキシ基、
置換されていてもよいＣ１－６アルキルチオ基、
置換されていてもよいＣ１－６アルキルスルホニル基、または
置換されていてもよいＣ１－６アルキルスルフィニル基；
ｎａが、１または２；
Ｙａが、
結合手、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
－ＣＯＮ（Ｒｂ１）ＳＯ２－
　　　（式中、Ｒａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレン；
　　　Ｒｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）；
環Ａａが、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいオキサゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，３－トリアゾール環、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，４－トリアゾール環、または
置換されていてもよいＣ１－６アルキル基をさらに有していてもよいピラゾール環
〔上記式（Ｉａ）において、部分構造式： Where
R 1a is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
R 2a and R 3a are the same or different,
Hydrogen atom,
Halogen atoms,
Hydroxy,
An optionally substituted C 1-6 alkyl group,
An optionally substituted C 1-6 alkoxy group,
An optionally substituted C 1-6 alkylthio group,
An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group;
n a is 1 or 2;
Y a is
Join hands,
-Ra 1 CON (Rb 1 )-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
—CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
Wherein Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene;
Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group);
Ring A a is
An oxazole ring which may further have an optionally substituted C 1-6 alkyl group,
A 1,2,3-triazole ring optionally further having an optionally substituted C 1-6 alkyl group,
It may have an optionally substituted C 1-6 alkyl group may further have a 1,2,4-triazole ring, or a C 1-6 alkyl group which may be substituted further Pyrazole ring [in the above formula (Ia), partial structural formula:
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
（式中、各記号は前記のとおりである。環Ａａは、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい。）における、 In the formula, each symbol is as described above. Ring A a may further have an optionally substituted C 1-6 alkyl group.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
部分が、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，３－オキサゾール－５－イル、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１Ｈ－１，２，３－トリアゾール－１－イル、
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１Ｈ－１，２，４－トリアゾール－１－イル、または
置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１Ｈ－ピラゾール－４－イル
である場合（即ち、上記式（Ｉａ）において、部分構造式： Part is
1,3-oxazol-5-yl which may further have an optionally substituted C 1-6 alkyl group,
1H-1,2,3-triazol-1-yl which may further have an optionally substituted C 1-6 alkyl group,
Further have a substituent which do may be C 1-6 alkyl groups further may have IH-1,2,4-triazol-1-yl, or optionally substituted C 1-6 alkyl group, 1H-pyrazol-4-yl (that is, in the above formula (Ia), the partial structural formula:
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
が、下記式： But the following formula:
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式中、各記号は前記のとおりである。各環は、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい。））が好ましい。〕；
環Ｂａが、環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環；
環Ｄａが、置換されていてもよい複素環；
環Ｅａが、
ｉ）置換されていてもよいベンゼン環、
ｉｉ）置換されていてもよいナフタレン環、
ｉｉｉ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環、
ｉｖ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環、
ｖ）置換されていてもよい３～７員飽和炭素環、または
ｖｉ）置換されていてもよい９～１３員の縮合炭素環；
である、本発明化合物。
　上記式（Ｉａ）で表される化合物のなかでも、環Ｄａが、オキソ基以外の置換基を有していてもよい複素環である化合物が好ましい。 (Wherein each symbol is as described above. Each ring may further have an optionally substituted C 1-6 alkyl group)). ];
Ring Ba may have 1 or 2 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and may be further substituted 6-membered aromatic ring;
Ring Da is an optionally substituted heterocycle;
Ring E a is
i) an optionally substituted benzene ring,
ii) an optionally substituted naphthalene ring,
iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms;
v) an optionally substituted 3- to 7-membered saturated carbocycle, or vi) an optionally substituted 9- to 13-membered fused carbocycle;
The compound of the present invention.
Among the compounds represented by the formula (Ia), a compound in which the ring Da is a heterocyclic ring optionally having a substituent other than an oxo group is preferable.
［化合物（Ｉｂ）］
　式（Ｉｂ）： [Compound (Ib)]
Formula (Ib):
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　式中、
Ｒ１ｂが、水素原子または置換されていてもよいＣ１－６アルキル基；
Ｒ２ｂおよびＲ３ｂが、同一または異なって、
水素原子、
ハロゲン原子、
ヒドロキシ、
置換されていてもよいＣ１－６アルキル基、
置換されていてもよいＣ１－６アルコキシ基、
置換されていてもよいＣ１－６アルキルチオ基、
置換されていてもよいＣ１－６アルキルスルホニル基、または
置換されていてもよいＣ１－６アルキルスルフィニル基；
ｎｂが、１または２；
Ｙｂが、
結合手、
－Ｒａ１－、
－Ｒａ１ＣＯ－、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、
－Ｒａ１Ｏ－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
－ＣＯＮ（Ｒｂ１）ＳＯ２－
　　　（式中、Ｒａ１およびＲａ２が、同一または異なって、置換されていてもよいＣ１－６アルキレン；
　　　Ｒｂ１およびＲｂ２が、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）；
環Ａｂが、酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい、５員芳香族複素環；
環Ｂｂが、環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環；
環Ｄｂが、１個または２個のオキソ基を有する、さらに置換されていてもよい複素環；
環Ｅｂが、
ｉ）置換されていてもよいベンゼン環、
ｉｉ）置換されていてもよいナフタレン環、
ｉｉｉ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環、
ｉｖ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環、
ｖ）置換されていてもよい３～７員飽和炭素環、または
ｖｉ）置換されていてもよい９～１３員の縮合炭素環；
である、本発明化合物。
　　上記式（Ｉｂ）で表される化合物のなかでも、
Ｙｂが、
結合手、
－Ｒａ１－、
－Ｒａ１ＣＯ－、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、または
－Ｒａ１Ｏ－
　　　（式中、Ｒａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレン；
　　　Ｒｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）；
である化合物が好ましい。 Where
R 1b is a hydrogen atom or an optionally substituted C 1-6 alkyl group;
R 2b and R 3b are the same or different and
Hydrogen atom,
Halogen atoms,
Hydroxy,
An optionally substituted C 1-6 alkyl group,
An optionally substituted C 1-6 alkoxy group,
An optionally substituted C 1-6 alkylthio group,
An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group;
n b is 1 or 2;
Y b is
Join hands,
-Ra 1- ,
-Ra 1 CO-,
-Ra 1 CON (Rb 1 )-,
-Ra 1 CON (Rb 1 ) Ra 2- ,
-Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-,
-Ra 1 CON (Rb 1 ) Ra 2 O-,
-Ra 1 O-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
—CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
Wherein Ra 1 and Ra 2 are the same or different and optionally substituted C 1-6 alkylene;
Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group);
Ring A b is an oxygen atom, having 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen atoms, which may further have a C 1-6 alkyl group which may be substituted, 5-membered aromatic Family heterocycles;
Ring B b may have 1 or 2 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and may be further substituted 6-membered aromatic ring;
Ring Db has 1 or 2 oxo groups and may be further substituted heterocycle;
Ring Eb is
i) an optionally substituted benzene ring,
ii) an optionally substituted naphthalene ring,
iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms;
v) an optionally substituted 3- to 7-membered saturated carbocycle, or vi) an optionally substituted 9- to 13-membered fused carbocycle;
The compound of the present invention.
Among the compounds represented by the above formula (Ib),
Y b is
Join hands,
-Ra 1- ,
-Ra 1 CO-,
-Ra 1 CON (Rb 1 )-,
-Ra 1 CON (Rb 1 ) Ra 2- ,
-Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-,
—Ra 1 CON (Rb 1 ) Ra 2 O—, or —Ra 1 O—
Wherein Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene;
Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group);
Is preferred.
［化合物（Ｉｃ）］
　Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基；
ｎが、１または２；
Ｙが、－ＣＯ－、－Ｒａ１－、－ＣＯＲａ１－、－ＣＯＮ（Ｒｂ１）－、－ＣＯＮ（Ｒｂ１）Ｒａ１－または－Ｒａ１ＣＯＮ（Ｒｂ１）－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上存在する場合には、該置換基同士が結合して環を形成してもよい）；
　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）；
環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
環Ｂが、ベンゼン環；
環Ｄが、オキソ基、Ｃ１－６アルキル基およびＣ１－６アルコキシ－カルボニル基から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）；
環Ｅが、それぞれ（１）ハロゲン原子、（２）ハロゲン原子で置換されたＣ１－６アルキル基、（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環；
である、本発明化合物。
　該化合物（Ｉｃ）のなかでも、
Ｙが、－ＣＯ－、Ｃ１－６アルキレン、－ＣＯＮＨ－、－ＣＯＮＨＲａ１－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基を示す）
である、本発明化合物が好ましい。
　さらに別の好ましい態様としては、該化合物（Ｉｃ）のなかでも、
Ｙが、－Ｒａ１ＣＯＮ（Ｒｂ１）－
　　　（式中、Ｒａ１は、Ｃ１－６アルキレン基；
　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）
である、本発明化合物が挙げられる。
　なおさらに別の好ましい態様としては、該化合物（Ｉｃ）のなかでも、
Ｒ２およびＲ３の、一方が水素原子またはハロゲン原子、他方が水素原子またはＣ１－６アルコキシ基である、本発明化合物が挙げられる。 [Compound (Ic)]
R 1 is a C 1-6 alkyl group;
R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group;
n is 1 or 2;
Y is, -CO -, - Ra 1 - , - CORa 1 -, - CON (Rb 1) -, - CON (Rb 1) Ra 1 - or -Ra 1 CON (Rb 1) -
(In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
Ring B is a benzene ring;
Ring D is a heterocycle optionally substituted with 1 to 3 substituents selected from an oxo group, a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (two or more such substituents When present, the substituents may be bonded to form a crosslinked structure);
Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a halogen atom. A benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring;
The compound of the present invention.
Among the compounds (Ic),
Y is —CO—, C 1-6 alkylene, —CONH—, —CONHRa 1 —
(In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group)
The compounds of the present invention are preferred.
In still another preferred embodiment, among the compounds (Ic),
Y is —Ra 1 CON (Rb 1 ) —
Wherein Ra 1 is a C 1-6 alkylene group;
Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom)
And the compounds of the present invention.
As still another preferred embodiment, among the compounds (Ic),
Examples of the compound of the present invention include one in which R 2 and R 3 are one of a hydrogen atom or a halogen atom and the other is a hydrogen atom or a C 1-6 alkoxy group.
［化合物（Ｉｄ）］ 
　Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基；
ｎが、１または２；
Ｙが、－ＣＯ－、－ＣＯＲａ１－、－ＣＯＮ（Ｒｂ１）－、または－ＣＯＮ（Ｒｂ１）Ｒａ１－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上存在する場合には、該置換基同士が結合して環を形成してもよい）；
　　　Ｒｂ１は、水素原子を示す）；
環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
環Ｂが、ベンゼン環；
環Ｄが、Ｃ１－６アルキル基およびＣ１－６アルコキシ－カルボニル基から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）；
環Ｅが、それぞれ（１）ハロゲン原子、（２）ハロゲン原子で置換されたＣ１－６アルキル基、（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環；
である、本発明化合物。
　該化合物（Ｉｄ）のなかでも、
Ｙが、－ＣＯ－、－ＣＯＮＨ－、－ＣＯＮＨＲａ１－
　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基）
である、本発明化合物が好ましい。
　さらに別の好ましい態様としては、該化合物（Ｉｄ）のなかでも、
Ｒ２およびＲ３の、一方が水素原子またはハロゲン原子、他方が水素原子またはＣ１－６アルコキシ基
である、本発明化合物が挙げられる。 [Compound (Id)]
R 1 is a C 1-6 alkyl group;
R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group;
n is 1 or 2;
Y is —CO—, —CORa 1 —, —CON (Rb 1 ) —, or —CON (Rb 1 ) Ra 1 —.
(In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
Rb 1 represents a hydrogen atom);
Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
Ring B is a benzene ring;
Ring D may be substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (when two or more substituents are present) May be bonded to each other to form a crosslinked structure);
Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a halogen atom. A benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring;
The compound of the present invention.
Among the compounds (Id),
Y is —CO—, —CONH—, —CONHRa 1 —
(In the formula, Ra 1 is a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group)
The compounds of the present invention are preferred.
In still another preferred embodiment, among the compounds (Id),
Examples of the compound of the present invention include one in which R 2 and R 3 are one of a hydrogen atom or a halogen atom and the other is a hydrogen atom or a C 1-6 alkoxy group.
［化合物（Ｉｅ）］ 
　Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３の、一方が水素原子、他方が水素原子またはＣ１－６アルコキシ基；
ｎは、１または２；
Ｙが、Ｃ１－６アルキレン基または－Ｒａ１ＣＯＮ（Ｒｂ１）－
　　　（式中、Ｒａ１は、Ｃ１－６アルキレン基；
　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）；
環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
環Ｂが、ベンゼン環；
環Ｄが、1個のオキソ基を有する複素環；
環Ｅが、１～３個のハロゲン原子で置換されたベンゼン環；
である、本発明化合物。 [Compound (Ie)]
R 1 is a C 1-6 alkyl group;
One of R 2 and R 3 is a hydrogen atom, the other is a hydrogen atom or a C 1-6 alkoxy group;
n is 1 or 2;
Y is a C 1-6 alkylene group or —Ra 1 CON (Rb 1 ) —
Wherein Ra 1 is a C 1-6 alkylene group;
Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
Ring B is a benzene ring;
Ring D is a heterocycle having one oxo group;
A benzene ring in which ring E is substituted with 1 to 3 halogen atoms;
The compound of the present invention.
［化合物（Ｉｆ）］
　Ｒ１が、Ｃ１－６アルキル基；
Ｒ２およびＲ３の一方が水素原子、他方がＣ１－６アルコキシ基；
ｎが、１；
Ｙが、－ＣＯＮ（Ｒｂ１）Ｒａ１－
　　　（Ｒａ１はヒドロキシ基で置換されていてもよいＣ１－６アルキル基で置換されていてもよい、Ｃ１－６アルキレン基；
　　　Ｒｂ１は水素原子）；
環Ａが、オキサゾール環；
環Ｂが、ベンゼン環；
環Ｄが、複素環；
環Ｅが、ハロゲン原子で置換されたＣ１－６アルキル基で置換された、ベンゼン環；
である、本発明化合物。 [Compound (If)]
R 1 is a C 1-6 alkyl group;
One of R 2 and R 3 is a hydrogen atom and the other is a C 1-6 alkoxy group;
n is 1;
Y is —CON (Rb 1 ) Ra 1 —
(Ra 1 is a C 1-6 alkylene group which may be substituted with a C 1-6 alkyl group which may be substituted with a hydroxy group;
Rb 1 is a hydrogen atom);
Ring A is an oxazole ring;
Ring B is a benzene ring;
Ring D is a heterocycle;
A benzene ring, wherein ring E is substituted with a C 1-6 alkyl group substituted with a halogen atom;
The compound of the present invention.
［化合物（Ｉｇ）］
　Ｒ１が、水素原子またはＣ１－６アルキル基（好ましくは、水素原子、メチル、エチル、プロピル、イソプロピル）；
Ｒ２およびＲ３が、同一または異なって、
（１）水素原子、
（２）ハロゲン原子、
（３）ヒドロキシ、
（４）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよい、Ｃ１－６アルキル基、
（５）（ａ）ハロゲン原子（例、フッ素原子）、および
　　　（ｂ）フェニル基
からなる群から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基、
（６）Ｃ１－６アルキルチオ基、または
（７）Ｃ１－６アルキルスルフィニル基
（好ましくは、水素原子、塩素原子、フッ素原子、ヒドロキシ、メチル、トリフルオロメチル、メトキシ、エトキシ、プロポキシ、イソプロポキシ、トリフルオロメトキシ、ジフルオロエトキシ、トリフルオロエトキシ、ベンジルオキシ、ヒドロキシ、メチルチオまたはメチルスルフィニル）；
ｎが、１または２；
Ｙが、
結合手、
－Ｒａ１－、
－Ｒａ１ＣＯ－、
－Ｒａ１ＣＯＮ（Ｒｂ１）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－、
－Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、
－Ｒａ１Ｏ－、
－ＣＯ－、
－ＣＯ－ＣＯ－、
－ＣＯ－ＣＨ＝ＣＨ－、
－ＣＯＲａ１－、
－ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）－、
－ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
－ＣＯＲａ１Ｏ－、
－ＣＯＲａ１ＳＲａ２－、
－ＣＯＮ（Ｒｂ１）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１－、
－ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
－ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
－ＣＯＮ（Ｒｂ１）ＳＯ２－
　　　［式中、Ｒａ１およびＲａ２が、同一または異なって、
　　　（１）シアノ
　　　（２）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　　（ｂ）３～８員の複素環基、
　　　　　　（ｃ）ヒドロキシ、
　　　　　　（ｄ）Ｃ１－６アルキル－カルボニル
　　　　　　（ｅ）Ｃ１－６アルコキシ（例、メトキシ）
　　　から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル）、
　　　（３）１～５個のハロゲン原子を有していてもよいＣ３－８シクロアルキル（例、シクロプロピル）
　　　（４）１～３個のハロゲン原子を有していてもよいＣ１－６アルキルを有していてもよいＣ６－１４アリール（例、フェニル）
　　　（５）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）、
　　　（６）ヒドロキシ、および
　　　（７）（ａ）ハロゲン原子、および
　　　　　　（ｂ）Ｃ３－８シクロアルキル
　　　から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ（例、メトキシ）、
　　　から選ばれる１または２個の置換基で置換されていてもよい、Ｃ１－６アルキレン（例、メチレン、エチレン、プロピレン）であり、該置換基同士は結合して環（例、シクロプロパン、シクロペンタン）を形成してもよい
　　　｛Ｒａ１およびＲａ２として、好ましくは、メチレン、メチルメチレン、ジメチルメチレン、エチルメチレン、メチレン、シアノメチレン、メトキシカルボニルメチレン、ヒドロキシメチルメチレン、エチレン、フェニルエチレン、ヒドロキシエチレン、プロピレンであり、該置換基同士が結合して環を形成してもよい。｝；
　　　Ｒｂ１およびＲｂ２が、同一または異なって、
　　　水素原子、
　　　（１）ハロゲン原子（フッ素原子）、
　　　（２）シアノ、
　　　（３）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ）、および
　　　（４）Ｃ３－８シクロアルキル（例、シクロプロピル）
　　　から選ばれる１～３個の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル、イソブチル）
　　　（好ましくは、水素原子、メチル、エチル、イソブチル、シクロプロピルメチル、２－シアノエチル、２－（ジメチルアミノ）エチル、２，２－ジフルオロエチル、２，２，２－トリフルオロエチル）；
環Ａが、酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、Ｃ１－６アルキル基をさらに有していてもよい、５員芳香族複素環（好ましくは、オキサゾール環、トリアゾール環（例、１，２，３－トリアゾール、１，２，４－トリアゾール）、ピラゾール環、オキサジアゾール環、イソオキサゾール環、チアゾール環、チオフェン環、イミダゾール環）；
環Ｂが、ベンゼン環、ピリジン環、ピリミジン環；
環Ｄが、
（１）オキソ、
（２）（ａ）ハロゲン原子、
　　　（ｂ）３～８員の複素環基、
　　　（ｃ）ヒドロキシ、および
　　　（ｄ）Ｃ１－６アルキル－カルボニル
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル）、
（３）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）、
（４）モノ－Ｃ１－６アルキル－カルバモイル（例、エチルカルバモイル）、および
（５）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルルカルバモイル、ジエチルカルバモイル）
から選択される１～３個の置換基（好ましくは、メチル、エチル、ヒドロキシメチル、エチルカルバモイル、ジエチルカルバモイル、オキソ、メトキシカルボニル、ジメチルカルバモイル）で置換されていてもよい、環構成原子として炭素原子以外に窒素原子を２個有する、６または７員の非芳香族複素環（好ましくは、ピペラジニル、１，４－ジアゼパニル）
［該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい（好ましくは、２，６－ジアザビシクロ［３．２．２］ノナン－３－オン、３，９－ジアザビシクロ［４．２．１］ノナン－４－オン、３，６－ジアザビシクロ［３．２．１］オクタン－７－オン、８－オキサ－３，１０－ジアザビシクロ［４．３．１］デカン－４－オン、３，９－ジアザビシクロ［３．３．１］ノナン－２，４－ジオン、３，９－ジアザビシクロ［３．３．１］ノナン）］；および
環Ｅが、
ｉ）（１）ハロゲン原子（例、塩素原子、フッ素原子）、
　　（２）ニトロ、
　　（３）ヒドロキシ、
　　（４）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　（ｂ）３～８員の複素環基、
　　　　　（ｃ）ヒドロキシ、
　　　　　（ｄ）Ｃ１－６アルキル－カルボニル、および
　　　　　（ｅ）Ｃ１－６アルコキシ（例、メトキシ）
から選ばれる１～５個の置換基を有していてもよいＣ１－６アルキル（例、メチル、イソプロピル、ｔｅｒｔ－ブチル）、
　　（５）（ａ）ハロゲン原子（例、塩素原子、フッ素原子）、
　　　　　（ｂ）シアノ、
　　　　　（ｃ）１～３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　（ｄ）Ｃ１－６アルコキシ
から選ばれる１～３個の置換基を有していてもよいＣ６－１４アリール（例、フェニル）
　　（６）（ａ）ハロゲン原子（例、フッ素原子）、および
　　　　　（ｂ）Ｃ３－８シクロアルキル（例、シクロプロピル）
から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ（例、メトキシ）、
　　（７）Ｃ６－１４アリールオキシ（例、フェニルオキシ）、
　　（８）Ｃ１－６アルキルスルホニル（例、メチルスルホニル）
　　（９）アミノスルホニル
　　（１０）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ）、
　　（１１）Ｃ１－６アルキルで置換されていてもよい３～１４員複素環（例、オキサジアゾリル、ピラゾリル）、
　　（１２）Ｃ７－１６アラルキル（例、ベンジル）、
　　（１３）シアノ、
　　（１４）Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ）、
　　（１５）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）、
　　（１６）Ｃ３－８シクロアルキルで置換されていてもよいＣ１－６アルコキシ（例、シクロプロピルメトキシ）、
　　（１７）３～１４員複素環－オキシ（例、ピリジン－２－イルオキシ）、
　　（１８）ジ－Ｃ１－６アルキルスルファモイル（例、ジメチルスルファモイル）、
　　（１９）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル）、および
　　（２０）Ｃ１－６アルキル－カルボニル（例、アセチル）
から選択される１～３個の置換基で置換されていてもよいベンゼン環；
ｉｉ）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよいナフタレン環；
ｉｉｉ）（１）ハロゲン原子（例、塩素原子）、
　　　　（２）ヒドロキシ、
　　　　（３）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよい１～３個のＣ１－６アルキル（例、メチル）で置換されていてもよい、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１～３種のヘテロ原子を、１～５個（例、１～３個）含む３～１４員（単環、２環又は３環式）複素環基［例、芳香族複素環基（例、フリル、チエニル、ピラゾリル、ピリミジニル、ピリジル、オキサジアゾリル）；非芳香族複素環基（例、ピロリジニル、ピペリジニル］
　　　　（４）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　　　（ｂ）３～８員の複素環基（例、１，３－ベンゾジオキソール）、
　　　　　　　（ｃ）ヒドロキシ、および
　　　　　　　（ｄ）Ｃ１－６アルキル－カルボニル
　　　　から選ばれる１～５個（例、１～３個）の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル）、および
　　　　（５）（ａ）ハロゲン原子（例、塩素原子、フッ素原子）、
　　　　　　　（ｂ）シアノ、
　　　　　　　（ｃ）１～３個のハロゲン原子（例、フッ素原子）を有していてもよいＣ１－６アルキル（例、メチル）、および
　　　　　　　（ｄ）Ｃ１－６アルコキシ（例、メトキシ、エトキシ）
　　　　から選ばれる１～３個（例、１または２個）の置換基を有していてもよいＣ６－１４アリール（例、フェニル）、
　　　　（６）（ａ）ハロゲン原子（例、フッ素原子）、および
　　　　　　　（ｂ）Ｃ３－８シクロアルキル
　　　　から選ばれる１～３個の置換基を有していてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ）（例、トリフルオロエトキシ）、
　　　　（７）１～３個のハロゲン原子を有していてもよいＣ３－８シクロアルキル（例、シクロプロピル）、
　　　　（８）オキソ
　　　　（９）シアノ、
　　　　（１０）Ｃ１－６アルキル－カルボニル（例、アセチル）、
　　　　（１１）Ｃ７－１６アラルキル（例、ベンジル、ジフェニルメチル、フェニルエチル、ベンゾジオキソリルメチル）、
　　　　（１２）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ）、
　　　　（１３）Ｃ１－６アルキルスルホニル（例、エチルスルホニル）、
　　　　（１４）Ｃ１－６アルキルで置換されていてもよい、Ｃ１－６アルキル－カルボニルアミノ（例、メチルカルボニルアミノ、Ｎ－（エチル）アセチルアミノ）、
　　　　（１５）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル）、および
　　　　（１６）カルバモイル、
から選択される１～４個の置換基で置換されていてもよい、
窒素原子、酸素原子および硫黄原子から選ばれる１～３個（例、１または２個）のヘテロ原子を有する、
単環式４～７員芳香族複素環（例、ピリジル、チエニル、ピラゾリル、フリル、ピラジニル、イミダゾリル、チアゾリル、チアジアゾリル、オキサジアゾリル（好ましくは、１，２，４－オキサジアゾリル）、オキサゾリル、ピラゾリル）、または
単環式４～７員非芳香族複素環（例、アゼチジニル、ピロリジニル、モルホリニル、テトラヒドロフラニル、アゼパニル、ピペリジニル、ピペラジニル、ジアゼパニル、ジヒドロイソオキサゾリル、チオモルホリニル）；
ｉｖ）（１）ハロゲン原子（例、塩素原子、フッ素原子、臭素原子）、
　　　（２）（ａ）ハロゲン原子（例、フッ素原子）、
　　　　　　（ｂ）３～８員の複素環基、
　　　　　　（ｃ）ヒドロキシ、
　　　　　　（ｄ）Ｃ１－６アルキル－カルボニル、および
　　　から選ばれる１～５個（例、１～３個）の置換基を有していてもよいＣ１－６アルキル（例、メチル、エチル、イソプロピル）、
　　　（３）オキソ、
　　　（４）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよい、Ｃ１－６アルコキシ（例、メトキシ、エトキシ）（例、ジフルオロメトキシ、トリフルオロメトキシ、トリフルオロエトキシ）、および
　　　（５）Ｃ７－１６アラルキル（例、ベンジル）
から選択される１～３個の置換基で置換されていてもよい、
窒素原子、酸素原子および硫黄原子から選ばれる１～３個（例、１または２個）のヘテロ原子（例、窒素原子、硫黄原子、酸素原子）を有する、
（１）５または６員（例、６員）の単環式非芳香族複素環とベンゼン環が縮合した、９または１０員の縮合非芳香族複素環（例、ジヒドロイソキノリル、ベンゾオキサゾリル、インドリニル、イソインドリル、１，２，３，４－テトラヒドロキノリル、１，２，３，４－テトラヒドロイソキノリル、２，３－ジヒドロベンゾフリル、３，４－ジヒドロ－１，４－ベンゾオキサジン）、
（２）５または６員（例、５員）の単環式芳香族複素環とベンゼン環が縮合した、９または１０員の縮合芳香族複素環（例、インドリル、ベンゾイミダゾリル、ベンゾピラゾリル、ベンゾチエニル、インダゾリル、１，２－ベンゾイソオキサゾリル、ベンゾトリアゾリル、ベンゾフリル）、または
（３）５または６員の単環式芳香族複素環と、６員の単環式芳香族複素環が縮合した、９または１０員の縮合芳香族複素環（例、１Ｈ－ピロロ［２，３－ｂ］ピリジル、イミダゾ［１，２－ａ］ピリジル、ピラゾロ［１，５ａ］ピリジル、１，４，５，６－テトラヒドロピラノ［２，３－ｃ］ピラゾリル）；
ｖ）（１）１～３個のハロゲン原子（例、塩素原子）で置換されていてもよい、Ｃ６－１４アリール（例、フェニル）、および
　　（２）Ｃ７－１４アラルキルオキシ（例、ベンジルオキシ）、
から選ばれる１～５個（例、１～３個）の置換基を有していてもよい、
３～７員（例、３～６員）飽和炭素環（例、シクロプロピル、シクロペンチル、シクロヘキシル）；
ｖｉ）１～３個のハロゲン原子（例、塩素原子）で置換されていてもよい、
５～７員（例、５員）の飽和炭素環と、１または２個の６～１０員の単環式芳香族炭素環（例、ベンゼン）が縮合した、９～１３員の縮合炭素環（例、インダニル、フルオレニル）；または
ｖｉｉ）１～３個（例、１個）のハロゲン原子（塩素原子）で置換されていてもよい１３～１５員のスピロ複素環（例、スピロ［１，３－ジヒドロイソベンゾフラン－１，４’－ピペリジン］）；
である、本発明化合物。 [Compound (Ig)]
R 1 is a hydrogen atom or a C 1-6 alkyl group (preferably a hydrogen atom, methyl, ethyl, propyl, isopropyl);
R 2 and R 3 are the same or different,
(1) a hydrogen atom,
(2) a halogen atom,
(3) hydroxy,
(4) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom),
(5) a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom (eg, fluorine atom), and (b) a phenyl group,
(6) C 1-6 alkylthio group, or (7) C 1-6 alkylsulfinyl group (preferably a hydrogen atom, a chlorine atom, a fluorine atom, hydroxy, methyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy , Trifluoromethoxy, difluoroethoxy, trifluoroethoxy, benzyloxy, hydroxy, methylthio or methylsulfinyl);
n is 1 or 2;
Y is
Join hands,
-Ra 1- ,
-Ra 1 CO-,
-Ra 1 CON (Rb 1 )-,
-Ra 1 CON (Rb 1 ) Ra 2- ,
-Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-,
-Ra 1 CON (Rb 1 ) Ra 2 O-,
-Ra 1 O-,
-CO-,
-CO-CO-,
-CO-CH = CH-,
-CORa 1- ,
-CORa 1 CON (Rb 1 )-,
-CORa 1 N (Rb 1 )-,
-CORa 1 N (Rb 1 ) CO-,
-CORa 1 O-,
-CORa 1 SRa 2- ,
-CON (Rb 1 )-,
-CON (Rb 1 ) Ra 1- ,
-CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
-CON (Rb 1 ) Ra 1 O-,
—CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
[Wherein, Ra 1 and Ra 2 are the same or different,
(1) Cyano (2) (a) Halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy,
(D) C 1-6 alkyl-carbonyl (e) C 1-6 alkoxy (eg, methoxy)
C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl) optionally having 1 to 5 substituents selected from
(3) C 3-8 cycloalkyl optionally having 1 to 5 halogen atoms (eg, cyclopropyl)
(4) C 6-14 aryl optionally having 1 to 3 halogen atoms and optionally having C 1-6 alkyl (eg, phenyl)
(5) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(6) hydroxy, and (7) (a) a halogen atom, and (b) C 1-6 alkoxy optionally having 1 to 3 substituents selected from C 3-8 cycloalkyl (eg, Methoxy),
C 1-6 alkylene (eg, methylene, ethylene, propylene) which may be substituted with one or two substituents selected from the above, and the substituents are bonded to each other to form a ring (eg, cyclopropane, (Cyclopentane) may be formed. Preferably, as Ra 1 and Ra 2 , methylene, methylmethylene, dimethylmethylene, ethylmethylene, methylene, cyanomethylene, methoxycarbonylmethylene, hydroxymethylmethylene, ethylene, phenylethylene, hydroxy These are ethylene and propylene, and the substituents may be bonded to form a ring. };
Rb 1 and Rb 2 are the same or different,
Hydrogen atom,
(1) halogen atom (fluorine atom),
(2) cyano,
(3) di-C 1-6 alkylamino (eg, dimethylamino), and (4) C 3-8 cycloalkyl (eg, cyclopropyl).
C 1-6 alkyl optionally having 1 to 3 substituents selected from (eg, methyl, ethyl, isobutyl)
(Preferably a hydrogen atom, methyl, ethyl, isobutyl, cyclopropylmethyl, 2-cyanoethyl, 2- (dimethylamino) ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl);
Ring A may further have a C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (preferably, Oxazole ring, triazole ring (eg, 1,2,3-triazole, 1,2,4-triazole), pyrazole ring, oxadiazole ring, isoxazole ring, thiazole ring, thiophene ring, imidazole ring);
Ring B is a benzene ring, a pyridine ring, a pyrimidine ring;
Ring D is
(1) oxo,
(2) (a) a halogen atom,
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy, and (d) C 1-6 alkyl - 1-5 may have a substituent group C 1-6 alkyl selected from carbonyl (e.g., methyl, ethyl),
(3) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(4) mono-C 1-6 alkyl-carbamoyl (eg, ethylcarbamoyl), and (5) di-C 1-6 alkyl-carbamoyl (eg, dimethyllcarbamoyl, diethylcarbamoyl)
A carbon atom as a ring atom which may be substituted with 1 to 3 substituents selected from: (preferably methyl, ethyl, hydroxymethyl, ethylcarbamoyl, diethylcarbamoyl, oxo, methoxycarbonyl, dimethylcarbamoyl) 6- or 7-membered non-aromatic heterocycle having 2 nitrogen atoms (preferably piperazinyl, 1,4-diazepanyl)
[When two or more of the substituents are present, the substituents may be bonded to each other to form a crosslinked structure (preferably 2,6-diazabicyclo [3.2.2] nonane-3- ON, 3,9-diazabicyclo [4.2.1] nonane-4-one, 3,6-diazabicyclo [3.2.1] octane-7-one, 8-oxa-3,10-diazabicyclo [4. 3.1] decan-4-one, 3,9-diazabicyclo [3.3.1] nonane-2,4-dione, 3,9-diazabicyclo [3.3.1] nonane)]; ,
i) (1) a halogen atom (eg, chlorine atom, fluorine atom),
(2) Nitro,
(3) hydroxy,
(4) (a) a halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy,
(D) C 1-6 alkyl-carbonyl, and (e) C 1-6 alkoxy (eg, methoxy)
C 1-6 alkyl (eg, methyl, isopropyl, tert-butyl) optionally having 1 to 5 substituents selected from
(5) (a) a halogen atom (eg, chlorine atom, fluorine atom),
(B) cyano,
(C) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(D) C 6-14 aryl optionally having 1 to 3 substituents selected from C 1-6 alkoxy (eg, phenyl)
(6) (a) a halogen atom (eg, fluorine atom), and (b) a C 3-8 cycloalkyl (eg, cyclopropyl)
C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 substituents selected from
(7) C 6-14 aryloxy (eg, phenyloxy),
(8) C 1-6 alkylsulfonyl (eg, methylsulfonyl)
(9) aminosulfonyl (10) di-C 1-6 alkylamino (eg, dimethylamino),
(11) a 3 to 14-membered heterocyclic ring (eg, oxadiazolyl, pyrazolyl) optionally substituted with C 1-6 alkyl,
(12) C 7-16 aralkyl (eg, benzyl),
(13) Cyano,
(14) C 1-6 alkyl-carbonylamino (eg, acetylamino),
(15) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl),
(16) C 1-6 alkoxy optionally substituted with C 3-8 cycloalkyl (eg, cyclopropylmethoxy),
(17) 3-14 membered heterocyclic-oxy (eg, pyridin-2-yloxy),
(18) di-C 1-6 alkylsulfamoyl (eg, dimethylsulfamoyl),
(19) Di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl), and (20) C 1-6 alkyl-carbonyl (eg, acetyl)
A benzene ring optionally substituted with 1 to 3 substituents selected from:
ii) a naphthalene ring optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom);
iii) (1) a halogen atom (eg, a chlorine atom),
(2) hydroxy,
(3) In addition to carbon atoms that may be substituted with 1 to 3 C 1-6 alkyls (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atoms) 3 to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing 1 to 5 (eg, 1 to 3) of 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms Groups [eg, aromatic heterocyclic groups (eg, furyl, thienyl, pyrazolyl, pyrimidinyl, pyridyl, oxadiazolyl); non-aromatic heterocyclic groups (eg, pyrrolidinyl, piperidinyl])
(4) (a) a halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group (eg, 1,3-benzodioxole),
C 1-6 alkyl (eg, methyl) optionally having 1 to 5 (eg, 1 to 3) substituents selected from (c) hydroxy, and (d) C 1-6 alkyl-carbonyl , Ethyl), and (5) (a) a halogen atom (eg, chlorine atom, fluorine atom),
(B) cyano,
(C) C 1-6 alkyl (eg, methyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom), and (d) C 1-6 alkoxy (eg, methoxy, ethoxy)
C 6-14 aryl (eg, phenyl) optionally having 1 to 3 (eg, 1 or 2) substituents selected from
(6) C 1-6 alkoxy (eg, optionally having 1 to 3 substituents selected from (a) a halogen atom (eg, fluorine atom), and (b) C 3-8 cycloalkyl Methoxy, ethoxy) (eg, trifluoroethoxy),
(7) C 3-8 cycloalkyl (eg, cyclopropyl) optionally having 1 to 3 halogen atoms,
(8) Oxo (9) Cyano,
(10) C 1-6 alkyl-carbonyl (eg, acetyl),
(11) C 7-16 aralkyl (eg, benzyl, diphenylmethyl, phenylethyl, benzodioxolylmethyl),
(12) Di-C 1-6 alkylamino (eg, dimethylamino),
(13) C 1-6 alkylsulfonyl (eg, ethylsulfonyl),
(14) C 1-6 alkyl-carbonylamino (eg, methylcarbonylamino, N- (ethyl) acetylamino) optionally substituted with C 1-6 alkyl,
(15) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl), and (16) carbamoyl,
May be substituted with 1 to 4 substituents selected from:
Having 1 to 3 (eg, 1 or 2) heteroatoms selected from nitrogen, oxygen and sulfur atoms,
A monocyclic 4-7 membered aromatic heterocycle (eg, pyridyl, thienyl, pyrazolyl, furyl, pyrazinyl, imidazolyl, thiazolyl, thiadiazolyl, preferably oxadiazolyl (preferably 1,2,4-oxadiazolyl), oxazolyl, pyrazolyl), or Monocyclic 4-7 membered non-aromatic heterocycle (eg, azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, azepanyl, piperidinyl, piperazinyl, diazepanyl, dihydroisoxazolyl, thiomorpholinyl);
iv) (1) halogen atom (eg, chlorine atom, fluorine atom, bromine atom),
(2) (a) a halogen atom (eg, fluorine atom),
(B) a 3- to 8-membered heterocyclic group,
(C) hydroxy,
(D) C 1-6 alkyl-carbonyl, and C 1-6 alkyl (eg, methyl, ethyl, isopropyl) optionally having 1 to 5 (eg, 1 to 3) substituents selected from ),
(3) oxo,
(4) C 1-6 alkoxy (eg, methoxy, ethoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) (eg, difluoromethoxy, trifluoromethoxy, trifluoroethoxy) And (5) C 7-16 aralkyl (eg, benzyl)
May be substituted with 1 to 3 substituents selected from:
Having 1 to 3 (eg, 1 or 2) heteroatoms (eg, nitrogen, sulfur, oxygen) selected from nitrogen, oxygen and sulfur atoms,
(1) A 9- or 10-membered condensed non-aromatic heterocyclic ring (eg, dihydroisoquinolyl, benzoxane) in which a 5- or 6-membered (eg, 6-membered) monocyclic non-aromatic heterocyclic ring and a benzene ring are condensed Zolyl, indolinyl, isoindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 2,3-dihydrobenzofuryl, 3,4-dihydro-1,4- Benzoxazine),
(2) A 9- or 10-membered condensed aromatic heterocycle in which a 5- or 6-membered (eg, 5-membered) monocyclic aromatic heterocycle and a benzene ring are condensed (eg, indolyl, benzimidazolyl, benzopyrazolyl, benzothienyl) , Indazolyl, 1,2-benzisoxazolyl, benzotriazolyl, benzofuryl), or (3) a 5- or 6-membered monocyclic aromatic heterocycle and a 6-membered monocyclic aromatic heterocycle Fused 9- or 10-membered fused aromatic heterocycles (eg, 1H-pyrrolo [2,3-b] pyridyl, imidazo [1,2-a] pyridyl, pyrazolo [1,5a] pyridyl, 1,4, 5,6-tetrahydropyrano [2,3-c] pyrazolyl);
v) (1) C 6-14 aryl (eg, phenyl) optionally substituted with 1 to 3 halogen atoms (eg, chlorine atom), and (2) C 7-14 aralkyloxy (eg, Benzyloxy),
Optionally having 1 to 5 (eg, 1 to 3) substituents selected from
3-7 membered (eg, 3-6 membered) saturated carbocycle (eg, cyclopropyl, cyclopentyl, cyclohexyl);
vi) optionally substituted by 1 to 3 halogen atoms (eg, chlorine atoms),
A 9 to 13-membered condensed carbocycle in which a 5- to 7-membered (eg, 5-membered) saturated carbocycle and one or two 6- to 10-membered monocyclic aromatic carbocycles (eg, benzene) are condensed (Eg, indanyl, fluorenyl); or vii) 13-15 membered spiro heterocycle (eg, spiro [1, 1) optionally substituted with 1 to 3 (eg, 1) halogen atom (chlorine atom) 3-dihydroisobenzofuran-1,4′-piperidine]);
The compound of the present invention.
　本発明化合物としては、実施例に記載の化合物が特に好ましい。
　なかでも、
４－［３－メトキシ－４－（２－メチル－１，３－オキサゾール－５－イル）フェニル］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピペラジン－１－カルボキサミド（実施例９０に記載の化合物）またはその塩；
Ｎ－｛２－ヒドロキシ－２－メチル－１－［４－（トリフルオロメチル）フェニル］プロピル｝－４－［３－メトキシ－４－（２－メチル－１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－カルボキサミド（実施例６９３に記載の化合物）またはその塩；
が特に好ましい。 As the compounds of the present invention, the compounds described in the examples are particularly preferred.
Above all,
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- [4- (trifluoromethyl) benzyl] piperazine-1-carboxamide (described in Example 90) Or a salt thereof;
N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) Phenyl] piperazine-1-carboxamide (the compound described in Example 693) or a salt thereof;
Is particularly preferred.
　本発明化合物が塩である場合、そのような塩としては、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。金属塩の好適な例としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩等のアルカリ土類金属塩；アルミニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’－ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸等との塩が挙げられる。
　このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩等）等の無機塩、アンモニウム塩等、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機酸との塩が挙げられる。 When the compound of the present invention is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. Etc. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts When the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
　本発明化合物およびその原料化合物は、自体公知の手段を用いて、例えば以下のスキームで示される方法〔製造法Ａ及びＢ（反応０１～反応０４）〕などによって製造できる。以下「室温」は通常０～３０℃を示し、スキーム中に記載されている化学構造式中の各記号は、特記しない限り前記と同意義を示す。なお、式中の化合物は、塩を形成している場合も含み、このような塩としては、例えば本発明化合物の塩と同様のものなどがあげられる。各工程で得られた化合物は反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、再結晶、蒸留、クロマトグラフィーなどの分離手段により容易に精製することができる。式中の化合物が市販されている場合には市販品をそのまま用いることもできる。また、環Ａ、Ｂ、Ｄ、またはＥが置換基を有している場合、対応する前駆体においても同様の置換基を有しているものとする。
　原料化合物がアミノ、カルボキシ、ヒドロキシ、複素環基を有する場合、これらの基は、ペプチド化学などで一般的に用いられるような保護基で保護されていてもよい。この場合、反応後に、必要に応じて、保護基を除去することにより目的化合物を得ることができる。これらの保護基の導入あるいは除去は、自体公知の方法、例えば、Wiley-Interscience社1999年刊「Protective Groups in Organic Synthesis, 3rdEd.」（Theodora W. Greene, Peter G. M. Wuts著）に記載の方法などに準じて行えばよい。式中、Ｐ１～Ｐ３とはアミンやアミドの窒素原子の保護基、ヒドロキシ基の保護基、または水素原子を示し、自体公知のものを用いることができる。例えば、Ｐ１～Ｐ３として好ましくは、ｔｅｒｔ－ブチルカルバマート基、ベンジルカルバマート基、ベンジル基、メチル基、エチル基などが挙げられる。また、Ｐ１～Ｐ３自体が化合物（１）の置換基となり得る場合があり、例えば、ｔｅｒｔ－ブチルカルバマート基、ベンジルカルバマート基、ベンジル基、メチル基、エチル基などが挙げられる。
　Ｌ１～Ｌ７は脱離基を示し、例えば、ハロゲン原子（例えば、塩素原子、臭素原子、ヨウ素原子など）、Ｃ１－６アルキルスルホニルオキシ（例えば、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシなど）、Ｃ６－１０アリールスルホニルオキシ（例えば、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシなど）、Ｃ１－６アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニルなど）などが用いられる。脱離基としては、特にハロゲン原子（例えば、ヨウ素原子など）、メタンスルホニルオキシが好ましい。また、Ｌ１～Ｌ７は脱離基に変換可能な置換基も含み、該置換基は、所望の工程で自体公知の反応によって脱離基へと変換できる。例えば、Ｌ１～Ｌ７がメチルチオ基である場合に、酸化反応によってメタンスルホニル基に変換する場合などがあげられる。
　また、式中、Ｒ５～Ｒ１０、Ｒ１２およびＲ１３は、置換基を有していてもよいＣ１－６アルキル基、または水素原子を示し、Ｒ１１は、置換基を有していてもよいＣ１－６アルキル基、または置換基を有していてもよいＣ６－１０アリール基を示す。 The compound of the present invention and its starting compound can be produced by a method known per se, for example, by the method shown in the following scheme [Production methods A and B (reaction 01 to reaction 04)]. Hereinafter, “room temperature” usually indicates 0 to 30 ° C., and each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified. The compound in the formula includes a case where a salt is formed. Examples of such a salt include the same salts as those of the compound of the present invention. The compound obtained in each step can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be easily purified. When the compound in the formula is commercially available, a commercially available product can be used as it is. In addition, when ring A, B, D, or E has a substituent, the corresponding precursor also has the same substituent.
When the raw material compound has an amino, carboxy, hydroxy, or heterocyclic group, these groups may be protected with a protecting group generally used in peptide chemistry or the like. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction. Introduction or removal of these protecting groups, a method known per se, for example, Wiley-Interscience, Inc. 1999 annual "Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to This may be done according to the above. In the formula, P 1 to P 3 represent a protecting group for a nitrogen atom of amine or amide, a protecting group for a hydroxy group, or a hydrogen atom, and those known per se can be used. For example, P 1 to P 3 are preferably tert-butyl carbamate group, benzyl carbamate group, benzyl group, methyl group, ethyl group and the like. In some cases, P 1 to P 3 itself can be a substituent of the compound (1), and examples thereof include a tert-butyl carbamate group, a benzyl carbamate group, a benzyl group, a methyl group, and an ethyl group.
L 1 to L 7 each represent a leaving group such as a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethane) Sulfonyloxy, etc.), C 6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), C 1-6 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like are used. As the leaving group, a halogen atom (for example, iodine atom) and methanesulfonyloxy are particularly preferable. L 1 to L 7 also contain a substituent that can be converted into a leaving group, and the substituent can be converted into the leaving group by a reaction known per se in a desired step. For example, when L 1 to L 7 are methylthio groups, they are converted to methanesulfonyl groups by an oxidation reaction.
In the formula, R 5 to R 10 , R 12 and R 13 each represents a C 1-6 alkyl group which may have a substituent, or a hydrogen atom, and R 11 has a substituent. And an optionally substituted C 1-6 alkyl group or an optionally substituted C 6-10 aryl group.
　以下に述べる各工程は、無溶媒、あるいは適当な溶媒に溶解または懸濁して行うことができ、二種以上の溶媒を適宜の割合で混合して用いてもよい。本発明化合物の製造法において用いられる溶媒の例として記載されるもののうち、具体的には下記の溶媒が用いられる。
アルコール類：
メタノール、エタノール、１－プロパノール、２－プロパノール、ｔｅｒｔ－ブチルアルコールなど
エーテル類：
ジエチルエーテル、ジイソプロピルエーテル、ジフェニルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタンなど
芳香族炭化水素類：
ベンゼン、クロロベンゼン、トルエン、キシレンなど
飽和炭化水素類：
シクロヘキサン、ヘキサンなど
アミド類：
Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ヘキサメチルホスホリックトリアミドなど
ハロゲン化炭化水素類：
ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタンなど
ニトリル類：
アセトニトリル、プロピオニトリルなど
スルホキシド類：
ジメチルスルホキシドなど
芳香族有機塩基類：
ピリジン、ルチジンなど
酸無水物類：
無水酢酸など
有機酸類：
ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、メタンスルホン酸など
無機酸類：
塩酸、硫酸など
エステル類：
酢酸メチル、酢酸エチル、酢酸ブチルなど
ケトン類：
アセトン、メチルエチルケトンなど Each step described below can be performed without solvent or by dissolving or suspending in an appropriate solvent, and two or more solvents may be mixed and used in an appropriate ratio. Among those described as examples of the solvent used in the production method of the compound of the present invention, specifically, the following solvents are used.
Alcohols:
Ethers such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol:
Aromatic hydrocarbons such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane:
Saturated hydrocarbons such as benzene, chlorobenzene, toluene, xylene:
Amides such as cyclohexane and hexane:
Halogenated hydrocarbons such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide:
Nitriles such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane:
Sulfoxides such as acetonitrile and propionitrile:
Aromatic organic bases such as dimethyl sulfoxide:
Acid anhydrides such as pyridine and lutidine:
Organic acids such as acetic anhydride:
Inorganic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid:
Esters such as hydrochloric acid and sulfuric acid:
Ketones such as methyl acetate, ethyl acetate, butyl acetate:
Acetone, methyl ethyl ketone, etc.
　本発明化合物の製造法において用いられる塩基または脱酸剤の例として記載されるもののうち、具体的には下記の塩基または脱酸剤が用いられる。
無機塩基類：
水酸化ナトリウム、水酸化カリウム、水酸化マグネシウムなど
塩基性塩類：
炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸カルシウム、炭酸水素ナトリウムなど
有機塩基類：
トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリン、１，５－ジアザビシクロ［４.３.０］－５－ノネン、１，４－ジアザビシクロ［２.２.２］オクタン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセンなど
金属アルコキシド類：
ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシドなど
アルカリ金属水素化物類：
水素化ナトリウム、水素化カリウムなど
金属アミド類：
ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジドなど
有機リチウム類：
メチルリチウム、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウムなど Among those described as examples of bases or deoxidizing agents used in the production method of the compound of the present invention, specifically, the following bases or deoxidizing agents are used.
Inorganic bases:
Basic salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide:
Organic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate:
Triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [ Metal alkoxides such as 4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene:
Alkali metal hydrides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide:
Metal amides such as sodium hydride and potassium hydride:
Organic lithiums such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide:
Methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.
　本発明化合物の製造法において用いられる酸、または酸性触媒の例として記載されるもののうち、具体的には、下記の酸、または酸性触媒が用いられる。
無機酸類：
塩酸、硫酸、硝酸、臭化水素酸、リン酸など
有機酸類：
酢酸、トリフルオロ酢酸、シュウ酸、フタル酸、フマル酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸、１０－カンファースルホン酸など
ルイス酸：
三フッ化ホウ素エーテル錯体、ヨウ化亜鉛、無水塩化アルミニウム、無水塩化亜鉛、無水塩化鉄など Among the acids described as examples of the acid or acidic catalyst used in the method for producing the compound of the present invention, specifically, the following acids or acidic catalysts are used.
Inorganic acids:
Organic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid:
Lewis acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid:
Boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.
　本発明化合物の製造法Ａ
（反応０１） Production method A of the compound of the present invention
(Reaction 01)
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（式中、各記号は前記のとおりである）
　本発明化合物は、工程Ａ－１に従い、化合物（２）と化合物（３）を金属触媒存在下縮合させることによって製造することができる。該金属触媒としては、さまざまな配位子を有する金属複合体が用いられ、例えばパラジウム化合物〔例：酢酸パラジウム（II）、テトラキス(トリフェニルホスフィン)パラジウム（0）、塩化ビス(トリフェニルホスフィン)パラジウム(II)、ジクロロビス(トリエチルホスフィン)パラジウム（0）、トリス(ジベンジリデンアセトン)ジパラジウム（0）、酢酸パラジウム（II）と１，１’－ビス(ジフェニルホスフィノ)フェロセンの複合体、トリス(ジベンジリデンアセトン)ジパラジウム（0）と２－ジシクロヘキシルホスフィノ－２’－（Ｎ，Ｎ－ジメチルアミノ)ビフェニル（ＤａｖｅＰｈｏｓ）、または、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル（ＸＰｈｏｓ）との複合体など〕、ニッケル化合物〔例：テトラキス(トリフェニルホスフィン)ニッケル（0）、塩化ビス(トリエチルホスフィン)ニッケル（II）、塩化ビス(トリフェニルホスフィン)ニッケル（II）など〕、ロジウム化合物〔例：塩化トリス(トリフェニルホスフィン)ロジウム（III）など〕、コバルト化合物、銅化合物〔例：酸化銅、ヨウ化銅（I）、硫酸銅、塩化銅（II）など〕、白金化合物などが挙げられる。なかでも、パラジウム化合物および銅化合物が好ましい。化合物（３）は、化合物（２）１モルに対し約０．８～１０モル、好ましくは約１．０～３．０モル用いる。金属触媒は、化合物（２）１モルに対し、約０．０００１～５モル、好ましくは約０．００１～１モル用いる。本反応は、塩基の存在下反応を行うことが好ましい。該塩基としては、例えば無機塩基類、有機塩基類、金属アルコキシド類、アルカリ金属水素化物類、金属アミド類などが挙げられる。塩基は、化合物（２）１モルに対し、約１．０～２０モル、好ましくは約１．０～５．０モル用いる。また、本反応で酸素に不安定な金属触媒を用いる場合には、例えばアルゴンガス、窒素ガスなどの不活性なガス気流中で反応を行うことが好ましい。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ニトリル類、スルホキシド類、エステル類、水などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～１００時間、好ましくは３０分～５０時間である。反応温度は－１０～２５０℃、好ましくは５０～１５０℃である。また、反応を促進させる目的で、マイクロ波を照射してもよい。 (Wherein each symbol is as described above)
The compound of the present invention can be produced by condensing compound (2) and compound (3) in the presence of a metal catalyst according to Step A-1. As the metal catalyst, metal complexes having various ligands are used. For example, palladium compounds [eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) chloride. Palladium (II), dichlorobis (triethylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), palladium acetate (II) and 1,1′-bis (diphenylphosphino) ferrocene complex, Tris (Dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl (DavePhos) or 2-dicyclohexylphosphino-2', 4 ', 6'- Complexes with triisopropylbiphenyl (XPhos), etc.], nickel compounds [e.g. tetrakis (Triphenylphosphine) nickel (0), bis (triethylphosphine) nickel (II) chloride, bis (triphenylphosphine) nickel (II) chloride, etc.], rhodium compounds [Example: tris (triphenylphosphine) rhodium chloride (III ), Etc.], cobalt compounds, copper compounds [e.g., copper oxide, copper iodide (I), copper sulfate, copper chloride (II), etc.], platinum compounds and the like. Of these, palladium compounds and copper compounds are preferred. Compound (3) is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (2). The metal catalyst is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (2). This reaction is preferably performed in the presence of a base. Examples of the base include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (2). Moreover, when using a metal catalyst unstable to oxygen in this reaction, it is preferable to perform the reaction in an inert gas stream such as argon gas or nitrogen gas. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but solvents such as alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, nitriles, sulfoxides, esters, water, etc. Alternatively, a mixed solvent thereof is preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr. The reaction temperature is −10 to 250 ° C., preferably 50 to 150 ° C. In addition, microwaves may be irradiated for the purpose of promoting the reaction.
　本発明化合物は、工程Ａ－１に従い、化合物（２）と化合物（３）を縮合することによって製造することもできる。化合物（３）は、化合物（２）１モルに対し約１．０～２０モル、好ましくは約１．０～５モル用いる。また、反応を促進させる目的で、塩基の存在下反応を行うこともでき、該塩基としては、例えば無機塩基類、塩基性塩類、有機塩基類、金属アルコキシド類、アルカリ金属水素化物類、金属アミド類、有機リチウム類などが挙げられる。塩基は、化合物（２）１モルに対し約１．０～２０モル、好ましくは約１．０～３．０モル用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類、エステル類、ケトン類、芳香族有機塩基類、水などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～１００時間、好ましくは３０分～５０時間である。反応温度は通常０～２５０℃、好ましくは０～２００℃である。また、反応を促進させる目的で、マイクロ波を照射してもよい。 The compound of the present invention can also be produced by condensing compound (2) and compound (3) according to Step A-1. Compound (3) is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 5 mol, per 1 mol of compound (2). In order to accelerate the reaction, the reaction can be carried out in the presence of a base. Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides. And organic lithiums. The base is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (2). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, esters , Ketones, aromatic organic bases, solvents such as water or mixed solvents thereof are preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr. The reaction temperature is usually 0 to 250 ° C., preferably 0 to 200 ° C. In addition, microwaves may be irradiated for the purpose of promoting the reaction.
　化合物（２）および化合物（３）は、市販品を用いてもよく、自体公知の方法あるいはそれらに準じた方法によって製造することもできる。 Compound (2) and compound (3) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
　化合物（２）、および、化合物（２）のうち、例えば（２ａ）、（２ｂ）、（２ｃ）の製造法
（反応０２） Of the compound (2) and the compound (2), for example, a method for producing (2a), (2b), (2c) (reaction 02)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式中、各記号は前記のとおりである）
　化合物（２）は、工程Ｂ－１に従い、化合物（４）と化合物（５ａ）を縮合させることにより製造することができる。反応は工程Ａ－１と同様の方法に従って行えばよい。 (Wherein each symbol is as described above)
Compound (2) can be produced by condensing compound (4) and compound (5a) according to Step B-1. The reaction may be performed according to the same method as in step A-1.
　化合物（２）は、工程Ｂ－１に従い、化合物（４）と化合物（５ｂ）を縮合させることによっても製造することができる。式中、Ｒ４は、有機ボロン酸または有機ボロン酸エステルのホウ素原子部分、トリＣ１－６アルキルスタニル基、または水素原子などを示す。該有機ボロン酸または有機ボロン酸エステルとしては、例えばジヒドロキシボラニル基、４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル基などが好ましく、該トリＣ１－６アルキルスタニル基としては、トリブチルスタニル基などが好ましい。縮合反応は、化合物（４）と化合物（５ｂ）を金属触媒の存在下反応させることにより行う。該金属触媒としては、パラジウム化合物〔例：酢酸パラジウム（II）、テトラキス(トリフェニルホスフィン)パラジウム（0）、塩化ビス(トリフェニルホスフィン)パラジウム(II)、ジクロロビス(トリエチルホスフィン)パラジウム（0）、トリス(ジベンジリデンアセトン)ジパラジウム（0）、酢酸パラジウム（II）と１，１’－ビス(ジフェニルホスフィノ)フェロセンの複合体など〕が好ましい。反応は通常、塩基の存在下に行う。該塩基としては、例えば無機塩基類、塩基性塩類などが挙げられる。化合物（５ｂ）は、化合物（４）１モルに対し約０．１～１０モル、好ましくは約０．８～２．０モル用いる。金属触媒は、化合物（４）１モルに対し約０．０００００１～５．０モル、好ましくは約０．０００１～１．０モル用いる。また、塩基は、化合物（４）１モルに対し約１．０～２０モル、好ましくは約１．０～５．０モル用いる。これらの反応で酸素に不安定な金属触媒を用いる場合には、例えばアルゴンガス、窒素ガスなどの不活性なガス気流中で反応を行うことが好ましい。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、エステル類、水などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１分～２００時間、好ましくは５分～１００時間である。反応温度は－１０～２５０℃、好ましくは０～１５０℃である。また、反応を促進させる目的で、マイクロ波を照射してもよい。 Compound (2) can also be produced by condensing compound (4) and compound (5b) according to Step B-1. In the formula, R 4 represents a boron atom portion, a tri-C 1-6 alkylstannyl group, a hydrogen atom, or the like of an organic boronic acid or organic boronic acid ester. Examples of the organic boronic acid or organic boronic acid ester, for example dihydroxyboranyl group, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group are preferable, the tri C 1- The 6- alkylstannyl group is preferably a tributylstannyl group. The condensation reaction is carried out by reacting compound (4) with compound (5b) in the presence of a metal catalyst. Examples of the metal catalyst include palladium compounds [eg, palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, dichlorobis (triethylphosphine) palladium (0), Tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate and 1,1′-bis (diphenylphosphino) ferrocene complex, etc.] are preferred. The reaction is usually performed in the presence of a base. Examples of the base include inorganic bases and basic salts. Compound (5b) is used in an amount of about 0.1-10 mol, preferably about 0.8-2.0 mol, per 1 mol of compound (4). The metal catalyst is used in an amount of about 0.000001 to 5.0 mol, preferably about 0.0001 to 1.0 mol, per 1 mol of compound (4). The base is used in an amount of about 1.0 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (4). When a metal catalyst unstable to oxygen is used in these reactions, the reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, esters, water Or a mixed solvent thereof. While the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 5 min to 100 hr. The reaction temperature is −10 to 250 ° C., preferably 0 to 150 ° C. In addition, microwaves may be irradiated for the purpose of promoting the reaction.
　化合物（２ａ）は、工程Ｂ－６に従い、化合物（６）を塩基の存在下１－［（イソシアノメチル）スルホニル］－４－メチルベンゼンとの縮合反応に付すことにより製造することができる。該塩基としては、例えば無機塩基類、塩基性塩類、有機塩基類、金属アルコキシド類などが挙げられる。塩基は化合物（６）１モルに対し約０．８～２０モル、好ましくは約１．０～５．０モル用いる。１－［（イソシアノメチル）スルホニル］－４－メチルベンゼンは化合物（６）１モルに対し約０．８～２０モル、好ましくは約１．０～５．０モル用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒として反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～５０時間、好ましくは１時間～２４時間である。反応温度は通常－２０～２００℃、好ましくは０～１００℃である。 Compound (2a) can be produced according to Step B-6 by subjecting compound (6) to a condensation reaction with 1-[(isocyanomethyl) sulfonyl] -4-methylbenzene in the presence of a base. Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides and the like. The base is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (6). 1-[(Isocyanomethyl) sulfonyl] -4-methylbenzene is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (6). This reaction is advantageously performed using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, solvents, such as alcohol, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, etc. Alternatively, a mixed solvent thereof is preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 1 hr-24 hr. The reaction temperature is usually −20 to 200 ° C., preferably 0 to 100 ° C.
　化合物（２ａ）は、工程Ｂ－７に従い、化合物（８）と化合物（９）を酸化剤および酸の存在下、縮合反応に付すことによっても製造することができる。該酸化剤としては、例えば過安息香酸、ｍ－クロロ過安息香酸（ＭＣＰＢＡ）、過酢酸などの有機過酸類、例えば過塩素酸リチウム、過塩素酸銀、過塩素酸テトラブチルアンモニウムなどの過塩素酸塩類、例えばヨードベンゼンジアセテート、過ヨウ素酸ナトリウム、デス－マーチン　ペルヨージナン、ｏ－ヨードオキシ安息香酸（ＩＢＸ）などの過ヨウ素酸類、例えば二酸化マンガン、過マンガン酸カリウムなどのマンガン酸類、例えば四酢酸鉛などの鉛類、例えばクロロクロム酸ピリジニウム、二クロム酸ピリジニウムなどのクロム酸塩、例えば硝酸アシル、四酸化二窒素などの無機窒素化合物類、例えばハロゲン、Ｎ－ブロモスクシンイミド（ＮＢＳ）、Ｎ－クロロスクシンイミド（ＮＣＳ）などのハロゲン化合物類、塩化スルフリル、クロラミンＴ、酸素、過酸化水素などが挙げられる。酸化剤は、化合物（８）１モルに対し、約０．８～２０モル、好ましくは約１．０～５．０モル用いる。該酸としては、例えば無機酸類、有機酸類、ルイス酸などが挙げられる。酸は、化合物（８）１モルに対し、約０．８～２０モル、好ましくは約１．０～１０モル用いる。化合物（９）としては、例えばアセトニトリル、プロピオニトリルなどのＣ１－６アルキルニトリル類などが挙げられる。化合物（９）は、化合物（８）１モルに対し、約０．８モル以上用い、溶媒としても用いることができる。溶媒としては反応が進行する限り特に限定されないが、例えばエーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～１００時間、好ましくは３０分～４８時間である。反応温度は通常－２０～２００℃、好ましくは－１０～１００℃である。 Compound (2a) can also be produced by subjecting compound (8) and compound (9) to a condensation reaction in the presence of an oxidizing agent and an acid according to Step B-7. Examples of the oxidizing agent include organic peracids such as perbenzoic acid, m-chloroperbenzoic acid (MCPBA), and peracetic acid such as perchloric acid such as lithium perchlorate, silver perchlorate, and tetrabutylammonium perchlorate. Acid salts such as iodobenzene diacetate, sodium periodate, Dess-Martin periodinane, periodate such as o-iodooxybenzoic acid (IBX), manganic acid such as manganese dioxide, potassium permanganate, such as lead tetraacetate Leads such as, for example, chromate such as pyridinium chlorochromate, pyridinium dichromate, inorganic nitrogen compounds such as acyl nitrate, dinitrogen tetroxide, such as halogen, N-bromosuccinimide (NBS), N-chloro Halogen compounds such as succinimide (NCS), sulfuryl chloride, Examples include chloramine T, oxygen, hydrogen peroxide, and the like. The oxidizing agent is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (8). Examples of the acid include inorganic acids, organic acids, Lewis acids and the like. The acid is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 10 mol, per 1 mol of compound (8). Examples of the compound (9) include C 1-6 alkyl nitriles such as acetonitrile and propionitrile. Compound (9) is used in an amount of about 0.8 mol or more per 1 mol of compound (8) and can also be used as a solvent. The solvent is not particularly limited as long as the reaction proceeds. Etc. are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-48 hr. The reaction temperature is usually −20 to 200 ° C., preferably −10 to 100 ° C.
　化合物（２ａ）は、工程Ｂ－８に従い、化合物（１０）と化合物（１１）を酸の存在下、縮合反応に付すことによっても製造することができる。該酸としては、例えば無機酸類、有機酸類、ルイス酸などが挙げられる。酸は、化合物（１０）１モルに対し、約０．００１～１０モル、好ましくは約０．１～２．０モル用いる。化合物（１１）としては、例えばオルト酢酸トリメチル、オルトプロピオン酸トリエチル、オルトギ酸トリメチルなどのオルト酸エステル類などが挙げられる。化合物（１１）は、化合物（１０）１モルに対し、約０．８モル以上用い、溶媒としても用いることができる。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒として反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～５０時間、好ましくは１時間～２４時間である。反応温度は通常－２０～２００℃、好ましくは０～１００℃である。 Compound (2a) can also be produced by subjecting compound (10) and compound (11) to a condensation reaction in the presence of an acid according to Step B-8. Examples of the acid include inorganic acids, organic acids, Lewis acids and the like. The acid is used in an amount of about 0.001 to 10 mol, preferably about 0.1 to 2.0 mol, per 1 mol of compound (10). Examples of the compound (11) include ortho acid esters such as trimethyl orthoacetate, triethyl orthopropionate and trimethyl orthoformate. Compound (11) is used in an amount of about 0.8 mol or more per 1 mol of compound (10), and can also be used as a solvent. This reaction is advantageously performed using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, solvents, such as alcohol, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, etc. Alternatively, a mixed solvent thereof is preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-50 hr, preferably 1 hr-24 hr. The reaction temperature is usually −20 to 200 ° C., preferably 0 to 100 ° C.
　化合物（２ａ）は、自体公知の方法、例えばバイオオーガニック　アンド　メディシナル　ケミストリー レターズ（Bioorganic & Medicinal Chemistry Letters）、13巻、2059頁（2003年）などに記載の方法、またはこれらに準じた方法に従って製造することもできる。 Compound (2a) is produced according to a method known per se, for example, the method described in Bioorganic & Medicinal Chemistry Letters, Vol. 13, p. 2059 (2003), or a method analogous thereto. You can also.
　化合物（８）は、工程Ｂ－２に従い化合物（４）から、工程Ｂ－４に従い化合物（６）から、または、工程Ｂ－３に従い化合物（７）から製造することができる。化合物（１０）は、工程Ｂ－５に従い化合物（８）から製造することができる。工程Ｂ－２としては、例えば、化合物（４）とトリブチル（エトキシビニル）－チンなどを、化合物（４）と化合物（５ｂ）から化合物（２）を製造する方法と同様の反応に付す方法などがあげられ、工程Ｂ－４としては、例えば、アルデヒド基にＲ５ＣＨ２ＭｇＢｒであらわされるグリニャール試薬などを付加した後、酸化反応に付す方法などがあげられ、工程Ｂ－３としては、例えば、カルボキシル基をワインレブアミドに変換した後、Ｒ５ＣＨ２ＭｇＢｒであらわされるグリニャール試薬などとの反応に付す方法などがあげられ、工程Ｂ－５としては、例えば、ケトンにハロゲン化剤を作用させてαーハロケトンとした後、アミノ化剤などとの反応に付す方法などがあげられる。これらの反応は、例えば新実験化学講座、14、15巻（日本化学会編）、オーガニック　ファンクショナル　グループ　プレパレーションズ（ORGANIC FUNCTIONAL GROUP PREPARATIONS）第２版、アカデミックプレス社（ACADEMIC PRESS, INC．）1989年刊；コンプリヘンシブ・オーガニック・トランスフォーメーション(Comprehensive Organic Transformations) VCH Publishers Inc.　1989年刊等などに記載された方法に準じて行えばよい。 Compound (8) can be produced from compound (4) according to step B-2, from compound (6) according to step B-4, or from compound (7) according to step B-3. Compound (10) can be produced from compound (8) according to Step B-5. Step B-2 includes, for example, a method of subjecting compound (4) and tributyl (ethoxyvinyl) -tin to the same reaction as the method of producing compound (2) from compound (4) and compound (5b), etc. Step B-4 includes, for example, a method of adding a Grignard reagent represented by R 5 CH 2 MgBr to an aldehyde group, and then subjecting it to an oxidation reaction. Step B-3 includes, for example, And a method in which a carboxyl group is converted to wine levamide and then subjected to a reaction with a Grignard reagent represented by R 5 CH 2 MgBr. Step B-5 includes, for example, an action of a halogenating agent on a ketone. And an α-haloketone, followed by a reaction with an aminating agent. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations, 2nd edition, ACADEMIC PRESS, INC., 1989. Comprehensive Organic Transformations (Comprehensive Organic Transformations) VCH Publishers Inc. may be carried out according to the method described in 1989, etc.
　化合物（２ｂ）は、工程Ｂ－１０に従い、化合物（１３）と化合物（１４）を縮合した後、オルト酸エステル類との縮合反応に付すことにより製造することができる。化合物（１４）としては、例えばメチル　エタンイミドチオアート　ヨウ化水素酸塩、メチル　プロパンイミドチオアート　塩化水素酸塩などのアルキルイミドチオアート類が挙げられ、自体公知の方法、例えばインディアン　ジャーナル　オブ　ケミストリー、セクションＢ：オーガニック　ケミストリー　インクルーディング　メディシナル　ケミストリー（Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry）、21巻、272頁（1982年）などに記載の方法、またはこれらに準じた方法に従って製造することができる。化合物（１４）は、化合物（１３）１モルに対し、約０．８～１０モル、好ましくは約１．０～５モル用いる。該オルト酸エステル類としては、例えばオルト酢酸トリメチル、オルトプロピオン酸トリエチル、オルトギ酸トリメチルなどが挙げられる。オルト酸エステル類は、化合物（１３）１モルに対し、約０．８モル以上用い、溶媒としても用いることができる。化合物（１３）と化合物（１４）との縮合反応における溶媒としては、反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常５分～１００時間、好ましくは１０分～２４時間である。反応温度は通常－２０～２００℃、好ましくは－１０～１００℃である。オルト酸エステルとの縮合反応における溶媒としては、反応が進行する限り特に限定されないが、例えばアルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類、芳香族有機塩基類、有機塩基類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～２００時間、好ましくは１０分～４８時間である。反応温度は通常－２０～２００℃、好ましくは－１０～１５０℃である。 Compound (2b) can be produced by condensing compound (13) and compound (14) according to Step B-10, followed by condensation reaction with ortho acid esters. Examples of the compound (14) include alkylimide thioates such as methyl ethaneimide thioate hydroiodide, methyl propanimide thioate hydrochloride, etc., and methods known per se, such as Indian Journal of Chemistry, Section B: Organic Chemistry Inclusion Medicinal Chemistry (Indian Journal of Chemistry, Section Organic: Chemistry, Including Medicinal Chemistry), Volume 21, page 272 (1982), etc. Can do. Compound (14) is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 5 mol, per 1 mol of compound (13). Examples of the ortho acid esters include trimethyl orthoacetate, triethyl orthopropionate, trimethyl orthoformate and the like. Ortho acid esters are used in an amount of about 0.8 mol or more per 1 mol of compound (13), and can also be used as a solvent. The solvent in the condensation reaction between the compound (13) and the compound (14) is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogens Solvents such as fluorinated hydrocarbons, nitriles, sulfoxides or a mixed solvent thereof are preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr. The reaction temperature is usually −20 to 200 ° C., preferably −10 to 100 ° C. The solvent in the condensation reaction with the ortho acid ester is not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles , Sulfoxides, aromatic organic bases, organic bases, or a mixed solvent thereof. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-200 hr, preferably 10 min-48 hr. The reaction temperature is usually −20 to 200 ° C., preferably −10 to 150 ° C.
　化合物（１３）は、工程Ｂ－９に従い、化合物（１２）を酸の存在下、亜硝酸類と反応させた後、還元反応に付すことにより製造することができる。該酸としては、例えば無機酸類、有機酸類、ルイス酸などが挙げられる。酸は、化合物（１２）１モルに対し、約０．０１モル以上用い、溶媒としても用いることができる。該亜硝酸類としては、亜硝酸ナトリウム、亜硝酸カリウムなどの亜硝酸塩類、亜硝酸イソアミルなどの亜硝酸エステル類などが挙げられる。亜硝酸類は、化合物（１２）１モルに対し、約０．８～１０モル、好ましくは約１．０～５モル用いる。該還元剤としては、例えば塩化すずなどの還元剤などが挙げられる。還元剤は、化合物（１２）１モルに対し、約０．８～２０モル、好ましくは約１．０～１０モル用いる。亜硝酸類との反応における溶媒としては、反応が進行する限り特に限定されないが、例えば無機酸類、有機酸類、アルコール類、エーテル類、アミド類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常５分～１００時間、好ましくは１０分～２４時間である。反応温度は通常－３０～１００℃、好ましくは－２０～８０℃である。還元反応における溶媒としては、反応が進行する限り特に限定されないが、例えば無機酸類、有機酸類、アルコール類、エーテル類、アミド類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常５分～１００時間、好ましくは１０分～２４時間である。反応温度は通常－３０～１００℃、好ましくは－２０～８０℃である。 Compound (13) can be produced by reacting compound (12) with nitrous acid in the presence of an acid, followed by a reduction reaction according to Step B-9. Examples of the acid include inorganic acids, organic acids, Lewis acids and the like. The acid is used in an amount of about 0.01 mol or more per 1 mol of compound (12), and can also be used as a solvent. Examples of the nitrites include nitrites such as sodium nitrite and potassium nitrite, and nitrites such as isoamyl nitrite. Nitrous acid is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 5 mol, per 1 mol of compound (12). Examples of the reducing agent include reducing agents such as tin chloride. The reducing agent is used in an amount of about 0.8 to 20 mol, preferably about 1.0 to 10 mol, per 1 mol of compound (12). The solvent in the reaction with nitrous acid is not particularly limited as long as the reaction proceeds. For example, a solvent such as inorganic acids, organic acids, alcohols, ethers, amides, nitriles, sulfoxides or a mixed solvent thereof. Etc. are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr. The reaction temperature is usually −30 to 100 ° C., preferably −20 to 80 ° C. The solvent in the reduction reaction is not particularly limited as long as the reaction proceeds. For example, solvents such as inorganic acids, organic acids, alcohols, ethers, amides, nitriles, sulfoxides or a mixed solvent thereof are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr. The reaction temperature is usually −30 to 100 ° C., preferably −20 to 80 ° C.
　化合物（２ｃ）は、工程Ｂ－１２に従い、化合物（１２）と化合物（１７）を縮合させることにより製造することができる。化合物（１２）は、化合物（１７）１モルに対し、約０．１～１０モル、好ましくは約０．２～５モル用いる。溶媒としては、反応が進行する限り特に限定されないが、例えば無機酸類、有機酸類、アルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類、芳香族有機塩基類、有機塩基類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常５分～１００時間、好ましくは１０分～２４時間である。反応温度は通常－３０～１００℃、好ましくは－２０～８０℃である。 Compound (2c) can be produced by condensing compound (12) and compound (17) according to Step B-12. Compound (12) is used in an amount of about 0.1 to 10 mol, preferably about 0.2 to 5 mol, per 1 mol of compound (17). The solvent is not particularly limited as long as the reaction proceeds. For example, inorganic acids, organic acids, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, Solvents such as sulfoxides, aromatic organic bases and organic bases, or mixed solvents thereof are preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr. The reaction temperature is usually −30 to 100 ° C., preferably −20 to 80 ° C.
　化合物（１７）は、工程Ｂ－１１に従い、酸の存在下、化合物（１５）と化合物（１６）を縮合させることにより製造することができる。該酸としては、例えば無機酸類、有機酸類、ルイス酸などが挙げられる。酸は、化合物（１６）１モルに対し、約０．０１モル以上用い、溶媒としても用いることができる。溶媒としては、反応が進行する限り特に限定されないが、例えば無機酸類、有機酸類、アルコール類、エーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常５分～１００時間、好ましくは１０分～２４時間である。反応温度は通常－３０～１００℃、好ましくは－２０～８０℃である。 Compound (17) can be produced by condensing compound (15) and compound (16) in the presence of an acid according to Step B-11. Examples of the acid include inorganic acids, organic acids, Lewis acids and the like. The acid is used in an amount of about 0.01 mol or more per 1 mol of compound (16), and can also be used as a solvent. The solvent is not particularly limited as long as the reaction proceeds. For example, inorganic acids, organic acids, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, Solvents such as sulfoxides or mixed solvents thereof are preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min-100 hr, preferably 10 min-24 hr. The reaction temperature is usually −30 to 100 ° C., preferably −20 to 80 ° C.
　化合物（２）は自体公知の方法、例えば、ユーロピアン　ジャーナル　オブ　オーガニック　ケミストリー（European journal of organic chemistry）、13巻、2970頁（2006年）、シンセティック　コミュニケーションズ（Synthetic communications）、36巻、2927頁（2006年）、ジャーナル　オブ　オーガニック　ケミストリー（Journal of organic chemistry）、44巻、4160頁（1979年）、ジャーナル　オブ　ザ　ケミカル　ソサエティー（Journal of the chemical society）、4251頁（1954年）、ＷＯ　２００８／７７６４９号広報などに記載の方法、またはこれらに準じた方法に従って製造することもできる。 Compound (2) is a method known per se, for example, European Journal of Organic Chemistry, Vol. 13, p. 2970 (2006), Synthetic Communications, Vol. 36, p. 2927 (2006). ), Journal of Organic Chemistry, 44, 4160 (1979), Journal of the Chemical Society, 4251 (1954), WO 2008/77649, etc. It can also be produced according to the method described in 1. or a method analogous thereto.
　化合物（２）、（２ａ）（２ｂ）、（２ｃ）は、さらに、公知の置換基変換反応、縮合反応、酸化反応、還元反応などを各々、単独あるいはその二以上を組み合わせて行うことにより、所望化合物へと導くことができる。これらの反応は、例えば新実験化学講座、14、15巻（日本化学会編）、オーガニック　ファンクショナル　グループ　プレパレーションズ（ORGANIC FUNCTIONAL GROUP PREPARATIONS）第２版、アカデミックプレス社（ACADEMIC PRESS, INC．）1989年刊；コンプリヘンシブ・オーガニック・トランスフォーメーション (Comprehensive Organic Transformations) VCH Publishers Inc.　1989年刊等などに記載された方法に準じて行えばよい。例えば、Ｒ２基またはＲ３基のうち１または２個がハロゲン原子である場合において、それらのハロゲン原子に、自体公知の方法あるいはそれに準じた方法に従ってＣ１－６アルキルオキシドを作用させ、Ｒ２基またはＲ３基のうち１または２個をＣ１－６アルキルオキシ基に変換する場合などがあげられる。 Compounds (2), (2a), (2b), and (2c) are further subjected to a known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, and the like, each alone or in combination of two or more thereof. Can lead to the desired compound. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations, 2nd edition, ACADEMIC PRESS, INC., 1989. Comprehensive Organic Transformations VCH Publishers Inc. may be performed according to the method described in 1989 and the like. For example, when one or two of the R 2 or R 3 groups are halogen atoms, a C 1-6 alkyl oxide is allowed to act on those halogen atoms according to a method known per se or a method analogous thereto, and R Examples include the case where one or two of the two groups or R 3 groups are converted into a C 1-6 alkyloxy group.
　化合物（２ｂ）、（２ｃ）、（４）、（５ａ）、（５ｂ）、（６）、（７）、（８）、（９）、（１０）、（１１）、（１２）、（１３）、（１４）、（１５）、（１６）および（１７）は、市販品を用いてもよく、自体公知の方法あるいはそれらに準じた方法によって製造することもできる。 Compounds (2b), (2c), (4), (5a), (5b), (6), (7), (8), (9), (10), (11), (12), ( Commercially available products may be used for 13), (14), (15), (16) and (17), and they can also be produced by a method known per se or a method analogous thereto.
　化合物（３）、および、化合物（３）のうち、例えば、化合物（３ａ）、（３ｂ）、（３ｃ）、（３ｄ）、（３ｅ）などの製造法（ただし、式中、Ｙ１－４は、－Ｙ１－、－ＣＯ－Ｙ２－、－ＣＯ－Ｎ（Ｒ１２）－Ｙ３－、および－ＣＨ２－ＣＯ－Ｎ（Ｒ１３）－Ｙ４－が、前記の－Ｙ－の定義を構成するように定義される。）
（反応０３） Among compound (3) and compound (3), for example, production methods of compounds (3a), (3b), (3c), (3d), (3e) and the like (where Y 1-4 —Y 1 —, —CO—Y 2 —, —CO—N (R 12 ) —Y 3 —, and —CH 2 —CO—N (R 13 ) —Y 4 — are the above-mentioned —Y— Defined to constitute the definition of
(Reaction 03)
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、各記号は前記のとおりである）
　化合物（３ａ）は、工程Ｃ－１に従い、化合物（１８）を化合物（２０ａ）へと導いた後、化合物（２０ａ）の保護基を除去することにより製造することができる。保護基の除去は、自体公知の方法、例えば、Wiley-Interscience社1999年刊「Protective Groups in Organic Synthesis, 3rdEd.」（Theodora W. Greene, Peter G. M. Wuts著）に記載の方法などに準じて行えばよい。また、化合物（１８）が無保護の場合（Ｐ１が水素原子の場合）においても、工程Ｃ－１に従い、化合物（３ａ）へと導くことができる。その場合、保護基の除去を省略することができる。 (Wherein each symbol is as described above)
Compound (3a) can be produced according to Step C-1 by introducing compound (18) to compound (20a) and then removing the protecting group of compound (20a). Removal of the protecting group, a method known per se, for example, Wiley-Interscience, Inc. 1999 annual "Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) according the like to the method described in Just do it. Even when compound (18) is unprotected (when P 1 is a hydrogen atom), it can be led to compound (3a) according to Step C-1. In that case, removal of the protecting group can be omitted.
　化合物（３ｂ）は化合物（１８）から工程Ｃ－２および保護基の除去により、化合物（３ｃ）は化合物（１８）から工程Ｃ－３および保護基の除去により、化合物（２０ｅ）は化合物（１８）から工程Ｃ－４および保護基の除去により、化合物（３ｄ）は化合物（２０ｅ）から工程Ｃ－５および保護基の除去により、化合物（３ｅ）は化合物（１８）から工程Ｃ－６および保護基の除去により、または、化合物（３）は化合物（１８）から工程Ｃ－７および保護基の除去により製造することができる。保護基の除去は化合物（２０ａ）から化合物（３ａ）を製造する方法と同様の方法により行えばよく、Ｐ１－２が水素原子の場合も、化合物（１８）から化合物（３ａ）を製造する方法と同様の方法により行えばよい。 Compound (3b) is obtained by removing Step C-2 and the protecting group from Compound (18), Compound (3c) is obtained by removing Step C-3 and the protecting group from Compound (18), and Compound (20e) is obtained by Compound (18). ) From step C-4 and removal of the protecting group, compound (3d) is obtained from compound (20e) by removal of step C-5 and the protecting group, and compound (3e) is converted from compound (18) to step C-6 and the protecting group. By removal of the group or compound (3) can be prepared from compound (18) by step C-7 and removal of the protecting group. Removal of the protecting group may be carried out by the same method as the method for producing compound (3a) from compound (20a). Even when P 1-2 is a hydrogen atom, compound (3a) is produced from compound (18). A method similar to the method may be used.
　化合物（２０ａ）は、工程Ｃ－１に従い、化合物（１８）とアルキル化剤（１９ａ）を塩基の存在下反応させることによって製造することができる。該塩基としては、例えば無機塩基類、塩基性塩類、有機塩基類、金属アルコキシド類、アルカリ金属水素化物類、金属アミド類などが挙げられる。化合物（１８）１モルに対し塩基を約１．０～５．０モル、好ましくは約１．０～２．０モル用いる。また、反応を促進させる目的で、好ましくは、例えば、ヨウ化ナトリウム、ヨウ化カリウム等を添加させてもよい。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばエーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～１００時間、好ましくは３０分～２４時間である。反応温度は通常－２０～２００℃、好ましくは－１０～１５０℃である。 Compound (20a) can be produced by reacting compound (18) and alkylating agent (19a) in the presence of a base according to Step C-1. Examples of the base include inorganic bases, basic salts, organic bases, metal alkoxides, alkali metal hydrides, metal amides and the like. The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (18). Further, for the purpose of promoting the reaction, for example, sodium iodide, potassium iodide or the like may be added. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like A mixed solvent of While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-24 hr. The reaction temperature is usually −20 to 200 ° C., preferably −10 to 150 ° C.
　化合物（２０ｂ）は、工程Ｃ－２に従い、化合物（１８）とカルボン酸（１９ｂ）、その塩もしくはその反応性誘導体とを反応させることによって製造することができる。該カルボン酸の反応性誘導体としては、例えば酸塩化物、酸臭化物などの酸ハロゲン化物、ピラゾール、イミダゾール、ベンゾトリアゾールなどとの酸アミド、無水酢酸、無水プロピオン酸、無水酪酸などの酸無水物、酸アジド、ジエトキシリン酸エステル、ジフェノキシリン酸エステル、ｐ－ニトロフェニルエステル、２，４－ジニトロフェニルエステル、シアノメチルエステル、ペンタクロロフェニルエステル、Ｎ－ヒドロキシスクシンイミドとのエステル、Ｎ－ヒドロキシフタルイミドとのエステル、１－ヒドロキシベンゾトリアゾールとのエステル、６－クロロ－１－ヒドロキシベンゾトリアゾールとのエステル、１－ヒドロキシ－１Ｈ－２－ピリドンとのエステルなどの活性エステル、２－ピリジルチオエステル、２－ベンゾチアゾリルチオエステルなどの活性チオエステルなどが挙げられる。また該反応性誘導体を用いる代わりに、該カルボン酸またはその塩を適当な縮合剤の存在下、直接化合物（１８）と反応させても良い。縮合剤としては、例えばＮ，Ｎ'－ジシクロヘキシルカルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＷＳＣ）塩酸塩などのＮ，Ｎ'－ジ置換カルボジイミド類、Ｎ，Ｎ'－カルボニルジイミダゾールなどのアゾライド類、Ｎ－エトキシカルボニル－２－エトキシ－１，２－ジヒドロキノリン、オキシ塩化リン、アルコキシアセチレンなどの脱水剤、２－クロロメチルピリジニウムヨージド、２－フルオロ－１－メチルピリジニウムヨージドなどの２－ハロゲノピリジニウム塩などが挙げられる。これらの縮合剤を用いた場合、反応はカルボン酸の反応性誘導体を経て進行すると考えられる。カルボン酸、その塩またはその反応性誘導体は、化合物（１８）１モルに対し通常約１．０～５．０モル、好ましくは約１．０～２．０モル用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばエーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類、芳香族有機塩基類などの溶媒もしくはそれらの混合溶媒などが好ましい。また、反応により酸性物質が放出される場合は、それらを反応系内から除去する目的で、脱酸剤の存在下に反応を行うことができる。このような脱酸剤としては、例えば塩基性塩類、有機塩基類などが使用される。反応時間は用いる試薬や溶媒により異なるが通常１０分～７２時間、好ましくは３０分～２４時間である。反応温度は通常０～１００℃、好ましくは０～７０℃である。 Compound (20b) can be produced by reacting compound (18) with carboxylic acid (19b), a salt thereof or a reactive derivative thereof according to Step C-2. Examples of the reactive derivative of the carboxylic acid include acid halides such as acid chlorides and acid bromides, acid amides such as pyrazole, imidazole and benzotriazole, acid anhydrides such as acetic anhydride, propionic anhydride and butyric anhydride, Acid azide, diethoxyphosphate, diphenoxyphosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide , Esters with 1-hydroxybenzotriazole, esters with 6-chloro-1-hydroxybenzotriazole, esters with 1-hydroxy-1H-2-pyridone, 2-pyridylthioester, 2-benzothia Like activity thioesters such as Li thioester thereof. Instead of using the reactive derivative, the carboxylic acid or a salt thereof may be directly reacted with the compound (18) in the presence of a suitable condensing agent. As the condensing agent, for example, N, N′-disubstituted carbodiimides such as N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride, N, N′— Azolides such as carbonyldiimidazole, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, 2-chloromethylpyridinium iodide, 2-fluoro-1-methyl And 2-halogenopyridinium salts such as pyridinium iodide. When these condensing agents are used, the reaction is considered to proceed through a reactive derivative of carboxylic acid. The carboxylic acid, salt thereof or reactive derivative thereof is generally used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (18). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases Or a solvent mixture thereof is preferred. When acidic substances are released by the reaction, the reaction can be performed in the presence of a deoxidizing agent for the purpose of removing them from the reaction system. Examples of such a deoxidizer include basic salts and organic bases. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 72 hr, preferably 30 min to 24 hr. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 70 ° C.
　化合物（２０ｃ）は、工程Ｃ－３に従い、化合物（１８）とイソシアネート（１９ｃ）を反応させることによって製造することができる。また、化合物（１８）の反応性誘導体に対して化合物（１９ｄ）を反応させることによっても製造することができる。該反応性誘導体としては、例えばイミダゾールなどとのカルボキサミドなどが挙げられる。また該反応性誘導体を用いる代わりに、化合物（１９ｄ）を適当な縮合剤の存在下、直接化合物（１８）と反応させても良い。該縮合剤としては、例えばホスゲン、トリホスゲンなどのホスゲン類、Ｎ，Ｎ'－カルボニルジイミダゾールなどのアゾライド類などが挙げられる。これらの縮合剤を用いた場合、反応は化合物（１８）の反応性誘導体を経て進行すると考えられる。イソシアネート（１９ｃ）または化合物（１９ｄ）は、化合物（１８）またはその反応性誘導体１モルに対し通常約１．０～５．０モル、好ましくは約１．０～２．０モル用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えばエーテル類、芳香族炭化水素類、飽和炭化水素類、アミド類、ハロゲン化炭化水素類、ニトリル類、スルホキシド類、芳香族有機塩基類などの溶媒もしくはそれらの混合溶媒などが好ましい。反応時間は用いる試薬や溶媒により異なるが通常１０分～２４時間、好ましくは３０分～４時間である。反応温度は通常０～１００℃、好ましくは０～７０℃である。また、化合物（２０ｃ）においてＲ１２基が水素原子である場合は、所望によりさらにアルキル化反応に付すこともできる。該アルキル化剤としては例えばＬ６－Ｒ１２で表される化合物が挙げられる。アルキル化反応は、工程Ｃ－１と同様の方法により行えばよい。 Compound (20c) can be produced by reacting compound (18) with isocyanate (19c) according to Step C-3. It can also be produced by reacting compound (19d) with a reactive derivative of compound (18). Examples of the reactive derivative include carboxamide with imidazole and the like. Instead of using the reactive derivative, the compound (19d) may be directly reacted with the compound (18) in the presence of a suitable condensing agent. Examples of the condensing agent include phosgenes such as phosgene and triphosgene, and azolides such as N, N′-carbonyldiimidazole. When these condensing agents are used, the reaction is considered to proceed via a reactive derivative of compound (18). The isocyanate (19c) or compound (19d) is generally used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (18) or a reactive derivative thereof. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases Or a solvent mixture thereof is preferred. While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 24 hr, preferably 30 min to 4 hr. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 70 ° C. Moreover, when R < 12 > group is a hydrogen atom in a compound (20c), it can also attach to alkylation reaction if desired. Examples of the alkylating agent include compounds represented by L 6 -R 12 . The alkylation reaction may be performed by the same method as in Step C-1.
　化合物（２０ｄ）は、工程Ｃ－４に従い、化合物（１８）とアルキル化剤（１９e）を塩基の存在下反応させることによって製造することができる。アルキル化反応は、工程Ｃ－１と同様の方法により行えばよい。 Compound (20d) can be produced by reacting compound (18) and alkylating agent (19e) in the presence of a base according to Step C-4. The alkylation reaction may be performed by the same method as in Step C-1.
　化合物（２０ｆ）は、工程Ｃ－５に従い、化合物（２０e）と化合物（１９ｆ）を縮合させることにより製造することができる。縮合反応は、工程Ｃ－２と同様の方法により行えばよい。また、化合物（２０ｆ）においてＲ１３基が水素原子である場合は、所望によりさらにアルキル化反応に付すこともできる。該アルキル化剤としては例えばＬ７－Ｒ１３で表される化合物が挙げられる。アルキル化反応は、工程Ｃ－１と同様の方法により行えばよい。 Compound (20f) can be produced by condensing compound (20e) and compound (19f) according to Step C-5. The condensation reaction may be performed by the same method as in Step C-2. Moreover, when R < 13 > group is a hydrogen atom in a compound (20f), it can also be further attached | subjected to alkylation reaction if desired. Examples of the alkylating agent include compounds represented by L 7 -R 13 . The alkylation reaction may be performed by the same method as in Step C-1.
　化合物（２０ｇ）は、工程Ｃ－６に従い、化合物（１８）と化合物（１９ｇ）を縮合させることによって製造することができる。縮合反応は、化合物（２）と化合物（３）から本発明化合物を製造する方法と同様の方法により行えばよい。 Compound (20 g) can be produced by condensing compound (18) and compound (19 g) according to Step C-6. The condensation reaction may be performed by a method similar to the method for producing the compound of the present invention from the compound (2) and the compound (3).
　化合物（２０ｈ）は、化合物（１８）から工程Ｃ－７により、公知の置換基変換反応、縮合反応、酸化反応、還元反応などを各々、単独あるいはその二以上を組み合わせて行うことによって製造することができる。これらの反応は、例えば新実験化学講座、14、15巻（日本化学会編）、オーガニック　ファンクショナル　グループ　プレパレーションズ（ORGANIC FUNCTIONAL GROUP PREPARATIONS）第２版、アカデミックプレス社（ACADEMIC PRESS, INC．）1989年刊；コンプリヘンシブ・オーガニック・トランスフォーメーション (Comprehensive Organic Transformations) VCH Publishers Inc.　1989年刊等などに記載された方法に準じて行えばよい。 Compound (20h) is produced from compound (18) by carrying out known substituent conversion reaction, condensation reaction, oxidation reaction, reduction reaction, etc., alone or in combination of two or more thereof, in Step C-7. Can do. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations (ORGANIC ア カ FUNCTIONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PRESS, INC.) Comprehensive Organic Transformation (Comprehensive Organic Transformations) VCH Publishers Inc. 1989, etc. may be used.
　化合物（３ａ－e）、（１８）、（１９ａ－ｇ）、および（２０ａ－ｈ）は、市販品を用いてもよく、自体公知の方法あるいはそれらに準じた方法によって製造することもできる。 Compounds (3a-e), (18), (19a-g), and (20a-h) may be commercially available products, or can be produced by a method known per se or a method analogous thereto.
　本発明化合物の製造法Ｂ
（反応０４） Production method B of the compound of the present invention
(Reaction 04)
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
（式中、各記号は前記のとおりである）
　本発明化合物は、化合物（２）から工程Ｄ－１、脱保護、および、工程Ｄ－２の一連の反応工程に付すことによっても製造することもできる。また、本発明化合物は、化合物（２３）から工程Ｄ－３、脱保護、工程Ｄ－５、および、工程Ｄ－７の一連の反応工程に付すことによっても製造することもできる。式中、Ｒ１４は、ハロゲン、カルボキシル基、アルデヒド基、アミノ基、Ｃ１－６アルキルカルボニル基などの置換基を表す。化合物（２１）は工程Ｄ－４に従い化合物（２４）から、化合物（２６）は工程Ｄ－６に従い化合物（３）から製造することもできる。工程Ｄ－１～Ｄ－７に例示した反応工程は、工程Ａ－１、工程Ｂ－１～Ｂ－１２、および工程Ｃ－１～Ｃ－７に例示した反応工程などを各々、単独あるいはその二以上を組み合わせることによって行うことができる。 (Wherein each symbol is as described above)
The compound of the present invention can also be produced by subjecting compound (2) to a series of reaction steps of Step D-1, deprotection, and Step D-2. The compound of the present invention can also be produced by subjecting compound (23) to a series of reaction steps of Step D-3, Deprotection, Step D-5, and Step D-7. In the formula, R 14 represents a substituent such as a halogen, a carboxyl group, an aldehyde group, an amino group, or a C 1-6 alkylcarbonyl group. Compound (21) can also be produced from compound (24) according to step D-4, and compound (26) from compound (3) according to step D-6. The reaction steps exemplified in Steps D-1 to D-7 are the reaction steps exemplified in Step A-1, Steps B-1 to B-12, and Steps C-1 to C-7, etc. This can be done by combining two or more.
　化合物（１８ｂ）、（２１）、（２２）、（２３）、（２４）、（２５）、および（２６）は、市販品を用いてもよく、自体公知の方法あるいはそれらに準じた方法によって製造することもできる。 As the compounds (18b), (21), (22), (23), (24), (25), and (26), commercially available products may be used, and by a method known per se or a method analogous thereto. It can also be manufactured.
　本発明化合物は、配置異性体または立体異性体の単独、またはそれらの混合物として製造することができる。これらの異性体は、自体公知の合成手法、分離手法（例、濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶など）、光学分割手法（例、分別再結晶法、キラルカラム法、ジアステレオマー法など）などによりそれぞれを単品として得ることができる。また新実験化学講座、14巻、251-253頁（日本化学会編）、第4版実験化学講座、19巻、273-274頁（日本化学会編）などに記載の方法およびそれに準じた方法に従って、加熱、酸触媒、遷移金属錯体、金属触媒、ラジカル種触媒、光照射あるいは強塩基触媒などにより所望の異性体に変換することもできる。 The compound of the present invention can be produced as a configurational isomer or stereoisomer alone or as a mixture thereof. These isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) And the like can be obtained individually. In addition, the method described in the New Experimental Chemistry Course, Vol. 14, pp. 251-253 (edited by the Chemical Society of Japan), the 4th edition Experimental Chemistry Course, Vol. 19, pages 273-274 (edited by the Chemical Society of Japan), etc. Accordingly, the compound can be converted to a desired isomer by heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation or a strong base catalyst.
　前記の化合物（２）～（２６）のうち配置異性体を有するものについては、異性化が生じた時点で、例えば抽出、再結晶、蒸留、クロマトグラフィーなどの通常の分離手段により単離、精製することができ、純粋な化合物を製造することができる。また新実験化学講座、14巻、51-253頁（日本化学会編）、第4版実験化学講座、19巻、273-274頁（日本化学会編）などに記載の方法およびそれに準じた方法に従って、加熱、酸触媒、遷移金属錯体、金属触媒、ラジカル種触媒、光照射あるいは強塩基触媒などにより二重結合の異性化を進行させ、対応する純粋な異性体を得ることもできる。本発明化合物は置換基の種類によっては立体異性体が生ずるが、この異性体単独のみならず、それらの混合物も本発明に含まれる。上記の反応工程において、さらに所望により、公知の加水分解反応、脱保護反応、アシル化反応、アルキル化反応、水素添加反応、酸化反応、還元反応、炭素鎖延長反応、置換基交換反応、縮合反応などを各々、単独あるいはその二以上を組み合わせて行うことによっても本発明化合物を製造することができる。これらの反応は、例えば新実験化学講座、14、15巻（日本化学会編）、オーガニック　ファンクショナル　グループ　プレパレーションズ（ORGANIC FUNCTIONAL GROUP PREPARATIONS）第２版、アカデミックプレス社（ACADEMIC PRESS, INC．）1989年刊；コンプリヘンシブ・オーガニック・トランスフォーメーション (Comprehensive Organic Transformations) VCH Publishers Inc.　1989年刊等などに記載された方法に準じて行えばよい。
　本発明化合物は、公知の手段、例えば、転溶、濃縮、溶媒抽出、分溜、液性変換、晶出、再結晶、クロマトグラフィーなどによって単離、精製することができる。 Of the compounds (2) to (26), those having configurational isomers are isolated and purified by usual separation means such as extraction, recrystallization, distillation, chromatography, etc., when isomerization occurs. And pure compounds can be produced. In addition, the method described in the New Experimental Chemistry Course, Volume 14, pages 51-253 (Edition of the Chemical Society of Japan), Fourth Edition Experimental Chemistry Course, Volume 19, pages 273-274 (Edition of the Chemical Society of Japan), etc. Accordingly, the isomerization of the double bond can proceed by heating, acid catalyst, transition metal complex, metal catalyst, radical species catalyst, light irradiation or strong base catalyst, and the corresponding pure isomer can be obtained. The compound of the present invention may have a stereoisomer depending on the type of substituent, and not only this isomer alone but also a mixture thereof is also included in the present invention. In the above reaction step, a known hydrolysis reaction, deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, substituent exchange reaction, condensation reaction may be performed as desired. The compounds of the present invention can also be produced by performing each of these alone or in combination of two or more thereof. These reactions are described in, for example, New Experimental Chemistry Course, Volumes 14 and 15 (edited by the Chemical Society of Japan), Organic Functional Group Preparations, 2nd edition, ACADEMIC PRESS, INC., 1989. Comprehensive Organic Transformations VCH Publishers Inc. may be performed according to the method described in 1989 and the like.
The compound of the present invention can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractional distillation, liquid conversion, crystallization, recrystallization, chromatography and the like.
　本発明化合物が遊離化合物として得られた場合には、自体公知の方法あるいはそれに準ずる方法によって、目的とする塩に変換することができ、逆に塩で得られた場合には、自体公知の方法あるいはそれに準ずる方法により、遊離体または目的とする他の塩に変換することができる。
　本発明化合物が、光学異性体、立体異性体、位置異性体、回転異性体等の異性体を有する場合には、いずれか一方の異性体も混合物も本発明化合物に包含される。例えば、本発明化合物に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も本発明化合物に包含される。これらの異性体は、自体公知の合成手法、分離手法（例、濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶など）、光学分割手法（例、分別再結晶法、キラルカラム法、ジアステレオマー法など）などによりそれぞれを単品として得ることができる。
　本発明化合物は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても本発明化合物に包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　本発明化合物は、溶媒和物（例、水和物等）であっても、無溶媒和物（例、非水和物等）であってもよく、いずれも本発明化合物に包含される。
　同位元素（例、３Ｈ、１４Ｃ、３５Ｓ、１２５Ｉなど）などで標識された化合物も、本発明化合物に包含される。また、本発明化合物は重水素変換体であってもよい。
　本発明化合物のプロドラッグは、生体内における生理条件下で酵素、胃酸等による反応により本発明化合物に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして本発明化合物に変化する化合物、胃酸等により加水分解等を起こして本発明化合物に変化する化合物をいう。
　本発明化合物のプロドラッグとしては、本発明化合物のアミノ基がアシル化、アルキル化、リン酸化された化合物（例、本発明化合物のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、t－ブチル化された化合物等）；本発明化合物のヒドロキシル基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物（例、本発明化合物のヒドロキシル基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等）；本発明化合物のカルボキシ基がエステル化、アミド化された化合物（例、本発明化合物のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等）；等が挙げられる。これらの化合物は自体公知の方法によって本発明化合物から製造することができる。
　また、本発明化合物のプロドラッグは、医薬品の開発、第7巻 (分子設計)、163-198頁（広川書店）に記載されているような生理的条件で本発明化合物に変化するものであってもよい。 When the compound of the present invention is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, a method known per se Alternatively, it can be converted to a free form or other desired salt by a method equivalent thereto.
When the compound of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, any one of the isomers and a mixture are also included in the compound of the present invention. For example, when an optical isomer exists in the compound of the present invention, an optical isomer separated from a racemate is also encompassed in the compound of the present invention. These isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) And the like can be obtained individually.
The compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a mixture of crystal forms. Crystals can be produced by crystallization by applying a crystallization method known per se.
The compound of the present invention may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non-hydrate etc.), and both are included in the compound of the present invention.
Compounds labeled with isotopes (eg, 3 H, 14 C, 35 S, 125 I, etc.) are also encompassed in the compounds of the present invention. The compound of the present invention may be a deuterium converter.
A prodrug of the compound of the present invention is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidizes, reduces, hydrolyzes, etc. and changes to the compound of the present invention A compound that undergoes hydrolysis or the like due to a compound, gastric acid or the like and changes to the compound of the present invention.
As a prodrug of the compound of the present invention, a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated (eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.); compounds of the present invention Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethyl Aminomethylcarbonylated compounds, etc.); the carboxy group of the compound of the present invention is Compound (eg, carboxy group of the present invention is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl ester) , Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, and the like). These compounds can be produced from the compound of the present invention by a method known per se.
The prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Drug Development, Volume 7 (Molecular Design), pp. 163-198 (Hirokawa Shoten). May be.
　本発明化合物またはそのプロドラッグは、優れたアミロイドβ産生抑制活性を有し、また毒性（例、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、薬物相互作用、癌原性など）が低く、さらに、安定性および体内動態（吸収性、分布、代謝、排泄など）にも優れているので、医薬品として有用である。本発明化合物またはそのプロドラッグは、哺乳動物（例、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）に対して、アミロイドβの産生を阻害する作用を有し、アミロイドβの産生に関連する可能性のある疾患の予防・治療薬として使用できる。「アミロイドβの産生に関連する可能性のある疾患」としては、例えば、神経変性疾患（例、老年期認知症、アルツハイマー病、パーキンソン病など）、記憶障害（例、老年期認知症、軽度認知障害（ＭＣＩ）、健忘症など）、虚血性の中枢神経障害（例、脳のアミロイドアンギオパチー（ＣＡＡ）など）、ダウン症などが挙げられる。
　本発明化合物またはそのプロドラッグは、好ましくは、アミロイドβ産生抑制薬、軽度認知障害またはアルツハイマー病の予防または治療薬として有用である。 The compound of the present invention or a prodrug thereof has excellent amyloid β production inhibitory activity and has toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.) It is also useful as a pharmaceutical because it is low and has excellent stability and pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.). The compound of the present invention or a prodrug thereof has an action of inhibiting amyloid β production on mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It can be used as a prophylactic / therapeutic agent for diseases that may be related to the production of amyloid β. “Diseases that may be related to amyloid β production” include, for example, neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Parkinson's disease), memory disorders (eg, senile dementia, mild cognition) Disorders (MCI), amnesia, etc.), ischemic central nervous disorders (eg, brain amyloid angiopathy (CAA), etc.), Down's syndrome and the like.
The compound of the present invention or a prodrug thereof is preferably useful as an agent for inhibiting or treating amyloid β production, mild cognitive impairment or Alzheimer's disease.
　本発明化合物またはそのプロドラッグを含有する医薬は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、本発明化合物またはそのプロドラッグを単独で、あるいは薬理学的に許容される担体と混合して、例えば錠剤（糖衣錠、フィルムコーティング錠なども含む）、散剤、顆粒剤、カプセル剤、液剤、乳剤、懸濁剤、注射剤、坐剤、徐放剤（例、舌下錠、マイクロカプセル等）、貼布剤、口腔内崩壊錠、口腔内崩壊フィルムなどとして、経口的または非経口的（例、皮下、局所、直腸、静脈投与等）に安全に投与することができる。
　本発明化合物またはそのプロドラッグの本発明医薬中の含有量は、医薬全体の約０.０１～１００重量％である。本発明化合物またはそのプロドラッグの投与量は、投与対象、投与ルート、疾患、症状等により異なるが、例えばアルツハイマー病の治療の目的で成人患者に経口投与する場合、有効成分である本発明化合物またはそのプロドラッグとして約０.００１～約１００mg／kg体重、好ましくは約０.００５～約５０mg／kg体重、さらに好ましくは約０.０１～約２mg／kg体重であり、これらの服用量を症状に応じて１日約１～３回投与するのが望ましい。 The medicament containing the compound of the present invention or a prodrug thereof can be used alone or in accordance with a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia, etc.) For example, tablets (including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained release ( For example, sublingual tablets, microcapsules, etc.), patches, orally disintegrating tablets, orally disintegrating films, etc., orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) can do.
The content of the compound of the present invention or a prodrug thereof in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament. The dose of the compound of the present invention or a prodrug thereof varies depending on the administration subject, administration route, disease, symptom and the like. For example, when orally administered to an adult patient for the purpose of treating Alzheimer's disease, The prodrug is about 0.001 to about 100 mg / kg body weight, preferably about 0.005 to about 50 mg / kg body weight, more preferably about 0.01 to about 2 mg / kg body weight. Depending on the dose, it is desirable to administer about 1 to 3 times a day.
　上記薬理学的に許容される担体としては、製剤素材として慣用の各種有機または無機担体物質があげられ、例えば固形製剤における賦形剤、滑沢剤、結合剤および崩壊剤、または液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤および無痛化剤等があげられる。更に必要に応じ、通常の防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物を適宜、適量用いることもできる。
　賦形剤としては、例えば乳糖、白糖、Ｄ－マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸などが挙げられる。滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカなどが挙げられる。結合剤としては、例えば結晶セルロース、白糖、Ｄ－マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウムなどが挙げられる。崩壊剤としては、例えばデンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、Ｌ－ヒドロキシプロピルセルロースなどが挙げられる。溶剤としては、例えば注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油などが挙げられる。溶解補助剤としては、例えばポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウムなどが挙げられる。懸濁化剤としては、例えばステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリンなどの界面活性剤；例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースなどの親水性高分子などが挙げられる。等張化剤としては、例えばブドウ糖、 Ｄ－ソルビトール、塩化ナトリウム、グリセリン、Ｄ－マンニトールなどが挙げられる。緩衝剤としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩衝液などが挙げられる。無痛化剤としては、例えばベンジルアルコールなどが挙げられる。防腐剤としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。抗酸化剤としては、例えば亜硫酸塩、アスコルビン酸、α－トコフェロールなどが挙げられる。 Examples of the pharmacologically acceptable carrier include various organic or inorganic carrier substances that are conventionally used as pharmaceutical materials. For example, excipients, lubricants, binders and disintegrants in solid preparations, or solvents in liquid preparations. , Solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Examples of soothing agents include benzyl alcohol. Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.
　本発明化合物またはそのプロドラッグを上記各疾患に適用する際には、それら疾患に通常用いられる薬剤または治療法と適宜併用することが可能である。
　以下、本発明化合物またはそのプロドラッグと併用薬物を併用して使用することを「本発明の併用剤」と称する。
　併用薬物としては、例えばアセチルコリンエステラーゼ阻害剤（例、ドネペジル、リバスチグミン、ガランタミン等）、アミロイドβ蛋白産生、分泌、蓄積、凝集および／または沈着抑制剤、βセクレターゼ阻害剤、アミロイドβ蛋白凝集阻害作用剤、アミロイドβワクチン、アミロイドβ抗体、アミロイドβ分解酵素等、脳機能賦活薬（例、イデベノン、メマンチン、ビンポセチン等）、認知症の進行に伴う異常行動、徘徊等の治療薬（例、鎮静剤、抗不安剤等）、アルツハイマー病進展抑制薬等（アルツメッド等）、アポトーシス阻害薬、神経分化・再生促進剤、抗パーキンソン薬（例、Ｌ－ドーパ、デプレニル、カルビドパ＋レボドパ、ペルゴライド、ロピニロール、カベルゴリン、プラミペキソール、エンタカプロン、ラザベミド等）、筋萎縮性側索硬化症治療薬（例、リルゾール等、神経栄養因子等）、抗うつ薬（例、フルオキセチン、サートラリン、パロキセチン、ベンラファキシン、ネファゾドン、レボキセチン、ミルタザピン、塩酸イミプラミン、デュロキセチン、エスシタロプラム、ミフェプリストン、ドキセピン等）、抗不安薬（例、アルプラゾラム、ブロマゼパム、クロルジアゼポキシド、ジアゼパム、エチゾラム、フルトプラゼパム、ロラゼパム等）、抗てんかん薬（例、ラモトリジン等）、睡眠薬（例、ブロチゾラム、エスタゾラム、フルラゼパム、ニトラゼパム、トリアゾラム、フルニトラゼパム、ロルメタゼパム、リルマザホン、クアゼパム、ゾピクロン、エスゾピクロン、ゾルピデム、ザレプロン、インディプロン、ギャバキサドール等のＧＡＢＡ系睡眠薬；エプリバセリン、プルバンセリン、ジフェンヒドラミン、トラゾドン、ドキセピン等の非ＧＡＢＡ系睡眠薬、ラメルテオン等）、過眠症治療薬、統合失調症治療薬（例、オランザピン、リスペリドン、クエチアピン、イロペリドン等）、抗肥満薬、非ステロイド性抗炎症薬（例、インドメタシン、イブプロフェン、アセチルサリチル酸、ジクロフェナク、ナプロキセン、ピロキシカム等）、ＣＯＸ－２阻害薬（例、セレコキシブ、ロフェコキシブ等）、脳循環代謝改善薬（例、ニセルゴリン、イブジラスト、イフェンプロジル等）、疾患修飾性抗リウマチ薬（ＤＭＡＲＤｓ）、抗サイトカイン薬（ＴＮＦ阻害薬、ＭＡＰキナーゼ阻害薬など）、ステロイド薬（例、デキサメサゾン、ヘキセストロール、酢酸コルチゾン等）、尿失禁・頻尿治療剤（例、塩酸フラボキサート、塩酸オキシブチニン、塩酸プロピベリン等）、骨粗鬆症治療薬、抗高脂血症薬（例、シンバスタチン、フルバスタチン、プラバスタチン、アトロバスタチン等）、血圧降下薬（例、カプトプリル、デラプリル、エナラプリル、ニフェジピン、ニカルジピン、アムロジピン、アルプレノロール、プロプラノロール、メトプロロール、ロサルタン、バルサルタン、カンデサルタン等）、糖尿病治療薬（例、ピオグリタゾン、ロシグリタゾン、メトフォルミン、グリベンクラミド、ナテグリニド、ボグリボース等）、抗血小板薬（例、チクロピジン、ヘパリン、ウロキナーゼ、アルテプラーゼ、チソキナーゼ、ナサルプラーゼ、シロスタゾール等）、抗酸化薬（例、リノレン酸、アスコルビン酸、イコサペンタエン酸、ドコサヘキサエン酸、トコフェロール等）、ビタミン類（例、トコフェロール、アスコルビン酸等）、性ホルモン（例、エストロゲン、エストロン、エストラジオール等）、抗痙攣薬（例、カルバマゼピン、バルプロ酸、クロナゼパム、ビガバトリン、ラモトリジン、ガバペンチン等）などが挙げられる。 When the compound of the present invention or a prodrug thereof is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or a therapeutic method usually used for those diseases.
Hereinafter, the combined use of the compound of the present invention or a prodrug thereof and a concomitant drug is referred to as “the combination agent of the present invention”.
Examples of concomitant drugs include acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, etc.), amyloid β protein production, secretion, accumulation, aggregation and / or deposition inhibitors, β secretase inhibitors, amyloid β protein aggregation inhibitors , Amyloid β vaccine, amyloid β antibody, amyloid β-degrading enzyme, etc., brain function activator (eg, idebenone, memantine, vinpocetine, etc.), abnormal behavior associated with progression of dementia, therapeutic agent for epilepsy (eg, sedative, Anti-anxiety agents, etc.), Alzheimer's disease progression inhibitors, etc. (Alzmed, etc.), apoptosis inhibitors, neuronal differentiation / regeneration promoters, anti-Parkinson drugs (eg, L-dopa, deprenyl, carbidopa + levodopa, pergolide, ropinirole, cabergoline, Pramipexole, entacapron, lazabemide) Atrophic lateral sclerosis drug (eg, riluzole, etc.), antidepressant (eg, fluoxetine, sertraline, paroxetine, venlafaxine, nefazodone, reboxetine, mirtazapine, imipramine hydrochloride, duloxetine, escitalopram, mi Fepristone, doxepin, etc.), anxiolytics (eg, alprazolam, bromazepam, chlordiazepoxide, diazepam, etizolam, furtoprazepam, lorazepam, etc.), antiepileptic drugs (eg, lamotrigine, etc.) , Triazolam, flunitrazepam, lormetazepam, rilmazaphone, quazepam, zopiclone, eszopiclone, zolpidem, zaleplon, indiplon, gabaxador, etc. Hypnotics: Non-GABA hypnotics such as eprivaserin, prubanserin, diphenhydramine, trazodone, doxepin, ramelteon, etc., hypersomnia, schizophrenia (eg, olanzapine, risperidone, quetiapine, iloperidone, etc.), anti-obesity Non-steroidal anti-inflammatory drugs (eg, indomethacin, ibuprofen, acetylsalicylic acid, diclofenac, naproxen, piroxicam, etc.), COX-2 inhibitors (eg, celecoxib, rofecoxib, etc.), cerebral circulation metabolism improving drugs (eg, nicergoline, ibudilast) , Ifenprodil, etc.), disease-modifying anti-rheumatic drugs (DMARDs), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), steroid drugs (eg, dexamethasone, hexestrol, cortisone acetate), urinary incontinence / frequency Urine treatment (eg, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride, etc.), osteoporosis treatment, antihyperlipidemic (eg, simvastatin, fluvastatin, pravastatin, atorvastatin, etc.), antihypertensive (eg, captopril, Delapril, enalapril, nifedipine, nicardipine, amlodipine, alprenolol, propranolol, metoprolol, losartan, valsartan, candesartan, etc.), antidiabetic drugs (eg, pioglitazone, rosiglitazone, metformin, glibenclamide, nateglinide, antiplatelet) (Eg, ticlopidine, heparin, urokinase, alteplase, thisokinase, nasarplase, cilostazol, etc.), antioxidants (eg, linolenic acid, ascorbic acid, icosapenta) Acid, docosahexaenoic acid, tocopherol, etc.), vitamins (eg, tocopherol, ascorbic acid, etc.), sex hormones (eg, estrogen, estrone, estradiol, etc.), anticonvulsants (eg, carbamazepine, valproic acid, clonazepam, vigabatrin, Lamotrigine, gabapentin, etc.).
　本発明化合物またはそのプロドラッグと併用薬物とを組み合わせることにより、
（1）本発明化合物またはそのプロドラッグ、あるいは併用薬物を単独で投与する場合に比べて、その投与量を軽減することができる、
（2）患者の症状（軽症、重症など）に応じて、併用薬物を選択することができる、
（3）本発明化合物またはそのプロドラッグと作用機序が異なる併用薬物を選択することにより、治療期間を長く設定することができる、
（4）本発明化合物またはそのプロドラッグと作用機序が異なる併用薬物を選択することにより、治療効果の持続を図ることができる、
（5）本発明化合物またはそのプロドラッグと併用薬物とを併用することにより、相乗効果が得られる、などの優れた効果を得ることができる。 By combining the compound of the present invention or a prodrug thereof and a concomitant drug,
(1) The dose can be reduced compared to the case where the compound of the present invention or a prodrug thereof, or a concomitant drug is administered alone.
(2) Concomitant drugs can be selected according to the patient's symptoms (mild, severe, etc.)
(3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the treatment period can be set longer.
(4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the therapeutic effect can be sustained.
(5) By using the compound of the present invention or a prodrug thereof together with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
　本発明の併用剤は、毒性が低く、例えば、本発明化合物またはそのプロドラッグ、あるいは（および）上記併用薬物を自体公知の方法に従って、薬理学的に許容される担体と混合して医薬組成物、例えば錠剤（糖衣錠、フィルムコーティング錠なども含む）、散剤、顆粒剤、カプセル剤、液剤、乳剤、懸濁剤、注射剤、坐剤、徐放剤（例、舌下錠、マイクロカプセル等）、貼布剤、口腔内崩壊錠、口腔内崩壊フィルムなどとして、経口的または非経口的（例、皮下、局所、直腸、静脈投与等）に安全に投与することができる。
　本発明の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、製剤素材として慣用の各種有機または無機担体物質があげられ、例えば固形製剤における賦形剤、滑沢剤、結合剤および崩壊剤、または液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤および無痛化剤等があげられる。更に必要に応じ、通常の防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物を適宜、適量用いることもできる。 The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention or a prodrug thereof, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se. For example, tablets (including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.) It can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) as a patch, orally disintegrating tablet, orally disintegrating film and the like.
Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients and lubricants in solid preparations. , Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
　本発明の併用剤の使用に際しては、本発明化合物またはそのプロドラッグと併用薬物の投与時期は限定されず、本発明化合物またはそのプロドラッグあるいはその医薬組成物と、併用薬物またはその医薬組成物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。 When using the concomitant drug of the present invention, the timing of administration of the compound of the present invention or a prodrug thereof and the concomitant drug is not limited, and the compound of the present invention or prodrug thereof or a pharmaceutical composition thereof, and the concomitant drug or pharmaceutical composition thereof May be administered to the administration subject at the same time or may be administered with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
　本発明の併用剤の投与形態は、特に限定されず、投与時に、本発明化合物と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、（1）本発明化合物またはそのプロドラッグと併用薬物とを同時に製剤化して得られる単一の製剤の投与、
（2）本発明化合物またはそのプロドラッグと併用薬物とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、
（3）本発明化合物またはそのプロドラッグと併用薬物とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、
（4）本発明化合物またはそのプロドラッグと併用薬物とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、
（5）本発明化合物またはそのプロドラッグと併用薬物とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例、本発明化合物またはそのプロドラッグ；併用薬物の順序での投与、または逆の順序での投与など）などが挙げられる。 The administration form of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention or a prodrug thereof and a concomitant drug,
(2) Co-administration of two preparations obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug by the same administration route,
(3) Administration of the two compounds obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug with a time difference in the same administration route,
(4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention or a prodrug thereof and a concomitant drug at different administration routes (eg, the compound of the present invention or a prodrug thereof; concomitant use) Administration in the order of drugs, or administration in the reverse order, etc.).
　本発明の併用剤における本発明化合物またはそのプロドラッグと併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。
　例えば、本発明の併用剤における本発明化合物またはそのプロドラッグの含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１～１００重量％、好ましくは約０．１～５０重量％、さらに好ましくは約０．５～２０重量％である。
　本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１～１００重量％、好ましくは約０．１～５０重量％、さらに好ましくは約０．５～２０重量％である。
　本発明の併用剤における担体等の添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１～９９．９９重量％、好ましくは約１０～９０重量％である。
　また、本発明化合物またはそのプロドラッグおよび併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 The compounding ratio of the compound of the present invention or a prodrug thereof and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound of the present invention or a prodrug thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 0.1% by weight based on the whole preparation. 50% by weight, more preferably about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
Further, when the compound of the present invention or a prodrug thereof and a concomitant drug are formulated separately, the same content may be used.
　本発明は、さらに以下の参考例、実施例、製剤例および試験例によって詳しく説明されるが、これらの例は単なる実施例であって、本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention is further explained in detail by the following reference examples, examples, formulation examples and test examples, but these examples are merely examples and do not limit the present invention, and the scope of the present invention. You may change in the range which does not deviate from.
　実施例に記載した化合物の構造式において「－Ｎ－」とある部分は、「－ＮＨ－」を示す場合がある。
　また、実施例中の記号は次のような意味である。
　ＮＭＲ　　　　　：核磁気共鳴スペクトル（特記なき限り、「ＮＭＲ」は「１Ｈ－ＮＭＲ」を示す）
　ｓ　　　　　　　：シングレット（ｓｉｎｇｌｅｔ）
　ｄ　　　　　　　：ダブレット（ｄｏｕｂｌｅｔ）
　ｔ　　　　　　　：トリプレット（ｔｒｉｐｌｅｔ）
　ｑ　　　　　　　：クワルテット（ｑｕａｒｔｅｔ）
　ｑｕｉｎ　　　　：クインテット（ｑｕｉｎｔｅｔ）
　ｄｄ　　　　　　：ダブル　ダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）
　ｔｄ　　　　　　：トリプル　ダブレット（ｔｒｉｐｌｅ　ｄｏｕｂｌｅｔ）
　ｄｔ　　　　　　：ダブル　トリプレット（ｄｏｕｂｌｅ　ｔｒｉｐｌｅｔ）
　ｍ　　　　　　　：マルチプレット（ｍｕｌｔｉｐｌｅｔ）
　ｂｒ　　　　　　：ブロード（ｂｒｏａｄ）
　ｂｒｓ　　　　　：ブロード　シングレット（ｂｒｏａｄ　ｓｉｎｇｌｅｔ）
　Ｊ　　　　　　　：カップリング定数（ｃｏｕｐｌｉｎｇ　ｃｏｎｓｔａｎｔ）
　ＴＨＦ　　　　　：テトラヒドロフラン
　ＭｅＯＨ　　　　：メタノール
　ＤＭＦ　　　　　：Ｎ，Ｎ－ジメチルホルムアミド
　ＤＭＳＯ　　　　：ジメチルスルホキシド
　ＬＣ／ＭＳ　　　：液体クロマトグラフィー－質量分析スペクトル
　ＥＳＩ　　　　　：エレクトロスプレーイオン化法
　［Ｍ＋Ｈ］＋　　　：分子イオンピーク
　ＴＦＡ　　　　　：トリフルオロ酢酸
　Ｍ　　　　　　　：モル濃度
　Ｎ　　　　　　　：規定濃度
　ＤＭＴ－ＭＭ　　：４－（４，６－ジメトキシ［１．３．５］トリアジン－２－イル）－４－メチルモルホリニウム　クロリド
　ＷＳＣ　　　　　：Ｎ－（３－ジメチルアミノプロピル）－Ｎ’－エチルカルボジイミド塩酸塩
　ＨＯＢｔ　　　　：１－ヒドロキシベンゾトリアゾール一水和物
　ＤＥＰＣ　　　　：シアノリン酸ジエチル
　ＩＰＥ　　　　　：ジイソプロピルエーテル
　Ｐｄ／Ｃ　　　　：１０％パラジウムカーボン（５０％含水）
　ＤａｖｅＰｈｏｓ：２－ジシクロヘキシルホスフィノ－２’－（Ｎ，Ｎ－ジメチルアミノ）ビフェニル
　Ｘａｎｔｐｈｏｓ：４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン
　ＣＤＩ　　　　　：Ｎ，Ｎ－カルボニルジイミダゾール
　ＨＡＴＵ　　　　：２－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－ヘキサフルオロホスフェイト
　ＤＭＡ　　　　　：ジメチルアセトアミド
　ＤＭＥ　　　　　：１，２－ジメトキシエタン
　ＥｔＯＨ　　　　：エタノール
　Ｐｄ２（ｄｂａ）３：トリス（ジベンジリデンアセトン）ジパラジウム
　Ｐｄ（ＰＰｈ３）４：テトラキストリフェニルホスフィンパラジウム
　ＨＰＬＣ　　　　：高速液体クロマトグラフィー
　ＵＶ　　　　　　：紫外線
　ｑｕａｎｔ．　　：定量的 In the structural formulas of the compounds described in the examples, a portion with “—N—” sometimes represents “—NH—”.
Moreover, the symbol in an Example has the following meaning.
NMR: Nuclear magnetic resonance spectrum (“NMR” means “ 1 H-NMR” unless otherwise specified)
s: singlet
d: doublet
t: triplet
q: quartet
quint: quintet
dd: double doublet (double doublet)
td: triple doublet (triple doublet)
dt: double triplet (double triplet)
m: multiplet
br: broad
brs: broad singlet
J: Coupling constant
THF: Tetrahydrofuran MeOH: Methanol DMF: N, N-dimethylformamide DMSO: Dimethyl sulfoxide LC / MS: Liquid chromatography-mass spectrometry spectrum ESI: Electrospray ionization method [M + H] + : Molecular ion peak TFA: Trifluoroacetic acid M: Molar concentration N: Normal concentration DMT-MM: 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride WSC: N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole monohydrate DEPC: diethyl cyanophosphate IPE: diisopropyl ether Pd / C: 10% palladium carbon ( 50% water content)
DavePhos: 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene CDI: N, N-carbonyldiimidazole HATU: 2- (7-azabenzotriazol-1-yl) -1,1,3,3-hexafluorophosphate DMA: dimethylacetamide DME: 1,2-dimethoxyethane EtOH: ethanol Pd 2 (dba) 3 : Tris ( Dibenzylideneacetone) dipalladium Pd (PPh 3 ) 4 : tetrakistriphenylphosphine palladium HPLC: high performance liquid chromatography UV: ultraviolet quant. :quantitative
　実施例、参考例のカラムクロマトグラフィーにおける溶出は、ＴＬＣ（Ｔｈｉｎ　Ｌａｙｅｒ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，薄層クロマトグラフィー）による観察下に行なわれた。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍｅｒｃｋ）社製の６０Ｆ２５４または富士シリシア化学社製のＮＨを、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を、検出法としてＵＶ検出器を採用した。カラム用シリカゲルは同じくメルク社製のキーゼルゲル６０（７０ないし２３０メッシュ）、キーゼルゲル６０（２３０ないし４００メッシュ）または、ＭＯＲＩＴＥＸ社Ｐｕｒｉｆ－Ｐａｃｋを用いた。カラム用塩基性シリカゲル（ＮＨシリカゲル）は富士シリシア化学社製の塩基性シリカＮＨ－ＤＭ１０２０（１００ないし２００メッシュ）または、ＭＯＲＩＴＥＸ社Ｐｕｒｉｆ－Ｐａｃｋを用いた。ＮＭＲスペクトルは内部又は外部基準としてテトラメチルシランを用いてＢｒｕｋｅｒ　ＡＶＡＮＣＥ－３００型またはＶａｒｉａｎ　ＶＮＭＲＳ－４００型スペクトロメーターで測定し、化学シフトをδ値で、カップリング定数をＨｚで示した。混合溶媒においてカッコ内に示した数値は各溶媒の容量混合比である。また溶液における％は溶液１００ｍＬ中のｇ数を表わす。室温とあるのは通常約１０℃から３０℃の温度を意味する。 Elution in column chromatography of Examples and Reference Examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, 60F 254 manufactured by Merck or NH manufactured by Fuji Silysia Chemical Co. is used as a TLC plate, and a solvent used as an elution solvent in column chromatography is used as a developing solvent, and a UV detector is used as a detection method. It was adopted. As column silica gel, Kieselgel 60 (70 to 230 mesh), Kieselgel 60 (230 to 400 mesh), or Moritex Purif-Pack manufactured by Merck was used. As the basic silica gel for the column (NH silica gel), basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silysia Chemical Ltd. or Purite-Pack manufactured by MORITEX was used. NMR spectra were measured with a Bruker AVANCE-300 or Varian VNMRS-400 spectrometer using tetramethylsilane as an internal or external reference, chemical shifts expressed as δ values, and coupling constants expressed in Hz. The numerical value shown in parentheses in the mixed solvent is the volume mixing ratio of each solvent. Further,% in the solution represents the number of grams in 100 mL of the solution. Room temperature usually means a temperature of about 10 ° C to 30 ° C.
　実施例１～１１７、６６８～９６７および参考例におけるＬＣ／ＭＳは、以下１．～５．のいずれかの条件により測定した。
１．
測定機器：ウォーターズ社　ＬＣ／ＭＳシステム
カラム：ＣＡＰＣＥＬＬＰＡＫ　Ｃ１８、Ｓ－３μｍ、１．５×３．５ｍｍ（資生堂）
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、２．００分（Ａ液／Ｂ液＝５／９５）、２．７５分（Ａ液／Ｂ液＝５／９５）、２．７６分（Ａ液／Ｂ液＝９０／１０）、３．４５分（Ａ液／Ｂ液＝９０／１０）
注入量：１０μＬ、流速：０．５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
ＭＳ条件　イオン化法：ＥＳＩ
２．
測定機器：アジレント社　ＬＣ／ＭＳシステム
カラム：ＺＯＲＢＡＸ　Ｃ１８、Ｓ－１．８μｍ、３．０×３０ｍｍ（アジレント社）
溶媒：Ａ液；１０ｍＭ酢酸アンモニウム含有水、Ｂ液；１０ｍＭ酢酸アンモニウム含有セトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、２．００分（Ａ液／Ｂ液＝５／９５）、２．７５分（Ａ液／Ｂ液＝５／９５）、２．７６分（Ａ液／Ｂ液＝９０／１０）、３．４５分（Ａ液／Ｂ液＝９０／１０）
注入量：１０μＬ、流速：１．２ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
ＭＳ条件　イオン化法：ＥＳＩ
３．
測定機器：マイクロマス社　Ｑｕａｔｔｒｏ　Ｍｉｃｒｏおよびアジレントテクノロジー社　ＨＰ１１００、あるいは島津製作所　高速液体クロマトグラフ質量分析計ＬＣＭＳ－２０１０Ａ、あるいはウォーターズ社　ＭＵＸシステム（マイクロマス社　ＺＱ）
カラム：ＣＡＰＣＥＬＬＰＡＫ　Ｃ１８　ＵＧ－１２０、１．５×３５ｍｍ（資生堂）、あるいはＤＥＶＥＬＯＳＩＬ　ＣＯＭＢＩ－ＲＰ－５．２×３５ｍｍ（野村化学）
溶媒：Ａ液；５ｍＭ酢酸アンモニウム／２％アセトニトリル／水、Ｂ液；５ｍＭ酢酸アンモニウム／９５％アセトニトリル／水
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝１００／０）、２．００分（Ａ液／Ｂ液＝０／１００）、３．００分（Ａ液／Ｂ液＝０／１００）、３．０１分（Ａ液／Ｂ液＝１００／０）、３．８０分（Ａ液／Ｂ液＝１００／０）
注入量：１０μＬ、流速：０．５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
ＭＳ条件　イオン化法：ＥＳＩ
４．
測定機器：ウォーターズ社　ＭＵＸ　搭載４－ｃｈ　ＬＣ／ＭＳ　システム
カラム：ＣＡＰＣＥＬＬ　ＰＡＫ　Ｃ１８　ＵＧ－１２０、Ｓ－３μｍ、１．５×３５ｍｍ（資生堂）
溶媒：Ａ液；５ｍＭ酢酸アンモニウム含有水、Ｂ液；５ｍＭ酢酸アンモニウム含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝１００／０）、２．００分（Ａ液／Ｂ液＝０／１００）、３．００分（Ａ液／Ｂ液＝０／１００）、３．０１分（Ａ液／Ｂ液＝１００／０）、３．３０分（Ａ液／Ｂ液＝１００／０）
注入量：２μＬ、流速：０．５ｍＬ／ｍｉｎ、検出法：ＵＶ　２２０ｎｍ
イオン化法：ＥＳＩ
５．
ＨＰＬＣ部：アジレント　１２００
ＭＳ部：アジレント　６３００
カラム：Ｗｅｌｃｈｒｏｍ　ＸＢ－Ｃ１８、５μｍ、４．６×５０ｍｍ
溶媒：Ａ液；水、Ｂ液；アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９５／５）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）；または０．００分（Ａ液／Ｂ液＝９０／１０）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）；または０．００分（Ａ液／Ｂ液＝８０／２０）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）；または０．００分（Ａ液／Ｂ液＝７０／３０）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）；または０．００分（Ａ液／Ｂ液＝６０／４０）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）；または０．００分（Ａ液／Ｂ液＝５０／５０）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）；または０．００分（Ａ液／Ｂ液＝４０／６０）、６．００分（Ａ液／Ｂ液＝５／９５）、６．５０分（Ａ液／Ｂ液＝５／９５）
流速：１．５ｍＬ／ｍｉｎ、検出法：ＵＶ２１４または２５４ｎｍ
イオン化法：ＥＳＩ
実施例１８９におけるＬＣ／ＭＳ分析は、以下の条件により測定した。
測定機器：ウォーターズ社　ＬＣ／ＭＳシステム
ＨＰＬＣ部：アジレント社　ＨＰ１１００
ＭＳ部：マイクロマス社　ＺＭＤ
カラム：ＣＡＰＣＥＬＬ　ＰＡＫ　Ｃ１８　ＵＧ１２０、Ｓ－３μｍ、１．５×３５ｍｍ（資生堂）
溶媒：Ａ液；０．０５％ＴＦＡ含有水、Ｂ液；０．０４％ＴＦＡ含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、２．００分（Ａ液／Ｂ液＝５／９５）、２．７５分（Ａ液／Ｂ液＝５／９５）、２．７６分（Ａ液／Ｂ液＝９０／１０）、３．６０分（Ａ液／Ｂ液＝９０／１０）
注入量：２μＬ、流速：０．５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍＭＳ条件　イオン化法：ＥＳＩ
実施例２３７におけるＬＣ／ＭＳ分析は以下の条件により測定した。
測定機器：ウォーターズ社　ＬＣ／ＭＳシステム
ＨＰＬＣ部：アジレント社　ＨＰ１１００
ＭＳ部：マイクロマス社　ＺＭＤ
カラム：ＣＡＰＣＥＬＬ　ＰＡＫ　Ｃ１８　ＵＧ１２０、Ｓ－３μｍ、１．５×３５ｍｍ（資生堂）
溶媒：Ａ液；０．０５％ＴＦＡ含有水、Ｂ液；０．０４％ＴＦＡ含有アセトニトリルグラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、２．００分（Ａ液／Ｂ液＝５／９５）、２．７５分（Ａ液／Ｂ液＝５／９５）、２．７６分（Ａ液／Ｂ液＝９０／１０）、３．６０分（Ａ液／Ｂ液＝９０／１０）
注入量：２μＬ、流速：０．５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍＭＳ条件　イオン化法：ＥＳＩ LC / MS in Examples 1 to 117, 668 to 967, and Reference Examples are as follows. ~ 5. The measurement was performed under any of the following conditions.
1.
Measuring instrument: Waters LC / MS system Column: CAPCELLPAK C18, S-3 μm, 1.5 × 3.5 mm (Shiseido)
Solvent: A liquid; 0.1% trifluoroacetic acid-containing water, B liquid; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 90/10), 2.00 Minutes (A liquid / B liquid = 5/95), 2.75 minutes (A liquid / B liquid = 5/95), 2.76 minutes (A liquid / B liquid = 90/10), 3.45 minutes ( A liquid / B liquid = 90/10)
Injection volume: 10 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm
MS conditions Ionization method: ESI
2.
Measuring instrument: Agilent LC / MS system column: ZORBAX C18, S-1.8 μm, 3.0 × 30 mm (Agilent)
Solvent: A solution; 10 mM ammonium acetate-containing water, B solution; 10 mM ammonium acetate-containing cetonitrile gradient cycle: 0.00 minutes (A solution / B solution = 90/10), 2.00 minutes (A solution / B solution) = 5/95), 2.75 minutes (liquid A / liquid B = 5/95), 2.76 minutes (liquid A / liquid B = 90/10), 3.45 minutes (liquid A / liquid B = 90) / 10)
Injection volume: 10 μL, flow rate: 1.2 mL / min, detection method: UV 220 nm
MS conditions Ionization method: ESI
3.
Measuring instrument: Micromass Quattro Micro and Agilent Technologies HP1100, or Shimadzu high performance liquid chromatograph mass spectrometer LCMS-2010A, or Waters MUX system (Micromass ZQ)
Column: CAPCELLPAK C18 UG-120, 1.5 × 35 mm (Shiseido), or DEVELOSIL COMBI-RP-5.2 × 35 mm (Nomura Chemical)
Solvent: A solution; 5 mM ammonium acetate / 2% acetonitrile / water, B solution; 5 mM ammonium acetate / 95% acetonitrile / water Gradient cycle: 0.00 min (A solution / B solution = 100/0), 2.00 Minutes (A liquid / B liquid = 0/100), 3.00 minutes (A liquid / B liquid = 0/100), 3.01 minutes (A liquid / B liquid = 100/0), 3.80 minutes ( A liquid / B liquid = 100/0)
Injection volume: 10 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm
MS conditions Ionization method: ESI
4).
Measuring instrument: Waters MUX on-board 4-ch LC / MS System column: CAPCELL PAK C18 UG-120, S-3μm, 1.5x35mm (Shiseido)
Solvent: A solution; 5 mM ammonium acetate-containing water, B solution; 5 mM ammonium acetate-containing acetonitrile gradient cycle: 0.00 minutes (A solution / B solution = 100/0), 2.00 minutes (A solution / B solution = 0/100), 3.00 minutes (liquid A / liquid B = 0/100), 3.01 minutes (liquid A / liquid B = 100/0), 3.30 minutes (liquid A / liquid B = 100 / 0)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm
Ionization method: ESI
5.
HPLC part: Agilent 1200
MS Department: Agilent 6300
Column: Welchrom XB-C18, 5 μm, 4.6 × 50 mm
Solvent: liquid A; water, liquid B; acetonitrile gradient cycle: 0.00 minutes (liquid A / liquid B = 95/5), 6.00 minutes (liquid A / liquid B = 5/95), 6.50 Minutes (A liquid / B liquid = 5/95); or 0.00 minutes (A liquid / B liquid = 90/10), 6.00 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A liquid / B liquid = 5/95); or 0.00 minutes (A liquid / B liquid = 80/20), 6.00 minutes (A liquid / B liquid = 5/95), 6.50 minutes ( A liquid / B liquid = 5/95); or 0.00 minutes (A liquid / B liquid = 70/30), 6.00 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A Liquid / B liquid = 5/95); or 0.00 minutes (A liquid / B liquid = 60/40), 6.00 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A liquid) / B liquid = 5/95); or 0.00 minutes (A liquid / B liquid = 50 / 0), 6.00 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A liquid / B liquid = 5/95); or 0.00 minutes (A liquid / B liquid = 40/60) ), 6.00 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A liquid / B liquid = 5/95)
Flow rate: 1.5 mL / min, detection method: UV214 or 254 nm
Ionization method: ESI
The LC / MS analysis in Example 189 was measured under the following conditions.
Measuring instrument: Waters LC / MS system HPLC part: Agilent HP1100
MS Department: Micromass ZMD
Column: CAPCELL PAK C18 UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: A liquid; 0.05% TFA-containing water, B liquid; 0.04% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 90/10), 2.00 minutes (A liquid / B liquid = 5/95), 2.75 minutes (A liquid / B liquid = 5/95), 2.76 minutes (A liquid / B liquid = 90/10), 3.60 minutes (A liquid / B (Liquid = 90/10)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm MS conditions Ionization method: ESI
The LC / MS analysis in Example 237 was measured under the following conditions.
Measuring instrument: Waters LC / MS system HPLC part: Agilent HP1100
MS Department: Micromass ZMD
Column: CAPCELL PAK C18 UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: A liquid; 0.05% TFA-containing water, B liquid; 0.04% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 90/10), 2.00 minutes (A liquid / B liquid = 5/95), 2.75 minutes (A liquid / B liquid = 5/95), 2.76 minutes (A liquid / B liquid = 90/10), 3.60 minutes (A liquid / B (Liquid = 90/10)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm MS conditions Ionization method: ESI
　また、実施例１～１１７、６６８～６９１および参考例における分取ＨＰＬＣによる精製は以下１．～６．のいずれかの条件により実施した。
１．
機器：ギルソン社セミ分取精製システム
カラム：ＹＭＣ　ＣｏｍｂｉＰｒｅｐ　Ｐｒｏ　Ｃ１８　ＲＳ、　Ｓ－５μｍ、５０×２０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、１．２０分（Ａ液／Ｂ液＝９０／１０）、４．７５分（Ａ液／Ｂ液＝０／１００）、７．３０分（Ａ液／Ｂ液＝０／１００）、７．４０分（Ａ液／Ｂ液＝９０／１０）、７．５０分（Ａ液／Ｂ液＝９０／１０）
流速：２５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
２．
機器：ウォーターズ社分取精製システム
カラム：Ｗａｔｅｒｓ　ＳｕｎＦｉｒｅ　Ｃ１８、　Ｓ－５μｍ、３０×５０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、１．２０分（Ａ液／Ｂ液＝９０／１０）、５．２０分（Ａ液／Ｂ液＝０／１００）、７．００分（Ａ液／Ｂ液＝０／１００）、７．００分（Ａ液／Ｂ液＝９０／１０）、８．５０分（Ａ液／Ｂ液＝９０／１０）
流速：７０ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
３．
機器：ウォーターズ社分取精製システム
カラム：ＹＭＣ　ＣｏｍｂｉＰｒｅｐ　ＯＤＳ－Ａ、Ｓ－５μｍ、５０×２０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９０／１０）、０．２０分（Ａ液／Ｂ液＝９０／１０）、４．２０分（Ａ液／Ｂ液＝０／１００）、６．３０分（Ａ液／Ｂ液＝０／１００）、６．３０分（Ａ液／Ｂ液＝９０／１０）、７．５０分（Ａ液／Ｂ液＝９０／１０）
流速：２５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
４．
機器：ギルソン社ハイスループット精製システム
カラム：ＣＡＰＣＥＬＬ　ＰＡＫ　Ｃ１８　ＵＧ－１２０、Ｓ－５μｍ、２０×５０ｍｍまたはＹＭＣ　ＣｏｍｂｉＰｒｅｐ　Ｈｙｄｒｏｓｐｈｅｒｅ　Ｃ１８　ＨＳ－３４０－ＣＣ、Ｓ－５μｍ、２０×５０ｍｍ（資生堂）
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９５／５）、１．１０分（Ａ液／Ｂ液＝９５／５）、５．００分（Ａ液／Ｂ液＝０／１００）、６．４０分（Ａ液／Ｂ液＝０／１００）、６．５０分（Ａ液／Ｂ液＝９５／５）
流速：２０ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
５．
機器：ギルソン社ハイスループット精製システム
カラム：　ＹＭＣ　ＣｏｍｂｉＰｒｅｐ、Ｐｒｏ　Ｃ１８　ＲＳ　　Ｓ－５μｍ、２０×５０ｍｍ（ＹＭＣ）
溶媒：Ａ液；１０ｍＭ　炭酸アンモニウム含有水、Ｂ液；アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９５／５）、１．１０分（Ａ液／Ｂ液＝９５／５）、４．６０分（Ａ液／Ｂ液＝０／１００）、６．４０分（Ａ液／Ｂ液＝０／１００）、６．５０分（Ａ液／Ｂ液＝９５／５）、６．６０分（Ａ液／Ｂ液＝９５／５）
注入量：１０００μｌ、流速：２５ｍｌ／ｍｉｎ、検出放：ＵＶ　２２０ｎｍ、２５４ｎｍ
６．
機器：ギルソン社精製システム
カラム：Ｗｅｌｃｈｒｏｍ　ＸＢ－Ｃ１８、５μｍ、１５０×２０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有アセトニトリル、Ｂ液；０．１％トリフルオロ酢酸含有水
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝１０／９０）、５．００分（Ａ液／Ｂ液＝１０／９０）、２０．００分（Ａ液／Ｂ液＝７０／３０）、２５．００分（Ａ液／Ｂ液＝７０／３０）、３０．００分（Ａ液／Ｂ液＝１０／９０）；または０．００分（Ａ液／Ｂ液＝１０／９０）、５．００分（Ａ液／Ｂ液＝１０／９０）、２０．００分（Ａ液／Ｂ液＝８０／２０）、２５．００分（Ａ液／Ｂ液＝８０／２０）、３０．００分（Ａ液／Ｂ液＝１０／９０）；など
流速：２５ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
実施例１８９における分取ＨＰＬＣ精製は以下の条件により行った。
機器：ギルソン社ハイスループット精製システム
カラム：ＹＭＣ　ＣｏｍｂｉＰｒｅｐ　Ｐｒｏ　Ｃ１８　ＲＳ　Ｓ－５μｍ、１９×５０ｍｍ
溶媒：Ａ液；０．１％ＴＦＡ含有水、Ｂ液；０．１％ＴＦＡ含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９５／５）、１．００分（Ａ液／Ｂ液＝９５／５）、５．２０分（Ａ液／Ｂ液＝０／１００）、６．４０分（Ａ液／Ｂ液＝０／１００）、６．５０分（Ａ液／Ｂ液＝９５／５）、６．６０分（Ａ液／Ｂ液＝９５／５）
流速：２０ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ
実施例２３７における分取ＨＰＬＣ精製は以下の条件により行った。
機器：ギルソン社ハイスループット精製システム
カラム：ＹＭＣ　ＣｏｍｂｉＰｒｅｐ　Ｐｒｏ　Ｃ１８　ＲＳ　Ｓ－５μｍ、１９×５０ｍｍ
溶媒：Ａ液；０．１％ＴＦＡ含有水、Ｂ液；０．１％ＴＦＡ含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液／Ｂ液＝９５／５）、１．００分（Ａ液／Ｂ液＝９５／５）、５．２０分（Ａ液／Ｂ液＝０／１００）、６．４０分（Ａ液／Ｂ液＝０／１００）、６．５０分（Ａ液／Ｂ液＝９５／５）、６．６０分（Ａ液／Ｂ液＝９５／５）
流速：２０ｍＬ／ｍｉｎ、検出法：ＵＶ２２０ｎｍ Further, purification by preparative HPLC in Examples 1 to 117, 668 to 691 and Reference Examples is as follows. ~ 6. It implemented by either of these conditions.
1.
Equipment: Gilson semi-preparative purification system Column: YMC CombiPrep Pro C18 RS, S-5 μm, 50 × 20 mm
Solvent: solution A; 0.1% trifluoroacetic acid-containing water, solution B; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (solution A / solution B = 90/10), 1.20 Minutes (A liquid / B liquid = 90/10), 4.75 minutes (A liquid / B liquid = 0/100), 7.30 minutes (A liquid / B liquid = 0/100), 7.40 minutes ( A liquid / B liquid = 90/10), 7.50 minutes (A liquid / B liquid = 90/10)
Flow rate: 25 mL / min, detection method: UV 220 nm
2.
Equipment: Waters Preparative Purification System Column: Waters SunFire C18, S-5μm, 30x50mm
Solvent: solution A; 0.1% trifluoroacetic acid-containing water, solution B; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (solution A / solution B = 90/10), 1.20 Minutes (A liquid / B liquid = 90/10), 5.20 minutes (A liquid / B liquid = 0/100), 7.00 minutes (A liquid / B liquid = 0/100), 7.00 minutes ( A liquid / B liquid = 90/10), 8.50 minutes (A liquid / B liquid = 90/10)
Flow rate: 70 mL / min, detection method: UV 220 nm
3.
Equipment: Waters Preparative Purification System Column: YMC CombiPrep ODS-A, S-5 μm, 50 × 20 mm
Solvent: A liquid; 0.1% trifluoroacetic acid-containing water, B liquid; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 90/10), 0.20 Minutes (A liquid / B liquid = 90/10), 4.20 minutes (A liquid / B liquid = 0/100), 6.30 minutes (A liquid / B liquid = 0/100), 6.30 minutes ( A liquid / B liquid = 90/10), 7.50 minutes (A liquid / B liquid = 90/10)
Flow rate: 25 mL / min, detection method: UV 220 nm
4).
Equipment: Gilson High Throughput Purification System Column: CAPCELL PAK C18 UG-120, S-5 μm, 20 × 50 mm or YMC CombiPrep Hydrosphere C18 HS-340-CC, S-5 μm, 20 × 50 mm (Shiseido)
Solvent: A liquid; 0.1% trifluoroacetic acid-containing water, B liquid; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 95/5), 1.10 Minute (A liquid / B liquid = 95/5), 5.00 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes ( A liquid / B liquid = 95/5)
Flow rate: 20 mL / min, detection method: UV 220 nm
5.
Equipment: Gilson High Throughput Purification System Column: YMC CombiPrep, Pro C18 RS S-5 μm, 20 × 50 mm (YMC)
Solvent: A solution; 10 mM ammonium carbonate-containing water, B solution; acetonitrile gradient cycle: 0.00 minutes (A solution / B solution = 95/5), 1.10 minutes (A solution / B solution = 95/5) 4.60 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B liquid = 95/5), 6 60 minutes (A liquid / B liquid = 95/5)
Injection volume: 1000 μl, flow rate: 25 ml / min, detection release: UV 220 nm, 254 nm
6).
Equipment: Gilson purification system Column: Welchrom XB-C18, 5 μm, 150 × 20 mm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing acetonitrile, Solution B; 0.1% trifluoroacetic acid-containing water Gradient cycle: 0.00 min (A solution / B solution = 10/90), 5.00 Minute (A liquid / B liquid = 10/90), 20.00 minutes (A liquid / B liquid = 70/30), 25.00 minutes (A liquid / B liquid = 70/30), 30.00 minutes ( A liquid / B liquid = 10/90); or 0.00 minutes (A liquid / B liquid = 10/90), 5.00 minutes (A liquid / B liquid = 10/90), 20.00 minutes (A Liquid / B liquid = 80/20), 25.00 minutes (A liquid / B liquid = 80/20), 30.00 minutes (A liquid / B liquid = 10/90); etc. Method: UV220nm
Preparative HPLC purification in Example 189 was performed under the following conditions.
Equipment: Gilson High Throughput Purification System Column: YMC CombiPrep Pro C18 RS S-5 μm, 19 × 50 mm
Solvent: A liquid; 0.1% TFA-containing water, B liquid; 0.1% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 95/5), 1.00 minutes (A liquid / B liquid = 95/5), 5.20 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B Liquid = 95/5), 6.60 minutes (A liquid / B liquid = 95/5)
Flow rate: 20 mL / min, detection method: UV 220 nm
Preparative HPLC purification in Example 237 was performed under the following conditions.
Equipment: Gilson High Throughput Purification System Column: YMC CombiPrep Pro C18 RS S-5 μm, 19 × 50 mm
Solvent: A liquid; 0.1% TFA-containing water, B liquid; 0.1% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 95/5), 1.00 minutes (A liquid / B liquid = 95/5), 5.20 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B Liquid = 95/5), 6.60 minutes (A liquid / B liquid = 95/5)
Flow rate: 20 mL / min, detection method: UV 220 nm
実施例１
4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 1
4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　１塩酸塩(0.11 g, 0.4 mmol)のTHF(4 mL)溶液に、トリエチルアミン(0.17 mL, 1.2 mmol)及び、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(70 μL, 0.4 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をエーテル－酢酸エチルより再結晶して、題記化合物を白色固体(0.15 g, 84%)として得た。
LC/MS 441
NMR (DMSO-d6) δ: 1.51 (3 H, d, J=7.2 Hz), 2.44 (3 H, s), 3.09 - 3.25 (4 H, m), 3.38 - 3.60 (4 H, m), 5.59 - 5.77 (1 H, m), 6.95 - 7.13 (3 H, m), 7.29 (1 H, s), 7.42 - 7.63 (6 H, m), 7.79 (1 H, d, J=8.0 Hz), 7.86 - 7.99 (1 H, m), 8.09 - 8.21 (1 H, m). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine monohydrochloride (0.11 g, 0.4 mmol) in THF (4 mL) was added to triethylamine (0.17 mL, 1.2 mmol). Then, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (70 μL, 0.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-ethyl acetate to give the title compound as a white solid (0.15 g, 84%).
LC / MS 441
NMR (DMSO-d 6 ) δ: 1.51 (3 H, d, J = 7.2 Hz), 2.44 (3 H, s), 3.09-3.25 (4 H, m), 3.38-3.60 (4 H, m), 5.59-5.77 (1 H, m), 6.95-7.13 (3 H, m), 7.29 (1 H, s), 7.42-7.63 (6 H, m), 7.79 (1 H, d, J = 8.0 Hz) , 7.86-7.99 (1 H, m), 8.09-8.21 (1 H, m).
実施例２
4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[3-(トリフルオロメチル)フェニル]ピペラジン-1-カルボキサミド Example 2
4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -N- [3- (trifluoromethyl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　２塩酸塩(0.13 g, 0.4mmol)のTHF(4 mL)溶液に、トリエチルアミン(0.17 mL, 1.2 mmol)及び、3-(トリフルオロメチル)フェニルイソシアナート(55 μL, 0.4 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をエーテル－酢酸エチルより再結晶して、題記化合物を白色固体(67 mg, 39%)として得た。
LC/MS 431
NMR (DMSO-d6) δ: 2.44 (3 H, s), 3.17 - 3.30 (4 H, m), 3.46 - 3.72 (4 H, m), 7.06 (2 H, d, J=9.0 Hz), 7.23 - 7.36 (2 H, m), 7.41 - 7.63 (3 H, m), 7.71 - 7.86 (1H, m), 7.95 (1 H, t, J=2.1 Hz), 8.96 (1 H, s). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrochloride (0.13 g, 0.4 mmol) in THF (4 mL) was added to triethylamine (0.17 mL, 1.2 mmol). And 3- (trifluoromethyl) phenyl isocyanate (55 μL, 0.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-ethyl acetate to give the title compound as a white solid (67 mg, 39%).
LC / MS 431
NMR (DMSO-d 6 ) δ: 2.44 (3 H, s), 3.17-3.30 (4 H, m), 3.46-3.72 (4 H, m), 7.06 (2 H, d, J = 9.0 Hz), 7.23-7.36 (2 H, m), 7.41-7.63 (3 H, m), 7.71-7.86 (1H, m), 7.95 (1 H, t, J = 2.1 Hz), 8.96 (1 H, s).
実施例３
4-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 3
4- [4- (1-Methyl-1H-pyrazol-4-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　1-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン　１塩酸塩(42 mg, 0.15 mmol)のTHF(5 mL)溶液に、トリエチルアミン(42 μL, 0.3 mmol)及び、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(26 μL, 0.4 mmol)を加え、室温で1.5時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をジイソプロピルエーテル－酢酸エチルより再結晶して、題記化合物を白色固体(6 mg, 9%)として得た。
LC/MS 440
NMR (DMSO-d6) δ: 1.50 (3 H, d, J=6.8 Hz), 3.02 - 3.17 (4 H, m), 3.42 - 3.55 (4 H, m), 3.83 (3 H, s), 5.57 - 5.76 (1 H, m), 6.89 - 6.98 (2 H, m), 7.02 - 7.12 (1H, m), 7.40 (2 H, d, J=8.3 Hz), 7.45 - 7.63 (4 H, m), 7.73 (1 H, s), 7.79 (1 H, d, J=8.3 Hz), 7.89 - 7.95 (1 H, m), 7.98 (1 H, s), 8.16 (1 H, dd, J=8.1, 1.3 Hz). To a solution of 1- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine monohydrochloride (42 mg, 0.15 mmol) in THF (5 mL), triethylamine (42 μL, 0.3 mmol) and (S)-(+)-1- (1-naphthyl) ethyl isocyanate (26 μL, 0.4 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from diisopropyl ether-ethyl acetate to give the title compound as a white solid (6 mg, 9%).
LC / MS 440
NMR (DMSO-d 6 ) δ: 1.50 (3 H, d, J = 6.8 Hz), 3.02-3.17 (4 H, m), 3.42-3.55 (4 H, m), 3.83 (3 H, s), 5.57-5.76 (1 H, m), 6.89-6.98 (2 H, m), 7.02-7.12 (1H, m), 7.40 (2 H, d, J = 8.3 Hz), 7.45-7.63 (4 H, m ), 7.73 (1 H, s), 7.79 (1 H, d, J = 8.3 Hz), 7.89-7.95 (1 H, m), 7.98 (1 H, s), 8.16 (1 H, dd, J = 8.1, 1.3 Hz).
実施例４
N-(3,4-ジクロロベンジル)-4-[4-(5-メチルチオフェン-2-イル)フェニル]ピペラジン-1-カルボキサミド Example 4
N- (3,4-Dichlorobenzyl) -4- [4- (5-methylthiophen-2-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　1-[4-(5-メチルチオフェン-2-イル)フェニル]ピペラジン　１塩酸塩(33 mg, 0.1 mmol)のTHF(5 mL)溶液に、トリエチルアミン(56μL, 0.4 mmol)及び、3,4-ジクロロベンジルイソシアナート(15 μL, 0.1 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をジイソプロピルエーテル－酢酸エチルより再結晶して、題記化合物を白色固体(35 mg, 76%)として得た。
LC/MS 460
NMR (DMSO-d6) δ: 2.43 (3 H, s), 3.09 - 3.20 (4 H, m), 3.42 - 3.54 (4 H, m), 4.24 (2 H, d, J=5.7 Hz), 6.75 (1 H, dd, J=3.4, 1.1 Hz), 6.97 (2 H, d, J=9.1 Hz), 7.11 (1 H, d, J=3.4 Hz), 7.26 (2 H, dd, J=8.1, 2.1 Hz), 7.42 (2 H, d, J=8.7 Hz), 7.50 (1 H, d, J=2.3 Hz), 7.57 (1 H, d, J=8.3 Hz). To a solution of 1- [4- (5-methylthiophen-2-yl) phenyl] piperazine monohydrochloride (33 mg, 0.1 mmol) in THF (5 mL) was added triethylamine (56 μL, 0.4 mmol) and 3,4- Dichlorobenzyl isocyanate (15 μL, 0.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from diisopropyl ether-ethyl acetate to give the title compound as a white solid (35 mg, 76%).
LC / MS 460
NMR (DMSO-d 6 ) δ: 2.43 (3 H, s), 3.09-3.20 (4 H, m), 3.42-3.54 (4 H, m), 4.24 (2 H, d, J = 5.7 Hz), 6.75 (1 H, dd, J = 3.4, 1.1 Hz), 6.97 (2 H, d, J = 9.1 Hz), 7.11 (1 H, d, J = 3.4 Hz), 7.26 (2 H, dd, J = 8.1, 2.1 Hz), 7.42 (2 H, d, J = 8.7 Hz), 7.50 (1 H, d, J = 2.3 Hz), 7.57 (1 H, d, J = 8.3 Hz).
実施例５
N-(3,4-ジクロロベンジル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキサミド Example 5
N- (3,4-Dichlorobenzyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-1-carboxamide
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン　２臭化水素酸塩(0.20 g, 0.48 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.27 mL, 1.9 mmol)及び、3,4-ジクロロベンジルイソシアナート(71 μL, 0.48 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、題記化合物を淡緑色非定形固体(97 mg, 44%)として得た。
LC/MS 459
NMR (DMSO-d6) δ: 1.75 - 1.90 (2 H, m), 2.43 (3 H, s), 3.28 (2 H, t, J=6.0 Hz), 3.46 - 3.63 (6 H, m), 4.13 - 4.23 (2 H, m), 6.80 (2 H, d, J=9.0 Hz), 6.92 - 7.07 (2 H, m), 7.20 (1 H, s), 7.34 - 7.48 (4 H, m). To a solution of 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane dihydrobromide (0.20 g, 0.48 mmol) in THF (5 mL), Triethylamine (0.27 mL, 1.9 mmol) and 3,4-dichlorobenzyl isocyanate (71 μL, 0.48 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a pale green amorphous solid (97 mg, 44%).
LC / MS 459
NMR (DMSO-d 6 ) δ: 1.75-1.90 (2 H, m), 2.43 (3 H, s), 3.28 (2 H, t, J = 6.0 Hz), 3.46-3.63 (6 H, m), 4.13-4.23 (2 H, m), 6.80 (2 H, d, J = 9.0 Hz), 6.92-7.07 (2 H, m), 7.20 (1 H, s), 7.34-7.48 (4 H, m) .
実施例６
N-(3,4-ジクロロベンジル)-6,6-ジメチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキサミド Example 6
N- (3,4-dichlorobenzyl) -6,6-dimethyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxamide
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　6,6-ジメチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(90 mg, 0.32 mmol)のTHF(5 mL)溶液に、トリエチルアミン(45 μL, 0.32 mmol)及び、3,4-ジクロロベンジルイソシアナート(46 μL, 0.32 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、題記化合物を白色非定形固体(73 mg, 47%)として得た。
LC/MS 487
NMR (DMSO-d6) δ: 0.88 (6 H, s), 2.42 (3 H, s), 3.29 (2 H, s), 3.35 (2 H, s), 3.47 - 3.71 (4 H, m), 4.13 - 4.26 (2 H, m), 6.83 (2 H, d, J=9.0 Hz), 6.96 (1 H, t, J=5.8 Hz), 7.14 - 7.26 (2 H, m), 7.37 - 7.60 (4 H, m). To a solution of 6,6-dimethyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (90 mg, 0.32 mmol) in THF (5 mL), Triethylamine (45 μL, 0.32 mmol) and 3,4-dichlorobenzyl isocyanate (46 μL, 0.32 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a white amorphous solid (73 mg, 47%).
LC / MS 487
NMR (DMSO-d 6 ) δ: 0.88 (6 H, s), 2.42 (3 H, s), 3.29 (2 H, s), 3.35 (2 H, s), 3.47-3.71 (4 H, m) , 4.13-4.26 (2 H, m), 6.83 (2 H, d, J = 9.0 Hz), 6.96 (1 H, t, J = 5.8 Hz), 7.14-7.26 (2 H, m), 7.37-7.60 (4 H, m).
実施例７
N-(3,4-ジクロロベンジル)-4-[4-(2,4-ジメチル-1,3-チアゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 7
N- (3,4-Dichlorobenzyl) -4- [4- (2,4-dimethyl-1,3-thiazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　1-[4-(2,4-ジメチル-1,3-チアゾール-5-イル)フェニル]ピペラジン　２塩酸塩(0.19 g, 0.56 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.31 mL, 2.2 mmol)及び、3,4-ジクロロベンジルイソシアナート(82 μL, 0.56 mmol)を加え、室温で13時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物を酢酸エチルより再結晶して、題記化合物を白色固体(0.14 g, 53%)として得た。
LC/MS 475
NMR (DMSO-d6) δ: 2.34 (3 H, s), 2.59 (3 H, s), 3.11 - 3.23 (4 H, m), 3.42 - 3.56 (4 H, m), 4.24 (2 H, d, J=5.7 Hz), 7.03 (2 H, d, J=8.7 Hz), 7.20 - 7.33 (4 H, m), 7.50 (1 H, d, J=2.3 Hz), 7.57 (1 H, d, J=8.3 Hz). To a solution of 1- [4- (2,4-dimethyl-1,3-thiazol-5-yl) phenyl] piperazine dihydrochloride (0.19 g, 0.56 mmol) in THF (5 mL) was added triethylamine (0.31 mL, 2.2 mmol) and 3,4-dichlorobenzyl isocyanate (82 μL, 0.56 mmol) were added, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a white solid (0.14 g, 53%).
LC / MS 475
NMR (DMSO-d 6 ) δ: 2.34 (3 H, s), 2.59 (3 H, s), 3.11-3.23 (4 H, m), 3.42-3.56 (4 H, m), 4.24 (2 H, d, J = 5.7 Hz), 7.03 (2 H, d, J = 8.7 Hz), 7.20-7.33 (4 H, m), 7.50 (1 H, d, J = 2.3 Hz), 7.57 (1 H, d , J = 8.3 Hz).
実施例８
N-(3,4-ジクロロベンジル)-4-[4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル]ピペラジン-1-カルボキサミド Example 8
N- (3,4-Dichlorobenzyl) -4- [4- (3,5-dimethylisoxazol-4-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　1-[4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル]ピペラジン　２トリフルオロ酢酸塩(0.23 g, 0.5 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.28 mL, 2 mmol)及び、3,4-ジクロロベンジルイソシアナート(73 μL, 0.5 mmol)を加え、室温で13時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物を酢酸エチルより再結晶して、題記化合物を白色固体(0.16 g, 68%)として得た。
LC/MS 459
NMR (DMSO-d6) δ: 2.19 (3 H, s), 2.36 (3 H, s), 3.11 - 3.22 (4 H, m), 3.42 - 3.53 (4 H, m), 4.24 (2 H, d, J=6.1 Hz), 7.05 (2 H, d, J=8.7 Hz), 7.17 - 7.33 (4 H, m), 7.51 (1 H, d, J=2.3 Hz), 7.58 (1 H, d, J=8.3 Hz). 1- [4- (3,5-Dimethylisoxazol-4-yl) phenyl] piperazine ditrifluoroacetate (0.23 g, 0.5 mmol) in THF (5 mL) was added to triethylamine (0.28 mL, 2 mmol). And 3, 4- dichlorobenzyl isocyanate (73 microliters, 0.5 mmol) was added, and it stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a white solid (0.16 g, 68%).
LC / MS 459
NMR (DMSO-d 6 ) δ: 2.19 (3 H, s), 2.36 (3 H, s), 3.11-3.22 (4 H, m), 3.42-3.53 (4 H, m), 4.24 (2 H, d, J = 6.1 Hz), 7.05 (2 H, d, J = 8.7 Hz), 7.17-7.33 (4 H, m), 7.51 (1 H, d, J = 2.3 Hz), 7.58 (1 H, d , J = 8.3 Hz).
実施例９
N-(3,4-ジクロロベンジル)-4-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン-1-カルボキサミド Example 9
N- (3,4-dichlorobenzyl) -4- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　1-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン　２塩酸塩(0.15 g, 0.48 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.27 mL, 1.9 mmol)及び、3,4-ジクロロベンジルイソシアナート(71 μL, 0.48 mmol)を加え、室温で13時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をメタノールより再結晶して、題記化合物を白色固体(52 mg, 24%)として得た。
LC/MS 444
NMR (DMSO-d6) δ: 3.02 - 3.19 (4 H, m), 3.40 - 3.58 (4 H, m), 3.83 (3 H, s), 4.24 (2 H, d, J=5.7 Hz), 6.95 (2 H, d, J=8.7 Hz), 7.20 - 7.33 (2 H, m), 7.40 (2 H, d, J=8.7 Hz), 7.50 (1 H, d, J=2.3 Hz), 7.57 (1 H, d, J=8.3 Hz), 7.73 (1 H, s), 7.98 (1 H, s). To a solution of 1- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine dihydrochloride (0.15 g, 0.48 mmol) in THF (5 mL), triethylamine (0.27 mL, 1.9 mmol) and 3,4-Dichlorobenzyl isocyanate (71 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to give the title compound as a white solid (52 mg, 24%).
LC / MS 444
NMR (DMSO-d 6 ) δ: 3.02-3.19 (4 H, m), 3.40-3.58 (4 H, m), 3.83 (3 H, s), 4.24 (2 H, d, J = 5.7 Hz), 6.95 (2 H, d, J = 8.7 Hz), 7.20-7.33 (2 H, m), 7.40 (2 H, d, J = 8.7 Hz), 7.50 (1 H, d, J = 2.3 Hz), 7.57 (1 H, d, J = 8.3 Hz), 7.73 (1 H, s), 7.98 (1 H, s).
実施例１０
3-メチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 10
3-Methyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　2-メチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　２塩酸塩(0.24 g, 0.7 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.29 mL, 2.1 mmol)及び、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.15 mL, 0.77 mmol)を加え、室温で終夜攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製した後、酢酸エチル－メタノールより再結晶して、題記化合物を白色固体(0.15 g, 46%)として得た。
LC/MS 454
NMR (DMSO-d6) δ: 0.94 (3 H, d, J=6.4 Hz), 1.51 (3 H, d, J=7.2 Hz), 2.44 (3 H, s), 2.86 - 3.06 (2 H, m), 3.15 (1 H, dd, J=13.2, 3.4 Hz), 3.35 - 3.42 (1 H, m), 3.86 - 4.17 (3 H, m), 5.56 - 5.76 (1 H, m), 6.90 - 7.07 (3 H, m), 7.27 (1 H, s), 7.43 - 7.65 (6 H, m), 7.80 (1 H, d, J=7.9 Hz), 7.87 - 7.97 (1 H, m), 8.10 - 8.22 (1 H, m). To a solution of 2-methyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrochloride (0.24 g, 0.7 mmol) in THF (5 mL) was added triethylamine (0.29 mL). , 2.1 mmol) and (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.15 mL, 0.77 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane only to ethyl acetate only), and recrystallized from ethyl acetate-methanol to give the title compound as a white solid (0.15 g, 46%).
LC / MS 454
NMR (DMSO-d 6 ) δ: 0.94 (3 H, d, J = 6.4 Hz), 1.51 (3 H, d, J = 7.2 Hz), 2.44 (3 H, s), 2.86-3.06 (2 H, m), 3.15 (1 H, dd, J = 13.2, 3.4 Hz), 3.35-3.42 (1 H, m), 3.86-4.17 (3 H, m), 5.56-5.76 (1 H, m), 6.90- 7.07 (3 H, m), 7.27 (1 H, s), 7.43-7.65 (6 H, m), 7.80 (1 H, d, J = 7.9 Hz), 7.87-7.97 (1 H, m), 8.10 -8.22 (1 H, m).
実施例１１
4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1-{[(1S)-1-ナフタレン-1-イルエチル]カルバモイル}ピペラジン-2-カルボン酸メチル Example 11
4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -1-{[(1S) -1-naphthalen-1-ylethyl] carbamoyl} piperazine-2-carboxylate methyl
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　メチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-2-カルボキシラート　２塩酸塩(0.22 g, 0.6 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.25 mL, 1.8 mmol)及び、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.12 mL, 0.66 mmol)を加え、室温で終夜攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製した後、分取HPLCにて精製した。分取したフラクションを濃縮し、残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をヘキサン‐酢酸エチルより再結晶して題記化合物を白色固体(52 mg, 17%)として得た。
LC/MS 499
NMR (DMSO-d6) δ: 1.51 (3 H, d, J=6.8 Hz), 2.44 (3 H, s), 2.62 - 3.26 (3 H, m), 3.53 - 3.75 (4 H, m), 3.89 - 4.21 (2 H, m), 4.78 - 5.00 (1 H, m), 5.58 - 5.78 (1H, m), 7.00 (2 H, d, J=8.7 Hz), 7.18 (1 H, dd, J=14.4, 7.6 Hz), 7.32 (1 H, s), 7.42 - 7.66 (6 H, m), 7.74 - 7.85 (1 H, m), 7.89 - 7.99 (1 H, m), 8.06 - 8.19 (1H, m). Methyl 4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-2-carboxylate dihydrochloride (0.22 g, 0.6 mmol) in THF (5 mL) was added to triethylamine ( (0.25 mL, 1.8 mmol) and (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.12 mL, 0.66 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane only to ethyl acetate only) and then purified by preparative HPLC. The fraction collected was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (52 mg, 17%).
LC / MS 499
NMR (DMSO-d 6 ) δ: 1.51 (3 H, d, J = 6.8 Hz), 2.44 (3 H, s), 2.62-3.26 (3 H, m), 3.53-3.75 (4 H, m), 3.89-4.21 (2 H, m), 4.78-5.00 (1 H, m), 5.58-5.78 (1H, m), 7.00 (2 H, d, J = 8.7 Hz), 7.18 (1 H, dd, J = 14.4, 7.6 Hz), 7.32 (1 H, s), 7.42-7.66 (6 H, m), 7.74-7.85 (1 H, m), 7.89-7.99 (1 H, m), 8.06-8.19 (1H , m).
実施例１２
2-メチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 12
2-Methyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　3-メチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　２臭化水素酸塩(0.23 g, 0.55 mmol)のTHF(5 mL)溶液に、トリエチルアミン(0.31 mL, 2.2 mmol)及び、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.11 mL, 0.61 mmol)を加え、室温で終夜攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をエーテル－酢酸エチルより再結晶して、題記化合物を白色固体(0.19 g, 76%)として得た。
LC/MS 455
NMR (DMSO-d6) δ: 1.09 - 1.24 (3 H, m), 1.40 - 1.61 (3 H, m), 2.44 (3 H, s), 2.54 - 3.21 (4 H, m), 3.46 - 4.53 (3 H, m), 5.50 - 5.88 (1 H, m), 6.89 - 7.10 (3 H, m), 7.29 (1 H, s), 7.39 - 7.67 (6 H, m), 7.73 - 7.85 (1 H, m), 7.93 (1 H, dd, J=7.6, 1.9 Hz), 8.00 - 8.35 (1 H, m). To a solution of 3-methyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrobromide (0.23 g, 0.55 mmol) in THF (5 mL) was added triethylamine. (0.31 mL, 2.2 mmol) and (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.11 mL, 0.61 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-ethyl acetate to give the title compound as a white solid (0.19 g, 76%).
LC / MS 455
NMR (DMSO-d 6 ) δ: 1.09-1.24 (3 H, m), 1.40-1.61 (3 H, m), 2.44 (3 H, s), 2.54-3.21 (4 H, m), 3.46-4.53 (3 H, m), 5.50-5.88 (1 H, m), 6.89-7.10 (3 H, m), 7.29 (1 H, s), 7.39-7.67 (6 H, m), 7.73-7.85 (1 H, m), 7.93 (1 H, dd, J = 7.6, 1.9 Hz), 8.00-8.35 (1 H, m).
実施例１３
N-(3,4-ジクロロベンジル)-9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3,9-ジアザビシクロ[3.3.1]ノナン-3-カルボキサミド Example 13
N- (3,4-dichlorobenzyl) -9- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,9-diazabicyclo [3.3.1] nonane- 3-carboxamide
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3,9-ジアザビシクロ[3.3.1]ノナン(0.12 g, 0.38 mmol)のTHF(4 mL)溶液に、トリエチルアミン(53μL, 0.38 mmol)及び、3,4-ジクロロベンジルイソシアナート(56 μL, 0.38 mmol)を加え、室温で0.5時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製した後、ジイソプロピルエーテル－酢酸エチルより再結晶して、題記化合物を白色固体(65 mg, 33%)として得た。
LC/MS 515
NMR (DMSO-d6) δ: 1.33 - 1.55 (1 H, m), 1.56 - 1.72 (2 H, m), 1.73 - 2.18 (3 H, m), 2.43 (3 H, s), 3.03 - 3.23 (2 H, m), 3.89 (3 H, s), 3.97 - 4.19 (4 H, m), 4.26 (2 H, d, J=5.7 Hz), 6.49 - 6.68 (2 H, m), 7.10 (1 H, s), 7.17 - 7.32 (2 H, m), 7.44 (1 H, d, J=8.3 Hz), 7.50 (1 H, d, J=1.9 Hz), 7.58 (1 H, d, J=8.3 Hz). 9- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,9-diazabicyclo [3.3.1] nonane (0.12 g, 0.38 mmol) in THF (4 mL ) To the solution were added triethylamine (53 μL, 0.38 mmol) and 3,4-dichlorobenzyl isocyanate (56 μL, 0.38 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane only to ethyl acetate only), and recrystallized from diisopropyl ether-ethyl acetate to give the title compound as a white solid (65 mg, 33%).
LC / MS 515
NMR (DMSO-d 6 ) δ: 1.33-1.55 (1 H, m), 1.56-1.72 (2 H, m), 1.73-2.18 (3 H, m), 2.43 (3 H, s), 3.03-3.23 (2 H, m), 3.89 (3 H, s), 3.97-4.19 (4 H, m), 4.26 (2 H, d, J = 5.7 Hz), 6.49-6.68 (2 H, m), 7.10 ( 1 H, s), 7.17-7.32 (2 H, m), 7.44 (1 H, d, J = 8.3 Hz), 7.50 (1 H, d, J = 1.9 Hz), 7.58 (1 H, d, J = 8.3 Hz).
実施例１４
N-(3,4-ジクロロベンジル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2,2-ジメチルピペラジン-1-カルボキサミド Example 14
N- (3,4-dichlorobenzyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2,2-dimethylpiperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　ベンジル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2,2-ジメチルピペラジン-1-カルボキシラート(0.14 g, 0.32 mmol)のTHF(10 mL)溶液に、Pd/C(14 mg)を加え、水素雰囲気下室温にて終夜攪拌した。反応混合物にトリエチルアミン(45μL, 0.32 mmol)及び、3,4-ジクロロベンジルイソシアナート(47 μL, 0.32 mmol)を加え、室温で1時間攪拌した。反応混合物にトルエン(5 mL)を加え、THFを減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、題記化合物を無色非定形固体(0.11 g, 70%)として得た。
LC/MS 503
NMR (DMSO-d6) δ: 1.39 (6 H, s), 2.42 (3 H, s), 3.35 - 3.49 (4 H, m), 3.54 - 3.73 (2 H, m), 3.91 (3 H, s), 4.21 (2 H, d, J=5.7 Hz), 6.39 - 6.54 (2 H, m), 6.99 (1 H, t, J=5.8 Hz), 7.09 (1 H, s), 7.26 (1 H, dd, J=8.3, 2.3 Hz), 7.43 (1 H, d, J=8.3 Hz), 7.49 (1 H, d, J=1.9 Hz), 7.57 (1 H, d, J=8.3 Hz). Benzyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2,2-dimethylpiperazine-1-carboxylate (0.14 g, 0.32 mmol) in THF (10 To the solution was added Pd / C (14 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Triethylamine (45 μL, 0.32 mmol) and 3,4-dichlorobenzyl isocyanate (47 μL, 0.32 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Toluene (5 mL) was added to the reaction mixture, and THF was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless amorphous solid (0.11 g, 70%).
LC / MS 503
NMR (DMSO-d 6 ) δ: 1.39 (6 H, s), 2.42 (3 H, s), 3.35-3.49 (4 H, m), 3.54-3.73 (2 H, m), 3.91 (3 H, s), 4.21 (2 H, d, J = 5.7 Hz), 6.39-6.54 (2 H, m), 6.99 (1 H, t, J = 5.8 Hz), 7.09 (1 H, s), 7.26 (1 H, dd, J = 8.3, 2.3 Hz), 7.43 (1 H, d, J = 8.3 Hz), 7.49 (1 H, d, J = 1.9 Hz), 7.57 (1 H, d, J = 8.3 Hz) .
実施例１５
N-(3,4-ジクロロベンジル)-2-エチル-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 15
N- (3,4-dichlorobenzyl) -2-ethyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　ベンジル 2-エチル-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.17 g, 0.4 mmol)のTHF(10 mL)溶液に、Pd/C(10 mg)を加え、水素雰囲気下室温にて終夜攪拌した。反応混合物にトリエチルアミン(59 μL, 0.4 mmol)及び、3,4-ジクロロベンジルイソシアナート(56 μL, 0.4 mmol)を加え、室温で1時間攪拌した。反応混合物にトルエン(5 mL)を加え、THFを減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、題記化合物を無色非定形固体(0.11 g, 54%)として得た。
LC/MS 503
NMR (DMSO-d6) δ: 0.86 (3 H, t, J=7.3 Hz), 1.65 (2 H, quin, J=7.4 Hz), 2.43 (3 H, s), 2.60 - 2.79 (1 H, m), 2.85 (1 H, dd, J=12.6, 4.0 Hz), 2.99 - 3.22 (1 H, m), 3.71 (2 H, d, J=12.1 Hz), 3.79 - 4.00 (4 H, m), 4.08 (1 H, brs), 4.25 (2 H, d, J=6.8 Hz), 6.54 - 6.69 (2 H, m), 7.09 - 7.21 (2 H, m), 7.21 - 7.32 (1 H, m), 7.45 (1 H, d, J=9.0 Hz), 7.49 (1 H, d, J=2.3 Hz), 7.57 (1 H, d, J=8.3 Hz). Benzyl 2-ethyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.17 g, 0.4 mmol) in THF (10 mL) Pd / C (10 mg) was added to the solution, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Triethylamine (59 μL, 0.4 mmol) and 3,4-dichlorobenzyl isocyanate (56 μL, 0.4 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Toluene (5 mL) was added to the reaction mixture, and THF was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless amorphous solid (0.11 g, 54%).
LC / MS 503
NMR (DMSO-d 6 ) δ: 0.86 (3 H, t, J = 7.3 Hz), 1.65 (2 H, quin, J = 7.4 Hz), 2.43 (3 H, s), 2.60-2.79 (1 H, m), 2.85 (1 H, dd, J = 12.6, 4.0 Hz), 2.99-3.22 (1 H, m), 3.71 (2 H, d, J = 12.1 Hz), 3.79-4.00 (4 H, m) , 4.08 (1 H, brs), 4.25 (2 H, d, J = 6.8 Hz), 6.54-6.69 (2 H, m), 7.09-7.21 (2 H, m), 7.21-7.32 (1 H, m ), 7.45 (1 H, d, J = 9.0 Hz), 7.49 (1 H, d, J = 2.3 Hz), 7.57 (1 H, d, J = 8.3 Hz).
実施例１６
N-(3,4-ジクロロベンジル)-3-エチル-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 16
N- (3,4-dichlorobenzyl) -3-ethyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　tert-ブチル 3-エチル-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.10 g, 0.25 mmol)の酢酸エチル(2 mL)溶液に4N塩酸酢酸エチル溶液(2 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去して得られた固体のTHF(5 mL)懸濁液に、トリエチルアミン(0.11 mL, 0.75 mmol)及び、3,4-ジクロロベンジルイソシアナート(37 μL, 0.25 mmol)を加え、室温で終夜攪拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製した後、分取HPLCにて精製した。分取したフラクションを濃縮し、残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物を無色非定形固体(23 mg, 18%)として得た。
LC/MS 503
NMR (DMSO-d6) δ: 0.87 (3 H, t, J=7.4 Hz), 1.17 - 1.65 (2 H, m), 2.43 (3 H, s), 2.93 - 3.21 (3 H, m), 3.43 - 3.58 (1 H, m), 3.72 - 3.85 (1 H, m), 3.89 (3 H, s), 3.92 - 4.10 (2 H, m), 4.13 - 4.36 (2 H, m), 6.48 - 6.61 (2 H, m), 7.12 (1 H, s), 7.16 - 7.34 (2 H, m), 7.44 (1 H, d, J=9.5 Hz), 7.49 (1 H, d, J=1.9 Hz), 7.57 (1H, d, J=8.3 Hz). tert-Butyl 3-ethyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.10 g, 0.25 mmol) in ethyl acetate ( 2N solution was added 4N hydrochloric acid ethyl acetate solution (2 mL) and stirred at room temperature for 1.5 hours. Triethylamine (0.11 mL, 0.75 mmol) and 3,4-dichlorobenzyl isocyanate (37 μL, 0.25 mmol) were added to a solid THF (5 mL) suspension obtained by evaporating the solvent under reduced pressure, Stir at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) and then purified by preparative HPLC. The fraction collected was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless amorphous solid (23 mg, 18%).
LC / MS 503
NMR (DMSO-d 6 ) δ: 0.87 (3 H, t, J = 7.4 Hz), 1.17-1.65 (2 H, m), 2.43 (3 H, s), 2.93-3.21 (3 H, m), 3.43-3.58 (1 H, m), 3.72-3.85 (1 H, m), 3.89 (3 H, s), 3.92-4.10 (2 H, m), 4.13-4.36 (2 H, m), 6.48- 6.61 (2 H, m), 7.12 (1 H, s), 7.16-7.34 (2 H, m), 7.44 (1 H, d, J = 9.5 Hz), 7.49 (1 H, d, J = 1.9 Hz ), 7.57 (1H, d, J = 8.3 Hz).
実施例17
4-[3-フルオロ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 17
4- [3-Fluoro-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　tert-ブチル 4-[3-フルオロ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(140 mg, 0.40 mmol)の酢酸エチル(4.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で14時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(4 mL)に懸濁し、N-エチルジイソプロピルアミン(200 μL, 1.2 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(100 μL, 0.59 mmol)を加え、室温で1.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝2/8～8/2)で精製した。得られた固形物を酢酸エチル/ヘキサンより再結晶して、題記化合物を無色固体(150 mg, 84%(2 steps))として得た。
LC/MS 459
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 2.51 (3 H, s), 3.17 - 3.30 (4 H, m), 3.43 - 3.61 (4 H, m), 4.71 (1 H, d, J=7.5 Hz), 5.86 (1 H, quin, J=6.8 Hz), 6.61 (1H, dd, J=13.8, 2.4 Hz), 6.68 (1 H, dd, J=8.7, 2.4 Hz), 7.17 (1 H, d, J=4.1 Hz), 7.42 - 7.64 (5 H, m), 7.77 - 7.94 (2 H, m), 8.16 (1 H, d, J=8.7 Hz). tert-Butyl 4- [3-fluoro-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (140 mg, 0.40 mmol) in ethyl acetate (4.0 mL) 4N Hydrochloric acid ethyl acetate solution (2.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 14 hr. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (4 mL), and N-ethyldiisopropylamine (200 μL, 1.2 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (100 μL, 0.59 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/8 to 8/2). The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (150 mg, 84% (2 steps)).
LC / MS 459
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 2.51 (3 H, s), 3.17-3.30 (4 H, m), 3.43-3.61 (4 H, m), 4.71 ( 1 H, d, J = 7.5 Hz), 5.86 (1 H, quin, J = 6.8 Hz), 6.61 (1H, dd, J = 13.8, 2.4 Hz), 6.68 (1 H, dd, J = 8.7, 2.4 Hz), 7.17 (1 H, d, J = 4.1 Hz), 7.42-7.64 (5 H, m), 7.77-7.94 (2 H, m), 8.16 (1 H, d, J = 8.7 Hz).
実施例18
4-[6-(2-メチル-1,3-オキサゾール-5-イル)ピリジン-3-イル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 18
4- [6- (2-Methyl-1,3-oxazol-5-yl) pyridin-3-yl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　tert-ブチル 4-[6-(2-メチル-1,3-オキサゾール-5-イル)ピリジン-3-イル]ピペラジン-1-カルボキシラート(150 mg, 0.44 mmol)の酢酸エチル(4.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で2.5時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(4.0 mL)に懸濁し、N-エチルジイソプロピルアミン(220 μL, 1.3 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(110 μL, 0.66 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝4/6～酢酸エチルのみ～メタノール/酢酸エチル＝1/19)で精製した。得られた固形物を酢酸エチル/ヘキサンより再結晶して、題記化合物を無色固体(146 mg, 76%(2 steps))として得た。
LC/MS 442
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 2.51 (3 H, s), 3.44 - 3.69 (8 H, m), 4.71 (1 H, d, J=7.6 Hz), 5.74 - 5.98 (1 H, m), 6.64 (1 H, d, J=9.1 Hz), 7.05 (1 H, s), 7.41 - 7.60 (4 H, m), 7.67 (1 H, dd, J=9.1, 2.5 Hz), 7.80 (1 H, d, J=8.0 Hz), 7.85 - 7.90 (1 H, m), 8.17 (1 H, d, J=8.3 Hz), 8.42 (1 H, d, J=2.5 Hz). tert-butyl 4- [6- (2-methyl-1,3-oxazol-5-yl) pyridin-3-yl] piperazine-1-carboxylate (150 mg, 0.44 mmol) in ethyl acetate (4.0 mL) 4N Hydrochloric acid ethyl acetate solution (2.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 2.5 hr. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (4.0 mL), and N-ethyldiisopropylamine (220 μL, 1.3 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (110 μL, 0.66 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 4 / 6-ethyl acetate only-methanol / ethyl acetate = 1/19). The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (146 mg, 76% (2 steps)).
LC / MS 442
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 2.51 (3 H, s), 3.44-3.69 (8 H, m), 4.71 (1 H, d, J = 7.6 Hz) , 5.74-5.98 (1 H, m), 6.64 (1 H, d, J = 9.1 Hz), 7.05 (1 H, s), 7.41-7.60 (4 H, m), 7.67 (1 H, dd, J = 9.1, 2.5 Hz), 7.80 (1 H, d, J = 8.0 Hz), 7.85-7.90 (1 H, m), 8.17 (1 H, d, J = 8.3 Hz), 8.42 (1 H, d, J = 2.5 Hz).
実施例19
4-[5-(1-メチル-1H-ピラゾール-4-イル)ピリミジン-2-イル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 19
4- [5- (1-Methyl-1H-pyrazol-4-yl) pyrimidin-2-yl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　tert-ブチル 4-[5-(1-メチル-1H-ピラゾール-4-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート(160 mg, 0.48 mmol)の酢酸エチル(4.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3.5時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(4.0 mL)に懸濁し、N-エチルジイソプロピルアミン(240 μL, 1.4 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(120 μL, 0.71 mmol)を加え、室温で2.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝4/6～酢酸エチルのみ～メタノール/酢酸エチル＝6/94)で精製した。得られた固形物をメタノールより再結晶して、題記化合物を無色固体(140 mg, 67%(2 steps))として得た。
LC/MS 442
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 3.36 - 3.56 (4 H, m), 3.83 (4 H, t, J=4.9 Hz), 3.95 (3 H, s), 4.70 (1 H, d, J=7.6 Hz), 5.79 - 5.93 (1 H, m), 7.42 - 7.60 (5 H, m), 7.64 (1 H, s), 7.77 - 7.91 (2 H, m), 8.18 (1 H, d, J=8.7 Hz), 8.42 (2 H, s). Suspension of tert-butyl 4- [5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl] piperazine-1-carboxylate (160 mg, 0.48 mmol) in ethyl acetate (4.0 mL) To the mixture was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (4.0 mL), and N-ethyldiisopropylamine (240 μL, 1.4 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (120 μL, 0.71 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 4 / 6-ethyl acetate only-methanol / ethyl acetate = 6/94). The obtained solid was recrystallized from methanol to give the title compound as a colorless solid (140 mg, 67% (2 steps)).
LC / MS 442
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 3.36-3.56 (4 H, m), 3.83 (4 H, t, J = 4.9 Hz), 3.95 (3 H, s) , 4.70 (1 H, d, J = 7.6 Hz), 5.79-5.93 (1 H, m), 7.42-7.60 (5 H, m), 7.64 (1 H, s), 7.77-7.91 (2 H, m ), 8.18 (1 H, d, J = 8.7 Hz), 8.42 (2 H, s).
実施例20
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 20
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート (370 mg, 1.0 mmol)の酢酸エチル(1.0 mL)とメタノール(3.0 mL)の懸濁液に4N塩酸酢酸エチル溶液(5.0 mL)を加え、室温で5時間攪拌した。溶媒を減圧留去し、得られた残渣の1/3をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(170 μL, 1.0 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(87 μL, 0.50 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～酢酸エチルのみ)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(130 mg, 81%(2 steps))として得た。
LC/MS 471
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 2.50 (3 H, s), 3.23 (4 H, t, J=5.3 Hz), 3.45 - 3.62 (4 H, m), 3.92 (3 H, s), 4.71 (1 H, d, J=7.2 Hz), 5.79 - 5.94 (1 H, m), 6.45 (1 H, d, J=2.3 Hz), 6.53 (1 H, dd, J=8.7, 2.3 Hz), 7.24 (1 H, s), 7.41 - 7.64 (5 H, m), 7.74 - 7.92 (2 H, m), 8.17 (1 H, d, J=8.3 Hz).  tert-butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (370 mg, 1.0 mmol) in ethyl acetate (1.0 mL) To a suspension of methanol (3.0 mL) was added 4N hydrochloric acid ethyl acetate solution (5.0 mL), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and 1/3 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (170 μL, 1.0 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (87 μL, 0.50 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to ethyl acetate only). The residue was washed with hexane to give the title compound as a colorless amorphous solid (130 mg, 81% (2 steps)).
LC / MS 471
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 2.50 (3 H, s), 3.23 (4 H, t, J = 5.3 Hz), 3.45-3.62 (4 H, m) , 3.92 (3 H, s), 4.71 (1 H, d, J = 7.2 Hz), 5.79-5.94 (1 H, m), 6.45 (1 H, d, J = 2.3 Hz), 6.53 (1 H, dd, J = 8.7, 2.3 Hz), 7.24 (1 H, s), 7.41-7.64 (5 H, m), 7.74-7.92 (2 H, m), 8.17 (1 H, d, J = 8.3 Hz) .
実施例21
4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメチル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 21
4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethyl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメチル)フェニル]ピペラジン-1-カルボキシラート(300 mg, 0.73 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で6.5時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(190 μL, 1.1 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(95 μL, 0.55 mmol)を加え、室温で2時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝6/94)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(150 mg, 81％(2 steps))として得た。
LC/MS 509
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.8 Hz), 2.47 (3 H, s), 3.21 - 3.39 (4 H, m), 3.48 - 3.65 (4 H, m), 4.71 (1 H, d, J=7.5 Hz), 5.86 (1 H, quin, J=6.7 Hz), 7.04 (1H, dd, J=9.0, 2.6 Hz), 7.16 (1 H, d, J=2.6 Hz), 7.34 (1 H, d, J=9.0 Hz), 7.41 - 7.65 (4 H, m), 7.81 (1 H, d, J=7.9 Hz), 7.85 - 7.94 (1 H, m), 8.09 (1 H, s), 8.16 (1 H, d, J=8.3 Hz). tert-Butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethyl) phenyl] piperazine-1-carboxylate (300 mg, 0.73 mmol) Of ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 6.5 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (190 μL, 1.1 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (95 μL, 0.55 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate only to methanol / ethyl acetate = 6/94). The residue was washed with hexane to give the title compound as a colorless amorphous solid (150 mg, 81% (2 steps)).
LC / MS 509
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.8 Hz), 2.47 (3 H, s), 3.21-3.39 (4 H, m), 3.48-3.65 (4 H, m), 4.71 ( 1 H, d, J = 7.5 Hz), 5.86 (1 H, quin, J = 6.7 Hz), 7.04 (1H, dd, J = 9.0, 2.6 Hz), 7.16 (1 H, d, J = 2.6 Hz) , 7.34 (1 H, d, J = 9.0 Hz), 7.41-7.65 (4 H, m), 7.81 (1 H, d, J = 7.9 Hz), 7.85-7.94 (1 H, m), 8.09 (1 H, s), 8.16 (1 H, d, J = 8.3 Hz).
実施例22
4-[3-エトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 22
4- [3-Ethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　tert-ブチル 4-[3-エトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(270 mg, 0.71 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(180 μL, 1.1 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(92 μL, 0.53 mmol)を加え、室温で4.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝2/8～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(170 mg, 98％(2 steps))として得た。
LC/MS 485
NMR (CDCl3) δ: 1.41 (3 H, t, J=7.1 Hz), 1.70 (3 H, d, J=6.8 Hz), 2.47 (3 H, s), 3.06 - 3.30 (4 H, m), 3.36 - 3.70 (4 H, m), 4.08 (2 H, q, J=7.1 Hz), 4.70 (1 H, d, J=6.8 Hz), 5.76 - 5.95 (1 H, m), 6.42 - 6.70 (2 H, m), 7.37 - 7.64 (5 H, m), 7.76 - 7.94 (2 H, m), 8.17 (1 H, d, J=8.3 Hz), 8.52 (1 H, s). tert-butyl 4- [3-ethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (270 mg, 0.71 mmol) in ethyl acetate ( 1.0 mL) To the suspension was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (180 μL, 1.1 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (92 μL, 0.53 mmol) was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/8 to ethyl acetate alone) to give the title compound as a colorless amorphous solid (170 mg, 98% (2 steps)).
LC / MS 485
NMR (CDCl 3 ) δ: 1.41 (3 H, t, J = 7.1 Hz), 1.70 (3 H, d, J = 6.8 Hz), 2.47 (3 H, s), 3.06-3.30 (4 H, m) , 3.36-3.70 (4 H, m), 4.08 (2 H, q, J = 7.1 Hz), 4.70 (1 H, d, J = 6.8 Hz), 5.76-5.95 (1 H, m), 6.42-6.70 (2 H, m), 7.37-7.64 (5 H, m), 7.76-7.94 (2 H, m), 8.17 (1 H, d, J = 8.3 Hz), 8.52 (1 H, s).
実施例23
4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 23
4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) -3- (2,2,2-trifluoroethoxy) phenyl] -N-[(1S) -1- Naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート (390 mg, 1.1 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(290 μL, 1.7 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(150 μL, 0.86 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(220 mg, 72％(2 steps))として得た。
LC/MS 539
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.4 Hz), 2.47 (3 H, s), 3.07 - 3.34 (4 H, m), 3.41 - 3.68 (4 H, m), 4.35 (2 H, q, J=8.0 Hz), 4.71 (1 H, d, J=7.2 Hz), 5.73 - 5.96 (1 H, m), 6.47 (1 H, d, J=2.7 Hz), 6.65 (1 H, dd, J=8.7, 2.7 Hz), 7.39 - 7.65 (5 H, m), 7.81 (1 H, d, J=8.0 Hz), 7.84 - 7.92 (1 H, m), 8.16 (1 H, d, J=8.0 Hz), 8.41 (1 H, s). tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxylate ( To a suspension of 390 mg, 1.1 mmol) in ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (290 μL, 1.7 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (150 μL, 0.86 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone) to give the title compound as a colorless amorphous solid (220 mg, 72% (2 steps)).
LC / MS 539
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.4 Hz), 2.47 (3 H, s), 3.07-3.34 (4 H, m), 3.41-3.68 (4 H, m), 4.35 ( 2 H, q, J = 8.0 Hz), 4.71 (1 H, d, J = 7.2 Hz), 5.73-5.96 (1 H, m), 6.47 (1 H, d, J = 2.7 Hz), 6.65 (1 H, dd, J = 8.7, 2.7 Hz), 7.39-7.65 (5 H, m), 7.81 (1 H, d, J = 8.0 Hz), 7.84-7.92 (1 H, m), 8.16 (1 H, d, J = 8.0 Hz), 8.41 (1 H, s).
実施例24
4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメトキシ)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 24
4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethoxy) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメトキシ)フェニル]ピペラジン-1-カルボキシラート(400 mg, 0.94 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で5時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(160 μL, 1.4 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(120 μL, 0.71 mmol)を加え、室温で4時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(200 mg, 82％(2 steps))として得た。
LC/MS 525
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.8 Hz), 2.48 (3 H, s), 3.20 - 3.31 (4 H, m), 3.44 - 3.66 (4 H, m), 4.71 (1 H, d, J=7.2 Hz), 5.72 - 5.96 (1 H, m), 6.80 (1 H, m, J=1.5 Hz), 6.86 (1 H, dd, J=9.1, 2.7 Hz), 7.41 - 7.64 (5 H, m), 7.81 (1 H, d, J=8.0 Hz), 7.85 - 7.92 (1 H, m), 8.16 (1 H, d, J=8.3 Hz), 8.28 (1 H, s). tert-Butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethoxy) phenyl] piperazine-1-carboxylate (400 mg, 0.94 mmol) Of ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (160 μL, 1.4 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (120 μL, 0.71 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to ethyl acetate only). The residue was washed with hexane to give the title compound as a colorless amorphous solid (200 mg, 82% (2 steps)).
LC / MS 525
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.8 Hz), 2.48 (3 H, s), 3.20-3.31 (4 H, m), 3.44-3.66 (4 H, m), 4.71 ( 1 H, d, J = 7.2 Hz), 5.72-5.96 (1 H, m), 6.80 (1 H, m, J = 1.5 Hz), 6.86 (1 H, dd, J = 9.1, 2.7 Hz), 7.41 -7.64 (5 H, m), 7.81 (1 H, d, J = 8.0 Hz), 7.85-7.92 (1 H, m), 8.16 (1 H, d, J = 8.3 Hz), 8.28 (1 H, s).
実施例25
4-[2-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 25
4- [2-Fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　tert-ブチル 4-[2-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(320 mg, 0.81 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で6時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(210 μL, 1.2 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(91 μL, 0.52 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(170 mg, 88%(2 steps))として得た。
LC/MS 489
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.4 Hz), 2.46 (3 H, s), 3.02 - 3.19 (4 H, m), 3.44 - 3.65 (4 H, m), 3.87 (3 H, s), 4.73 (1 H, d, J=7.6 Hz), 5.86 (1 H, quin, J=6.4 Hz), 6.55 (1 H, d, J=7.2 Hz), 7.39 - 7.61 (5 H, m), 7.81 (1 H, d, J=8.0 Hz), 7.84 - 7.92 (1 H, m), 8.17 (1 H, d, J=8.3 Hz), 8.58 (1 H, s). tert-Butyl 4- [2-fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (320 mg, 0.81 mmol) 4N hydrochloric acid ethyl acetate solution (4.0 mL) was added to an ethyl acetate (1.0 mL) suspension, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (210 μL, 1.2 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (91 μL, 0.52 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-ethyl acetate alone) to give the title compound as a colorless amorphous solid (170 mg, 88% (2 steps)).
LC / MS 489
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.4 Hz), 2.46 (3 H, s), 3.02-3.19 (4 H, m), 3.44-3.65 (4 H, m), 3.87 ( 3 H, s), 4.73 (1 H, d, J = 7.6 Hz), 5.86 (1 H, quin, J = 6.4 Hz), 6.55 (1 H, d, J = 7.2 Hz), 7.39-7.61 (5 H, m), 7.81 (1 H, d, J = 8.0 Hz), 7.84-7.92 (1 H, m), 8.17 (1 H, d, J = 8.3 Hz), 8.58 (1 H, s).
実施例26
4-[3-メチル-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 26
4- [3-Methyl-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　tert-ブチル 4-[3-メチル-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(220 mg, 0.61 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(3.0 mL)を加え、室温で6時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(310 μL, 1.8 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(140 μL, 0.79 mmol)を加え、室温で5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(260 mg, 95%(2 steps))として得た。
LC/MS 455
NMR (CDCl3) δ: 1.70 (3 H, d, J=7.0 Hz), 2.16 (3 H, s), 2.47 (3 H, s), 3.15 - 3.28 (4 H, m), 3.42 - 3.64 (4 H, m), 4.72 (1 H, d, J=7.2 Hz), 5.86 (1 H, quin, J=7.0 Hz), 6.67 - 6.83 (2 H, m), 7.16 (1 H, d, J=8.7 Hz), 7.41 - 7.61 (4 H, m), 7.81 (1 H, d, J=8.0 Hz), 7.84 - 7.92 (1 H, m), 8.04 (1 H, s), 8.17 (1 H, d, J=8.3 Hz). tert-Butyl 4- [3-methyl-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (220 mg, 0.61 mmol) in ethyl acetate ( 1.0 mL) 4N hydrochloric acid ethyl acetate solution (3.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (310 μL, 1.8 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (140 μL, 0.79 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone) to give the title compound as a colorless amorphous solid (260 mg, 95% (2 steps)).
LC / MS 455
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 7.0 Hz), 2.16 (3 H, s), 2.47 (3 H, s), 3.15-3.28 (4 H, m), 3.42-3.64 ( 4 H, m), 4.72 (1 H, d, J = 7.2 Hz), 5.86 (1 H, quin, J = 7.0 Hz), 6.67-6.83 (2 H, m), 7.16 (1 H, d, J = 8.7 Hz), 7.41-7.61 (4 H, m), 7.81 (1 H, d, J = 8.0 Hz), 7.84-7.92 (1 H, m), 8.04 (1 H, s), 8.17 (1 H , d, J = 8.3 Hz).
実施例27
4-[3,5-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 27
4- [3,5-Difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine- 1-carboxamide
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　tert-ブチル 4-[3,5-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(290 mg, 0.77 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で5時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(200 μL, 1.2 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(87 μL, 0.50 mmol)を加え、室温で13.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～8/2)で精製し、題記化合物を無色非定形固体(180 mg, quant.)として得た。
LC/MS 477
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 2.49 (3 H, s), 3.21 - 3.38 (4 H, m), 3.39 - 3.66 (4 H, m), 4.71 (1 H, d, J=7.2 Hz), 5.85 (1 H, quin, J=6.8 Hz), 6.32 - 6.64 (2 H, m), 7.38 - 7.65 (4 H, m), 7.81 (1 H, d, J=7.9 Hz), 7.85 - 7.92 (1 H, m), 8.10 (1 H, s), 8.12 - 8.19 (1 H, m). Acetic acid of tert-butyl 4- [3,5-difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (290 mg, 0.77 mmol) 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the ethyl (1.0 mL) suspension, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (200 μL, 1.2 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (87 μL, 0.50 mmol) was added, and the mixture was stirred at room temperature for 13.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-8 / 2) to give the title compound as a colorless amorphous solid (180 mg, quant.).
LC / MS 477
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 2.49 (3 H, s), 3.21-3.38 (4 H, m), 3.39-3.66 (4 H, m), 4.71 ( 1 H, d, J = 7.2 Hz), 5.85 (1 H, quin, J = 6.8 Hz), 6.32-6.64 (2 H, m), 7.38-7.65 (4 H, m), 7.81 (1 H, d , J = 7.9 Hz), 7.85-7.92 (1 H, m), 8.10 (1 H, s), 8.12-8.19 (1 H, m).
実施例２８
N-(3,4-ジクロロベンジル)-4-[4-(5-メチル-1,3,4-オキサジアゾール-2-イル)フェニル]ピペラジン-1-カルボキサミド Example 28
N- (3,4-dichlorobenzyl) -4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　tert-ブチル 4-[4-(5-メチル-1,3,4-オキサジアゾール-2-イル)フェニル]ピペラジン-1-カルボキシラート(0.17 g, 0.20 mmol)のトルエン(3.0 mL)溶液にTFA(1.5 mL)を加え、室温で1時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にTHF(2.0 mL)及びトリエチルアミン(0.17 mL, 1.2 mmol)を加え、室温で1時間攪拌した。さらに、氷冷下3,4-ジクロロベンジルイソシアナート(73 μL, 0.20 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ)で精製して、題記化合物を白色非定形固体(2.0 mg, 0.9%)として得た。
LC/MS 446
NMR (DMSO-d6) δ: 2.54 (3 H, s), 3.30 (4 H, m), 3.49 (4 H, m), 4.24 (2 H, d, J=5.4 Hz), 7.09 (2 H, d, J=9.0 Hz), 7.23 (2 H, m), 7.50 (1 H, s), 7.56 (1 H, d, J=8.1 Hz), 7.78 (2 H, d, J=8.7 Hz). To a toluene (3.0 mL) solution of tert-butyl 4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] piperazine-1-carboxylate (0.17 g, 0.20 mmol) TFA (1.5 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, THF (2.0 mL) and triethylamine (0.17 mL, 1.2 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hr. Furthermore, 3,4-dichlorobenzyl isocyanate (73 μL, 0.20 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to give the title compound as a white amorphous solid (2.0 mg, 0.9%).
LC / MS 446
NMR (DMSO-d 6 ) δ: 2.54 (3 H, s), 3.30 (4 H, m), 3.49 (4 H, m), 4.24 (2 H, d, J = 5.4 Hz), 7.09 (2 H , d, J = 9.0 Hz), 7.23 (2 H, m), 7.50 (1 H, s), 7.56 (1 H, d, J = 8.1 Hz), 7.78 (2 H, d, J = 8.7 Hz) .
実施例２９
N-(3,4-ジクロロベンジル)-4-[4-(2-メチル-2H-1,2,3-トリアゾール-4-イル)フェニル]ピペラジン-1-カルボキサミド Example 29
N- (3,4-dichlorobenzyl) -4- [4- (2-methyl-2H-1,2,3-triazol-4-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　tert-ブチル 4-[4-(2-メチル-2H-1,2,3-トリアゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート(59 mg, 0.17 mmol)に4N塩酸酢酸エチル溶液(2 mL)を加え、室温で1時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にTHF(2.0 mL)及びトリエチルアミン(72 μL, 0.52 mmol)を加え、室温で1時間攪拌した。さらに、3,4-ジクロロベンジルイソシアナート(73 μL, 0.20 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を淡黄色固体(45 mg, 59%)として得た。
LC/MS 445
NMR (CDCl3) δ: 3.28 (4 H, t, J=5.1 Hz), 3.60 (4 H, t, J=5.1 Hz), 4.23 (3 H, s),
4.42 (2 H, d, J=5.4 Hz), 4.86 (1 H, t, J=5.4 Hz), 6.97 (2 H, d, J=8.7 Hz), 7.18 (1 H, dd, J=1.5 Hz, 8.1Hz), 7.40 - 7.42 (2 H, m), 7.69 (2 H, d, J=8.7 Hz), 7.74 (1 H, s). tert-Butyl 4- [4- (2-methyl-2H-1,2,3-triazol-4-yl) phenyl] piperazine-1-carboxylate (59 mg, 0.17 mmol) in 4N hydrochloric acid ethyl acetate solution (2 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, THF (2.0 mL) and triethylamine (72 μL, 0.52 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hr. Furthermore, 3,4-dichlorobenzyl isocyanate (73 μL, 0.20 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound as a pale yellow solid (45 mg, 59%).
LC / MS 445
NMR (CDCl 3 ) δ: 3.28 (4 H, t, J = 5.1 Hz), 3.60 (4 H, t, J = 5.1 Hz), 4.23 (3 H, s),
4.42 (2 H, d, J = 5.4 Hz), 4.86 (1 H, t, J = 5.4 Hz), 6.97 (2 H, d, J = 8.7 Hz), 7.18 (1 H, dd, J = 1.5 Hz) , 8.1Hz), 7.40-7.42 (2 H, m), 7.69 (2 H, d, J = 8.7 Hz), 7.74 (1 H, s).
実施例３０
4-[4-(2-エチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 30
4- [4- (2-Ethyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　tert-ブチル 4-[4-(2-エチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.10 g, 0.28 mmol)に4N塩酸酢酸エチル溶液(4 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(2.0 mL)及びトリエチルアミン(0.12 mL, 0.84 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(49 μL, 0.28 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝7/3～4/6)で精製した後、エタノールより再結晶して、題記化合物を白色固体(36 mg, 28%)として得た。
LC/MS 455
NMR (CDCl3) δ: 1.39 (3 H, t, J=7.8 Hz), 1.72 (3 H, d, J= 6.9 Hz), 2.85 (2 H, q, J=7.5 Hz), 3.22 (4 H, t, J=5.1 Hz), 3.49 - 3.59 (4 H, m), 4.73 (1 H, d, J=7.2 Hz), 5.87 (1 H, m), 6.91 (2 H, d, J=8.7 Hz), 7.07 (1 H, s), 7.45 - 7.58 (6 H, m), 7.81 (1 H, d, J=8.1 Hz), 7.88 (1 H, d, J=7.5 Hz), 8.17 (1 H, d, J=8.4 Hz). Add 4N hydrochloric acid ethyl acetate solution (4 mL) to tert-butyl 4- [4- (2-ethyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.10 g, 0.28 mmol) And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (2.0 mL) and triethylamine (0.12 mL, 0.84 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (49 μL, 0.28 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 7 / 3-4 / 6) and recrystallized from ethanol to give the title compound as a white solid (36 mg, 28%). It was.
LC / MS 455
NMR (CDCl 3 ) δ: 1.39 (3 H, t, J = 7.8 Hz), 1.72 (3 H, d, J = 6.9 Hz), 2.85 (2 H, q, J = 7.5 Hz), 3.22 (4 H , t, J = 5.1 Hz), 3.49-3.59 (4 H, m), 4.73 (1 H, d, J = 7.2 Hz), 5.87 (1 H, m), 6.91 (2 H, d, J = 8.7 Hz), 7.07 (1 H, s), 7.45-7.58 (6 H, m), 7.81 (1 H, d, J = 8.1 Hz), 7.88 (1 H, d, J = 7.5 Hz), 8.17 (1 (H, d, J = 8.4 Hz).
実施例３１
N-[(1S)-1-ナフタレン-1-イルエチル]-4-[4-(2-プロピル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 31
N-[(1S) -1-Naphthalen-1-ylethyl] -4- [4- (2-propyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　tert-ブチル 4-[4-(2-プロピル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.30 g, 0.81 mmol)に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.34 mL, 2.4 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.14 mL, 0.81 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝8/2～2/8)で精製した後、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を淡桃白色固体(0.11 g, 30%)として得た。
LC/MS 469
NMR (CDCl3) δ: 1.04 (3 H, t, J=7.5 Hz), 1.71 (3 H, d, J=6.9 Hz), 1.85 (2 H, m), 2.79 (2 H, t, J=7.8 Hz), 3.22 (4 H, t, J=5.4 Hz), 3.48 - 3.59 (4 H, m), 4.74 (1 H, d, J=7.2 Hz), 5.86 (1 H, m), 6.91 (2 H, d, J=8.7 Hz), 7.08 (1 H, s), 7.45 - 7.58 (6 H, m), 7.81 (1 H, d, J=8.1 Hz), 7.88 (1 H, d, J=7.5 Hz), 8.17 (1 H, d, J=8.4 Hz). Add 4N hydrochloric acid ethyl acetate solution (10 mL) to tert-butyl 4- [4- (2-propyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.30 g, 0.81 mmol) And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.34 mL, 2.4 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.14 mL, 0.81 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8/2 to 2/8), and the residue was recrystallized from hexane-ethyl acetate to give the title compound as a pale pink white solid ( 0.11 g, 30%).
LC / MS 469
NMR (CDCl 3 ) δ: 1.04 (3 H, t, J = 7.5 Hz), 1.71 (3 H, d, J = 6.9 Hz), 1.85 (2 H, m), 2.79 (2 H, t, J = 7.8 Hz), 3.22 (4 H, t, J = 5.4 Hz), 3.48-3.59 (4 H, m), 4.74 (1 H, d, J = 7.2 Hz), 5.86 (1 H, m), 6.91 ( 2 H, d, J = 8.7 Hz), 7.08 (1 H, s), 7.45-7.58 (6 H, m), 7.81 (1 H, d, J = 8.1 Hz), 7.88 (1 H, d, J = 7.5 Hz), 8.17 (1 H, d, J = 8.4 Hz).
実施例３２
4-{4-[2-(1-メチルエチル)-1,3-オキサゾール-5-イル]フェニル}-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 32
4- {4- [2- (1-Methylethyl) -1,3-oxazol-5-yl] phenyl} -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　tert-ブチル 4-{4-[2-(1-メチルエチル)-1,3-オキサゾール-5-イル]フェニル}ピペラジン-1-カルボキシラート(0.25 g, 0.67 mmol)に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.28 mL, 2.0 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.12 mL, 0.67 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝8/2～4/6)で精製した後、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を淡桃白色固体(55 mg, 17%)として得た。
LC/MS 469
NMR (CDCl3) δ: 1.41 (6 H, d, J=6.9 Hz), 1.71 (3 H, d, J=6.6 Hz), 3.09 - 3.24 (5 H, m), 3.49 - 3.59 (4 H, m), 4.73 (1 H, d, J=7.2 Hz), 5.86 (1 H, m), 6.91 (2 H, d, J=8.7 Hz), 7.07 (1 H, s), 7.45 - 7.58 (6 H, m), 7.81 (1 H, d, J=8.1 Hz), 7.88 (1 H, d, J=7.8 Hz), 8.17 (1 H, d, J=8.1 Hz). tert-butyl 4- {4- [2- (1-methylethyl) -1,3-oxazol-5-yl] phenyl} piperazine-1-carboxylate (0.25 g, 0.67 mmol) in 4N hydrochloric acid ethyl acetate solution ( 10 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.28 mL, 2.0 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.12 mL, 0.67 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8 / 2-4 / 6), and the residue was recrystallized from hexane-ethyl acetate to give the title compound as a pale pink white solid ( 55 mg, 17%).
LC / MS 469
NMR (CDCl 3 ) δ: 1.41 (6 H, d, J = 6.9 Hz), 1.71 (3 H, d, J = 6.6 Hz), 3.09-3.24 (5 H, m), 3.49-3.59 (4 H, m), 4.73 (1 H, d, J = 7.2 Hz), 5.86 (1 H, m), 6.91 (2 H, d, J = 8.7 Hz), 7.07 (1 H, s), 7.45-7.58 (6 H, m), 7.81 (1 H, d, J = 8.1 Hz), 7.88 (1 H, d, J = 7.8 Hz), 8.17 (1 H, d, J = 8.1 Hz).
実施例３３
4-[4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 33
4- [4- (3-Methyl-1,2,4-oxadiazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　tert-ブチル 4-[4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.28 g, 0.81 mmol)に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.34 mL, 2.4 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.14 mL, 0.81 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～2/8)で精製した後、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を白色固体(54 mg, 15%)として得た。
LC/MS 442
NMR (CDCl3) δ: 1.72 (3 H, d, J=6.9 Hz), 2.45 (3 H, s), 3.37 - 3.39 (4 H, m), 3.51 - 3.59 (4 H, m), 4.70 (1 H, d, J=6.9 Hz), 5.87 (1 H, m), 6.91 (2 H, d, J=9.0 Hz), 7.45 - 7.56 (4 H, m), 7.84 (2 H, m), 7.98 (2 H, d, J=8.7 Hz), 8.17 (1 H, d, J=8.1 Hz). tert-Butyl 4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazine-1-carboxylate (0.28 g, 0.81 mmol) in 4N hydrochloric acid ethyl acetate solution (10 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.34 mL, 2.4 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.14 mL, 0.81 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to 2/8), and the residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (54 mg , 15%).
LC / MS 442
NMR (CDCl 3 ) δ: 1.72 (3 H, d, J = 6.9 Hz), 2.45 (3 H, s), 3.37-3.39 (4 H, m), 3.51-3.59 (4 H, m), 4.70 ( 1 H, d, J = 6.9 Hz), 5.87 (1 H, m), 6.91 (2 H, d, J = 9.0 Hz), 7.45-7.56 (4 H, m), 7.84 (2 H, m), 7.98 (2 H, d, J = 8.7 Hz), 8.17 (1 H, d, J = 8.1 Hz).
実施例３４
4-[4-(5-メチル-1,2,4-オキサジアゾール-3-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 34
4- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　tert-ブチル 4-[4-(5-メチル-1,2,4-オキサジアゾール-3-イル)フェニル]ピペラジン-1-カルボキシラート(0.28 g, 0.81 mmol)に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.34 mL, 2.4 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.14 mL, 0.81 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～2/8)で精製した後、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を白色固体(0.12 g, 34%)として得た。
LC/MS 442
NMR (CDCl3) δ: 1.75 (3 H, d, J=6.9 Hz), 2.68 (3 H, s), 3.33 - 3.37 (4 H, m), 3.53 - 3.64 (4 H, m), 4.75 (1 H, d, J=6.9 Hz), 5.91 (1 H, m), 6.96 (2 H, d, J=9.3 Hz), 7.49 - 7.60 (4 H, m), 7.84 - 7.97 (2 H, m), 7.98 (2 H, d, J=8.7 Hz), 8.21 (1 H, d, J=8.4 Hz). tert-Butyl 4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] piperazine-1-carboxylate (0.28 g, 0.81 mmol) in 4N hydrochloric acid ethyl acetate solution (10 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.34 mL, 2.4 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.14 mL, 0.81 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to 2/8), and the residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.12 g , 34%).
LC / MS 442
NMR (CDCl 3 ) δ: 1.75 (3 H, d, J = 6.9 Hz), 2.68 (3 H, s), 3.33-3.37 (4 H, m), 3.53-3.64 (4 H, m), 4.75 ( 1 H, d, J = 6.9 Hz), 5.91 (1 H, m), 6.96 (2 H, d, J = 9.3 Hz), 7.49-7.60 (4 H, m), 7.84-7.97 (2 H, m ), 7.98 (2 H, d, J = 8.7 Hz), 8.21 (1 H, d, J = 8.4 Hz).
実施例３５
4-[4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 35
4- [4- (4-Methyl-1H-1,2,3-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　tert-ブチル 4-[4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(0.35 g, 1.02 mmol)に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.43 mL, 3.1 mmol)を加え、室温で1時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.18 mL, 1.02 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～0/1)で精製した後、残留物をヘキサン－酢酸エチル－MeOHより再結晶して、題記化合物を白
色固体(0.13 g, 29%)として得た。
LC/MS 441
NMR (CDCl3) δ: 1.72 (3 H, d, J=6.9 Hz), 2.44 (3 H, s), 3.24 (4 H, t, J=5.1 Hz), 3.50 - 3.61 (4 H, m), 4.74 (1 H, d, J=7.2 Hz), 5.87 (1 H, m), 6.97 (2 H, d, J=8.7 Hz), 7.45 - 7.63 (7 H, m), 7.81 (1 H, d, J=8.1 Hz), 7.88 (1 H, d, J=8.4 Hz), 8.17 (1 H, d, J=8.1 Hz). tert-butyl 4- [4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] piperazine-1-carboxylate (0.35 g, 1.02 mmol) in 4N hydrochloric acid ethyl acetate solution (10 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.43 mL, 3.1 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hr. Further, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.18 mL, 1.02 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 1-0 / 1), and the residue was recrystallized from hexane-ethyl acetate-MeOH to give the title compound as a white solid ( 0.13 g, 29%).
LC / MS 441
NMR (CDCl 3 ) δ: 1.72 (3 H, d, J = 6.9 Hz), 2.44 (3 H, s), 3.24 (4 H, t, J = 5.1 Hz), 3.50-3.61 (4 H, m) , 4.74 (1 H, d, J = 7.2 Hz), 5.87 (1 H, m), 6.97 (2 H, d, J = 8.7 Hz), 7.45-7.63 (7 H, m), 7.81 (1 H, d, J = 8.1 Hz), 7.88 (1 H, d, J = 8.4 Hz), 8.17 (1 H, d, J = 8.1 Hz).
実施例３６
4-[2-クロロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 36
4- [2-Chloro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　tert-ブチル 4-[2-クロロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(0.33 g, 0.87 mmol)に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.37 mL, 2.6 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.15 mL, 0.87 mmol)を加え、室温で12時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝8/2～3/7)で精製し、題記化合物を淡黄色非定形固体(0.10 g, 25%)として得た。
LC/MS 475
NMR (CDCl3) δ: 1.72 (3 H, d, J=6.9 Hz), 2.49 (3 H, s), 3.05 (4 H, t, J=5.1 Hz), 3.50 - 3.61 (4 H, m), 4.75 (1 H, d, J=7.2 Hz), 5.87 (1 H, m), 7.08 (2 H, d, J=8.7 Hz), 7.45 - 7.57 (5 H, m), 7.71 (1 H, d, J=2.7 Hz), 7.81 (1 H, d, J=8.1 Hz), 7.88 (1 H, d, J=8.1 Hz), 8.18 (1 H, d, J=8.4 Hz), 8.35 (1 H, s). tert-Butyl 4- [2-chloro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (0.33 g, 0.87 mmol) in 4N hydrochloric acid Ethyl solution (10 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.37 mL, 2.6 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.15 mL, 0.87 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8 / 2-3 / 7) to give the title compound as a pale yellow amorphous solid (0.10 g, 25%).
LC / MS 475
NMR (CDCl 3 ) δ: 1.72 (3 H, d, J = 6.9 Hz), 2.49 (3 H, s), 3.05 (4 H, t, J = 5.1 Hz), 3.50-3.61 (4 H, m) , 4.75 (1 H, d, J = 7.2 Hz), 5.87 (1 H, m), 7.08 (2 H, d, J = 8.7 Hz), 7.45-7.57 (5 H, m), 7.71 (1 H, d, J = 2.7 Hz), 7.81 (1 H, d, J = 8.1 Hz), 7.88 (1 H, d, J = 8.1 Hz), 8.18 (1 H, d, J = 8.4 Hz), 8.35 (1 H, s).
実施例３７
4-[3-クロロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 37
4- [3-Chloro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　tert-ブチル 4-[3-クロロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(0.40 g, 1.1 mmol)に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.44 mL, 3.2 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.19 mL, 1.1 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1)で精製し、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を白色固体(0.17 g, 33%)として得た。
LC/MS 475
NMR (CDCl3) δ: 1.72 (3 H, d, J=6.6 Hz), 2.50 (3 H, s), 3.27 (4 H, t, J=4.8 Hz), 3.50 - 3.60 (4 H, m), 4.72 (1 H, d, J=6.9 Hz), 5.87 (1 H, m), 6.83 (1 H, dd, J=2.4 Hz, 8.7 Hz), 6.94 (1 H, d, J=2.4 Hz), 7.37 (1 H, d, J=8.7 Hz), 7.48 - 7.58 (4 H, m), 7.82 (1 H, d, J=8.1 Hz), 8.16 (1 H, d, J=7.8 Hz), 8.26 (1 H, s). tert-Butyl 4- [3-chloro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (0.40 g, 1.1 mmol) in 4N hydrochloric acid Ethyl solution (5 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.44 mL, 3.2 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.19 mL, 1.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1), and the residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.17 g, 33%). Obtained.
LC / MS 475
NMR (CDCl 3 ) δ: 1.72 (3 H, d, J = 6.6 Hz), 2.50 (3 H, s), 3.27 (4 H, t, J = 4.8 Hz), 3.50-3.60 (4 H, m) , 4.72 (1 H, d, J = 6.9 Hz), 5.87 (1 H, m), 6.83 (1 H, dd, J = 2.4 Hz, 8.7 Hz), 6.94 (1 H, d, J = 2.4 Hz) , 7.37 (1 H, d, J = 8.7 Hz), 7.48-7.58 (4 H, m), 7.82 (1 H, d, J = 8.1 Hz), 8.16 (1 H, d, J = 7.8 Hz), 8.26 (1 H, s).
実施例３８
4-[3-フルオロ-4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 38
4- [3-Fluoro-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　tert-ブチル 4-[3-フルオロ-4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(0.26 g, 0.72 mmol)に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.30 mL, 2.2 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(0.13 mL, 0.72 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1)で精製し、残留物を酢酸エチル－MeOHより再結晶して、題記化合物を白色固体(49 mg, 15%)として得た。
LC/MS 459
NMR (CDCl3) δ: 1.73 (3 H, d, J=6.6 Hz), 2.44 (3 H, s), 3.27 (4 H, t, J=5.4 Hz), 3.53 - 3.61 (4 H, m), 4.72 (1 H, d, J=7.2 Hz), 5.87 (1 H, m), 6.66 - 6.76 (2 H, m), 7.45 - 7.56 (4 H, m), 7.70 - 7.88 (4 H, m), 8.17 (1 H, d, J=8.1 Hz). tert-Butyl 4- [3-fluoro-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] piperazine-1-carboxylate (0.26 g, 0.72 mmol) in 4N hydrochloric acid Ethyl solution (5 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.30 mL, 2.2 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (0.13 mL, 0.72 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1), and the residue was recrystallized from ethyl acetate-MeOH to give the title compound as a white solid (49 mg, 15%). Obtained.
LC / MS 459
NMR (CDCl 3 ) δ: 1.73 (3 H, d, J = 6.6 Hz), 2.44 (3 H, s), 3.27 (4 H, t, J = 5.4 Hz), 3.53-3.61 (4 H, m) , 4.72 (1 H, d, J = 7.2 Hz), 5.87 (1 H, m), 6.66-6.76 (2 H, m), 7.45-7.56 (4 H, m), 7.70-7.88 (4 H, m ), 8.17 (1 H, d, J = 8.1 Hz).
実施例３９
4-[3-ヒドロキシ-4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 39
4- [3-Hydroxy-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　tert-ブチル 4-[3-tert-ブトキシ-4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.14 g, 0.34 mmol)に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.24 mL, 1.7 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(59 μL, 0.34 mmol)を加え、室温で16時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～0/1)で精製し、題記化合物を淡黄色非定形固体(61 mg, 40%)として得た。
LC/MS 458
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.9 Hz), 2.46 (3 H, s), 3.39 (4 H, t, J=5.4 Hz), 3.5 (4 H, m), 4.70 (1 H, d, J=7.2 Hz), 5.86 (1 H, m), 6.42 (1 H, d, J=2.7 Hz), 6.48 (1 H, dd, J=1.8 Hz, 8.7 Hz), 7.4 - 7.58 (4 H, m), 7.74 - 7.58 (4 H, m), 7.74 - 7.90 (3 H, m), 8.17 (1 H, d, J=8.4 Hz), 10.49 (1 H, s). tert-butyl 4- [3-tert-butoxy-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazine-1-carboxylate (0.14 g, 0.34 mmol) to 4N Hydrochloric acid ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.24 mL, 1.7 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (59 μL, 0.34 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 1 / 1-0 / 1) to give the title compound as a pale yellow amorphous solid (61 mg, 40%).
LC / MS 458
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.9 Hz), 2.46 (3 H, s), 3.39 (4 H, t, J = 5.4 Hz), 3.5 (4 H, m), 4.70 (1 H, d, J = 7.2 Hz), 5.86 (1 H, m), 6.42 (1 H, d, J = 2.7 Hz), 6.48 (1 H, dd, J = 1.8 Hz, 8.7 Hz), 7.4 -7.58 (4 H, m), 7.74-7.58 (4 H, m), 7.74-7.90 (3 H, m), 8.17 (1 H, d, J = 8.4 Hz), 10.49 (1 H, s).
実施例４０
4-[3-メトキシ-4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 40
4- [3-Methoxy-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　tert-ブチル 4-[3-メトキシ-4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(0.20 g, 0.54 mmol)の酢酸エチル(4 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.37 mL, 2.7 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(94 μL, 0.54 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～0/1)で精製し、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を白色固体(0.15 g, 59%)として得た。
LC/MS 471
NMR (CDCl3) δ: 1.57 (3 H, d, J=6.9 Hz), 2.44 (3 H, s), 3.26 (4 H, t, J=5.4 Hz), 3.53 - 3.59 (4 H, m), 3.85 (3 H, s), 4.73 (1 H, d, J=7.2 Hz), 5.87 (1 H, m), 6.51-6.57 (2 H, m), 7.45 - 7.59 (5 H, m), 7.71 (1 H, s), 7.82 (1 H, d, J=8.1 Hz), 7.89 (1 H, d, J=7.5 Hz), 8.18 (1 H, d, J=8.4 Hz). tert-Butyl 4- [3-methoxy-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] piperazine-1-carboxylate (0.20 g, 0.54 mmol) in ethyl acetate ( 4N) 4N hydrochloric acid ethyl acetate solution (5 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.37 mL, 2.7 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (94 μL, 0.54 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 3 / 7-0 / 1), the residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.15 g , 59%).
LC / MS 471
NMR (CDCl 3 ) δ: 1.57 (3 H, d, J = 6.9 Hz), 2.44 (3 H, s), 3.26 (4 H, t, J = 5.4 Hz), 3.53-3.59 (4 H, m) , 3.85 (3 H, s), 4.73 (1 H, d, J = 7.2 Hz), 5.87 (1 H, m), 6.51-6.57 (2 H, m), 7.45-7.59 (5 H, m), 7.71 (1 H, s), 7.82 (1 H, d, J = 8.1 Hz), 7.89 (1 H, d, J = 7.5 Hz), 8.18 (1 H, d, J = 8.4 Hz).
実施例４１
4-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 41
4- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　tert-ブチル 4-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート(0.16 g, 0.43 mmol)の酢酸エチル(2 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残留物にDMF(5.0 mL)及びトリエチルアミン(0.30 mL, 2.2 mmol)を加え、室温で2時間攪拌した。さらに、(S)-(+)-1-(1-ナフチル)エチルイソシアナート(75 μL, 0.43 mmol)を加え、室温で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝6/4～0/1)で精製し、残留物をヘキサン－酢酸エチルより再結晶して、題記化合物を白色固体(0.13 g, 66%)として得た。
LC/MS 469
NMR (CDCl3) δ: 1.73 (3 H, d, J=6.6 Hz), 3.19 (4 H, t, J=5.1 Hz), 3.49 - 3.57 (4 H, m), 3.89 (3 H, s), 3.93 (3 H,s), 4.74 (1 H, d, J=6.9 Hz), 5.87 (1 H, m), 6.51-6.54 (2 H, m), 7.37 - 7.56 (5 H, m), 7.75 - 7.90 (4 H, m), 8.18 (1 H, d, J=8.4 Hz). Add 4N to a solution of tert-butyl 4- [3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine-1-carboxylate (0.16 g, 0.43 mmol) in ethyl acetate (2 mL) Hydrochloric acid ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, DMF (5.0 mL) and triethylamine (0.30 mL, 2.2 mmol) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. Furthermore, (S)-(+)-1- (1-naphthyl) ethyl isocyanate (75 μL, 0.43 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 6 / 4-0 / 1), the residue was recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.13 g , 66%).
LC / MS 469
NMR (CDCl 3 ) δ: 1.73 (3 H, d, J = 6.6 Hz), 3.19 (4 H, t, J = 5.1 Hz), 3.49-3.57 (4 H, m), 3.89 (3 H, s) , 3.93 (3 H, s), 4.74 (1 H, d, J = 6.9 Hz), 5.87 (1 H, m), 6.51-6.54 (2 H, m), 7.37-7.56 (5 H, m), 7.75-7.90 (4 H, m), 8.18 (1 H, d, J = 8.4 Hz).
実施例４２
4-[4-(5-メチル-4H-1,2,4-トリアゾール-3-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 42
4- [4- (5-Methyl-4H-1,2,4-triazol-3-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　4-[4-(5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール-3-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミドに1Mテトラブチルアンモニウムフルオリド(1.3 mL)を加え、50℃で1時間攪拌した。さらに、テトラブチルアンモニウムフルオリド３水和物(0.28 g, 0.88mmol)を加え、50℃で20時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/MeOH＝1/0～95/5)で精製した。得られた生成物にDMF(5.0 mL)及びトリエチルアミン(0.30 mL, 2.2 mmol)を加え、さらにジtert-ブチル ジカルボネート(0.20 mL, 0.88 mmol)を加え、室温で3時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝6/4～0/1)で精製した。残留物の酢酸エチル(10 mL)溶液に4N塩酸酢酸エチル溶液(0.5 mL)を加え、室温で1時間攪拌した。反応混合物を飽和炭酸水素ナトリウム水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/MeOH＝1/0～95/5)で精製し、題記化合物を白色固体(3.8 mg, 2%)として得た。
LC/MS 441
NMR (CDCl3) δ: 1.50 (3 H, d, J=6.9 Hz), 3.17 (4 H, br), 3.50 (4 H, br), 5.66 (1 H, m), 7.00 - 7.09 (3 H, m), 7.45 - 7.57 (4 H, m), 7.77 - 7.81 (3 H, m), 7.91 (1 H, d, J=7.5 Hz), 8.14 (1 H, d, J=8.4 Hz). 4- [4- (5-Methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazol-3-yl) phenyl] -N-[(1S) -1- 1M Tetrabutylammonium fluoride (1.3 mL) was added to [naphthalen-1-ylethyl] piperazine-1-carboxamide, and the mixture was stirred at 50 ° C. for 1 hour. Furthermore, tetrabutylammonium fluoride trihydrate (0.28 g, 0.88 mmol) was added and stirred at 50 ° C. for 20 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / MeOH = 1/0 to 95/5). DMF (5.0 mL) and triethylamine (0.30 mL, 2.2 mmol) were added to the obtained product, ditert-butyl dicarbonate (0.20 mL, 0.88 mmol) was further added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 4-0 / 1). To a solution of the residue in ethyl acetate (10 mL) was added 4N hydrochloric acid ethyl acetate solution (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / MeOH = 1/0 to 95/5) to give the title compound as a white solid (3.8 mg, 2%).
LC / MS 441
NMR (CDCl 3 ) δ: 1.50 (3 H, d, J = 6.9 Hz), 3.17 (4 H, br), 3.50 (4 H, br), 5.66 (1 H, m), 7.00-7.09 (3 H , m), 7.45-7.57 (4 H, m), 7.77-7.81 (3 H, m), 7.91 (1 H, d, J = 7.5 Hz), 8.14 (1 H, d, J = 8.4 Hz).
実施例43
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-(2,3,5-トリフルオロベンジル)-1,4-ジアゼパン-1-カルボキサミド Example 43
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- (2,3,5-trifluorobenzyl) -1,4-diazepan-1-carboxamide
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　CDI(71 mg, 0.44 mmol)のDMF(1.0 mL)溶液に2,3,5-トリフルオロベンジルアミン(71 mg, 0.44 mmol)のDMF(1.0 mL)溶液を0 ℃で加えた。反応混合物を0 ℃で30分攪拌した後に、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.0 mL)溶液を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ)で精製した。得られた固形物を酢酸エチル/ヘキサンより再結晶して、題記化合物を無色固体(86 mg, 45%(2 steps))として得た。
LC/MS 475
NMR (CDCl3) δ: 1.98 - 2.11 (2 H, m), 2.49 (3 H, s), 3.32 (2 H, t, J=6.2 Hz), 3.57 - 3.69 (6 H, m), 3.91 (3 H, s), 4.46 (2 H, d, J=6.0 Hz), 4.83 (1 H, t, J=6.0 Hz), 6.25 (1 H, d, J=2.3 Hz), 6.36 (1 H, dd, J=8.7, 2.3 Hz), 6.70 - 6.90 (2 H, m), 7.17 (1 H, s), 7.54 (1 H, d, J=8.7 Hz). To a DMF (1.0 mL) solution of CDI (71 mg, 0.44 mmol), a DMF (1.0 mL) solution of 2,3,5-trifluorobenzylamine (71 mg, 0.44 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes before 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol). ) In DMF (1.0 mL) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate only). The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (86 mg, 45% (2 steps)).
LC / MS 475
NMR (CDCl 3 ) δ: 1.98-2.11 (2 H, m), 2.49 (3 H, s), 3.32 (2 H, t, J = 6.2 Hz), 3.57-3.69 (6 H, m), 3.91 ( 3 H, s), 4.46 (2 H, d, J = 6.0 Hz), 4.83 (1 H, t, J = 6.0 Hz), 6.25 (1 H, d, J = 2.3 Hz), 6.36 (1 H, dd, J = 8.7, 2.3 Hz), 6.70-6.90 (2 H, m), 7.17 (1 H, s), 7.54 (1 H, d, J = 8.7 Hz).
実施例44
4-[3-(メチルスルファニル)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 44
4- [3- (Methylsulfanyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine -1-carboxamide
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　tert-ブチル 4-[3-(メチルスルファニル)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(110 mg, 0.27 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で2時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(2.0 mL)に懸濁し、N-エチルジイソプロピルアミン(140 μL, 0.82 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(62 μL, 0.36 mmol)を加え、室温で2.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(110 mg, 80%(2 steps))として得た。
LC/MS 487
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.8 Hz), 2.34 (3 H, s), 2.49 (3 H, s), 3.16 - 3.31 (4 H, m), 3.45 - 3.65 (4 H, m), 4.71 (1 H, d, J=7.2 Hz), 5.73 - 5.99 (1 H, m), 6.72 (1 H, dd, J=8.7, 2.6 Hz), 6.79 (1 H, d, J=2.6 Hz), 7.22 (1 H, d, J=8.7 Hz), 7.40 - 7.63 (4 H, m), 7.81 (1 H, d, J=8.3 Hz), 7.84 - 7.94 (1 H, m), 8.12 - 8.21 (2 H, m). of tert-butyl 4- [3- (methylsulfanyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (110 mg, 0.27 mmol) To a suspension of ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (2.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (140 μL, 0.82 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (62 μL, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-ethyl acetate alone) to give the title compound as a colorless amorphous solid (110 mg, 80% (2 steps)).
LC / MS 487
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.8 Hz), 2.34 (3 H, s), 2.49 (3 H, s), 3.16-3.31 (4 H, m), 3.45-3.65 ( 4 H, m), 4.71 (1 H, d, J = 7.2 Hz), 5.73-5.99 (1 H, m), 6.72 (1 H, dd, J = 8.7, 2.6 Hz), 6.79 (1 H, d , J = 2.6 Hz), 7.22 (1 H, d, J = 8.7 Hz), 7.40-7.63 (4 H, m), 7.81 (1 H, d, J = 8.3 Hz), 7.84-7.94 (1 H, m), 8.12-8.21 (2 H, m).
実施例45
4-[3-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 45
4- [3-Fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　tert-ブチル 4-[3-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(140 mg, 0.35 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(120 μL, 1.1 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(80 μL, 0.46 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(133.6 mg, 78%(2 steps))として得た。
LC/MS 489
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.8 Hz), 2.48 (3 H, s), 3.22 - 3.34 (4 H, m), 3.45 - 3.62 (4 H, m), 3.77 (3 H, s), 4.70 (1 H, d, J=6.8 Hz), 5.75 - 5.97 (1 H, m), 6.20 (1 H, s), 6.26 (1 H, dd, J=12.5, 2.3 Hz), 7.41 - 7.62 (4 H, m), 7.81 (1 H, d, J=8.3 Hz), 7.88 (1 H, d, J=8.3 Hz), 8.03 (1 H, s), 8.16 (1 H, d, J=8.3 Hz). tert-Butyl 4- [3-fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (140 mg, 0.35 mmol) 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added to an ethyl acetate (1.0 mL) suspension, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (120 μL, 1.1 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (80 μL, 0.46 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-ethyl acetate alone) to give the title compound as a colorless amorphous solid (133.6 mg, 78% (2 steps)).
LC / MS 489
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.8 Hz), 2.48 (3 H, s), 3.22-3.34 (4 H, m), 3.45-3.62 (4 H, m), 3.77 ( 3 H, s), 4.70 (1 H, d, J = 6.8 Hz), 5.75-5.97 (1 H, m), 6.20 (1 H, s), 6.26 (1 H, dd, J = 12.5, 2.3 Hz ), 7.41-7.62 (4 H, m), 7.81 (1 H, d, J = 8.3 Hz), 7.88 (1 H, d, J = 8.3 Hz), 8.03 (1 H, s), 8.16 (1 H , d, J = 8.3 Hz).
実施例46
4-[3,5-ジメトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 46
4- [3,5-Dimethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine- 1-carboxamide
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　tert-ブチル 4-[3,5-ジメトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(230 mg, 0.56 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(3.0 mL)を加え、室温で5.5時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(290 μL, 1.7 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(130 μL, 0.73 mmol)を加え、室温で5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝7/93)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(230 mg, 82%(2 steps))として得た。
LC/MS 501
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.8 Hz), 2.48 (3 H, s), 3.18 - 3.32 (4 H, m), 3.43 - 3.65 (4 H, m), 3.73 (6 H, s), 4.71 (1 H, d, J=6.8 Hz), 5.79 - 5.95 (1 H, m), 6.07 (2 H, s), 7.40 - 7.61 (4 H, m), 7.81 (1 H, d, J=8.0 Hz), 7.85 - 7.91 (1 H, m), 7.95 (1 H, s), 8.14 - 8.20 (1 H, m). Acetic acid of tert-butyl 4- [3,5-dimethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (230 mg, 0.56 mmol) 4N Hydrochloric acid ethyl acetate solution (3.0 mL) was added to the ethyl (1.0 mL) suspension, and the mixture was stirred at room temperature for 5.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (290 μL, 1.7 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (130 μL, 0.73 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 7/93). The residue was washed with hexane to give the title compound as a colorless amorphous solid (230 mg, 82% (2 steps)).
LC / MS 501
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.8 Hz), 2.48 (3 H, s), 3.18-3.32 (4 H, m), 3.43-3.65 (4 H, m), 3.73 ( 6 H, s), 4.71 (1 H, d, J = 6.8 Hz), 5.79-5.95 (1 H, m), 6.07 (2 H, s), 7.40-7.61 (4 H, m), 7.81 (1 H, d, J = 8.0 Hz), 7.85-7.91 (1 H, m), 7.95 (1 H, s), 8.14-8.20 (1 H, m).
実施例47
4-[3-(メチルスルフィニル)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 47
4- [3- (Methylsulfinyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine -1-carboxamide
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　tert-ブチル 4-[3-(メチルスルファニル)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(110 mg, 0.27 mmol)のアセトニトリル(3.0 mL)懸濁液にm-クロロ過安息香酸(140 mg, 0.60 mmol)を0 ℃で加え、0 ℃で5.5時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をメタノールに懸濁し4N塩酸酢酸エチル溶液を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(2.0 mL)に懸濁し、N-エチルジイソプロピルアミン(190 μL, 1.1 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(62 μL, 0.36 mmol)を加え、室温で14時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製した。残留物を分取HPLCにて精製し、分取したフラクションを濃縮した。残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色非定形固体(5.8 mg, 4.1%(3 steps))として得た。
LC/MS 503
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.4 Hz), 2.46 (3 H, s), 2.79 (3 H, s), 3.28 - 3.41 (4 H, m), 3.46 - 3.63 (4 H, m), 4.76 (1 H, brs), 5.79 - 5.93 (1 H, m), 6.95 (1 H, dd, J=8.9, 2.8 Hz), 7.27 - 7.30 (1 H, m), 7.45 - 7.61 (5 H, m), 7.81 (1 H, d, J=7.9 Hz), 7.87 (1 H, d, J=7.9 Hz), 8.16 (1 H, d, J=8.3 Hz), 8.21 (1 H, s). of tert-butyl 4- [3- (methylsulfanyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (110 mg, 0.27 mmol) M-Chloroperbenzoic acid (140 mg, 0.60 mmol) was added to acetonitrile (3.0 mL) suspension at 0 ° C., and the mixture was stirred at 0 ° C. for 5.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in methanol, 4N hydrochloric acid ethyl acetate solution was added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (190 μL, 1.1 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (62 μL, 0.36 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to ethyl acetate only). The residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless amorphous solid (5.8 mg, 4.1% (3 steps)).
LC / MS 503
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.4 Hz), 2.46 (3 H, s), 2.79 (3 H, s), 3.28-3.41 (4 H, m), 3.46-3.63 ( 4 H, m), 4.76 (1 H, brs), 5.79-5.93 (1 H, m), 6.95 (1 H, dd, J = 8.9, 2.8 Hz), 7.27-7.30 (1 H, m), 7.45 -7.61 (5 H, m), 7.81 (1 H, d, J = 7.9 Hz), 7.87 (1 H, d, J = 7.9 Hz), 8.16 (1 H, d, J = 8.3 Hz), 8.21 ( 1 H, s).
実施例48
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]-1,4-ジアゼパン-1-カルボキサミド Example 48
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] -1,4-diazepan-1 -Carboxamide
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート(600 mg, 1.5 mmol)の酢酸エチル(1.0 mL)溶液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣の1/4をTHF(2.0 mL)に懸濁し、N-エチルジイソプロピルアミン(200 μL, 1.2 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(88 μL, 0.50 mmol)を加え、室温で14時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝6/4～1/9)で精製し、題記化合物を無色非定形固体(180 mg, 95%)として得た。
LC/MS 485
NMR (CDCl3) δ: 1.66 (3 H, d, J=6.9 Hz), 1.71 - 2.03 (2 H, m), 2.49 (3 H, s), 3.23 (2 H, t, J=6.0 Hz), 3.50 - 3.67 (5 H, m), 3.67 - 3.79 (1 H, m), 3.87 (3 H, s), 4.56 (1 H, d, J=7.2 Hz), 5.81 (1 H, quin, J=6.9 Hz), 6.21 (1 H, d, J=2.3 Hz), 6.33 (1 H, dd, J=8.7, 2.3 Hz), 7.17 (1 H, s), 7.39 - 7.50 (4 H, m), 7.52 (1 H, d, J=8.7 Hz), 7.78 (1 H, d, J=7.9 Hz), 7.81 - 7.90 (1 H, m), 8.04 - 8.20 (1 H, m). tert-Butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate (600 mg, 1.5 mmol) in ethyl acetate 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the (1.0 mL) solution, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and 1/4 of the obtained residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (200 μL, 1.2 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (88 μL, 0.50 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 6/4 to 1/9) to give the title compound as a colorless amorphous solid (180 mg, 95%).
LC / MS 485
NMR (CDCl 3) δ: 1.66 (3 H, d, J = 6.9 Hz), 1.71 - 2.03 (2 H, m), 2.49 (3 H, s), 3.23 (2 H, t, J = 6.0 Hz) , 3.50-3.67 (5 H, m), 3.67-3.79 (1 H, m), 3.87 (3 H, s), 4.56 (1 H, d, J = 7.2 Hz), 5.81 (1 H, quin, J = 6.9 Hz), 6.21 (1 H, d, J = 2.3 Hz), 6.33 (1 H, dd, J = 8.7, 2.3 Hz), 7.17 (1 H, s), 7.39-7.50 (4 H, m) , 7.52 (1 H, d, J = 8.7 Hz), 7.78 (1 H, d, J = 7.9 Hz), 7.81-7.90 (1 H, m), 8.04-8.20 (1 H, m).
実施例49
4-[6-メトキシ-5-(3-メチル-1H-1,2,4-トリアゾール-1-イル)ピリジン-2-イル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 49
4- [6-Methoxy-5- (3-methyl-1H-1,2,4-triazol-1-yl) pyridin-2-yl] -N-[(1S) -1-naphthalen-1-ylethyl] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　tert-ブチル 4-[6-メトキシ-5-(3-メチル-1H-1,2,4-トリアゾール-1-イル)ピリジン-2-イル]ピペラジン-1-カルボキシラート(49 mg, 0.13 mmol)の酢酸エチル(1.5 mL)懸濁液に4N塩酸酢酸エチル溶液(1.5 mL)を加え、室温で13時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(2.0 mL)に懸濁し、N-エチルジイソプロピルアミン(67 μL, 0.39 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(30 μL, 0.17 mmol)を加え、室温で2.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製し、題記化合物を淡黄色非定形固体(54 mg, 88%(2 steps))として得た。
LC/MS 472
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 2.46 (3 H, s), 3.44 - 3.56 (4 H, m), 3.55 - 3.64 (4 H, m), 3.94 (3 H, s), 4.70 (1 H, d, J=7.9 Hz), 5.86 (1 H, quin, J=6.9 Hz), 6.22 (1 H, d, J=8.7 Hz), 7.41 - 7.62 (4 H, m), 7.81 (2 H, d, J=8.7 Hz), 7.85 - 7.92 (1 H, m), 8.17 (1 H, d, J=8.3 Hz), 8.47 (1 H, s). tert-Butyl 4- [6-methoxy-5- (3-methyl-1H-1,2,4-triazol-1-yl) pyridin-2-yl] piperazine-1-carboxylate (49 mg, 0.13 mmol) 4N hydrochloric acid ethyl acetate solution (1.5 mL) was added to an ethyl acetate (1.5 mL) suspension, and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (67 μL, 0.39 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (30 μL, 0.17 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to ethyl acetate only) to give the title compound as a pale yellow amorphous solid (54 mg, 88% (2 steps)). .
LC / MS 472
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 2.46 (3 H, s), 3.44-3.56 (4 H, m), 3.55-3.64 (4 H, m), 3.94 ( 3 H, s), 4.70 (1 H, d, J = 7.9 Hz), 5.86 (1 H, quin, J = 6.9 Hz), 6.22 (1 H, d, J = 8.7 Hz), 7.41-7.62 (4 H, m), 7.81 (2 H, d, J = 8.7 Hz), 7.85-7.92 (1 H, m), 8.17 (1 H, d, J = 8.3 Hz), 8.47 (1 H, s).
実施例50
N-(3,4-ジクロロベンジル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3-メチル-1,4-ジアゼパン-1-カルボキサミド Example 50
N- (3,4-dichlorobenzyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3-methyl-1,4-diazepan-1- Carboxamide
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　4-ベンジル-1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン(76 mg, 0.19 mmol)のメタノール(2.0 mL)溶液に20%水酸化パラジウムカーボン(7.6 mg)を加え、室温、水素雰囲気下で15時間、50 ℃で6時間攪拌した。触媒を除去後、溶媒を減圧留去し、得られた残渣のメタノール(2.0 mL)溶液に20%水酸化パラジウムカーボン(15 mg)を加え、室温、水素雰囲気下で15時間攪拌した。触媒を除去後、溶媒を減圧留去した。得られた残渣のTHF(2.0 mL)溶液に3,4-ジクロロベンジルイソシアナート(37μL, 0.25 mmol)を加え、室温で2時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製して、題記化合物を無色固体(40 mg, 41%(2 steps))として得た。
LC/MS 503
NMR (CDCl3) δ: 1.16 (3 H, d, J=6.4 Hz), 1.58 - 1.78 (2 H, m), 1.88 - 2.03 (1 H, m), 2.49 (3 H, s), 2.80 - 3.13 (2 H, m), 3.29 - 3.49 (1 H, m), 3.60 - 3.75 (1 H, m), 3.82 - 3.96 (4 H, m), 4.20 - 4.38 (3 H, m), 4.78 (1 H, brs), 6.24 (1 H, s), 6.34 (1 H, dd, J=8.5, 2.1 Hz), 6.77 (1 H, d, J=8.3 Hz), 7.05 (1 H, d, J=8.3 Hz), 7.16 - 7.24 (2 H, m), 7.52 (1 H, d, J=9.1 Hz). 4-Benzyl-1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepane (76 mg, 0.19 mmol) in methanol ( 2.0 mL) solution was added with 20% palladium hydroxide carbon (7.6 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours and at 50 ° C. for 6 hours. After removing the catalyst, the solvent was distilled off under reduced pressure, 20% palladium hydroxide carbon (15 mg) was added to a solution of the resulting residue in methanol (2.0 mL), and the mixture was stirred at room temperature in a hydrogen atmosphere for 15 hours. After removing the catalyst, the solvent was distilled off under reduced pressure. 3,4-Dichlorobenzyl isocyanate (37 μL, 0.25 mmol) was added to a THF (2.0 mL) solution of the obtained residue, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-ethyl acetate alone) to give the title compound as a colorless solid (40 mg, 41% (2 steps)).
LC / MS 503
NMR (CDCl 3 ) δ: 1.16 (3 H, d, J = 6.4 Hz), 1.58-1.78 (2 H, m), 1.88-2.03 (1 H, m), 2.49 (3 H, s), 2.80- 3.13 (2 H, m), 3.29-3.49 (1 H, m), 3.60-3.75 (1 H, m), 3.82-3.96 (4 H, m), 4.20-4.38 (3 H, m), 4.78 ( 1 H, brs), 6.24 (1 H, s), 6.34 (1 H, dd, J = 8.5, 2.1 Hz), 6.77 (1 H, d, J = 8.3 Hz), 7.05 (1 H, d, J = 8.3 Hz), 7.16-7.24 (2 H, m), 7.52 (1 H, d, J = 9.1 Hz).
実施例51
N-(3,4-ジクロロベンジル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン-1-カルボキサミド Example 51
N- (3,4-dichlorobenzyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepan-1- Carboxamide
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン-1-カルボキシラート(340 mg, 0.85 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で13時間攪拌した。溶媒を減圧留去し、得られた残渣の1/3をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(150 μL, 0.85 mmol)と3,4-ジクロロベンジルイソシアナート(54 μL, 0.36 mmol)を加え、室温で2時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ～メタノール/酢酸エチル＝5/95)で精製した。得られた固形物をメタノール/酢酸エチルより再結晶して、題記化合物を無色固体(99 mg, 69%(2 steps))として得た。
LC/MS 503
NMR (CDCl3) δ: 1.16 (3 H, d, J=6.8 Hz), 1.59 - 1.74 (1 H, m), 1.98 - 2.17 (1 H, m), 2.51 (3 H, s), 2.98 - 3.23 (3 H, m), 3.88 (4 H, s), 3.96 - 4.15 (2 H, m), 4.15 - 4.25 (2 H, m), 4.42 - 4.62 (2 H, m), 6.25 (1 H, d, J=2.3 Hz), 6.36 (1 H, dd, J=8.7, 2.3 Hz), 6.58 (1 H, dd, J=8.3, 2.3 Hz), 7.11 (1 H, d, J=8.3 Hz), 7.17 (1 H, d, J=2.3 Hz), 7.22 (1 H, s), 7.53 (1 H, d, J=8.7 Hz). tert-Butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepane-1-carboxylate (340 mg, 0.85 mmol ) In ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and 1/3 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (150 μL, 0.85 mmol) and 3,4-dichlorobenzyl isocyanate (54 μL, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone to methanol / ethyl acetate = 5/95). The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (99 mg, 69% (2 steps)).
LC / MS 503
NMR (CDCl 3 ) δ: 1.16 (3 H, d, J = 6.8 Hz), 1.59-1.74 (1 H, m), 1.98-2.17 (1 H, m), 2.51 (3 H, s), 2.98- 3.23 (3 H, m), 3.88 (4 H, s), 3.96-4.15 (2 H, m), 4.15-4.25 (2 H, m), 4.42-4.62 (2 H, m), 6.25 (1 H , d, J = 2.3 Hz), 6.36 (1 H, dd, J = 8.7, 2.3 Hz), 6.58 (1 H, dd, J = 8.3, 2.3 Hz), 7.11 (1 H, d, J = 8.3 Hz ), 7.17 (1 H, d, J = 2.3 Hz), 7.22 (1 H, s), 7.53 (1 H, d, J = 8.7 Hz).
実施例52
4-[4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)ピリミジン-2-イル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 52
4- [4-Methoxy-5- (2-methyl-1,3-oxazol-5-yl) pyrimidin-2-yl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　tert-ブチル 4-[4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート(83 mg, 0.22 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で8時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(2.0 mL)に懸濁し、N-エチルジイソプロピルアミン(110 μL, 0.66 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(50 μL, 0.29 mmol)を加え、室温で13時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ)で精製した。得られた固形物を酢酸エチルより再結晶して、題記化合物を無色固体(66 mg, 63%(2 steps))として得た。
LC/MS 473
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz), 2.50 (3 H, s), 3.36 - 3.56 (4 H, m), 3.79 - 3.91 (4 H, m), 4.02 (3 H, s), 4.71 (1 H, d, J=7.2 Hz), 5.86 (1 H, quin, J=6.8 Hz), 7.12 (1 H, s), 7.38 - 7.63 (4 H, m), 7.80 (1 H, d, J=8.0 Hz), 7.84 - 7.90 (1 H, m), 8.17 (1 H, d, J=8.7 Hz), 8.43 (1 H, s). tert-Butyl 4- [4-methoxy-5- (2-methyl-1,3-oxazol-5-yl) pyrimidin-2-yl] piperazine-1-carboxylate (83 mg, 0.22 mmol) in ethyl acetate ( 1.0 mL) To the suspension was added 4N hydrochloric acid ethyl acetate solution (2.0 mL), and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (110 μL, 0.66 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (50 μL, 0.29 mmol) was added, and the mixture was stirred at room temperature for 13 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate only). The obtained solid was recrystallized from ethyl acetate to give the title compound as a colorless solid (66 mg, 63% (2 steps)).
LC / MS 473
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz), 2.50 (3 H, s), 3.36-3.56 (4 H, m), 3.79-3.91 (4 H, m), 4.02 ( 3 H, s), 4.71 (1 H, d, J = 7.2 Hz), 5.86 (1 H, quin, J = 6.8 Hz), 7.12 (1 H, s), 7.38-7.63 (4 H, m), 7.80 (1 H, d, J = 8.0 Hz), 7.84-7.90 (1 H, m), 8.17 (1 H, d, J = 8.7 Hz), 8.43 (1 H, s).
実施例53
1-[(3,4-ジクロロフェニル)カルボニル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン Example 53
1-[(3,4-Dichlorophenyl) carbonyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.5 mL)溶液に3,4-ジクロロ安息香酸(92 mg, 0.48 mmol)とシアホスホン酸ジエチル(72 μL, 0.48 mmol)を加えた。室温で30分攪拌した後、トリエチルアミン(170 μL, 1.2 mmol)を加え、室温で17時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～9/1)で精製した。得られた固形物を酢酸エチル‐ヘキサンより再結晶して、題記化合物を無色固体(140 mg, 76%)として得た。
LC/MS 460
NMR (CDCl3) δ: 1.73 - 1.89 (1 H, m), 2.09 - 2.25 (1 H, m), 2.51 (3 H, s), 3.23 - 4.00 (11 H, m), 5.98 - 6.48 (2 H, m), 6.66 - 6.82 (1 H, m), 6.93 - 7.24 (2 H, m), 7.28 - 7.62 (2 H, m). To a solution of 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) in DMF (1.5 mL), 3,4 -Dichlorobenzoic acid (92 mg, 0.48 mmol) and diethyl cyanophosphonate (72 μL, 0.48 mmol) were added. After stirring at room temperature for 30 minutes, triethylamine (170 μL, 1.2 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to 9/1). The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (140 mg, 76%).
LC / MS 460
NMR (CDCl 3 ) δ: 1.73-1.89 (1 H, m), 2.09-2.25 (1 H, m), 2.51 (3 H, s), 3.23-4.00 (11 H, m), 5.98-6.48 (2 H, m), 6.66-6.82 (1 H, m), 6.93-7.24 (2 H, m), 7.28-7.62 (2 H, m).
実施例54
1-[(3,4-ジクロロフェニル)アセチル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン Example 54
1-[(3,4-Dichlorophenyl) acetyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(2.0 mL)溶液に3,4-ジクロロフェニル酢酸(98 mg, 0.48 mmol)とシアノホスホン酸ジエチル(72 μL, 0.48 mmol)を加えた。室温で30分攪拌した後、トリエチルアミン(170 μL, 1.2 mmol)を加え、室温で16時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～9/1)で精製した。得られた固形物をヘキサンで洗浄して、題記化合物を淡黄色非定形固体(120 mg, 64%)として得た。
LC/MS 474
NMR (CDCl3) δ: 1.79 - 1.94 (1 H, m), 1.97 - 2.12 (1 H, m), 2.50 (3 H, s), 3.41 - 3.67 (9 H, m), 3.73 - 3.88 (1 H, m), 3.90 (3 H, d, J=1.5 Hz), 6.22 (1 H, s), 6.28 - 6.38 (1 H, m), 6.89 - 7.07 (1 H, m), 7.17 - 7.23 (1 H, m), 7.27 - 7.29 (1 H, m), 7.29 - 7.33 (1 H, m), 7.50 - 7.59 (1 H, m). To a solution of 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) in DMF (2.0 mL), 3,4 -Dichlorophenylacetic acid (98 mg, 0.48 mmol) and diethyl cyanophosphonate (72 μL, 0.48 mmol) were added. After stirring at room temperature for 30 minutes, triethylamine (170 μL, 1.2 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to 9/1). The obtained solid was washed with hexane to give the title compound as a pale yellow amorphous solid (120 mg, 64%).
LC / MS 474
NMR (CDCl 3 ) δ: 1.79-1.94 (1 H, m), 1.97-2.12 (1 H, m), 2.50 (3 H, s), 3.41-3.67 (9 H, m), 3.73-3.88 (1 H, m), 3.90 (3 H, d, J = 1.5 Hz), 6.22 (1 H, s), 6.28-6.38 (1 H, m), 6.89-7.07 (1 H, m), 7.17-7.23 ( 1 H, m), 7.27-7.29 (1 H, m), 7.29-7.33 (1 H, m), 7.50-7.59 (1 H, m).
実施例55
1-[(4-クロロピリジン-2-イル)カルボニル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン Example 55
1-[(4-Chloropyridin-2-yl) carbonyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.5 mL)溶液に4-クロロピリジン-2-カルボン酸(76 mg, 0.48 mmol)とシアノホスホン酸ジエチル(72 μL, 0.48 mmol)を加えた。室温で30分攪拌した後、トリエチルアミン(170 μL, 1.2 mmol)を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝2/3～酢酸エチルのみ)で精製して、題記化合物を淡黄色非定形固体(140 mg, 84%)として得た。
LC/MS 427
NMR (CDCl3) δ: 1.83 - 2.27 (2 H, m), 2.50 (3 H, s), 3.45 - 3.54 (1 H, m), 3.63 - 3.79 (6 H, m), 3.83 (2 H, s), 3.93 (1 H, s), 3.94 - 4.01 (1 H, m), 6.08 - 6.47 (2 H, m), 7.18 (1 H, s), 7.23 (1 H, d, J=1.5 Hz), 7.29 - 7.39 (1 H, m), 7.49 - 7.63 (1 H, m), 8.35 - 8.52 (1 H, m). 1- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) in DMF (1.5 mL) solution with 4-chloro Pyridine-2-carboxylic acid (76 mg, 0.48 mmol) and diethyl cyanophosphonate (72 μL, 0.48 mmol) were added. After stirring at room temperature for 30 minutes, triethylamine (170 μL, 1.2 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/3 to ethyl acetate alone) to give the title compound as a pale yellow amorphous solid (140 mg, 84%).
LC / MS 427
NMR (CDCl 3 ) δ: 1.83-2.27 (2 H, m), 2.50 (3 H, s), 3.45-3.54 (1 H, m), 3.63-3.79 (6 H, m), 3.83 (2 H, s), 3.93 (1 H, s), 3.94-4.01 (1 H, m), 6.08-6.47 (2 H, m), 7.18 (1 H, s), 7.23 (1 H, d, J = 1.5 Hz ), 7.29-7.39 (1 H, m), 7.49-7.63 (1 H, m), 8.35-8.52 (1 H, m).
実施例56
1-[3-(3,4-ジクロロフェニル)プロパノイル]-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン Example 56
1- [3- (3,4-Dichlorophenyl) propanoyl] -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.411 mmol)および3-(3,4-ジクロロフェニル)プロパン酸(108 mg, 0.493 mmol)のDMF(4 mL)溶液に、DEPC(73.5 μL, 0.493 mmol)を加え、室温で30分間攪拌後、反応液にトリエチルアミン(172 μL, 1.23 mmol)を加え、室温で2時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を無色固体(143 mg, 78%)として得た。これをEtOH－IPEより、再結晶して題記化合物を無色固体(84.2 mg)として得た。
LC/MS 444
NMR (CDCl3) δ: 2.51 (3 H, s), 2.61 - 2.70 (2 H, m), 2.94 - 3.01 (2 H, m), 3.11 - 3.25 (4 H, m), 3.53 - 3.62 (2 H, m), 3.76 - 3.83 (2 H, m), 6.88 - 6.96 (2 H, m), 7.05 - 7.10 (2 H, m), 7.30 - 7.37 (2 H, m), 7.47 - 7.54 (2 H, m). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.411 mmol) and 3- (3,4-dichlorophenyl) propanoic acid (108 mg, 0.493 mmol) DEPC (73.5 μL, 0.493 mmol) was added to the DMF (4 mL) solution, and after stirring at room temperature for 30 minutes, triethylamine (172 μL, 1.23 mmol) was added to the reaction solution, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a colorless solid (143 mg, 78%). This was recrystallized from EtOH-IPE to give the title compound as a colorless solid (84.2 mg).
LC / MS 444
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 2.61-2.70 (2 H, m), 2.94-3.01 (2 H, m), 3.11-3.25 (4 H, m), 3.53-3.62 (2 H, m), 3.76-3.83 (2 H, m), 6.88-6.96 (2 H, m), 7.05-7.10 (2 H, m), 7.30-7.37 (2 H, m), 7.47-7.54 (2 H, m).
実施例57
2-メチル-1-(2-{4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-2-オキソエチル)-1H-ベンゾイミダゾール Example 57
2-Methyl-1- (2- {4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.411 mmol)および(2-メチル-1H-ベンゾイミダゾール-1-イル)酢酸(93.8 mg, 0.493 mmol)のDMF(4 mL)溶液に、DEPC(73.5 μL, 0.493 mmol)を加え、室温で30分間攪拌後、反応液にトリエチルアミン(172 μL, 1.23 mmol)を加え、室温で1時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を無色固体(120 mg, 70%)として得た。これをEtOH－IPEより、再結晶して題記化合物を無色固体(62.1 mg)として得た。
LC/MS 416
NMR (CDCl3) δ: 2.51 (3 H, s), 2.58 (3 H, s), 3.21 - 3.34 (4 H, m), 3.69 - 3.88 (4 H, m), 4.92 (2 H, s), 6.91 - 6.97 (2 H, m), 7.08 (1 H, s), 7.13 - 7.24 (3 H, m), 7.49 - 7.56 (2 H, m), 7.67 - 7.73 (1 H, m). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.411 mmol) and (2-methyl-1H-benzimidazol-1-yl) acetic acid (93.8 mg, To a solution of 0.493 mmol) in DMF (4 mL), DEPC (73.5 μL, 0.493 mmol) was added and stirred at room temperature for 30 minutes. . The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a colorless solid (120 mg, 70%). This was recrystallized from EtOH-IPE to give the title compound as a colorless solid (62.1 mg).
LC / MS 416
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 2.58 (3 H, s), 3.21-3.34 (4 H, m), 3.69-3.88 (4 H, m), 4.92 (2 H, s) , 6.91-6.97 (2 H, m), 7.08 (1 H, s), 7.13-7.24 (3 H, m), 7.49-7.56 (2 H, m), 7.67-7.73 (1 H, m).
実施例58
1-(1-メチル-2-{4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-2-オキソエチル)-1H-ベンゾイミダゾール Example 58
1- (1-Methyl-2- {4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.411 mmol)および2-(1H-ベンゾイミダゾール-1-イル)プロパン酸(93.8 mg, 0.493 mmol)のDMF(4 mL)溶液に、DEPC(73.5 μL, 0.493 mmol)を加え、室温で30分間攪拌後、反応液にトリエチルアミン(172 μL, 1.23 mmol)を加え、室温で1時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を無色固体(113 mg, 66%)として得た。これをEtOH－IPEより、再結晶して題記化合物を無色固体(60.5 mg)として得た。
LC/MS 416
NMR (CDCl3) δ: 1.79 (3 H, d, J=6.9 Hz), 2.50 (3 H, s), 2.63 - 2.76 (1 H, m), 3.00 - 3.17 (2 H, m), 3.21 - 3.35 (1 H, m), 3.42 - 3.81 (3 H, m), 3.89 - 4.02 (1 H, m), 5.41 (1 H, q, J=6.9 Hz), 6.78 - 6.85 (2 H, m), 7.05 (1 H, s), 7.27 - 7.37 (2 H, m), 7.39 - 7.51 (3 H, m), 7.80 - 7.87 (1 H, m), 8.06 (1 H, s). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.411 mmol) and 2- (1H-benzimidazol-1-yl) propanoic acid (93.8 mg, 0.493 mmol) in DMF (4 mL) was added DEPC (73.5 μL, 0.493 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a colorless solid (113 mg, 66%). This was recrystallized from EtOH-IPE to give the title compound as a colorless solid (60.5 mg).
LC / MS 416
NMR (CDCl 3 ) δ: 1.79 (3 H, d, J = 6.9 Hz), 2.50 (3 H, s), 2.63-2.76 (1 H, m), 3.00-3.17 (2 H, m), 3.21- 3.35 (1 H, m), 3.42-3.81 (3 H, m), 3.89-4.02 (1 H, m), 5.41 (1 H, q, J = 6.9 Hz), 6.78-6.85 (2 H, m) , 7.05 (1 H, s), 7.27-7.37 (2 H, m), 7.39-7.51 (3 H, m), 7.80-7.87 (1 H, m), 8.06 (1 H, s).
実施例59
1-[(2Z)-3-(4-フルオロフェニル)プロパ-2-エノイル]-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン Example 59
1-[(2Z) -3- (4-Fluorophenyl) prop-2-enoyl] -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(200 mg, 0.822 mmol)および(2Z)-3-(4-フルオロフェニル)プロパ-2-エン酸(164 mg, 0.987 mmol)のDMF(4 mL)溶液に、DEPC(147 μL, 0.987 mmol)を加え、室温で30分間攪拌後、反応液にトリエチルアミン(345 μL, 2.48 mmol)を加え、室温で1時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を無色固体(246 mg, 76%)として得た。これをEtOH－IPEより、再結晶して題記化合物を無色固体(84.3 mg)として得た。
LC/MS 392
NMR (CDCl3) δ: 2.50 (3 H, s), 2.84 - 2.89 (2 H, m), 3.15 - 3.21 (2 H, m), 3.47 - 3.53 (2 H, m), 3.80 - 3.85 (2 H, m), 6.05 (1 H, d, J=12.4 Hz), 6.68 (1 H, d, J=12.4 Hz), 6.81 - 6.88 (2 H, m), 6.97 - 7.06 (3 H, m), 7.34 - 7.41 (2 H, m), 7.44 - 7.51 (2 H, m). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine (200 mg, 0.822 mmol) and (2Z) -3- (4-fluorophenyl) prop-2-enoic acid ( 164 mg, 0.987 mmol) in DMF (4 mL), DEPC (147 μL, 0.987 mmol) was added, stirred at room temperature for 30 minutes, triethylamine (345 μL, 2.48 mmol) was added to the reaction solution, and 1 mL at room temperature was added. Stir for hours. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a colorless solid (246 mg, 76%). This was recrystallized from EtOH-IPE to give the title compound as a colorless solid (84.3 mg).
LC / MS 392
NMR (CDCl 3) δ: 2.50 (3 H, s), 2.84 - 2.89 (2 H, m), 3.15 - 3.21 (2 H, m), 3.47 - 3.53 (2 H, m), 3.80 - 3.85 (2 H, m), 6.05 (1 H, d, J = 12.4 Hz), 6.68 (1 H, d, J = 12.4 Hz), 6.81-6.88 (2 H, m), 6.97-7.06 (3 H, m) , 7.34-7.41 (2 H, m), 7.44-7.51 (2 H, m).
実施例60
4-[3-エトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(2-エチルピラゾロ[1,5-a]ピリジン-3-イル)メチル]ピペラジン-1-カルボキサミド Example 60
4- [3-Ethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(2-ethylpyrazolo [1,5-a] pyridin-3-yl ) Methyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　tert-ブチル 4-[3-エトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート (270 mg, 0.71 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した後、溶媒を減圧留去し、得られた残渣の1/2にN-エチルジイソプロピルアミン(184 μL, 1.06 mmol)および、THF(1 mL)を加え、THF溶液を調製した。
　1-(2-エチルピラゾロ[1,5-a]ピリジン-3-イル)メタンアミン(80.0 mg, 0.457 mmol)のTHF(1 mL)溶液をCDI(73.4 mg, 0.458 mmol)のTHF(1 mL)懸濁液に0℃で加え30分間攪拌した後、先に調製したTHF溶液を0℃で加え、室温で12時間攪拌した。溶媒を減圧留去し、得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、題記化合物を無色固体(116 mg, 67%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(91.0 mg)として得た。
NMR (CDCl3) δ: 1.35 (3 H, t, J=7.7 Hz), 1.41 (3 H, t, J=7.0 Hz), 2.47 (3 H, s), 2.87 (2 H, q, J=7.7 Hz), 3.18 - 3.25 (4 H, m), 3.50 - 3.57 (4 H, m), 4.08 (2 H, q, J=7.0 Hz), 4.40 - 4.45 (1 H, m), 4.57 (2 H, d, J=4.7 Hz), 6.48 - 6.56 (2 H, m), 6.65 - 6.73 (1 H, m), 7.05 - 7.13 (1 H, m), 7.50 - 7.55 (1 H, m), 7.57 (1 H, d, J=8.5 Hz), 8.34 - 8.38 (1 H, m), 8.51 (1 H, s). tert-Butyl 4- [3-ethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (270 mg, 0.71 mmol) in ethyl acetate ( 1.0 mL) 4N hydrochloric acid ethyl acetate solution (4.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 3 hours.The solvent was distilled off under reduced pressure, and N-ethyldiisopropylamine (184 μL, 1.06 mmol) and THF (1 mL) were added to prepare a THF solution.
A solution of 1- (2-ethylpyrazolo [1,5-a] pyridin-3-yl) methanamine (80.0 mg, 0.457 mmol) in THF (1 mL) was added to CDI (73.4 mg, 0.458 mmol) in THF (1 mL). The suspension was added at 0 ° C. and stirred for 30 minutes, and then the previously prepared THF solution was added at 0 ° C. and stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to give the title compound as a colorless solid (116 mg, 67%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (91.0 mg).
NMR (CDCl 3 ) δ: 1.35 (3 H, t, J = 7.7 Hz), 1.41 (3 H, t, J = 7.0 Hz), 2.47 (3 H, s), 2.87 (2 H, q, J = 7.7 Hz), 3.18-3.25 (4 H, m), 3.50-3.57 (4 H, m), 4.08 (2 H, q, J = 7.0 Hz), 4.40-4.45 (1 H, m), 4.57 (2 H, d, J = 4.7 Hz), 6.48-6.56 (2 H, m), 6.65-6.73 (1 H, m), 7.05-7.13 (1 H, m), 7.50-7.55 (1 H, m), 7.57 (1 H, d, J = 8.5 Hz), 8.34-8.38 (1 H, m), 8.51 (1 H, s).
実施例61
5,6-ジクロロ-2-エチル-1-(1-メチル-2-{4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-イル}-2-オキソエチル)-1H-ベンゾイミダゾール Example 61
5,6-Dichloro-2-ethyl-1- (1-methyl-2- {4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (2, 2,2-trifluoroethoxy) phenyl] piperazin-1-yl} -2-oxoethyl) -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート (390 mg, 1.1 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌し、溶媒を減圧留去して塩酸塩を調製した。
　メチル 2-(5,6-ジクロロ-2-エチル-1H-ベンゾイミダゾール-1-イル)プロパノアート(103 mg, 0.342 mmol)、水酸化リチウム一水和物(28.7 mg, 0.684 mmol)および水(300 μL)のTHF(1.5 mL)混合液を40℃で1時間攪拌後、1N塩酸(1.5 mL)を加え、溶媒を減圧留去した。得られた残留物のDMF(3 mL)懸濁液に、先に調製した塩酸塩の1/2量、トリエチルアミン(238 μL, 1.71 mmol)、およびDEPC(84.9 μL, 0.570 mmol)を室温で加えた。2時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝5/5～10/0)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を無色固体(40.0 mg, 23%)として得た。
LC/MS 610
NMR (CDCl3) δ: 1.53 (3 H, t, J=7.7 Hz), 1.69 (3 H, d, J=7.0 Hz), 2.30 - 2.43 (1 H, m), 2.46 (3 H, s), 2.79 - 3.45 (7 H, m), 3.62 - 3.77 (1 H, m), 3.95 - 4.09 (1 H, m), 4.32 (2 H, q, J=7.7 Hz), 5.20 (1 H, q, J=7.0 Hz), 6.34 (1 H, d, J=2.2 Hz), 6.53 (1 H, dd, J=8.8, 2.2 Hz), 7.53 (1 H, s), 7.56 (1 H, d, J=8.8 Hz), 7.81 (1 H, s), 8.39 (1 H, s). tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxylate ( 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to a suspension of 390 mg, 1.1 mmol) in ethyl acetate (1.0 mL), stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure to prepare hydrochloride.
Methyl 2- (5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl) propanoate (103 mg, 0.342 mmol), lithium hydroxide monohydrate (28.7 mg, 0.684 mmol) and water (300 μL) THF (1.5 mL) was stirred at 40 ° C. for 1 hour, 1N hydrochloric acid (1.5 mL) was added, and the solvent was evaporated under reduced pressure. To the DMF (3 mL) suspension of the obtained residue, add 1/2 volume of the previously prepared hydrochloride, triethylamine (238 μL, 1.71 mmol), and DEPC (84.9 μL, 0.570 mmol) at room temperature. It was. After stirring for 2 hours, water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 5 / 5-10 / 0) and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (40.0 mg, 23%) Got as.
LC / MS 610
NMR (CDCl 3 ) δ: 1.53 (3 H, t, J = 7.7 Hz), 1.69 (3 H, d, J = 7.0 Hz), 2.30-2.43 (1 H, m), 2.46 (3 H, s) , 2.79-3.45 (7 H, m), 3.62-3.77 (1 H, m), 3.95-4.09 (1 H, m), 4.32 (2 H, q, J = 7.7 Hz), 5.20 (1 H, q , J = 7.0 Hz), 6.34 (1 H, d, J = 2.2 Hz), 6.53 (1 H, dd, J = 8.8, 2.2 Hz), 7.53 (1 H, s), 7.56 (1 H, d, J = 8.8 Hz), 7.81 (1 H, s), 8.39 (1 H, s).
実施例62
N-{2-[(3-クロロ-4-フルオロフェニル)アミノ]-2-オキソエチル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 62
N- {2-[(3-Chloro-4-fluorophenyl) amino] -2-oxoethyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　エチルN-({4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}カルボニル)グリシナート(100 mg, 0.248 mmol)、水酸化リチウム一水和物(20.8 mg, 0.496 mmol)および水(500 μL)のTHF(2.5 mL)混合液を40℃で30分間攪拌後、6N塩酸(124 μL)を加え、溶媒を減圧留去した。この残留物と、3-クロロ-4-フルオロアニリン(43.3 mg, 0.297 mmol)、WSC(57.0 mg, 0.297 mmol)、HOBt(45.6 mg, 0.298 mmol)およびトリエチルアミン(173 μL, 1.24 mmol)のDMF(2.5 mL)混合液を室温で2時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄し、題記化合物を無色固体 (6.5 mg, 5%)として得た。
LC/MS 502
NMR (DMSO-d6) δ: 2.43 (3 H, s), 3.20 - 3.27 (4 H, m), 3.43 - 3.52 (4 H, m), 3.80 (2 H, d, J=6.3 Hz), 3.91 (3 H, s), 6.60 - 6.68 (2 H, m), 7.04 - 7.11 (1 H, m), 7.15 (1 H, s), 7.32 - 7.40 (1 H, m), 7.44 - 7.53 (2 H, m), 7.92 (1 H, dd, J=6.7, 2.6 Hz), 10.12 (1 H, s). Ethyl N-({4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} carbonyl) glycinate (100 mg, 0.248 mmol), hydroxylated A mixture of lithium monohydrate (20.8 mg, 0.496 mmol) and water (500 μL) in THF (2.5 mL) was stirred at 40 ° C. for 30 min, 6N hydrochloric acid (124 μL) was added, and the solvent was evaporated under reduced pressure. . This residue was combined with 3-chloro-4-fluoroaniline (43.3 mg, 0.297 mmol), WSC (57.0 mg, 0.297 mmol), HOBt (45.6 mg, 0.298 mmol) and triethylamine (173 μL, 1.24 mmol) in DMF ( (2.5 mL) The mixture was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound as a colorless solid (6.5 mg, 5%).
LC / MS 502
NMR (DMSO-d 6) δ :   2.43 (3 H, s), 3.20-3.27 (4 H, m), 3.43-3.52 (4 H, m), 3.80 (2 H, d, J = 6.3 Hz), 3.91 (3 H, s), 6.60 -6.68 (2 H, m), 7.04-7.11 (1 H, m), 7.15 (1 H, s), 7.32-7.40 (1 H, m), 7.44-7.53 (2 H, m), 7.92 (1 H, dd, J = 6.7, 2.6 Hz), 10.12 (1 H, s).
実施例63
1-[1-({4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}カルボニル)プロピル]-1H-ベンゾイミダゾール Example 63
1- [1-({4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} carbonyl) propyl] -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　エチル2-(1H-ベンゾイミダゾール-1-イル)ブタノアート(102 mg, 0.439 mmol)、水酸化リチウム一水和物(36.8 mg, 0.877 mmol)および水(200 μL)のTHF(1 mL)混合液を室温で16時間攪拌後、6N塩酸(146 μL)を加え、溶媒を減圧留去した。得られた残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(90.0 mg, 0.329 mmol)およびDEPC(63.7 μL, 0.428 mmol)のDMF(1 mL)混合液を室温で30分間攪拌後、トリエチルアミン(138 μL, 0.990 mmol)を加えて、室温で1時間攪拌した。この反応液に水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝5/5～10/0)で精製し、題記化合物を無色固体 (67.7 mg, 45%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(59.1 mg)として得た。
LC/MS 460
NMR (CDCl3) δ: 0.94 (3 H, t, J=7.3 Hz), 2.15 - 2.38 (2 H, m), 2.49 (3 H, s), 2.60 - 2.74 (1 H, m), 2.98 - 3.19 (2 H, m), 3.21 - 3.33 (1 H, m), 3.45 - 3.78 (3 H, m), 3.86 - 4.01 (4 H, m), 5.09 - 5.18 (1 H, m), 6.36 (1 H, d, J=2.2 Hz), 6.43 (1 H, dd, J=8.5, 2.2 Hz), 7.22 (1 H, s), 7.27 - 7.37 (2 H, m), 7.41 - 7.47 (1 H, m), 7.55 (1 H, d, J=8.5 Hz), 7.79 - 7.86 (1 H, m), 8.09 (1 H, s). Ethyl 2- (1H-benzoimidazol-1-yl) butanoate (102 mg, 0.439 mmol), lithium hydroxide monohydrate (36.8 mg, 0.877 mmol) and water (200 μL) in THF (1 mL) Was stirred at room temperature for 16 hours, 6N hydrochloric acid (146 μL) was added, and the solvent was distilled off under reduced pressure. The resulting residue and 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (90.0 mg, 0.329 mmol) and DEPC (63.7 μL, 0.428 mmol) Of DMF (1 mL) was stirred at room temperature for 30 minutes, triethylamine (138 μL, 0.990 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 5 / 5-10 / 0) to give the title compound as a colorless solid (67.7 mg, 45%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (59.1 mg).
LC / MS 460
NMR (CDCl 3 ) δ: 0.94 (3 H, t, J = 7.3 Hz), 2.15-2.38 (2 H, m), 2.49 (3 H, s), 2.60-2.74 (1 H, m), 2.98- 3.19 (2 H, m), 3.21-3.33 (1 H, m), 3.45-3.78 (3 H, m), 3.86-4.01 (4 H, m), 5.09-5.18 (1 H, m), 6.36 ( 1 H, d, J = 2.2 Hz), 6.43 (1 H, dd, J = 8.5, 2.2 Hz), 7.22 (1 H, s), 7.27-7.37 (2 H, m), 7.41-7.47 (1 H , m), 7.55 (1 H, d, J = 8.5 Hz), 7.79-7.86 (1 H, m), 8.09 (1 H, s).
実施例64
1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-1-メチル-2-オキソエチル)-1H-インドール Example 64
1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -1-methyl-2-oxoethyl) -1H- Indole
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　メチル2-(1H-インドール-1-イル)プロパノアート(89.2 mg, 0.439 mmol)、水酸化リチウム一水和物(36.8 mg, 0.877 mmol)および水(200 μL)のTHF(1 mL)混合液を40℃で2時間攪拌後、6N塩酸(146 μL)を加え、溶媒を減圧留去した。この残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(90.0 mg, 0.329 mmol)およびDEPC(147 μL, 0.987 mmol)のDMF(1 mL)混合液を室温で30分間攪拌後、トリエチルアミン(183 μL, 1.31 mmol)を加えて、室温で2時間攪拌した。この反応液に水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝5/5～10/0)で精製し、題記化合物を無色固体 (61.5 mg, 42%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(56.6 mg)として得た。
LC/MS 445
NMR (CDCl3) δ: 1.67 (3 H, d, J=6.6 Hz), 2.40 - 2.59 (4 H, m), 2.92 - 3.12 (2 H, m), 3.24 - 3.50 (3 H, m), 3.58 - 3.72 (1 H, m), 3.86 (3 H, s), 3.96 - 4.14 (1 H, m), 5.35 (1 H, q, J=6.6 Hz), 6.32 (1 H, d, J=2.2 Hz), 6.40 (1 H, dd, J=8.5, 2.2 Hz), 6.54 - 6.57 (1 H, m), 7.10 - 7.18 (2 H, m), 7.20 - 7.32 (2 H, m), 7.35 - 7.40 (1 H, m), 7.52 (1 H, d, J=8.5 Hz), 7.61 - 7.67 (1 H, m).  A THF (1 mL) mixture of methyl 2- (1H-indol-1-yl) propanoate (89.2 mg, 0.439 mmol), lithium hydroxide monohydrate (36.8 mg, 0.877 mmol) and water (200 μL) was added. After stirring at 40 ° C. for 2 hours, 6N hydrochloric acid (146 μL) was added, and the solvent was distilled off under reduced pressure. This residue was combined with 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (90.0 mg, 0.329 mmol) and DEPC (147 μL, 0.987 mmol) in DMF. (1 mL) The mixture was stirred at room temperature for 30 minutes, triethylamine (183 μL, 1.31 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 5 / 5-10 / 0) to give the title compound as a colorless solid (61.5 mg, 42%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (56.6 mg).
LC / MS 445
NMR (CDCl 3 ) δ: 1.67 (3 H, d, J = 6.6 Hz), 2.40-2.59 (4 H, m), 2.92-3.12 (2 H, m), 3.24-3.50 (3 H, m), 3.58-3.72 (1 H, m), 3.86 (3 H, s), 3.96-4.14 (1 H, m), 5.35 (1 H, q, J = 6.6 Hz), 6.32 (1 H, d, J = 2.2 Hz), 6.40 (1 H, dd, J = 8.5, 2.2 Hz), 6.54-6.57 (1 H, m), 7.10-7.18 (2 H, m), 7.20-7.32 (2 H, m), 7.35 -7.40 (1 H, m), 7.52 (1 H, d, J = 8.5 Hz), 7.61-7.67 (1 H, m).
実施例65
5,6-ジフルオロ-1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-1-メチル-2-オキソエチル)-1H-ベンゾイミダゾール Example 65
5,6-difluoro-1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -1-methyl-2 -Oxoethyl) -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　メチル2-(5,6-ジフルオロ-1H-ベンゾイミダゾール-1-イル)プロパノアート(132 mg, 0.550 mmol)、水酸化リチウム一水和物(46.2 mg, 1.10 mmol)および水(260 μL)のTHF(1.3 mL)混合液を室温で16時間攪拌後、6N塩酸(183 μL)を加え、溶媒を減圧留去した。この残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.366 mmol)およびDEPC(164 μL, 1.10 mmol)のDMF(1 mL)混合液を室温で30分間攪拌後、トリエチルアミン(204 μL, 1.46 mmol)を加えて、室温で1時間攪拌した。この反応液に水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝4/6～10/0)で精製し、題記化合物を無色固体 (126 mg, 72%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(92.7 mg)として得た。
LC/MS 482
NMR (CDCl3) δ: 1.79 (3 H, d, J=6.9 Hz), 2.49 (3 H, s), 2.75 - 2.89 (1 H, m), 3.02 - 3.34 (3 H, m), 3.45 - 3.68 (2 H, m), 3.69 - 3.83 (1 H, m), 3.85 - 3.99 (4 H, m), 5.33 (1 H, q, J=6.9 Hz), 6.40 (1 H, d, J=2.2 Hz), 6.47 (1 H, dd, J=8.7, 2.2 Hz), 7.20 - 7.28 (2 H, m), 7.53 - 7.63 (2 H, m), 8.06 (1 H, s). Methyl 2- (5,6-difluoro-1H-benzimidazol-1-yl) propanoate (132 mg, 0.550 mmol), lithium hydroxide monohydrate (46.2 mg, 1.10 mmol) and water (260 μL) in THF (1.3 mL) The mixture was stirred at room temperature for 16 hours, 6N hydrochloric acid (183 μL) was added, and the solvent was evaporated under reduced pressure. This residue was combined with 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.366 mmol) and DEPC (164 μL, 1.10 mmol) in DMF. (1 mL) The mixture was stirred at room temperature for 30 minutes, triethylamine (204 μL, 1.46 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 4 / 6-10 / 0) to give the title compound as a colorless solid (126 mg, 72%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (92.7 mg).
LC / MS 482
NMR (CDCl 3 ) δ: 1.79 (3 H, d, J = 6.9 Hz), 2.49 (3 H, s), 2.75-2.89 (1 H, m), 3.02-3.34 (3 H, m), 3.45- 3.68 (2 H, m), 3.69-3.83 (1 H, m), 3.85-3.99 (4 H, m), 5.33 (1 H, q, J = 6.9 Hz), 6.40 (1 H, d, J = 2.2 Hz), 6.47 (1 H, dd, J = 8.7, 2.2 Hz), 7.20-7.28 (2 H, m), 7.53-7.63 (2 H, m), 8.06 (1 H, s).
実施例66
N-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-1,1-ジメチル-2-オキソエチル)-2-ニトロアニリン Example 66
N- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -1,1-dimethyl-2-oxoethyl)- 2-Nitroaniline
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(150 mg, 0.549 mmol)、2-メチル-N-(2-ニトロフェニル)アラニン(160 mg, 0.714 mmol)およびDEPC(98.1 μL, 0.659 mmol)のDMF(3 mL)混合液を室温で30分間攪拌後、トリエチルアミン(230 μL, 1.65 mmol)を加えて、室温で1時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水で洗浄して題記化合物を黄色固体(177 mg, 67%)として得た。
LC/MS 480
NMR (CDCl3) δ: 1.72 (6 H, s), 2.48 (3 H, s), 2.76 - 3.23 (4 H, m), 3.77 - 4.07 (7 H, m), 6.35 (1 H, d, J=2.2 Hz), 6.42 (1 H, dd, J=8.5, 2.2 Hz), 6.66 - 6.74 (1 H, m), 6.80 (1 H, d, J=8.5 Hz), 7.21 (1 H, s), 7.33 - 7.42 (1 H, m), 7.54 (1 H, d, J=8.5 Hz), 8.19 (1 H, dd, J=8.5, 1.6 Hz), 8.38 (1 H, s). 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (150 mg, 0.549 mmol), 2-methyl-N- (2-nitrophenyl) alanine (160 mg, 0.714 mmol) and DEPC (98.1 μL, 0.659 mmol) in DMF (3 mL) were stirred at room temperature for 30 minutes, triethylamine (230 μL, 1.65 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water to give the title compound as a yellow solid (177 mg, 67%).
LC / MS 480
NMR (CDCl 3 ) δ: 1.72 (6 H, s), 2.48 (3 H, s), 2.76-3.23 (4 H, m), 3.77-4.07 (7 H, m), 6.35 (1 H, d, J = 2.2 Hz), 6.42 (1 H, dd, J = 8.5, 2.2 Hz), 6.66-6.74 (1 H, m), 6.80 (1 H, d, J = 8.5 Hz), 7.21 (1 H, s ), 7.33-7.42 (1 H, m), 7.54 (1 H, d, J = 8.5 Hz), 8.19 (1 H, dd, J = 8.5, 1.6 Hz), 8.38 (1 H, s).
実施例67
3-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-2-オキソエチル)-1H-インダゾール Example 67
3- (2- {4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) -1H-indazole
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　エチル 1H-インダゾール-3-イルアセタート(105 mg, 0.514 mmol)、水酸化リチウム一水和物(46.3 mg, 1.10 mmol)および水(250 μL)のTHF(1 mL)混合液を40℃で2時間攪拌後、6N塩酸(183 μL)を加え、溶媒を減圧留去した。この残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.366 mmol)およびDEPC(164 μL, 1.10 mmol)のDMF(1 mL)混合液を室温で30分間攪拌後、トリエチルアミン(204 μL, 1.46 mmol)を加えて、室温で1時間攪拌した。この反応液に水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝5/5～10/0)で精製し、題記化合物を無色固体 (73.5 mg, 46%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(62.6 mg)として得た。
LC/MS 432
NMR (CDCl3) δ: 2.49 (3 H, s), 3.01 - 3.08 (2 H, m), 3.12 - 3.19 (2 H, m), 3.76 - 3.83 (4 H, m), 3.89 (3 H, s), 4.16 (2 H, s), 6.41 (1 H, d, J=2.2 Hz), 6.48 (1 H, dd, J=8.5, 2.2 Hz), 7.13 - 7.20 (1 H, m), 7.23 (1 H, s), 7.34 - 7.46 (2 H, m), 7.55 (1 H, d, J=8.5 Hz), 7.82 - 7.89 (1 H, m), 10.08 (1 H, brs). Ethyl 1H-indazol-3-yl acetate (105 mg, 0.514 mmol), lithium hydroxide monohydrate (46.3 mg, 1.10 mmol) and water (250 μL) in THF (1 mL) were mixed at 40 ° C for 2 hours. After stirring, 6N hydrochloric acid (183 μL) was added, and the solvent was distilled off under reduced pressure. This residue was combined with 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.366 mmol) and DEPC (164 μL, 1.10 mmol) in DMF. (1 mL) The mixture was stirred at room temperature for 30 minutes, triethylamine (204 μL, 1.46 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 5 / 5-10 / 0) to give the title compound as a colorless solid (73.5 mg, 46%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (62.6 mg).
LC / MS 432
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 3.01-3.08 (2 H, m), 3.12-3.19 (2 H, m), 3.76-3.83 (4 H, m), 3.89 (3 H, s), 4.16 (2 H, s), 6.41 (1 H, d, J = 2.2 Hz), 6.48 (1 H, dd, J = 8.5, 2.2 Hz), 7.13-7.20 (1 H, m), 7.23 (1 H, s), 7.34-7.46 (2 H, m), 7.55 (1 H, d, J = 8.5 Hz), 7.82-7.89 (1 H, m), 10.08 (1 H, brs).
実施例68
1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-1,1-ジメチル-2-オキソエチル)-1H-ベンゾイミダゾール Example 68
1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -1,1-dimethyl-2-oxoethyl)- 1H-benzimidazole
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　N-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-1,1-ジメチル-2-オキソエチル)-2-ニトロアニリン(150 mg, 0.313 mmol)、Pd/C(30 mg)、オルトギ酸トリメチル(2.5 mL)およびギ酸(500 μL)の混合物を水素雰囲気下、室温で16時間攪拌後、ろ過し、減圧濃縮した。残留物を酢酸エチルで希釈し、1N水酸化ナトリウム水溶液および飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝4/6～10/0)で精製し、題記化合物を無色固体 (92.5 mg, 64%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(59.0 mg)として得た。
LC/MS 460
NMR (CDCl3) δ: 1.98 (6 H, s), 2.17 - 2.45 (2 H, m), 2.47 (3 H, s), 2.83 - 3.24 (4 H, m), 3.66 - 3.95 (5 H, m), 6.20 (1 H, d, J=2.2 Hz), 6.29 (1 H, dd, J=8.5, 2.2 Hz), 7.19 (1 H, s), 7.23 - 7.31 (2 H, m), 7.31 - 7.37 (1 H, m), 7.49 (1 H, d, J=8.5 Hz), 7.80 - 7.86 (1 H, m), 8.10 (1 H, s). N- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -1,1-dimethyl-2-oxoethyl)- A mixture of 2-nitroaniline (150 mg, 0.313 mmol), Pd / C (30 mg), trimethyl orthoformate (2.5 mL) and formic acid (500 μL) was stirred in a hydrogen atmosphere at room temperature for 16 hours, filtered, Concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 4/6 to 10/0) to give the title compound as a colorless solid (92.5 mg, 64%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (59.0 mg).
LC / MS 460
NMR (CDCl 3 ) δ: 1.98 (6 H, s), 2.17-2.45 (2 H, m), 2.47 (3 H, s), 2.83-3.24 (4 H, m), 3.66-3.95 (5 H, m), 6.20 (1 H, d, J = 2.2 Hz), 6.29 (1 H, dd, J = 8.5, 2.2 Hz), 7.19 (1 H, s), 7.23-7.31 (2 H, m), 7.31 -7.37 (1 H, m), 7.49 (1 H, d, J = 8.5 Hz), 7.80-7.86 (1 H, m), 8.10 (1 H, s).
実施例69
3-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-1-メチル-2-オキソエチル)ピラゾロ[1,5-a]ピリジン Example 69
3- (2- {4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -1-methyl-2-oxoethyl) pyrazolo [1 , 5-a] pyridine
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(76.5 mg, 0.280 mmol)、2-ピラゾロ[1,5-a]ピリジン-3-イルプロパン酸(64.0 mg, 0.336 mmol)およびDEPC(50.1 μL, 0.336 mmol)のDMF(1.5 mL)混合液を室温で30分間攪拌後、トリエチルアミン(117 μL, 0.839 mmol)を加えて、室温で2時間攪拌した。この反応液に水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝5/5～10/0)およびシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、題記化合物を無色非定形固体(77.0 mg, 62%)として得た。
LC/MS 446
NMR (CDCl3) δ: 1.54 (3 H, d, J=6.9 Hz), 2.48 (3 H, s), 2.60 - 2.73 (1 H, m), 2.97 - 3.18 (2 H, m), 3.20 - 3.32 (1 H, m), 3.51 - 3.77 (3 H, m), 3.86 - 4.02 (4 H, m), 4.19 (1 H, q, J=6.9 Hz), 6.35 - 6.49 (2 H, m), 6.71 - 6.79 (1 H, m), 7.05 - 7.14 (1 H, m), 7.21 (1 H, s), 7.54 (1 H, d, J=8.5 Hz), 7.58 - 7.64 (1 H, m), 7.85 (1 H, s), 8.39 - 8.45 (1 H, m). 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (76.5 mg, 0.280 mmol), 2-pyrazolo [1,5-a] pyridin-3-yl After stirring a mixture of propanoic acid (64.0 mg, 0.336 mmol) and DEPC (50.1 μL, 0.336 mmol) in DMF (1.5 mL) at room temperature for 30 minutes, triethylamine (117 μL, 0.839 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Stir. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 5 / 5-10 / 0) and silica gel column chromatography (ethyl acetate) to give the title compound as a colorless amorphous solid (77.0 mg, 62 %).
LC / MS 446
NMR (CDCl 3) δ: 1.54 (3 H, d, J = 6.9 Hz), 2.48 (3 H, s), 2.60 - 2.73 (1 H, m), 2.97 - 3.18 (2 H, m), 3.20 - 3.32 (1 H, m), 3.51-3.77 (3 H, m), 3.86-4.02 (4 H, m), 4.19 (1 H, q, J = 6.9 Hz), 6.35-6.49 (2 H, m) , 6.71-6.79 (1 H, m), 7.05-7.14 (1 H, m), 7.21 (1 H, s), 7.54 (1 H, d, J = 8.5 Hz), 7.58-7.64 (1 H, m ), 7.85 (1 H, s), 8.39-8.45 (1 H, m).
実施例70
1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-2-オキソエチル)-1H-ピロロ[2,3-b]ピリジン Example 70
1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) -1H-pyrrolo [2, 3-b] pyridine
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　メチル 1H-ピロロ[2,3-b]ピリジン-1-イルアセタート(105 mg, 0.552 mmol)、水酸化リチウム一水和物(46.3 mg, 1.10 mmol)および水(200 μL)のTHF(1 mL)混合液を室温で12時間攪拌後、6N塩酸(183 μL)を加え、溶媒を減圧留去した。この残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.366 mmol)およびDEPC(164 μL, 1.10 mmol)のDMF(2 mL)混合液を室温で30分間攪拌後、トリエチルアミン(204 μL, 1.46 mmol)を加えて、室温で4時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を白色固体(131 mg, 83%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(109 mg)として得た。
LC/MS 432
NMR (CDCl3) δ: 2.50 (3 H, s), 3.13 - 3.26 (4 H, m), 3.76 - 3.84 (4 H, m), 3.92 (3 H, s), 5.20 (2 H, s), 6.45 (1 H, d, J=2.2 Hz), 6.49 - 6.57 (2 H, m), 7.08 (1 H, dd, J=7.8, 4.8 Hz), 7.24 (1 H, s), 7.33 (1 H, d, J=3.6 Hz), 7.58 (1 H, d, J=8.5 Hz), 7.92 (1 H, dd, J=7.8, 1.5 Hz), 8.29 (1 H, dd, J=4.8, 1.5 Hz). Methyl 1H-pyrrolo [2,3-b] pyridin-1-ylacetate (105 mg, 0.552 mmol), lithium hydroxide monohydrate (46.3 mg, 1.10 mmol) and water (200 μL) in THF (1 mL) The mixture was stirred at room temperature for 12 hours, 6N hydrochloric acid (183 μL) was added, and the solvent was evaporated under reduced pressure. This residue was combined with 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.366 mmol) and DEPC (164 μL, 1.10 mmol) in DMF. (2 mL) The mixture was stirred at room temperature for 30 min, triethylamine (204 μL, 1.46 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a white solid (131 mg, 83%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (109 mg).
LC / MS 432
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.13-3.26 (4 H, m), 3.76-3.84 (4 H, m), 3.92 (3 H, s), 5.20 (2 H, s) , 6.45 (1 H, d, J = 2.2 Hz), 6.49-6.57 (2 H, m), 7.08 (1 H, dd, J = 7.8, 4.8 Hz), 7.24 (1 H, s), 7.33 (1 H, d, J = 3.6 Hz), 7.58 (1 H, d, J = 8.5 Hz), 7.92 (1 H, dd, J = 7.8, 1.5 Hz), 8.29 (1 H, dd, J = 4.8, 1.5 Hz).
実施例71
5-クロロ-1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-2-オキソエチル)-1H-ピロロ[2,3-b]ピリジン Example 71
5-chloro-1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) -1H- Pyrrolo [2,3-b] pyridine
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　メチル (5-クロロ-1H-ピロロ[2,3-b]ピリジン-1-イル)アセタート(124 mg, 0.552 mmol)、水酸化リチウム一水和物(46.3 mg, 1.10 mmol)および水(200 μL)のTHF(1 mL)混合液を室温で12時間攪拌後、6N塩酸(183 μL)を加え、溶媒を減圧留去した。この残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.366 mmol)およびDEPC(164 μL, 1.10 mmol)のDMF(2 mL)混合液を室温で30分間攪拌後、トリエチルアミン(204 μL, 1.46 mmol)を加えて、室温で4時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を白色固体(116 mg, 68%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を白色固体(99.9 mg)として得た。
LC/MS 466
NMR (CDCl3) δ: 2.50 (3 H, s), 3.18 - 3.27 (4 H, m), 3.76 - 3.83 (4 H, m), 3.93 (3 H, s), 5.16 (2 H, s), 6.46 (1 H, d, J=2.2 Hz), 6.49 (1 H, d, J=3.6 Hz), 6.54 (1 H, dd, J=8.5, 2.2 Hz), 7.25 (1 H, s), 7.36 (1 H, d, J=3.6 Hz), 7.60 (1 H, d, J=8.5 Hz), 7.89 (1 H, d, J=2.2 Hz), 8.22 (1 H, d, J=2.2 Hz). Methyl (5-chloro-1H-pyrrolo [2,3-b] pyridin-1-yl) acetate (124 mg, 0.552 mmol), lithium hydroxide monohydrate (46.3 mg, 1.10 mmol) and water (200 μL ) Was stirred at room temperature for 12 hours, 6N hydrochloric acid (183 μL) was added, and the solvent was evaporated under reduced pressure. This residue was combined with 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.366 mmol) and DEPC (164 μL, 1.10 mmol) in DMF. (2 mL) The mixture was stirred at room temperature for 30 min, triethylamine (204 μL, 1.46 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a white solid (116 mg, 68%). This was recrystallized from ethyl acetate-hexane to give the title compound as a white solid (99.9 mg).
LC / MS 466
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.18-3.27 (4 H, m), 3.76-3.83 (4 H, m), 3.93 (3 H, s), 5.16 (2 H, s) , 6.46 (1 H, d, J = 2.2 Hz), 6.49 (1 H, d, J = 3.6 Hz), 6.54 (1 H, dd, J = 8.5, 2.2 Hz), 7.25 (1 H, s), 7.36 (1 H, d, J = 3.6 Hz), 7.60 (1 H, d, J = 8.5 Hz), 7.89 (1 H, d, J = 2.2 Hz), 8.22 (1 H, d, J = 2.2 Hz ).
実施例72
1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}-2-オキソエチル)-5-(トリフルオロメチル)-1H-ピロロ[2,3-b]ピリジン Example 72
1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) -5- (trifluoromethyl ) -1H-pyrrolo [2,3-b] pyridine
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　メチル[5-(トリフルオロメチル)-1H-ピロロ[2,3-b]ピリジン-1-イル]アセタート(142 mg, 0.550 mmol)、水酸化リチウム一水和物(46.3 mg, 1.10 mmol)および水(200 μL)のTHF(1 mL)混合液を室温で12時間攪拌後、6N塩酸(183 μL)を加え、溶媒を減圧留去した。この残留物と、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(100 mg, 0.366 mmol)およびDEPC(164 μL, 1.10 mmol)のDMF(2 mL)混合液を室温で30分間攪拌後、トリエチルアミン(204 μL, 1.46 mmol)を加えて、室温で2時間攪拌した。反応液を水で希釈し、生じた沈殿物を濾取し、水とIPEで洗浄して題記化合物を白色固体(109 mg, 60%)として得た。これを酢酸エチル－ヘキサンより、再結晶して題記化合物を無色固体(87.6 mg)として得た。
LC/MS 500
NMR (CDCl3) δ: 2.50 (3 H, s), 3.21 - 3.30 (4 H, m), 3.78 - 3.86 (4 H, m), 3.93 (3 H, s), 5.23 (2 H, s), 6.47 (1 H, d, J=2.2 Hz), 6.55 (1 H, dd, J=8.5, 2.2 Hz), 6.65 (1 H, d, J=3.6 Hz), 7.23 - 7.27 (1 H, m), 7.45 (1 H, d, J=3.6 Hz), 7.60 (1 H, d, J=8.5 Hz), 8.16 - 8.19 (1 H, m), 8.53 - 8.56 (1 H, m). Methyl [5- (trifluoromethyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] acetate (142 mg, 0.550 mmol), lithium hydroxide monohydrate (46.3 mg, 1.10 mmol) and A mixture of water (200 μL) in THF (1 mL) was stirred at room temperature for 12 hours, 6N hydrochloric acid (183 μL) was added, and the solvent was evaporated under reduced pressure. This residue was combined with 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (100 mg, 0.366 mmol) and DEPC (164 μL, 1.10 mmol) in DMF. (2 mL) The mixture was stirred at room temperature for 30 min, triethylamine (204 μL, 1.46 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration, and washed with water and IPE to give the title compound as a white solid (109 mg, 60%). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless solid (87.6 mg).
LC / MS 500
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.21-3.30 (4 H, m), 3.78-3.86 (4 H, m), 3.93 (3 H, s), 5.23 (2 H, s) , 6.47 (1 H, d, J = 2.2 Hz), 6.55 (1 H, dd, J = 8.5, 2.2 Hz), 6.65 (1 H, d, J = 3.6 Hz), 7.23-7.27 (1 H, m ), 7.45 (1 H, d, J = 3.6 Hz), 7.60 (1 H, d, J = 8.5 Hz), 8.16-8.19 (1 H, m), 8.53-8.56 (1 H, m).
実施例73
N-{[1-(3,4-ジクロロフェニル)シクロプロピル]メチル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 73
N-{[1- (3,4-dichlorophenyl) cyclopropyl] methyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　CDI (65 mg, 0.40 mmol)のDMF (1 mL)溶液に、N-エチルジイソプロピルアミン (0.12 mL, 0.73 mmol)及び、1-[1-(3,4-ジクロロフェニル)シクロプロピル]メタンアミン　１塩酸塩(0.10 g, 0.40 mmol)のDMF (1 mL)溶液を氷冷下で加えた。室温で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.10 g,0.37 mmol)を加え、室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝3/7～酢酸エチルのみ)で精製して、題記化合物を非定形固体 (0.10 g, 55%)として得た。
LC/MS 515
NMR (CDCl3) δ: 0.82 - 0.92 (2 H, m), 0.92 - 1.02 (2 H, m), 2.50 (3 H, s), 3.15 - 3.30 (4 H, m), 3.40 - 3.55 (6 H, m), 3.93 (3 H, s), 4.43 (1 H, t, J=5.6 Hz), 6.46 (1 H, d, J=2.2 Hz), 6.54 (1 H, dd, J=8.5, 2.5 Hz), 7.16 (1 H, dd, J=8.2, 2.2 Hz), 7.24 (1 H, s), 7.33 - 7.42 (2 H, m), 7.59 (1 H, d, J=8.5 Hz). To a solution of CDI (65 mg, 0.40 mmol) in DMF (1 mL), N-ethyldiisopropylamine (0.12 mL, 0.73 mmol) and 1- [1- (3,4-dichlorophenyl) cyclopropyl] methanamine monohydrochloride A solution of (0.10 g, 0.40 mmol) in DMF (1 mL) was added under ice cooling. After stirring at room temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.10 g, 0.37 mmol) was added and stirred at room temperature for 5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 3 / 7-ethyl acetate alone) to give the title compound as an amorphous solid (0.10 g, 55%).
LC / MS 515
NMR (CDCl 3 ) δ: 0.82-0.92 (2 H, m), 0.92-1.02 (2 H, m), 2.50 (3 H, s), 3.15-3.30 (4 H, m), 3.40-3.55 (6 H, m), 3.93 (3 H, s), 4.43 (1 H, t, J = 5.6 Hz), 6.46 (1 H, d, J = 2.2 Hz), 6.54 (1 H, dd, J = 8.5, 2.5 Hz), 7.16 (1 H, dd, J = 8.2, 2.2 Hz), 7.24 (1 H, s), 7.33-7.42 (2 H, m), 7.59 (1 H, d, J = 8.5 Hz).
実施例74
4-[4-(1,3-オキサゾール-5-イル)フェニル]-N-[3-(トリフルオロメチル)ベンジル]ピペラジン-1-カルボキサミド Example 74
4- [4- (1,3-oxazol-5-yl) phenyl] -N- [3- (trifluoromethyl) benzyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　tert-ブチル 4-[4-(1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート (0.84 g, 2.6 mmol)の酢酸エチル(10 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で３時間撹拌した後、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄し、淡黄色固体(0.83 g)を得た。
　CDI(0.15 g, 0.90 mmol)のTHF (3 mL)溶液に1-[3-(トリフルオロメチル)フェニル]メタンアミン (0.13 g, 0.90 mmol)のTHF (2 mL)溶液を氷冷下で加え氷冷下で1時間攪拌した
後、先で得られた淡黄色固体(0.20 g)とN-エチルジイソプロピルアミン(0.31 ml, 1.81 mmol)を加え、室温で6時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝7/3～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (0.10 g, 31%)として得た。
LC/MS 431
NMR (CDCl3) δ: 3.23 - 3.35 (4 H, m), 3.53 - 3.65 (4 H, m), 4.52 (2 H, d, J=5.5 Hz), 4.90 (1 H, brs), 6.88 - 7.00 (2 H, m), 7.21 (1 H, s), 7.40 - 7.50 (1 H, m), 7.50 - 7.64 (5 H, m), 7.85 (1 H, s). tert-Butyl 4- [4- (1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.84 g, 2.6 mmol) in ethyl acetate (10 mL) and 4N hydrochloric acid ethyl acetate solution (5 mL) was added and stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate to give a pale yellow solid (0.83 g).
To a solution of CDI (0.15 g, 0.90 mmol) in THF (3 mL) was added 1- [3- (trifluoromethyl) phenyl] methanamine (0.13 g, 0.90 mmol) in THF (2 mL) under ice-cooling. After stirring for 1 hour under cooling, the pale yellow solid obtained previously (0.20 g) and N-ethyldiisopropylamine (0.31 ml, 1.81 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7 / 3-ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.10 g, 31%) Got as.
LC / MS 431
NMR (CDCl 3) δ: 3.23 - 3.35 (4 H, m), 3.53 - 3.65 (4 H, m), 4.52 (2 H, d, J = 5.5 Hz), 4.90 (1 H, brs), 6.88 - 7.00 (2 H, m), 7.21 (1 H, s), 7.40-7.50 (1 H, m), 7.50-7.64 (5 H, m), 7.85 (1 H, s).
実施例75
4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[2-(メチルスルホニル)-5-(トリフルオロメチル)ベンジル]ピペラジン-1-カルボキサミド Example 75
4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -N- [2- (methylsulfonyl) -5- (trifluoromethyl) benzyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、N-エチルジイソプロピルアミン(0.15 mL, 0.86 mmol)及び、1-[2-(メチルスルホニル)-5-(トリフルオロメチル)フェニル]メタンアミン　1塩酸塩(0.21 g, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で2時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で4時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ～酢酸エチル/メタノール=9/1)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (0.18 g, 55%)として得た。
LC/MS 523
NMR (CDCl3) δ: 2.51 (3 H, s), 3.16 - 3.31 (7 H, m), 3.48 - 3.62 (4 H, m), 4.77 (2 H, d, J=6.0 Hz), 5.72 (1 H, t, J=5.9 Hz), 6.85 - 6.97 (2 H, m), 7.05 (1 H, s), 7.44 - 7.57 (2 H, m), 7.75 (1 H, dd, J=8.2, 1.9 Hz), 7.98 (1 H, d, J=1.4 Hz), 8.16 (1 H, d, J=8.2 Hz). To a solution of CDI (0.12 g, 0.74 mmol) in THF (3 mL), N-ethyldiisopropylamine (0.15 mL, 0.86 mmol) and 1- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl] A solution of methanamine monohydrochloride (0.21 g, 0.74 mmol) in THF (2 mL) was added under ice cooling. After stirring for 2 hours under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1-ethyl acetate only-ethyl acetate / methanol = 9/1) and recrystallized from hexane-ethyl acetate to give the title compound. Obtained as a white solid (0.18 g, 55%).
LC / MS 523
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 3.16-3.31 (7 H, m), 3.48-3.62 (4 H, m), 4.77 (2 H, d, J = 6.0 Hz), 5.72 ( 1 H, t, J = 5.9 Hz), 6.85-6.97 (2 H, m), 7.05 (1 H, s), 7.44-7.57 (2 H, m), 7.75 (1 H, dd, J = 8.2, 1.9 Hz), 7.98 (1 H, d, J = 1.4 Hz), 8.16 (1 H, d, J = 8.2 Hz).
実施例76
N-(6-クロロ-2,3-ジヒドロ-1H-インデン-1-イル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 76
N- (6-Chloro-2,3-dihydro-1H-inden-1-yl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、N-エチルジイソプロピルアミン(0.13 mL, 0.74 mmol)及び、6-クロロ-2,3-ジヒドロ-1H-インデン-1-アミン　1塩酸塩(0.15 g, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で4時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/4～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体(0.11 g, 42%)として得た。
LC/MS 437
NMR (CDCl3) δ: 1.73 - 1.91 (1 H, m), 2.51 (3 H, s), 2.59 - 2.74 (1 H, m), 2.75 - 3.01 (2 H, m), 3.22 - 3.32 (4 H, m), 3.54 - 3.64 (4 H, m), 4.66 (1 H, d, J=8.0 Hz), 5.42 (1 H, q, J=7.7 Hz), 6.89 - 6.98 (2 H, m), 7.06 (1 H, s), 7.12 - 7.24 (2 H, m), 7.31 (1 H, s), 7.45 - 7.58 (2 H, m). To a solution of CDI (0.12 g, 0.74 mmol) in THF (3 mL), N-ethyldiisopropylamine (0.13 mL, 0.74 mmol) and 6-chloro-2,3-dihydro-1H-inden-1-amine 1 hydrochloric acid A solution of salt (0.15 g, 0.74 mmol) in THF (2 mL) was added under ice cooling. After stirring for 1 hour under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.11 g, 42%) Got as.
LC / MS 437
NMR (CDCl 3 ) δ: 1.73-1.91 (1 H, m), 2.51 (3 H, s), 2.59-2.74 (1 H, m), 2.75-3.01 (2 H, m), 3.22-3.32 (4 H, m), 3.54-3.64 (4 H, m), 4.66 (1 H, d, J = 8.0 Hz), 5.42 (1 H, q, J = 7.7 Hz), 6.89-6.98 (2 H, m) , 7.06 (1 H, s), 7.12-7.24 (2 H, m), 7.31 (1 H, s), 7.45-7.58 (2 H, m).
実施例77
N-[2-(3,4-ジクロロフェニル)エチル]-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 77
N- [2- (3,4-Dichlorophenyl) ethyl] -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、2-(3,4-ジクロロフェニル)エタンアミン(0.11 mL, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で4時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/4～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (0.16 g, 55%)として得た。
LC/MS 459
NMR (CDCl3) δ: 2.51 (3 H, s), 2.82 (2 H, t, J=6.9 Hz), 3.18 - 3.27 (4 H, m), 3.43 - 3.57 (6 H, m), 4.55 (1 H, t, J=5.8 Hz), 6.87 - 6.96 (2 H, m), 6.99 - 7.08 (2 H, m), 7.29 (1 H, d, J=1.9 Hz), 7.37 (1 H, d, J=8.2 Hz), 7.45 - 7.54 (2 H, m). To a THF (3 mL) solution of CDI (0.12 g, 0.74 mmol), a THF (2 mL) solution of 2- (3,4-dichlorophenyl) ethanamine (0.11 mL, 0.74 mmol) was added under ice cooling. After stirring for 1 hour under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.16 g, 55%) Got as.
LC / MS 459
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 2.82 (2 H, t, J = 6.9 Hz), 3.18-3.27 (4 H, m), 3.43-3.57 (6 H, m), 4.55 ( 1 H, t, J = 5.8 Hz), 6.87-6.96 (2 H, m), 6.99-7.08 (2 H, m), 7.29 (1 H, d, J = 1.9 Hz), 7.37 (1 H, d , J = 8.2 Hz), 7.45-7.54 (2 H, m).
実施例78
N-[1-(3,4-ジクロロフェニル)シクロプロピル]-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 78
N- [1- (3,4-Dichlorophenyl) cyclopropyl] -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、N-エチルジイソプロピルアミン(0.13 mL, 0.74 mmol)及び、1-(3,4-ジクロロフェニル)シクロプロパンアミン　1塩酸塩(0.18 g, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で4時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をメタノールで洗浄後、酢酸エチル－メタノールから再結晶し、題記化合物を白色固体 (84 mg, 29%)として得た。
LC/MS 471
NMR (DMSO-d6) δ: 1.17 (4 H, d, J=9.1 Hz), 2.42 (3 H, s), 3.10 - 3.26 (4 H, m), 3.38 - 3.53 (4 H, m), 7.01 (2 H, d, J=8.5 Hz), 7.12 (1 H, dd, J=8.5, 2.2 Hz), 7.28 (1 H, s), 7.33 (1 H, d, J=1.6 Hz), 7.44 - 7.57 (4 H, m). To a solution of CDI (0.12 g, 0.74 mmol) in THF (3 mL) was added N-ethyldiisopropylamine (0.13 mL, 0.74 mmol) and 1- (3,4-dichlorophenyl) cyclopropanamine monohydrochloride (0.18 g, 0.74 mmol) in THF (2 mL) was added under ice cooling. After stirring for 1 hour under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with methanol and recrystallized from ethyl acetate-methanol to give the title compound as a white solid (84 mg, 29%).
LC / MS 471
NMR (DMSO-d 6 ) δ: 1.17 (4 H, d, J = 9.1 Hz), 2.42 (3 H, s), 3.10-3.26 (4 H, m), 3.38-3.53 (4 H, m), 7.01 (2 H, d, J = 8.5 Hz), 7.12 (1 H, dd, J = 8.5, 2.2 Hz), 7.28 (1 H, s), 7.33 (1 H, d, J = 1.6 Hz), 7.44 -7.57 (4 H, m).
実施例79
4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-(3-フェノキシベンジル)ピペラジン-1-カルボキサミド Example 79
4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -N- (3-phenoxybenzyl) piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、N-エチルジイソプロピルアミン(0.13 mL, 0.74 mmol)及び、1-(3-フェノキシフェニル)メタンアミン　1塩酸塩(0.17 g, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1.5時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体(0.11 g, 38%)として得た。
LC/MS 469
NMR (CDCl3) δ: 2.51 (3 H, s), 3.20 - 3.29 (4 H, m), 3.52 - 3.61 (4 H, m), 4.45 (2 H, d, J=5.5 Hz), 4.77 (1 H, t, J=5.6 Hz), 6.85 - 7.14 (9 H, m), 7.28 - 7.37 (3 H, m), 7.45 - 7.56 (2 H, m). To a solution of CDI (0.12 g, 0.74 mmol) in THF (3 mL), N-ethyldiisopropylamine (0.13 mL, 0.74 mmol) and 1- (3-phenoxyphenyl) methanamine monohydrochloride (0.17 g, 0.74 mmol) In THF (2 mL) was added under ice cooling. After stirring for 1.5 hours under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.11 g, 38%) Got as.
LC / MS 469
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 3.20-3.29 (4 H, m), 3.52-3.61 (4 H, m), 4.45 (2 H, d, J = 5.5 Hz), 4.77 ( 1 H, t, J = 5.6 Hz), 6.85-7.14 (9 H, m), 7.28-7.37 (3 H, m), 7.45-7.56 (2 H, m).
実施例80
N-(ビフェニル-3-イルメチル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 80
N- (biphenyl-3-ylmethyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、3-フェニルベンジルアミン(0.14 g, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1.5時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄後、酢酸エチル－メタノールから再結晶し、題記化合物を白色固体(0.15 mg, 52%)として得た。
LC/MS 453
NMR (CDCl3) δ: 2.51 (3 H, s), 3.15 - 3.35 (4 H, m), 3.51 - 3.67 (4 H, m), 4.53 (2 H, d, J=5.5 Hz), 4.82 (1 H, brs), 6.92 (2 H, d, J=9.1 Hz), 7.05 (1 H, s), 7.28 - 7.67 (11 H, m). To a THF (3 mL) solution of CDI (0.12 g, 0.74 mmol), a THF (2 mL) solution of 3-phenylbenzylamine (0.14 g, 0.74 mmol) was added under ice cooling. After stirring for 1.5 hours under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and recrystallized from ethyl acetate-methanol to give the title compound as a white solid (0.15 mg, 52%).
LC / MS 453
NMR (CDCl 3) δ: 2.51 (3 H, s), 3.15 - 3.35 (4 H, m), 3.51 - 3.67 (4 H, m), 4.53 (2 H, d, J = 5.5 Hz), 4.82 ( 1 H, brs), 6.92 (2 H, d, J = 9.1 Hz), 7.05 (1 H, s), 7.28-7.67 (11 H, m).
実施例81
N-(2,2-ジフェニルエチル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 81
N- (2,2-diphenylethyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　CDI(0.12 g, 0.74 mmol)のTHF(3 mL)溶液に、2,2-ジフェニルエタンアミン(0.15 g, 0.74 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で3時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、酢酸エチルから再結晶し、題記化合物を白色固体(98 mg, 34%)として得た。
LC/MS 467
NMR (CDCl3) δ: 2.51 (3 H, s), 3.08 - 3.20 (4 H, m), 3.35 - 3.44 (4 H, m), 3.90 (2 H, dd, J=7.8, 5.6 Hz), 4.25 (1 H, t, J=7.8 Hz), 4.39 (1 H, t, J=5.6 Hz), 6.83 - 6.93 (2 H, m), 7.05 (1 H, s), 7.18 - 7.26 (3 H, m), 7.26 - 7.36 (7 H, m), 7.45 - 7.53 (2 H, m). To a THF (3 mL) solution of CDI (0.12 g, 0.74 mmol), a THF (2 mL) solution of 2,2-diphenylethanamine (0.15 g, 0.74 mmol) was added under ice cooling. After stirring for 1 hour under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from ethyl acetate to give the title compound as a white solid (98 mg, 34%). It was.
LC / MS 467
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 3.08-3.20 (4 H, m), 3.35-3.44 (4 H, m), 3.90 (2 H, dd, J = 7.8, 5.6 Hz), 4.25 (1 H, t, J = 7.8 Hz), 4.39 (1 H, t, J = 5.6 Hz), 6.83-6.93 (2 H, m), 7.05 (1 H, s), 7.18-7.26 (3 H , m), 7.26-7.36 (7 H, m), 7.45-7.53 (2 H, m).
実施例82
2-({4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}カルボニル)-1H-インドール Example 82
2-({4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} carbonyl) -1H-indole
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.12 g, 0.49 mmol)と1H-インドール-2-カルボン酸(95 mg, 0.59 mmol)のDMF(5 mL)溶液に、DEPC(88 μL, 0.59 mmol)を加え、室温下で30分間攪拌した。反応混合物にトリエチルアミン(0.21 mL, 1.5 mmol)を加え、室温で終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をメタノールで洗浄後、メタノールから再結晶し、題記化合物を白色固体(0.12 g, 64%)として得た。
LC/MS 386
NMR (CDCl3) δ: 2.52 (3 H, s), 3.30 - 3.44 (4 H, m), 4.12 (4 H, brs), 6.84 (1 H, d, J=1.4 Hz), 6.92 - 7.00 (2 H, m), 7.08 (1 H, s), 7.11 - 7.20 (1 H, m), 7.31 (1 H, td, J=7.7, 1.1 Hz), 7.41 - 7.47 (1 H, m), 7.50 - 7.57 (2 H, m), 7.67 (1 H, d, J=8.0 Hz), 9.16 (1 H, brs). 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.12 g, 0.49 mmol) and 1H-indole-2-carboxylic acid (95 mg, 0.59 mmol) in DMF (5 To the solution, DEPC (88 μL, 0.59 mmol) was added and stirred at room temperature for 30 minutes. Triethylamine (0.21 mL, 1.5 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with methanol and recrystallized from methanol to give the title compound as a white solid (0.12 g, 64%).
LC / MS 386
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 3.30-3.44 (4 H, m), 4.12 (4 H, brs), 6.84 (1 H, d, J = 1.4 Hz), 6.92-7.00 ( 2 H, m), 7.08 (1 H, s), 7.11-7.20 (1 H, m), 7.31 (1 H, td, J = 7.7, 1.1 Hz), 7.41-7.47 (1 H, m), 7.50 -7.57 (2 H, m), 7.67 (1 H, d, J = 8.0 Hz), 9.16 (1 H, brs).
実施例83
1-{[2-(4-フルオロフェニル)ピロリジン-1-イル]カルボニル}-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン Example 83
1-{[2- (4-Fluorophenyl) pyrrolidin-1-yl] carbonyl} -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　炭酸ビス(トリクロロメチル)(56 mg, 0.19 mmol)のTHF(1 mL)溶液に、トリエチルアミン(64 μL, 0.47 mmol)と2-(4-フルオロフェニル)ピロリジン (77 mg, 0.47 mmol)のTHF(1 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、トリエチルアミン(0.11 mL, 0.80 mmol)と1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチル－メタノールで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、酢酸エチルから再結晶し、題記化合物を白色固体(81 mg, 40%)として得た。
LC/MS 435
NMR (CDCl3) δ: 1.66 - 1.82 (1 H, m), 1.82 - 2.04 (2 H, m), 2.27 - 2.43 (1 H, m), 2.51 (3 H, s), 3.07 - 3.19 (2 H, m), 3.19 - 3.32 (2 H, m), 3.33 - 3.45 (2 H, m), 3.46 - 3.58 (2 H, m), 3.59 - 3.70 (2 H, m), 5.02 (1 H, dd, J=8.9, 6.7 Hz), 6.87 - 7.03 (4 H, m), 7.05 (1 H, s), 7.17 - 7.26 (2 H, m), 7.42 - 7.57 (2 H, m). To a solution of bis (trichloromethyl carbonate) (56 mg, 0.19 mmol) in THF (1 mL), triethylamine (64 μL, 0.47 mmol) and 2- (4-fluorophenyl) pyrrolidine (77 mg, 0.47 mmol) in THF ( 1 mL) solution was added under ice cooling. After stirring for 1 hour under ice cooling, triethylamine (0.11 mL, 0.80 mmol) and 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) were added. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-methanol. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from ethyl acetate to give the title compound as a white solid (81 mg, 40%). It was.
LC / MS 435
NMR (CDCl 3 ) δ: 1.66-1.82 (1 H, m), 1.82-2.04 (2 H, m), 2.27-2.43 (1 H, m), 2.51 (3 H, s), 3.07-3.19 (2 H, m), 3.19-3.32 (2 H, m), 3.33-3.45 (2 H, m), 3.46-3.58 (2 H, m), 3.59-3.70 (2 H, m), 5.02 (1 H, dd, J = 8.9, 6.7 Hz), 6.87-7.03 (4 H, m), 7.05 (1 H, s), 7.17-7.26 (2 H, m), 7.42-7.57 (2 H, m).
実施例84
N-(1-ベンゾチオフェン-3-イルメチル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 84
N- (1-benzothiophen-3-ylmethyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　CDI(95 mg, 0.59 mmol)のTHF (3 mL)溶液に、N-エチルジイソプロピルアミン (0.10 mL, 0.59 mmol)及び、1-(1-ベンゾチオフェン-3-イル)メタンアミン　1塩酸塩 (0.12 g, 0.59 mmol)のTHF(2 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.12 g, 0.49 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (63 mg, 29%)として得た。
LC/MS 433
NMR (CDCl3) δ: 2.51 (3 H, s), 3.17 - 3.28 (4 H, m), 3.51 - 3.62 (4 H, m), 4.65 - 4.77 (3 H, m), 6.87 - 6.95 (2 H, m), 7.05 (1 H, s), 7.33 - 7.43 (3 H, m), 7.46 - 7.56 (2 H, m), 7.82 - 7.92 (2 H, m). To a solution of CDI (95 mg, 0.59 mmol) in THF (3 mL), N-ethyldiisopropylamine (0.10 mL, 0.59 mmol) and 1- (1-benzothiophen-3-yl) methanamine monohydrochloride (0.12 g , 0.59 mmol) in THF (2 mL) was added under ice cooling. After stirring for 1 hour under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.12 g, 0.49 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (63 mg, 29%).
LC / MS 433
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 3.17-3.28 (4 H, m), 3.51-3.62 (4 H, m), 4.65-4.77 (3 H, m), 6.87-6.95 (2 H, m), 7.05 (1 H, s), 7.33-7.43 (3 H, m), 7.46-7.56 (2 H, m), 7.82-7.92 (2 H, m).
実施例85
N-(1H-インドール-3-イルメチル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 85
N- (1H-Indol-3-ylmethyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　CDI(95 mg, 0.59 mmol)のTHF(5 mL)溶液に、1-(1H-インドール-3-イル)メタンアミン(87 mg, 0.59 mmol)を氷冷下で加えた。氷冷下で1時間攪拌した後、1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(0.15 g, 0.62 mmol)を加え、室温で3時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をメタノールで洗浄後、ヘキサン－メタノールから再結晶し、題記化合物を白色固体(79 mg, 39%)として得た。
LC/MS 416
NMR (CDCl3) δ: 2.50 (3 H, s), 3.13 - 3.28 (4 H, m), 3.44 - 3.61 (4 H, m), 4.53 - 4.70 (3 H, m), 6.85 - 6.97 (2 H, m), 7.05 (1 H, s), 7.10 - 7.25 (3 H, m), 7.37 - 7.44 (1 H, m), 7.45 - 7.53 (2 H, m), 7.69 (1 H, d, J=7.7 Hz), 8.12 (1 H, brs). To a solution of CDI (95 mg, 0.59 mmol) in THF (5 mL), 1- (1H-indol-3-yl) methanamine (87 mg, 0.59 mmol) was added under ice cooling. After stirring for 1 hour under ice cooling, 1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.15 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with methanol and recrystallized from hexane-methanol to give the title compound as a white solid (79 mg, 39%).
LC / MS 416
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.13-3.28 (4 H, m), 3.44-3.61 (4 H, m), 4.53-4.70 (3 H, m), 6.85-6.97 (2 H, m), 7.05 (1 H, s), 7.10-7.25 (3 H, m), 7.37-7.44 (1 H, m), 7.45-7.53 (2 H, m), 7.69 (1 H, d, J = 7.7 Hz), 8.12 (1 H, brs).
実施例86
4-({4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-イル}カルボニル)-3-フェニルモルホリン Example 86
4-({4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazin-1-yl} carbonyl) -3-phenylmorpholine
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　炭酸ビス(トリクロロメチル) (78 mg, 0.26 mmol)のTHF (2 mL)溶液に、トリエチルアミン (0.13 mL, 0.92 mmol)と1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン (0.18 g, 0.66 mmol)のTHF (2 mL)溶液を氷冷下で加えた。氷冷下で30分間攪拌した後、トリエチルアミン (0.20 mL, 1.4 mmol)と3-フェニルモルホリン１塩酸塩 (0.16 g, 0.79 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (0.18 g, 58%)として得た。
LC/MS 463
NMR (CDCl3) δ: 2.48 (3 H, s), 3.13 - 3.42 (6 H, m), 3.42 - 3.65 (4 H, m), 3.73 - 3.85 (2 H, m), 3.86 (3 H, s), 3.89 - 3.99 (1 H, m), 4.03 - 4.14 (1 H, m), 4.79 (1 H, t, J=4.0 Hz), 6.50 - 6.62 (2 H, m), 7.27 - 7.47 (5 H, m), 7.54 (1 H, d, J=8.5 Hz), 8.44 (1 H, s). To a solution of bis (trichloromethyl carbonate) (78 mg, 0.26 mmol) in THF (2 mL), triethylamine (0.13 mL, 0.92 mmol) and 1- [3-methoxy-4- (3-methyl-1H-1,2 , 4-Triazol-1-yl) phenyl] piperazine (0.18 g, 0.66 mmol) in THF (2 mL) was added under ice cooling. After stirring for 30 minutes under ice cooling, triethylamine (0.20 mL, 1.4 mmol) and 3-phenylmorpholine monohydrochloride (0.16 g, 0.79 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.18 g, 58% ).
LC / MS 463
NMR (CDCl 3 ) δ: 2.48 (3 H, s), 3.13-3.42 (6 H, m), 3.42-3.65 (4 H, m), 3.73-3.85 (2 H, m), 3.86 (3 H, s), 3.89-3.99 (1 H, m), 4.03-4.14 (1 H, m), 4.79 (1 H, t, J = 4.0 Hz), 6.50-6.62 (2 H, m), 7.27-7.47 ( 5 H, m), 7.54 (1 H, d, J = 8.5 Hz), 8.44 (1 H, s).
実施例87
N-エチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 87
N-ethyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
　4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド(0.12 g, 0.26 mmol)のDMF (2 mL)溶液に、水素化ナトリウム (13 mg, 0.33 mmol, 60%油状)を氷冷下で加え、同温度で30分間撹拌した。反応溶液にヨウ化エチル (26 μL, 0.33 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (33 mg, 27%)として得た。
LC/MS 469
NMR (CDCl3) δ: 0.98 (3 H, t, J=7.0 Hz), 1.77 (3 H, d, J=6.9 Hz), 2.50 (3 H, s), 2.81 - 3.08 (2 H, m), 3.10 - 3.51 (8 H, m), 5.94 (1 H, q, J=6.7 Hz), 6.91 (2 H, d, J=8.8 Hz), 7.05 (1 H, s), 7.41 - 7.53 (5 H, m), 7.53 - 7.61 (1 H, m), 7.75 - 7.91 (2 H, m), 7.94 - 8.06 (1 H, m). 4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide (0.12 g, 0.26 mmol) To a DMF (2 mL) solution of sodium hydride (13 mg, 0.33 mmol, 60% oil) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min. Ethyl iodide (26 μL, 0.33 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (33 mg, 27%) Got as.
LC / MS 469
NMR (CDCl 3 ) δ: 0.98 (3 H, t, J = 7.0 Hz), 1.77 (3 H, d, J = 6.9 Hz), 2.50 (3 H, s), 2.81-3.08 (2 H, m) , 3.10-3.51 (8 H, m), 5.94 (1 H, q, J = 6.7 Hz), 6.91 (2 H, d, J = 8.8 Hz), 7.05 (1 H, s), 7.41-7.53 (5 H, m), 7.53-7.61 (1 H, m), 7.75-7.91 (2 H, m), 7.94-8.06 (1 H, m).
実施例88
[(2R*,3R*)-3-(3,4-ジクロロフェニル)-1-({4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-イル}カルボニル)ピロリジン-2-イル]メタノール Example 88
[(2R * , 3R * )-3- (3,4-dichlorophenyl) -1-({4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl ) Phenyl] piperazin-1-yl} carbonyl) pyrrolidin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　炭酸ビス(トリクロロメチル) (52 mg, 0.18 mmol)のTHF (3 mL)溶液に、トリエチルアミン (0.22 mL, 1.6 mmol)と1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン (0.12 g, 0.44 mmol)を氷冷下で加えた。氷冷下で1時間攪拌した後、[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メタノール　1塩酸塩 (0.15 g, 0.53 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (79 mg, 33%)として得た。
LC/MS 545
NMR (CDCl3) δ: 2.07 - 2.38 (2 H, m), 2.48 (3 H, s), 3.18 - 3.38 (4 H, m), 3.43 (2 H, t, J=5.1 Hz), 3.47 - 3.66 (6 H, m), 3.66 - 3.84 (2 H, m), 3.88 (3 H, s), 4.38 - 4.54 (1 H, m), 6.50 - 6.65 (2 H, m), 7.08 (1 H, dd, J=8.1, 1.5 Hz), 7.33 (1 H, d, J=1.6 Hz), 7.40 (1 H, d, J=8.2 Hz), 7.55 (1 H, d, J=8.2 Hz), 8.44 (1 H, s). To a solution of bis (trichloromethyl carbonate) (52 mg, 0.18 mmol) in THF (3 mL), triethylamine (0.22 mL, 1.6 mmol) and 1- [3-methoxy-4- (3-methyl-1H-1,2 , 4-Triazol-1-yl) phenyl] piperazine (0.12 g, 0.44 mmol) was added under ice cooling. After stirring for 1 hour under ice cooling, [(2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methanol monohydrochloride (0.15 g, 0.53 mmol) was added, and at room temperature. Stir overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (79 mg, 33% ).
LC / MS 545
NMR (CDCl 3 ) δ: 2.07-2.38 (2 H, m), 2.48 (3 H, s), 3.18-3.38 (4 H, m), 3.43 (2 H, t, J = 5.1 Hz), 3.47- 3.66 (6 H, m), 3.66-3.84 (2 H, m), 3.88 (3 H, s), 4.38-4.54 (1 H, m), 6.50-6.65 (2 H, m), 7.08 (1 H , dd, J = 8.1, 1.5 Hz), 7.33 (1 H, d, J = 1.6 Hz), 7.40 (1 H, d, J = 8.2 Hz), 7.55 (1 H, d, J = 8.2 Hz), 8.44 (1 H, s).
実施例89
1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-4-[(2-フェニルアゼチジン-1-イル)カルボニル]ピペラジン Example 89
1- [3-Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -4-[(2-phenylazetidin-1-yl) carbonyl] piperazine
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　炭酸ビス(トリクロロメチル) (48 mg, 0.16 mmol)のTHF (1 mL)溶液に、トリエチルアミン (0.15 mL, 1.1 mmol)と1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン (0.11 g, 0.40 mmol)を氷冷下で加えた。氷冷下で1時間攪拌した後、2-フェニルアゼチジン(64 mg, 0.48 mmol)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (63 mg, 36%)として得た。
LC/MS 433
NMR (CDCl3) δ: 2.16 - 2.34 (1 H, m), 2.47 (3 H, s), 2.60 - 2.79 (1 H, m), 3.06 - 3.20 (4 H, m), 3.37 - 3.59 (4 H, m), 3.86 (3 H, s), 3.92 - 4.06 (1 H, m), 4.09 - 4.23 (1 H, m), 5.41 (1 H, dd, J=9.1, 6.9 Hz), 6.43 - 6.57 (2 H, m), 7.18 - 7.30 (1 H, m), 7.30 - 7.43 (4 H, m), 7.51 (1 H, d, J=8.5 Hz), 8.42 (1 H, s). To a solution of bis (trichloromethyl carbonate) (48 mg, 0.16 mmol) in THF (1 mL), triethylamine (0.15 mL, 1.1 mmol) and 1- [3-methoxy-4- (3-methyl-1H-1,2 , 4-Triazol-1-yl) phenyl] piperazine (0.11 g, 0.40 mmol) was added under ice cooling. After stirring for 1 hour under ice-cooling, 2-phenylazetidine (64 mg, 0.48 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (63 mg, 36%) Got as.
LC / MS 433
NMR (CDCl 3 ) δ: 2.16-2.34 (1 H, m), 2.47 (3 H, s), 2.60-2.79 (1 H, m), 3.06-3.20 (4 H, m), 3.37-3.59 (4 H, m), 3.86 (3 H, s), 3.92-4.06 (1 H, m), 4.09-4.23 (1 H, m), 5.41 (1 H, dd, J = 9.1, 6.9 Hz), 6.43- 6.57 (2 H, m), 7.18-7.30 (1 H, m), 7.30-7.43 (4 H, m), 7.51 (1 H, d, J = 8.5 Hz), 8.42 (1 H, s).
実施例90
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[4-(トリフルオロメチル)ベンジル]ピペラジン-1-カルボキサミド Example 90
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- [4- (trifluoromethyl) benzyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　CDI (65 mg, 0.40 mmol)のDMF (1 mL)溶液に、1-[4-(トリフルオロメチル)フェニル]メタンアミン (57 μL, 0.40 mmol)のDMF (1 mL)溶液を室温下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.10 g, 0.37 mmol)のDMF (1 mL)溶液を加え、室温で3日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝3/7～酢酸エチルのみ)で精製し、題記化合物を非定形固体 (0.10 g, 59%)として得た。
LC/MS 475
NMR (CDCl3) δ: 2.50 (3 H, s), 3.22 - 3.35 (4 H, m), 3.55 - 3.66 (4 H, m), 3.94 (3 H, s), 4.52 (2 H, d, J=5.5 Hz), 4.90 (1 H, t, J=5.8 Hz), 6.48 (1 H, d, J=2.2 Hz), 6.55 (1 H, dd, J=8.5, 2.2 Hz), 7.25 (1 H, s), 7.44 (2 H, d, J=8.0 Hz), 7.60 (3 H, d, J=8.5 Hz). To a solution of CDI (65 mg, 0.40 mmol) in DMF (1 mL) was added 1- [4- (trifluoromethyl) phenyl] methanamine (57 μL, 0.40 mmol) in DMF (1 mL) at room temperature. . After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.10 g, 0.37 mmol) in DMF (1 mL) solution And stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 7-ethyl acetate alone) to give the title compound as an amorphous solid (0.10 g, 59%).
LC / MS 475
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.22-3.35 (4 H, m), 3.55-3.66 (4 H, m), 3.94 (3 H, s), 4.52 (2 H, d, J = 5.5 Hz), 4.90 (1 H, t, J = 5.8 Hz), 6.48 (1 H, d, J = 2.2 Hz), 6.55 (1 H, dd, J = 8.5, 2.2 Hz), 7.25 (1 H, s), 7.44 (2 H, d, J = 8.0 Hz), 7.60 (3 H, d, J = 8.5 Hz).
実施例91
N-(シクロプロピルメチル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 91
N- (cyclopropylmethyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
　CDI (65 mg, 0.40 mmol)のDMF (1 mL)溶液に、1-シクロプロピルメタンアミン (35 μL, 0.40 mmol)のDMF (1 mL)溶液を室温下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.10 g, 0.37 mmol)のDMF (1 mL)溶液を加え、室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ) で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (30 mg, 22%)として得た。
LC/MS 371
NMR (CDCl3) δ: 0.14 - 0.28 (2 H, m), 0.45 - 0.61 (2 H, m), 0.89 - 1.09 (1 H, m), 2.51 (3 H, s), 3.13 (2 H, dd, J=7.0, 5.1 Hz), 3.22 - 3.33 (4 H, m), 3.51 - 3.63 (4 H, m), 3.94 (3 H, s), 4.57 (1 H, brs), 6.49 (1 H, d, J=2.2 Hz), 6.56 (1 H, dd, J=8.5, 2.2 Hz), 7.25 (1 H, s), 7.60 (1 H, d, J=8.5 Hz). To a DMF (1 mL) solution of CDI (65 mg, 0.40 mmol), a DMF (1 mL) solution of 1-cyclopropylmethanamine (35 μL, 0.40 mmol) was added at room temperature. After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.10 g, 0.37 mmol) in DMF (1 mL) solution And stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (30 mg, 22%) Got as.
LC / MS 371
NMR (CDCl 3 ) δ: 0.14-0.28 (2 H, m), 0.45-0.61 (2 H, m), 0.89-1.09 (1 H, m), 2.51 (3 H, s), 3.13 (2 H, dd, J = 7.0, 5.1 Hz), 3.22-3.33 (4 H, m), 3.51-3.63 (4 H, m), 3.94 (3 H, s), 4.57 (1 H, brs), 6.49 (1 H , d, J = 2.2 Hz), 6.56 (1 H, dd, J = 8.5, 2.2 Hz), 7.25 (1 H, s), 7.60 (1 H, d, J = 8.5 Hz).
実施例92
N-(シクロヘキシルメチル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 92
N- (Cyclohexylmethyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
　CDI (65 mg, 0.40 mmol)のDMF (1 mL)溶液に、1-シクロヘキシルメタンアミン (52 μL, 0.40 mmol)のDMF (1 mL)溶液を室温下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.10 g, 0.37 mmol)のDMF (1 mL)溶液を加え、室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ) で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体 (70 mg, 46%)として得た。
LC/MS 413
NMR (CDCl3) δ: 0.82 - 1.04 (2 H, m), 1.09 - 1.36 (3 H, m), 1.38 - 1.58 (1 H, m), 1.63 - 1.82 (5 H, m), 2.51 (3 H, s), 3.06 - 3.16 (2 H, m), 3.21 - 3.31 (4 H, m), 3.48 - 3.61 (4 H, m), 3.94 (3 H, s), 4.54 (1 H, t, J=5.5 Hz), 6.48 (1 H, d, J=2.2 Hz), 6.55 (1 H, dd, J=8.7, 2.3 Hz), 7.24 (1 H, s), 7.60 (1 H, d, J=8.5 Hz). To a DMF (1 mL) solution of CDI (65 mg, 0.40 mmol), a DMF (1 mL) solution of 1-cyclohexylmethanamine (52 μL, 0.40 mmol) was added at room temperature. After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.10 g, 0.37 mmol) in DMF (1 mL) solution And stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (70 mg, 46% ).
LC / MS 413
NMR (CDCl 3 ) δ: 0.82-1.04 (2 H, m), 1.09-1.36 (3 H, m), 1.38-1.58 (1 H, m), 1.63-1.82 (5 H, m), 2.51 (3 H, s), 3.06-3.16 (2 H, m), 3.21-3.31 (4 H, m), 3.48-3.61 (4 H, m), 3.94 (3 H, s), 4.54 (1 H, t, J = 5.5 Hz), 6.48 (1 H, d, J = 2.2 Hz), 6.55 (1 H, dd, J = 8.7, 2.3 Hz), 7.24 (1 H, s), 7.60 (1 H, d, J = 8.5 Hz).
実施例93
N-[シアノ(3,4-ジクロロフェニル)メチル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 93
N- [Cyano (3,4-dichlorophenyl) methyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125
　CDI (78 mg, 0.48 mmol)のDMF (1 mL)溶液に、アミノ(3,4-ジクロロフェニル)アセトニトリル (0.11 g, 0.53 mmol)のDMF (1 mL)溶液を氷冷下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.12 g, 0.44 mmol)のDMF (1 mL)溶液を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ) で精製し、題記化合物を非定形固体 (90 mg, 41%)として得た。
LC/MS 500
NMR (CDCl3) δ: 2.50 (3 H, s), 3.21 - 3.38 (4 H, m), 3.52 - 3.73 (4 H, m), 3.93 (3 H, s), 5.38 (1 H, brs), 6.09 (1 H, d, J=8.5 Hz), 6.44 - 6.51 (1 H, m), 6.55 (1 H, dd, J=8.4, 1.8 Hz), 7.23 (1 H, s), 7.33 - 7.46 (1 H, m), 7.46 - 7.57 (1 H, m), 7.58 - 7.70 (2 H, m). To a DMF (1 mL) solution of CDI (78 mg, 0.48 mmol), a DMF (1 mL) solution of amino (3,4-dichlorophenyl) acetonitrile (0.11 g, 0.53 mmol) was added under ice cooling. After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.12 g, 0.44 mmol) in DMF (1 mL) And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as an amorphous solid (90 mg, 41%).
LC / MS 500
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.21-3.38 (4 H, m), 3.52-3.73 (4 H, m), 3.93 (3 H, s), 5.38 (1 H, brs) , 6.09 (1 H, d, J = 8.5 Hz), 6.44-6.51 (1 H, m), 6.55 (1 H, dd, J = 8.4, 1.8 Hz), 7.23 (1 H, s), 7.33-7.46 (1 H, m), 7.46-7.57 (1 H, m), 7.58-7.70 (2 H, m).
実施例94
メチル (3,4-ジクロロフェニル)[({4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}カルボニル)アミノ]アセタート Example 94
Methyl (3,4-dichlorophenyl) [({4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} carbonyl) amino] acetate
Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126
　CDI (0.19 g, 1.1 mmol)のDMF (2 mL)溶液に、メチル アミノ(3,4-ジクロロフェニル)アセタート (0.27 g, 1.1 mmol)のDMF (3 mL)溶液を氷冷下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.28 g, 1.0 mmol)を加え、50 ℃で1時間撹拌した。反応混合物を水に注ぎ、析出物をろ取しヘキサン－酢酸エチルから再結晶して、題記化合物を白色固体(0.30 g, 53%)として得た。
LC/MS 533
NMR (CDCl3) δ: 2.51 (3 H, s), 3.20 - 3.32 (4 H, m), 3.55 - 3.68 (4 H, m), 3.76 (3 H, s), 3.93 (3 H, s), 5.48 (1 H, d, J=5.8 Hz), 5.66 (1 H, d, J=5.8 Hz), 6.48 (1 H, d, J=2.2 Hz), 6.55 (1 H, dd, J=8.5, 2.2 Hz), 7.21 - 7.29 (2 H, m), 7.43 (1 H, d, J=8.2 Hz), 7.48 (1 H, d, J=1.9 Hz), 7.60 (1 H, d, J=8.5 Hz). To a DMF (2 mL) solution of CDI (0.19 g, 1.1 mmol), a DMF (3 mL) solution of methylamino (3,4-dichlorophenyl) acetate (0.27 g, 1.1 mmol) was added under ice cooling. After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.28 g, 1.0 mmol) was added, and 1 at 50 ° C was added. Stir for hours. The reaction mixture was poured into water, and the precipitate was collected by filtration and recrystallized from hexane-ethyl acetate to give the title compound as a white solid (0.30 g, 53%).
LC / MS 533
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 3.20-3.32 (4 H, m), 3.55-3.68 (4 H, m), 3.76 (3 H, s), 3.93 (3 H, s) , 5.48 (1 H, d, J = 5.8 Hz), 5.66 (1 H, d, J = 5.8 Hz), 6.48 (1 H, d, J = 2.2 Hz), 6.55 (1 H, dd, J = 8.5 , 2.2 Hz), 7.21-7.29 (2 H, m), 7.43 (1 H, d, J = 8.2 Hz), 7.48 (1 H, d, J = 1.9 Hz), 7.60 (1 H, d, J = 8.5 Hz).
実施例95
N-(1-イミダゾ[1,2-a]ピリジン-3-イルエチル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 95
N- (1-imidazo [1,2-a] pyridin-3-ylethyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
　CDI (65 mg, 0.40 mmol)のDMF (1 mL)溶液に、1-イミダゾ[1,2-a]ピリジン-3-イルエタンアミン (65 mg, 0.40 mmol)のDMF (1 mL)溶液を氷冷下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.10 g, 0.37 mmol)のDMF (1 mL)溶液を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー (酢酸エチルのみ～酢酸エチル/メタノール＝9/1)と分取HPLCで精製した後、酢酸エチル－メタノールから再結晶し、題記化合物を白色固体 (31 mg, 18%)として得た。
LC/MS 461
NMR (CDCl3) δ: 1.72 (3 H, d, J=6.9 Hz), 2.49 (3 H, s), 3.15 - 3.33 (4 H, m), 3.48 - 3.70 (4 H, m), 3.92 (3 H, s), 5.07 (1 H, d, J=8.8 Hz), 5.46 - 5.65 (1 H, m), 6.46 (1 H, d, J=1.6 Hz), 6.53 (1 H, dd, J=8.6, 1.5 Hz), 6.84 (1 H, t, J=6.9 Hz), 7.14 - 7.21 (1 H, m), 7.23 (1 H, s), 7.35 (1 H, s), 7.49 - 7.64 (2 H, m), 8.21 (1 H, d, J=6.9 Hz). Add a solution of 1-imidazo [1,2-a] pyridin-3-ylethanamine (65 mg, 0.40 mmol) in DMF (1 mL) to a solution of CDI (65 mg, 0.40 mmol) in DMF (1 mL) on ice. Added under cold. After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.10 g, 0.37 mmol) in DMF (1 mL) solution And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate only to ethyl acetate / methanol = 9/1) and preparative HPLC, and recrystallized from ethyl acetate-methanol to give the title compound as a white solid (31 mg, 18%).
LC / MS 461
NMR (CDCl 3 ) δ: 1.72 (3 H, d, J = 6.9 Hz), 2.49 (3 H, s), 3.15-3.33 (4 H, m), 3.48-3.70 (4 H, m), 3.92 ( 3 H, s), 5.07 (1 H, d, J = 8.8 Hz), 5.46-5.65 (1 H, m), 6.46 (1 H, d, J = 1.6 Hz), 6.53 (1 H, dd, J = 8.6, 1.5 Hz), 6.84 (1 H, t, J = 6.9 Hz), 7.14-7.21 (1 H, m), 7.23 (1 H, s), 7.35 (1 H, s), 7.49-7.64 ( 2 H, m), 8.21 (1 H, d, J = 6.9 Hz).
実施例96
N-[2-(3,4-ジクロロフェニル)-2-ヒドロキシエチル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 96
N- [2- (3,4-Dichlorophenyl) -2-hydroxyethyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
　炭酸ビス(トリクロロメチル) (87 mg, 0.29 mmol)のTHF (5 mL)溶液に、トリエチルアミン (0.13 mL, 0.92 mmol)を氷冷下加え、氷冷下で15分間撹拌した。反応混合物にトリエチルアミン (0.13 mL, 0.92 mmol)と1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.20 g, 0.73 mmol)のTHF (3 mL)溶液を氷冷下で加えた。氷冷下で1時間攪拌した後、トリエチルアミン (0.38 mL, 2.8 mmol)と2-アミノ-1-(3,4-ジクロロフェニル)エタノール　シュウ酸塩 (0.24 g, 0.81 mmol)を加え、室温で3日間撹拌した。反応混合物に水を加え、酢酸エチル－メタノールで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (酢酸エチル/のみ～酢酸エチル/メタノール=19/1)で精製し、題記化合物を非定形固体 (61 mg, 17%)として得た。
LC/MS 505
NMR (CDCl3) δ: 2.49 (3 H, s), 3.14 - 3.28 (4 H, m), 3.28 - 3.41 (1 H, m), 3.51 - 3.59 (4 H, m), 3.59 - 3.70 (1 H, m), 3.92 (3 H, s), 4.84 (1 H, d, J=5.5 Hz), 4.95 (1 H, brs), 5.03 (1 H, t, J=5.5 Hz), 6.46 (1 H, s), 6.53 (1 H, d, J=8.5 Hz), 7.14 - 7.25 (2 H, m), 7.41 (1 H, d, J=8.2 Hz), 7.49 (1 H, s), 7.59 (1 H, d, J=8.5 Hz). Triethylamine (0.13 mL, 0.92 mmol) was added to a solution of bis (trichloromethyl) carbonate (87 mg, 0.29 mmol) in THF (5 mL) under ice cooling, and the mixture was stirred for 15 minutes under ice cooling. To the reaction mixture was added triethylamine (0.13 mL, 0.92 mmol) and 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.20 g, 0.73 mmol) in THF (3 mL) solution was added under ice cooling. After stirring for 1 hour under ice-cooling, triethylamine (0.38 mL, 2.8 mmol) and 2-amino-1- (3,4-dichlorophenyl) ethanol oxalate (0.24 g, 0.81 mmol) were added, and the mixture was stirred at room temperature for 3 days. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-methanol. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / only to ethyl acetate / methanol = 19/1) to give the title compound as an amorphous solid (61 mg, 17%).
LC / MS 505
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 3.14-3.28 (4 H, m), 3.28-3.41 (1 H, m), 3.51-3.59 (4 H, m), 3.59-3.70 (1 H, m), 3.92 (3 H, s), 4.84 (1 H, d, J = 5.5 Hz), 4.95 (1 H, brs), 5.03 (1 H, t, J = 5.5 Hz), 6.46 (1 H, s), 6.53 (1 H, d, J = 8.5 Hz), 7.14-7.25 (2 H, m), 7.41 (1 H, d, J = 8.2 Hz), 7.49 (1 H, s), 7.59 (1 H, d, J = 8.5 Hz).
実施例97
N-[1-(4-フルオロナフタレン-1-イル)エチル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 97
N- [1- (4-Fluoronaphthalen-1-yl) ethyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
　CDI (65 mg, 0.40 mmol)のDMF (1 mL)溶液に、 1-(4-フルオロナフタレン-1-イル)エタンアミン　1塩酸塩 (91 mg, 0.40 mmol)のDMF (1 mL)溶液を氷冷下で加えた。同温度で1時間攪拌した後、1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン (0.10 g, 0.37 mmol)を加え、室温で3日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ) で精製し、題記化合物を非定形固体 (0.12 g, 68%)として得た。
LC/MS 489
NMR (CDCl3) δ: 1.69 (3 H, d, J=6.9 Hz), 2.50 (3 H, s), 3.12 - 3.32 (4 H, m), 3.37 - 3.64 (4 H, m), 3.92 (3 H, s), 4.67 (1 H, d, J=7.4 Hz), 5.80 (1 H, quin, J=6.9 Hz), 6.45 (1 H, d, J=2.2 Hz), 6.52 (1 H, dd, J=8.7, 2.3 Hz), 7.11 (1 H, dd, J=10.2, 8.0 Hz), 7.23 (1 H, s), 7.45 (1 H, dd, J=7.8, 5.1 Hz), 7.52 - 7.67 (3 H, m), 8.05 - 8.21 (2 H, m). To a solution of CDI (65 mg, 0.40 mmol) in DMF (1 mL), 1- (4-fluoronaphthalen-1-yl) ethanamine monohydrochloride (91 mg, 0.40 mmol) in DMF (1 mL) was ice-cooled. Added below. After stirring at the same temperature for 1 hour, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.10 g, 0.37 mmol) was added, and the mixture was stirred at room temperature for 3 days. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as an amorphous solid (0.12 g, 68%).
LC / MS 489
NMR (CDCl 3 ) δ: 1.69 (3 H, d, J = 6.9 Hz), 2.50 (3 H, s), 3.12-3.32 (4 H, m), 3.37-3.64 (4 H, m), 3.92 ( 3 H, s), 4.67 (1 H, d, J = 7.4 Hz), 5.80 (1 H, quin, J = 6.9 Hz), 6.45 (1 H, d, J = 2.2 Hz), 6.52 (1 H, dd, J = 8.7, 2.3 Hz), 7.11 (1 H, dd, J = 10.2, 8.0 Hz), 7.23 (1 H, s), 7.45 (1 H, dd, J = 7.8, 5.1 Hz), 7.52- 7.67 (3 H, m), 8.05-8.21 (2 H, m).
実施例９８
N’1’-(3,4-ジクロロベンジル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N’2’,N’2’-ジメチルピペラジン-1,2-ジカルボキサミド Example 98
N'1 '-(3,4-dichlorobenzyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N'2', N'2 ' -Dimethylpiperazine-1,2-dicarboxamide
　4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N,N-ジメチルピペラジン-2-カルボキサミド(0.17 g, 0.5 mmol)のジクロロメタン(2 mL)溶液に、トリエチルアミン(84 μL, 0.6 mmol)および3,4-ジクロロベンジルイソシアナート(0.11 g, 0.56 mmol)を加え、室温にて1時間攪拌した。反応混合物に水(5 mL)を加え、ジクロロメタンで3回抽出した。有機層を合わせ、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物を、シリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝1/9)で精製して、題記化合物を白色固体(0.19 g, 68%)として得た。
LC/MS 546
NMR (CDCl3) δ: 2.50 (3 H, s), 2.95 (3 H, brs), 3.07 (1 H, td, J=11.2, 4.0 Hz), 3.16 (3 H, brs), 3.29 (1 H, dd, J=12.8, 4.8 Hz), 3.48 - 3.52 (1 H, m), 3.64 - 3.67 (1 H, m), 3.79 - 3.82 (1 H, m), 3.92 (3 H, s), 4.06 - 4.15 (1 H, m), 4.32 (1 H, dd, J=15.1, 5.7 Hz), 4.49 (1 H, dd, J=15.1, 5.5 Hz), 5.16 (1 H, t, J=5.6 Hz), 5.25 (1 H, t, J=3.2 Hz), 6.43 (1 H, d, J=2.4 Hz), 6.49 (1 H, dd, J=8.6, 2.2 Hz), 7.15 - 7.17 (1 H, m), 7.24 (1 H, s), 7.39 (1 H, d, J=8.0 Hz), 7.41 (1 H, d, J=2.0 Hz), 7.58 (1 H, d, J=8.4 Hz). 4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N, N-dimethylpiperazine-2-carboxamide (0.17 g, 0.5 mmol) in dichloromethane (2 mL) Triethylamine (84 μL, 0.6 mmol) and 3,4-dichlorobenzyl isocyanate (0.11 g, 0.56 mmol) were added to the solution, and the mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 1/9) to give the title compound as a white solid (0.19 g, 68%).
LC / MS 546
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 2.95 (3 H, brs), 3.07 (1 H, td, J = 11.2, 4.0 Hz), 3.16 (3 H, brs), 3.29 (1 H , dd, J = 12.8, 4.8 Hz), 3.48-3.52 (1 H, m), 3.64-3.67 (1 H, m), 3.79-3.82 (1 H, m), 3.92 (3 H, s), 4.06 -4.15 (1 H, m), 4.32 (1 H, dd, J = 15.1, 5.7 Hz), 4.49 (1 H, dd, J = 15.1, 5.5 Hz), 5.16 (1 H, t, J = 5.6 Hz ), 5.25 (1 H, t, J = 3.2 Hz), 6.43 (1 H, d, J = 2.4 Hz), 6.49 (1 H, dd, J = 8.6, 2.2 Hz), 7.15-7.17 (1 H, m), 7.24 (1 H, s), 7.39 (1 H, d, J = 8.0 Hz), 7.41 (1 H, d, J = 2.0 Hz), 7.58 (1 H, d, J = 8.4 Hz).
実施例９９
1-(3,4-ジクロロベンジル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-2-オン Example 99
1- (3,4-Dichlorobenzyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-2-one
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　1-(3,4-ジクロロベンジル)-1,4-ジアゼパン-2-オン(0.27 g, 1 mmol)のトルエン(5 mL)溶液に、5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.24 g, 1 mmol)、Xantphos(58 mg, 0.1 mmol)、炭酸セシウム(0.49 g, 1.5 mmol)、及び、Ｐｄ２(ｄｂａ)３(46 mg, 0.05 mmol)を加え、窒素雰囲気下90℃にて20時間攪拌した。室温に冷却後、反応混合物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製した後、酢酸エチルより再結晶して題記化合物を白色固体(0.14 g, 32%)として得た。
LC/MS 430
NMR (DMSO-d6) δ: 1.60 (2 H, brs), 2.44 (3 H, s), 3.45 - 3.58 (2 H, m), 3.62 - 3.77 (2 H, m), 4.32 (2 H, s), 4.41 (2 H, s), 6.94 (2 H, d, J=9.1 Hz), 7.03 (1 H, dd, J=8.1, 2.1 Hz), 7.21 (1 H, d, J=2.3 Hz), 7.24 (1 H, s), 7.41 (1 H, d, J=8.3 Hz), 7.47 (2 H, d, J=8.7 Hz). To a solution of 1- (3,4-dichlorobenzyl) -1,4-diazepan-2-one (0.27 g, 1 mmol) in toluene (5 mL) was added 5- (4-bromophenyl) -2-methyl-1 , 3-oxazole (0.24 g, 1 mmol), Xantphos (58 mg, 0.1 mmol), cesium carbonate (0.49 g, 1.5 mmol), and Pd 2 (dba) 3 (46 mg, 0.05 mmol) were added, and nitrogen was added. The mixture was stirred at 90 ° C. for 20 hours under an atmosphere. After cooling to room temperature, the reaction mixture was purified by NH silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) and then recrystallized from ethyl acetate to give the title compound as a white solid (0.14 g, 32%) Got as.
LC / MS 430
NMR (DMSO-d 6 ) δ: 1.60 (2 H, brs), 2.44 (3 H, s), 3.45-3.58 (2 H, m), 3.62-3.77 (2 H, m), 4.32 (2 H, s), 4.41 (2 H, s), 6.94 (2 H, d, J = 9.1 Hz), 7.03 (1 H, dd, J = 8.1, 2.1 Hz), 7.21 (1 H, d, J = 2.3 Hz) ), 7.24 (1 H, s), 7.41 (1 H, d, J = 8.3 Hz), 7.47 (2 H, d, J = 8.7 Hz).
実施例１００
1-(3,4-ジクロロベンジル)-6,6-ジメチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-2-オン Example 100
1- (3,4-Dichlorobenzyl) -6,6-dimethyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-2-one
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
　1-(3,4-ジクロロベンジル)-6,6-ジメチル-1,4-ジアゼパン-2-オン(0.30 g, 1 mmol)のトルエン(5 mL)溶液に、5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.24 g, 1 mmol)、Xantphos(58 mg, 0.1 mmol)、炭酸セシウム(0.49 g, 1.5 mmol)、及び、Ｐｄ２(ｄｂａ)３(46 mg, 0.05 mmol)を加え、窒素雰囲気下90℃にて20時間攪拌した。室温に冷却後、反応混合物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製した後、分取HPLCにて精製した。分取したフラクションを濃縮し、残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をメタノールより再結晶して題記化合物を白色結晶(80 mg, 17%)として得た。
LC/MS 458
NMR (DMSO-d6) δ: 0.78 (6 H, s), 2.43 (3 H, s), 3.22 - 3.68 (4 H, m), 4.14 - 4.56 (4 H, m), 7.01 (2 H, d, J=9.0 Hz), 7.21 (1 H, s), 7.26 (1 H, dd, J=8.3, 1.9 Hz), 7.42 (2 H, d, J=9.0 Hz), 7.53 (1 H, d, J=2.3 Hz), 7.58 (1 H, d, J=8.3 Hz). To a solution of 1- (3,4-dichlorobenzyl) -6,6-dimethyl-1,4-diazepan-2-one (0.30 g, 1 mmol) in toluene (5 mL), 5- (4-bromophenyl) -2-methyl-1,3-oxazole (0.24 g, 1 mmol), Xantphos (58 mg, 0.1 mmol), cesium carbonate (0.49 g, 1.5 mmol), and Pd 2 (dba) 3 (46 mg, 0.05 mmol) was added and the mixture was stirred at 90 ° C. for 20 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was purified by NH silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) and then purified by preparative HPLC. The fraction collected was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound as white crystals (80 mg, 17%).
LC / MS 458
NMR (DMSO-d 6 ) δ: 0.78 (6 H, s), 2.43 (3 H, s), 3.22-3.68 (4 H, m), 4.14-4.56 (4 H, m), 7.01 (2 H, d, J = 9.0 Hz), 7.21 (1 H, s), 7.26 (1 H, dd, J = 8.3, 1.9 Hz), 7.42 (2 H, d, J = 9.0 Hz), 7.53 (1 H, d , J = 2.3 Hz), 7.58 (1 H, d, J = 8.3 Hz).
実施例１０１
1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-5-オン Example 101
1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -4- (3,4,5-trifluorobenzyl) -1,4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.48 g, 2.0 mmol)、4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-5-オン(0.52 g, 2.0 mmol)、DavePhos(0.079 g, 0.20 mmol)、Pd2(dba)3(0.092 g, 0.10 mmol)、ナトリウム tert-ブトキシド(0.29 g, 1.9 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で5時間攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝17/3～酢酸エチルのみ)で精製し、題記化合物を白色固体(0.35 g, 42%)として得た。
LC/MS 416
NMR (CDCl3) δ: 2.51 (3 H, s), 2.83 - 3.00 (2 H, m), 3.38 - 3.68 (6 H, m), 4.55 (2 H, s), 6.82 - 6.97 (4 H, m), 7.07 (1 H, s), 7.50 (2 H, d, J=8.7 Hz). 5- (4-Bromophenyl) -2-methyl-1,3-oxazole (0.48 g, 2.0 mmol), 4- (3,4,5-trifluorobenzyl) -1,4-diazepan-5-one ( 0.52 g, 2.0 mmol), DavePhos (0.079 g, 0.20 mmol), Pd 2 (dba) 3 (0.092 g, 0.10 mmol), sodium tert-butoxide (0.29 g, 1.9 mmol) and toluene (5 mL) The mixture was stirred at 100 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 17 / 3-ethyl acetate alone) to give the title compound as a white solid (0.35 g, 42%).
LC / MS 416
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 2.83-3.00 (2 H, m), 3.38-3.68 (6 H, m), 4.55 (2 H, s), 6.82-6.97 (4 H, m), 7.07 (1 H, s), 7.50 (2 H, d, J = 8.7 Hz).
実施例１０２
N-(3-クロロ-4-フルオロフェニル)-2-{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセトアミド Example 102
N- (3-Chloro-4-fluorophenyl) -2- {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo -1,4-diazepan-1-yl} acetamide
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
　{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}酢酸 (0.054 g, 0.15 mmol)、3-クロロ-4-フルオロアニリン(0.032 g, 0.22 mmol)、HOBt(0.034 g, 0.22 mmol)、WSC(0.042 g, 0.22 mmol)、N,N-ジエチルエタンアミン(46μL, 0.33 mmol)、およびDMF(5 mL)の混合物を室温で4時間攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル=1/4)で精製し、題記化合物を白色非定形固体(0.027 g, 37%)として得た。
LC/MS 487
NMR (CDCl3) δ: 2.47 (3 H, s), 2.92 - 3.00 (2 H, m), 3.57 - 3.64 (4 H, m), 3.75 - 3.82 (2 H, m), 3.84 (3 H, s), 4.15 (2 H, s), 6.37 - 6.55 (2 H, m), 6.93 - 7.05 (1 H, m), 7.14 - 7.23 (1 H, m), 7.51 (1 H, d, J=8.7 Hz), 7.62 (1 H, dd, J=6.4, 2.7 Hz), 8.42 (1 H, s), 8.53 (1 H, brs). {4- [3-Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetic acid (0.054 g , 0.15 mmol), 3-chloro-4-fluoroaniline (0.032 g, 0.22 mmol), HOBt (0.034 g, 0.22 mmol), WSC (0.042 g, 0.22 mmol), N, N-diethylethanamine (46 μL, 0.33 mmol), and a mixture of DMF (5 mL) was stirred at room temperature for 4 hours. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 1/4) to obtain the title compound as a white amorphous solid (0.027 g, 37%).
LC / MS 487
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 2.92-3.00 (2 H, m), 3.57-3.64 (4 H, m), 3.75-3.82 (2 H, m), 3.84 (3 H, s), 4.15 (2 H, s), 6.37-6.55 (2 H, m), 6.93-7.05 (1 H, m), 7.14-7.23 (1 H, m), 7.51 (1 H, d, J = 8.7 Hz), 7.62 (1 H, dd, J = 6.4, 2.7 Hz), 8.42 (1 H, s), 8.53 (1 H, brs).
実施例１０３
1-(3,4-ジクロロベンジル)-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-5-オン Example 103
1- (3,4-Dichlorobenzyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
　1-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン(0.28 g, 1.0 mmol)、メチル (7-オキソ-1,4-ジアゼパン-1-イル)アセタート(0.24 g, 1.0 mmol)、Xantphos(0.087 g, 0.15 mmol)、Pd2(dba)3(0.046 g, 0.05 mmol)、炭酸セシウム(0.46 g, 1.4 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で4時間攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1～酢酸エチルのみ)で精製し、題記化合物を白色固体(0.029 g, 6.6%)として得た。
LC/MS 430
NMR (CDCl3) δ: 2.52 (3 H, s), 2.68 - 2.99 (6 H, m), 3.58 (2 H, s), 3.80 - 3.95 (2 H, m), 7.13 - 7.27 (4 H, m), 7.36 - 7.51 (2 H, m), 7.60 (2 H, d, J=8.7 Hz). 1- (3,4-dichlorobenzyl) -1,4-diazepan-5-one (0.28 g, 1.0 mmol), methyl (7-oxo-1,4-diazepan-1-yl) acetate (0.24 g, 1.0 mmol), Xantphos (0.087 g, 0.15 mmol), Pd 2 (dba) 3 (0.046 g, 0.05 mmol), cesium carbonate (0.46 g, 1.4 mmol) and toluene (5 mL) under a nitrogen atmosphere at 100 ° C. For 4 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 4/1 to ethyl acetate alone) to give the title compound as a white solid (0.029 g, 6.6%).
LC / MS 430
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 2.68-2.99 (6 H, m), 3.58 (2 H, s), 3.80-3.95 (2 H, m), 7.13-7.27 (4 H, m), 7.36-7.51 (2 H, m), 7.60 (2 H, d, J = 8.7 Hz).
実施例１０４
4-(3,4-ジクロロベンジル)-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-3-メチル-1,4-ジアゼパン-5-オン Example 104
4- (3,4-dichlorobenzyl) -1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -3-methyl-1,4- Diazepan-5-one
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
　1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(0.29 g, 1.0 mmol)、4-(3,4-ジクロロベンジル)-3-メチル-1,4-ジアゼパン-5-オン(0.27 g, 1.0 mmol)、DavePhos(0.046 g, 0.050 mmol)、Pd2(dba)3(0.039 g, 0.10 mmol)、ナトリウム tert-ブトキシド(0.14 g, 1.5 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(0.015 g, 2.4%)として得た。
LC/MS 474
NMR (CDCl3) δ: 1.31 (3 H, d, J=6.8 Hz), 2.47 (3 H, s), 2.79 - 3.08 (2 H, m), 3.40 - 3.74 (5 H, m), 3.77 (3 H, s), 4.01 (1 H, d, J=15.2 Hz), 5.09 (1 H, d, J=15.2 Hz), 6.18 (1 H, d, J=2.7 Hz), 6.28 (1 H, dd, J=8.7, 2.7 Hz), 7.02 (1 H, dd, J=8.1, 2.1 Hz), 7.26 (2 H, dd, J=5.7, 3.8 Hz), 7.41 (1 H, d, J=8.7 Hz), 8.42 (1 H, s). 1- (4-Bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.29 g, 1.0 mmol), 4- (3,4-dichlorobenzyl) -3-methyl-1 , 4-Diazepan-5-one (0.27 g, 1.0 mmol), DavePhos (0.046 g, 0.050 mmol), Pd 2 (dba) 3 (0.039 g, 0.10 mmol), sodium tert-butoxide (0.14 g, 1.5 mmol) And toluene (5 mL) were stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as a colorless amorphous solid (0.015 g, 2.4%).
LC / MS 474
NMR (CDCl 3 ) δ: 1.31 (3 H, d, J = 6.8 Hz), 2.47 (3 H, s), 2.79-3.08 (2 H, m), 3.40-3.74 (5 H, m), 3.77 ( 3 H, s), 4.01 (1 H, d, J = 15.2 Hz), 5.09 (1 H, d, J = 15.2 Hz), 6.18 (1 H, d, J = 2.7 Hz), 6.28 (1 H, dd, J = 8.7, 2.7 Hz), 7.02 (1 H, dd, J = 8.1, 2.1 Hz), 7.26 (2 H, dd, J = 5.7, 3.8 Hz), 7.41 (1 H, d, J = 8.7 Hz), 8.42 (1 H, s).
実施例１０５
N-(3-クロロ-4-フルオロフェニル)-2-{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}-N-(2,2,2-トリフルオロエチル)アセトアミド Example 105
N- (3-Chloro-4-fluorophenyl) -2- {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo -1,4-diazepan-1-yl} -N- (2,2,2-trifluoroethyl) acetamide
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　N-(3-クロロ-4-フルオロフェニル)-2-{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセトアミド (0.025 g, 0.050 mmol)のDMF (3 mL)溶液に、水素化ナトリウム(0.50 g、60%油状)を加え、次に1,1,1-トリフルオロ-2-[(トリフルオロメチル)スルホニル]エタン(15 μL, 0.10 mmol)を加え、室温にて5時間攪拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/4～酢酸エチルのみ)で精製し、題記化合物を白色非定形固体(0.011 g, 40%)として得た。
LC/MS 569
NMR (CDCl3) δ: 2.47 (3 H, s), 2.74 - 2.89 (2 H, m), 3.54 - 3.65 (4 H, m), 3.68 - 3.77 (2 H, m), 3.86 (3 H, s), 3.92 (2 H, s), 4.31 (2 H, d, J=8.7 Hz), 6.39 - 6.57 (2 H, m), 7.26 - 7.30 (2 H, m), 7.45 (1 H, dd, J=6.3, 2.1 Hz), 7.51 (1 H, d, J=8.7 Hz), 8.42 (1 H, s). N- (3-Chloro-4-fluorophenyl) -2- {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo To a solution of -1,4-diazepan-1-yl} acetamide (0.025 g, 0.050 mmol) in DMF (3 mL) was added sodium hydride (0.50 g, 60% oil), then 1,1,1- Trifluoro-2-[(trifluoromethyl) sulfonyl] ethane (15 μL, 0.10 mmol) was added and stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/4 to ethyl acetate alone) to give the title compound as a white amorphous solid (0.011 g, 40%).
LC / MS 569
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 2.74-2.89 (2 H, m), 3.54-3.65 (4 H, m), 3.68-3.77 (2 H, m), 3.86 (3 H, s), 3.92 (2 H, s), 4.31 (2 H, d, J = 8.7 Hz), 6.39-6.57 (2 H, m), 7.26-7.30 (2 H, m), 7.45 (1 H, dd , J = 6.3, 2.1 Hz), 7.51 (1 H, d, J = 8.7 Hz), 8.42 (1 H, s).
実施例１０６
4-(3,4-ジクロロベンジル)-1-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1,4-ジアゼパン-5-オン Example 106
4- (3,4-Dichlorobenzyl) -1- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
　1-(4-ブロモフェニル)-4-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン(0.30 g, 0.70 mmol)、1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(0.17 g, 0.80 mmol)、Pd(PPh3)4(0.093 g, 0.080 mmol)、2M炭酸セシウム水溶液(0.80 mL, 1.6 mmol)及びDME(5 mL)の混合物を窒素雰囲気下、80℃で終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、題記化合物を白色固体(0.067 g, 21%)として得た。
LC/MS 429
NMR (CDCl3) δ: 2.84 - 2.95 (2 H, m), 3.31 - 3.39 (2 H, m), 3.46 - 3.57 (4 H, m), 3.92 (3 H, s), 4.58 (2 H, s), 6.83 (2 H, d, J=8.7 Hz), 7.12 (1 H, dd, J=8.1, 2.1 Hz), 7.30 - 7.43 (4 H, m), 7.52 (1 H, s), 7.68 (1 H, s). 1- (4-Bromophenyl) -4- (3,4-dichlorobenzyl) -1,4-diazepan-5-one (0.30 g, 0.70 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (0.17 g, 0.80 mmol), Pd (PPh 3 ) 4 (0.093 g, 0.080 mmol), 2M aqueous cesium carbonate (0.80 mL) , 1.6 mmol) and DME (5 mL) were stirred at 80 ° C. overnight under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as a white solid (0.067 g, 21%).
LC / MS 429
NMR (CDCl 3 ) δ: 2.84-2.95 (2 H, m), 3.31-3.39 (2 H, m), 3.46-3.57 (4 H, m), 3.92 (3 H, s), 4.58 (2 H, s), 6.83 (2 H, d, J = 8.7 Hz), 7.12 (1 H, dd, J = 8.1, 2.1 Hz), 7.30-7.43 (4 H, m), 7.52 (1 H, s), 7.68 (1 H, s).
実施例１０７
4-ベンジル-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-メチル-1,4-ジアゼパン-5-オン
実施例１０８
4-ベンジル-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-メチル-1,4-ジアゼパン-5-オン Example 107
4-Benzyl-1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-methyl-1,4-diazepan-5-one Examples 108
4-Benzyl-1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-methyl-1,4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
　1-ベンジル-2-メチルピペリジン-4-オン(3.0 g, 15 mmol)(公知文献: EP1559428) のクロロホルム(30 mL)溶液に0℃で濃硫酸(7.7 mL, 150 mmol)を滴下して加えた。この混合物にアジ化ナトリウム (1.9 g, 29 mmol)を少しずつ加えて、0℃で1時間攪拌した。次に５０℃で5時間攪拌した。反応混合物を０℃に冷却し、氷水を加え、炭酸カリウムを加えて反応混合物を塩基性にし、室温で終夜攪拌した。有機層を分離し、水層をクロロホルムで抽出した。抽出液を合わせて無水硫酸マグネシウムで乾燥し、溶媒を留去し、白色固体 (3.3 g)を得た。この固体(0.44 g)のDMF (5 mL)溶液に、水素化ナトリウム(0.084 g、60%油状)を加え、次に(ブロモメチル)ベンゼン(0.34 g, 2.0 mmol)を加え、室温にて4時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、無色油状物(0.36 g)を得た。この油状物(0.36 g)のメタノール(50 mL)溶液に20%水酸化パラジウムカーボン(0.20 g)を加え、室温で水素雰囲気下、1時間攪拌した。反応混合物をセライト濾過し、溶媒を留去し、油状物(0.24 g)を得た。この油状物(0.24 g)、1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(0.30 g, 1.1 mmol)、DavePhos(0.039 g, 0.10 mmol)、Pd2(dba)3(0.046 g, 0.050 mmol)、ナトリウム tert-ブトキシド(0.14 g, 1.5 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、4-ベンジル-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-メチル-1,4-ジアゼパン-5-オンを無色非定形固体(0.053 g, 12%)として、4-ベンジル-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-メチル-1,4-ジアゼパン-5-オンを無色非定形固体(0.067 g, 15%)として得た。
4-ベンジル-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-メチル-1,4-ジアゼパン-5-オン：
LC/MS 406
NMR (CDCl3) δ: 1.20 (3 H, d, J=6.4 Hz), 2.47 (3 H, s), 2.70 - 2.86 (1 H, m), 3.04 - 3.27 (2 H, m), 3.30 - 3.44 (2 H, m), 3.59 - 3.74 (1 H, m), 3.82 (3 H, s), 4.16 - 4.25 (1 H, m), 4.48 - 4.75 (2 H, m), 6.33 - 6.58 (2 H, m), 7.28 - 7.35 (5 H, m), 7.47 (1 H, d, J=8.7 Hz), 8.41 (1 H, s).
4-ベンジル-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-メチル-1,4-ジアゼパン-5-オン：
LC/MS 406
NMR (CDCl3) δ: 1.06 (3 H, d, J=6.8 Hz), 2.47 (3 H, s), 2.86 - 3.16 (2 H, m), 3.41 - 3.63 (4 H, m), 3.69 - 3.89 (4 H, m), 4.22 (1 H, d, J=14.8 Hz), 4.94 (1 H, d, J=14.8 Hz), 6.22 - 6.43 (2 H, m), 7.17 - 7.33 (5 H, m), 7.45 (1 H, d, J=9.1 Hz), 8.35 - 8.45 (1 H, m). Concentrated sulfuric acid (7.7 mL, 150 mmol) was added dropwise at 0 ° C to a solution of 1-benzyl-2-methylpiperidin-4-one (3.0 g, 15 mmol) (public literature: EP1559428) in chloroform (30 mL). It was. Sodium azide (1.9 g, 29 mmol) was added little by little to this mixture, and the mixture was stirred at 0 ° C. for 1 hr. Next, it stirred at 50 degreeC for 5 hours. The reaction mixture was cooled to 0 ° C., ice water was added, potassium carbonate was added to basify the reaction mixture and stirred at room temperature overnight. The organic layer was separated and the aqueous layer was extracted with chloroform. The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a white solid (3.3 g). To a solution of this solid (0.44 g) in DMF (5 mL) was added sodium hydride (0.084 g, 60% oil), then (bromomethyl) benzene (0.34 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give a colorless oil (0.36 g). To a solution of this oil (0.36 g) in methanol (50 mL) was added 20% palladium hydroxide carbon (0.20 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through celite, and the solvent was evaporated to give an oil (0.24 g). This oil (0.24 g), 1- (4-bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.30 g, 1.1 mmol), DavePhos (0.039 g, 0.10 mmol) , Pd 2 (dba) 3 (0.046 g, 0.050 mmol), sodium tert-butoxide (0.14 g, 1.5 mmol) and toluene (5 mL) were stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only) to give 4-benzyl-1- [3-methoxy-4- (3-methyl-1H-1 , 2,4-Triazol-1-yl) phenyl] -7-methyl-1,4-diazepan-5-one as a colorless amorphous solid (0.053 g, 12%) as 4-benzyl-1- [3- Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-methyl-1,4-diazepan-5-one was obtained as a colorless amorphous solid (0.067 g, 15% ).
4-Benzyl-1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-methyl-1,4-diazepan-5-one:
LC / MS 406
NMR (CDCl 3 ) δ: 1.20 (3 H, d, J = 6.4 Hz), 2.47 (3 H, s), 2.70-2.86 (1 H, m), 3.04-3.27 (2 H, m), 3.30- 3.44 (2 H, m), 3.59-3.74 (1 H, m), 3.82 (3 H, s), 4.16-4.25 (1 H, m), 4.48-4.75 (2 H, m), 6.33-6.58 ( 2 H, m), 7.28-7.35 (5 H, m), 7.47 (1 H, d, J = 8.7 Hz), 8.41 (1 H, s).
4-Benzyl-1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-methyl-1,4-diazepan-5-one:
LC / MS 406
NMR (CDCl 3 ) δ: 1.06 (3 H, d, J = 6.8 Hz), 2.47 (3 H, s), 2.86-3.16 (2 H, m), 3.41-3.63 (4 H, m), 3.69- 3.89 (4 H, m), 4.22 (1 H, d, J = 14.8 Hz), 4.94 (1 H, d, J = 14.8 Hz), 6.22-6.43 (2 H, m), 7.17-7.33 (5 H , m), 7.45 (1 H, d, J = 9.1 Hz), 8.35-8.45 (1 H, m).
実施例１０９
4-(3,4-ジクロロベンジル)-1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-6,6-ジメチル-1,4-ジアゼパン-5-オン Example 109
4- (3,4-dichlorobenzyl) -1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -6,6-dimethyl-1, 4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
　1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(0.12 g, 0.45 mmol)、4-(3,4-ジクロロベンジル)-6,6-ジメチル-1,4-ジアゼパン-5-オン(0.14 g, 0.45 mmol)、DavePhos(0.018 g, 0.045 mmol)、Pd2(dba)3(0.021 g, 0.023 mmol)、ナトリウム tert-ブトキシド(0.065 g, 0.68 mmol)及びトルエン(4 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝85/15～ヘキサン/酢酸エチル＝1/3)で精製し、題記化合物を無色非定形固体(0.053 g, 24%)として得た。
LC/MS 488
NMR (CDCl3) δ: 1.22 (6 H, s), 2.45 (3 H, s), 3.05 (2 H, s), 3.38 - 3.50 (2 H, m), 3.62 - 3.72 (2 H, m), 3.80 (3 H, s), 4.56 (2 H, s), 6.29 - 6.52 (2 H, m), 7.06 (1 H, dd, J=8.3, 1.9 Hz), 7.24 - 7.34 (1 H, m), 7.41 (2 H, dd, J=12.8, 8.7 Hz), 8.37 (1 H, s). 1- (4-Bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.12 g, 0.45 mmol), 4- (3,4-dichlorobenzyl) -6,6-dimethyl -1,4-diazepan-5-one (0.14 g, 0.45 mmol), DavePhos (0.018 g, 0.045 mmol), Pd 2 (dba) 3 (0.021 g, 0.023 mmol), sodium tert-butoxide (0.065 g, 0.68 mmol) and toluene (4 mL) were stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 85/15 to hexane / ethyl acetate = 1/3) to give the title compound as a colorless amorphous solid (0.053 g, 24%). It was.
LC / MS 488
NMR (CDCl 3 ) δ: 1.22 (6 H, s), 2.45 (3 H, s), 3.05 (2 H, s), 3.38-3.50 (2 H, m), 3.62-3.72 (2 H, m) , 3.80 (3 H, s), 4.56 (2 H, s), 6.29-6.52 (2 H, m), 7.06 (1 H, dd, J = 8.3, 1.9 Hz), 7.24-7.34 (1 H, m ), 7.41 (2 H, dd, J = 12.8, 8.7 Hz), 8.37 (1 H, s).
実施例１１０
4-[4-メトキシ-2-メチル-5-(1-メチルエチル)ベンジル]-1-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1,4-ジアゼパン-5-オン Example 110
4- [4-Methoxy-2-methyl-5- (1-methylethyl) benzyl] -1- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-diazepan-5 -on
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
　4-(4-ブロモフェニル)-1-メチル-1H-ピラゾール(0.28 g, 1.2 mmol)、4-[4-メトキシ-2-メチル-5-(1-メチルエチル)ベンジル]-1,4-ジアゼパン-5-オン(0.34 g, 1.2 mmol)、DavePhos(0.075 g, 0.20 mmol)、Pd2(dba)3(0.055 g, 0.060 mmol)、ナトリウム tert-ブトキシド(0.17 g, 1.8 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で16時間攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1～酢酸エチルのみ)で精製し、題記化合物を白色固体(0.31 g, 59%)として得た。
LC/MS 447
NMR (CDCl3) δ: 1.19 (6 H, d, J=6.8 Hz), 2.27 (3 H, s), 2.83 - 2.94 (2 H, m), 3.17 - 3.32 (3 H, m), 3.35 - 3.44 (2 H, m), 3.48 - 3.55 (2 H, m), 3.81 (3 H, s), 3.92 (3 H, s), 4.60 (2 H, s), 6.65 (1 H, s), 6.82 (2 H, d, J=9.1 Hz), 6.98 (1 H, s), 7.34 (2 H, d, J=9.1 Hz), 7.51 (1 H, s), 7.67 (1 H, s). 4- (4-Bromophenyl) -1-methyl-1H-pyrazole (0.28 g, 1.2 mmol), 4- [4-methoxy-2-methyl-5- (1-methylethyl) benzyl] -1,4- Diazepan-5-one (0.34 g, 1.2 mmol), DavePhos (0.075 g, 0.20 mmol), Pd 2 (dba) 3 (0.055 g, 0.060 mmol), sodium tert-butoxide (0.17 g, 1.8 mmol) and toluene ( 5 mL) was stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to ethyl acetate alone) to give the title compound as a white solid (0.31 g, 59%).
LC / MS 447
NMR (CDCl 3 ) δ: 1.19 (6 H, d, J = 6.8 Hz), 2.27 (3 H, s), 2.83-2.94 (2 H, m), 3.17-3.32 (3 H, m), 3.35- 3.44 (2 H, m), 3.48-3.55 (2 H, m), 3.81 (3 H, s), 3.92 (3 H, s), 4.60 (2 H, s), 6.65 (1 H, s), 6.82 (2 H, d, J = 9.1 Hz), 6.98 (1 H, s), 7.34 (2 H, d, J = 9.1 Hz), 7.51 (1 H, s), 7.67 (1 H, s).
実施例１１１
4-[(6-クロロ-5-フルオロ-1H-ベンゾイミダゾール-2-イル)メチル]-1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-5-オン Example 111
4-[(6-Chloro-5-fluoro-1H-benzimidazol-2-yl) methyl] -1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
　{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}酢酸(0.36 g, 1.0 mmol)、4-クロロ-5-フルオロベンゼン-1,2-ジアミン(0.16 g, 1.0 mmol)、HATU (0.38 g, 1.0 mmol)、N,N-ジエチルエタンアミン (280 μL, 2.0 mmol)、およびDMF (5 mL)の混合物を室温で終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物の酢酸(20 mL)溶液を80℃にて4時間攪拌した。反応混合物を濃縮後、残留物に１N水酸化ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル=7/13)で精製し、題記化合物を白色固体(0.25 g, 52%)として得た。
LC/MS 484
NMR (CDCl3) δ: 2.51 (3 H, s), 2.90 - 3.02 (2 H, m), 3.33 - 3.43 (2 H, m), 3.54 (2 H, t, J=6.3 Hz), 3.76 - 3.84 (5 H, m), 4.70 (2 H, d, J=2.3 Hz), 6.14 (1 H, brs), 6.23 - 6.36 (1 H, m), 6.91 - 7.22 (2 H, m), 7.33 - 7.75 (2 H, m), 9.95 (1 H, d, J=10.6 Hz). {4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetic acid (0.36 g, 1.0 mmol) , 4-chloro-5-fluorobenzene-1,2-diamine (0.16 g, 1.0 mmol), HATU (0.38 g, 1.0 mmol), N, N-diethylethanamine (280 μL, 2.0 mmol), and DMF ( 5 mL) was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A solution of the obtained residue in acetic acid (20 mL) was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 7/13) to give the title compound as a white solid (0.25 g, 52%).
LC / MS 484
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 2.90-3.02 (2 H, m), 3.33-3.43 (2 H, m), 3.54 (2 H, t, J = 6.3 Hz), 3.76- 3.84 (5 H, m), 4.70 (2 H, d, J = 2.3 Hz), 6.14 (1 H, brs), 6.23-6.36 (1 H, m), 6.91-7.22 (2 H, m), 7.33 -7.75 (2 H, m), 9.95 (1 H, d, J = 10.6 Hz).
実施例１１２
N-(3-クロロ-4-フルオロフェニル)-2-{4-[4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)ピリミジン-2-イル]-7-オキソ-1,4-ジアゼパン-1-イル}アセトアミド Example 112
N- (3-Chloro-4-fluorophenyl) -2- {4- [4-methoxy-5- (2-methyl-1,3-oxazol-5-yl) pyrimidin-2-yl] -7-oxo -1,4-diazepan-1-yl} acetamide
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
　N-(3-クロロ-4-フルオロフェニル)-2-(7-オキソ-1,4-ジアゼパン-1-イル)アセトアミド(0.20 g, 0.65 mmol)、4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)-2-(メチルスルホニル)ピリミジン(0.080 g, 0.30 mmol)、炭酸水素ナトリウム(0.025 g, 0.30 mmol)及びDMF(5 mL)の混合物を100℃で3.5時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝1/9)で精製し、題記化合物を白色固体(0.037 g, 25%)として得た。
LC/MS 489
NMR (CDCl3) δ: 2.51 (3 H, s), 2.83 - 2.95 (2 H, m), 3.66 - 3.82 (2 H, m), 4.01 (3 H, s), 4.06 - 4.19 (6 H, m), 6.90 - 7.02 (1 H, m), 7.11 (1 H, s), 7.16 - 7.25 (1 H, m), 7.62 (1 H, dd, J=6.4, 2.7 Hz), 8.36 (1 H, s), 8.55 (1 H, brs). N- (3-Chloro-4-fluorophenyl) -2- (7-oxo-1,4-diazepan-1-yl) acetamide (0.20 g, 0.65 mmol), 4-methoxy-5- (2-methyl- A mixture of 1,3-oxazol-5-yl) -2- (methylsulfonyl) pyrimidine (0.080 g, 0.30 mmol), sodium bicarbonate (0.025 g, 0.30 mmol) and DMF (5 mL) at 100 ° C. for 3.5 hours. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 1/9) to give the title compound as a white solid (0.037 g, 25%).
LC / MS 489
NMR (CDCl 3 ) δ:   2.51 (3 H, s), 2.83-2.95 (2 H, m), 3.66-3.82 (2 H, m), 4.01 (3 H, s), 4.06-4.19 (6 H, m), 6.90-7.02 ( 1 H, m), 7.11 (1 H, s), 7.16-7.25 (1 H, m), 7.62 (1 H, dd, J = 6.4, 2.7 Hz), 8.36 (1 H, s), 8.55 (1 H, brs).
実施例１１３
9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3-(3,4,5-トリフルオロベンジル)-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン Example 113
9- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3- (3,4,5-trifluorobenzyl) -3,9-diazabicyclo [4.2.1 ] Nonan-4-one
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(0.42 g, 1.5 mmol)、3-(3,4,5-トリフルオロベンジル)-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン(0.40 g, 1.5 mmol)、DavePhos(0.055 g, 0.14 mmol)、Pd2(dba)3(0.068 g, 0.07 mmol)、ナトリウム tert-ブトキシド(0.22 g, 2.2 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で6時間攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝13/7～酢酸エチルのみ)で精製し、題記化合物を白色固体(0.46 g, 65%)として得た。
LC/MS 472
NMR (CDCl3) δ: 1.87 - 2.02 (1 H, m), 2.06 - 2.33 (2 H, m), 2.49 (3 H, s), 2.77 (1 H, dd, J=15.5, 5.7 Hz), 3.01 (1 H, dd, J=14.8, 5.3 Hz), 3.14 (1 H, d, J=15.9 Hz), 3.90 (3 H, s), 3.95 - 4.06 (2 H, m), 4.24 (1 H, d, J=14.8 Hz), 4.28 - 4.44 (2 H, m), 4.75 (1 H, d, J=14.8 Hz), 6.21 (1 H, d, J=1.9 Hz), 6.30 (1 H, dd, J=8.7, 2.3 Hz), 6.83 - 6.94 (2 H, m), 7.20 (1 H, s), 7.58 (1 H, d, J=8.7 Hz). 5- (4-Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole (0.42 g, 1.5 mmol), 3- (3,4,5-trifluorobenzyl) -3,9-diazabicyclo [ 4.2.1] nonan-4-one (0.40 g, 1.5 mmol), DavePhos (0.055 g, 0.14 mmol), Pd 2 (dba) 3 (0.068 g, 0.07 mmol), sodium tert-butoxide (0.22 g, 2.2 mmol) ) And toluene (5 mL) were stirred at 100 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 13 / 7-ethyl acetate alone) to give the title compound as a white solid (0.46 g, 65%).
LC / MS 472
NMR (CDCl 3 ) δ: 1.87-2.02 (1 H, m), 2.06-2.33 (2 H, m), 2.49 (3 H, s), 2.77 (1 H, dd, J = 15.5, 5.7 Hz), 3.01 (1 H, dd, J = 14.8, 5.3 Hz), 3.14 (1 H, d, J = 15.9 Hz), 3.90 (3 H, s), 3.95-4.06 (2 H, m), 4.24 (1 H , d, J = 14.8 Hz), 4.28-4.44 (2 H, m), 4.75 (1 H, d, J = 14.8 Hz), 6.21 (1 H, d, J = 1.9 Hz), 6.30 (1 H, dd, J = 8.7, 2.3 Hz), 6.83-6.94 (2 H, m), 7.20 (1 H, s), 7.58 (1 H, d, J = 8.7 Hz).
実施例１１４
1-(3,4-ジクロロベンジル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-2-オン Example 114
1- (3,4-Dichlorobenzyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-2-one
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
　4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-2-オン(0.10 g, 0.35 mmol)のDMF(2.0 mL)溶液に4N塩酸酢酸エチル溶液(2 mL)を加え、加熱還流下1時間攪拌した。室温とし、減圧下に濃縮した。残留物に酢酸エチル－飽和炭酸水素ナトリウム水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物にDMF(1.0 mL)次いで、ナトリウム tert-ブトキシド(37 mg, 0.38 mmol)を加え、室温で10分攪拌した。さらに、臭化 3,4-ジクロロベンジル(56 μL, 0.38 mmol)を加え、室温で2時間攪拌した。反応混合物に酢酸エチル－飽和食塩水を加え、水層を酢酸エチルで抽出し、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～1/1)で精製、残留物を酢酸エチル－ヘキサンより再結晶し、題記化合物を白色固体(3.3 mg, 2%)として得た。
LC/MS 446
NMR (CDCl3) δ: 2.52 (3 H, s), 3.43 (2 H, t, J=4.8 Hz), 3.54 (2 H, t, J=5.7 Hz), 3.95 (3 H, s), 4.05 (2 H, s), 4.64 (2 H, s), 6.43 (1 H, d, J=2.4 Hz), 6.52 (1 H, dd, J=2.4 Hz, 8.7 Hz), 7.16 (1 H, dd, J=2.1 Hz, 8.1 Hz), 7.25 (1 H, s), 7.40 (1 H, d, J=1.8 Hz), 7.43 (1 H, d, J=8.1 Hz), 7.63 (1 H, d, J=8.7 Hz). 4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1-{[2- (trimethylsilyl) ethoxy] methyl} piperazin-2-one (0.10 g, 0.35 mmol) in DMF (2.0 mL) was added 4N hydrochloric acid ethyl acetate solution (2 mL), and the mixture was stirred with heating under reflux for 1 hour. The mixture was brought to room temperature and concentrated under reduced pressure. Ethyl acetate-saturated aqueous sodium hydrogen carbonate was added to the residue, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, DMF (1.0 mL) and then sodium tert-butoxide (37 mg, 0.38 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Furthermore, 3,4-dichlorobenzyl bromide (56 μL, 0.38 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate-saturated brine was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate = 8/2 to 1/1), the residue was recrystallized from ethyl acetate-hexane to give the title compound as a white solid (3.3 mg, 2%).
LC / MS 446
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 3.43 (2 H, t, J = 4.8 Hz), 3.54 (2 H, t, J = 5.7 Hz), 3.95 (3 H, s), 4.05 (2 H, s), 4.64 (2 H, s), 6.43 (1 H, d, J = 2.4 Hz), 6.52 (1 H, dd, J = 2.4 Hz, 8.7 Hz), 7.16 (1 H, dd , J = 2.1 Hz, 8.1 Hz), 7.25 (1 H, s), 7.40 (1 H, d, J = 1.8 Hz), 7.43 (1 H, d, J = 8.1 Hz), 7.63 (1 H, d , J = 8.7 Hz).
実施例１１５
N-(3-クロロ-4-フルオロフェニル)-2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-オキソピペラジン-1-イル}アセトアミド Example 115
N- (3-Chloro-4-fluorophenyl) -2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-oxopiperazine-1- Ile} acetamide
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
　tert-ブチル {4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート(0.62 g, 1.5 mmol)にトリフルオロ酢酸(2 mL)を加え、室温で13.5時間攪拌し、50℃で1時間攪拌した。減圧下で濃縮し、残留物にDMF(6 mL)を加え、その半分量に0℃でトリエチルアミン(0.65 g, 4.6 mmol)を加え、0℃で1時間攪拌した。同温度で3-クロロ-4-フルオロアニリン(0.11 g, 0.77 mmol)、ＨＯＢｔ(0.12 g, 0.77 mmol)、ＷＳＣ(0.15 g, 0.77 mmol)を加え、50℃で3時間攪拌した。反応混合物に、酢酸エチル－飽和食塩水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。NHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝3/7～0/1)で精製し、残留物を酢酸エチル－MeOHより再結晶して題記化合物を白色固体(31 mg, 9%)として得た。
LC/MS 473
NMR (CDCl3) δ: 2.52 (3 H, s), 3.62 (2 H, t, J=4.8 Hz), 3.73 (2 H, t, J=5.1 Hz), 3.95 (3 H, s), 4.05 (2 H, s), 4.20 (2 H, s), 6.45 (1 H, d, J=1.8 Hz), 6.54 (1 H, dd, J=2.1 Hz, 8.4 Hz), 7.08 (1 H, dd, J=8.7 Hz, 9.0 Hz), 7.29 - 7.32 (2 H, m), 7.63 (1 H, d, J=8.7 Hz), 7.72 (1 H, dd, J=2.4 Hz, 6.3 Hz), 8.63 (1 H, s). tert-butyl {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-oxopiperazin-1-yl} acetate (0.62 g, 1.5 mmol) Fluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 13.5 hours and stirred at 50 ° C. for 1 hour. It concentrated under reduced pressure, DMF (6 mL) was added to the residue, triethylamine (0.65 g, 4.6 mmol) was added to the half amount at 0 degreeC, and it stirred at 0 degreeC for 1 hour. 3-Chloro-4-fluoroaniline (0.11 g, 0.77 mmol), HOBt (0.12 g, 0.77 mmol) and WSC (0.15 g, 0.77 mmol) were added at the same temperature, and the mixture was stirred at 50 ° C. for 3 hours. Ethyl acetate-saturated brine was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by NH silica gel column chromatography (hexane / ethyl acetate = 3 / 7-0 / 1), and the residue was recrystallized from ethyl acetate-MeOH to give the title compound as a white solid (31 mg, 9%) .
LC / MS 473
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 3.62 (2 H, t, J = 4.8 Hz), 3.73 (2 H, t, J = 5.1 Hz), 3.95 (3 H, s), 4.05 (2 H, s), 4.20 (2 H, s), 6.45 (1 H, d, J = 1.8 Hz), 6.54 (1 H, dd, J = 2.1 Hz, 8.4 Hz), 7.08 (1 H, dd , J = 8.7 Hz, 9.0 Hz), 7.29-7.32 (2 H, m), 7.63 (1 H, d, J = 8.7 Hz), 7.72 (1 H, dd, J = 2.4 Hz, 6.3 Hz), 8.63 (1 H, s).
実施例116
1-(4-メトキシベンジル)-4-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン-2-オン Example 116
1- (4-Methoxybenzyl) -4- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazin-2-one
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
　4-(4-ブロモフェニル)-1-メチル-1H-ピラゾール(129 mg, 0.544 mmol)、1-(4-メトキシベンジル)ピペラジン-2-オン　塩酸塩(140 mg, 0.545 mmol)、DavePhos(21.4 mg, 0.0544mmol)、Pd2(dba)3(49.8 mg, 0.0544 mmol)およびナトリウム tert-ブトキシド(131 mg, 1.36 mmol)のトルエン(2.5 mL)混合液を窒素雰囲気下、100℃で4時間攪拌した。反応液を酢酸エチル－水で希釈後、濾過し、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～10/0)で精製後、得られた粗生成物を酢酸エチルで洗浄し、題記化合物を無色固体(10.5 mg, 5%)として得た。
LC/MS 377
NMR (CDCl3) δ: 3.30 - 3.49 (4 H, m), 3.80 (3 H, s), 3.92 (3 H, s), 3.95 (2 H, s), 4.61 (2 H, s), 6.82 - 6.92 (4 H, m), 7.18 - 7.24 (2 H, m), 7.34 - 7.42 (2 H, m), 7.52 (1 H, s), 7.68 (1 H, s). 4- (4-Bromophenyl) -1-methyl-1H-pyrazole (129 mg, 0.544 mmol), 1- (4-methoxybenzyl) piperazin-2-one hydrochloride (140 mg, 0.545 mmol), DavePhos (21.4 mg, 0.0544 mmol), Pd 2 (dba) 3 (49.8 mg, 0.0544 mmol) and sodium tert-butoxide (131 mg, 1.36 mmol) in toluene (2.5 mL) stirred at 100 ° C for 4 hours under nitrogen atmosphere did. The reaction mixture was diluted with ethyl acetate-water, filtered, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-10 / 0), and the obtained crude product was washed with ethyl acetate to give the title compound as a colorless solid (10.5 mg, 5%).
LC / MS 377
NMR (CDCl 3 ) δ: 3.30-3.49 (4 H, m), 3.80 (3 H, s), 3.92 (3 H, s), 3.95 (2 H, s), 4.61 (2 H, s), 6.82 -6.92 (4 H, m), 7.18-7.24 (2 H, m), 7.34-7.42 (2 H, m), 7.52 (1 H, s), 7.68 (1 H, s).
実施例117
1-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-5-オン Example 117
1- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -4- (3,4,5-trifluorobenzyl) -1,4-diazepan-5-one
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
　1-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1,4-ジアゼパン-5-オン(26.3 mg, 0.0879 mmol)および水素化ナトリウム(4.2 mg、60%油状)のDMF(1 mL)混合液を室温で15分間攪拌後、3,4,5-トリフルオロベンジルブロミド(14.1 μL, 0.106 mmol)を室温で加え、15分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝2/8～8/2)で精製し、題記化合物を無色非定形固体(18.7 mg, 48%)として得た。
LC/MS 445
NMR (CDCl3) δ: 2.88 - 2.95 (2 H, m), 3.35 - 3.40 (2 H, m), 3.48 - 3.56 (4 H, m), 3.87 (3 H, s), 3.92 (3 H, s), 4.55 (2 H, s), 6.40 - 6.48 (2 H, m), 6.85 - 6.96 (2 H, m), 7.36 (1 H, d, J=8.2 Hz), 7.72 (1 H, s), 7.77 (1 H, s). 1- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-diazepan-5-one (26.3 mg, 0.0879 mmol) and sodium hydride (4.2 mg, 60 % Oily) DMF (1 mL) mixture was stirred at room temperature for 15 minutes, 3,4,5-trifluorobenzyl bromide (14.1 μL, 0.106 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2 / 8-8 / 2) to give the title compound as a colorless amorphous solid (18.7 mg, 48%).
LC / MS 445
NMR (CDCl 3 ) δ: 2.88-2.95 (2 H, m), 3.35-3.40 (2 H, m), 3.48-3.56 (4 H, m), 3.87 (3 H, s), 3.92 (3 H, s), 4.55 (2 H, s), 6.40-6.48 (2 H, m), 6.85-6.96 (2 H, m), 7.36 (1 H, d, J = 8.2 Hz), 7.72 (1 H, s ), 7.77 (1 H, s).
下記実施例１１８～６６７におけるＬＣ／ＭＳ分析は以下の条件により測定した。
測定機器：ウォーターズ社ＭＵＸ４－ｃｈ　ＬＣ／ＭＳシステム
ＨＰＬＣ部：ウォーターズ社　１５２５μ
ＭＳ部：マイクロマス社　ＺＱ
カラム：ＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８ＵＧ１２０、Ｓ－３μｍ、１．５×３５ｍｍ(資生堂)
溶媒：Ａ液；５ ｍＭ　酢酸アンモニウム水溶液、Ｂ液；５ ｍＭ　酢酸アンモニウムアセトニトリル溶液
グラジェントサイクル：０．００分(Ａ液/Ｂ液＝１００/０)、２．００分(Ａ液/Ｂ液＝０/１００)、３．００分(Ａ液/Ｂ液＝０/１００)、３．０１分(Ａ液/Ｂ液＝１００/０)、３．３０分(Ａ液/Ｂ液＝１００/０)
注入量：２μＬ、流速：０．５ｍＬ/ｍｉｎ、検出法：ＵＶ２２０ｎｍ、ＭＳ条件　イオン化法：ＥＳＩ
　また、下記実施例118における分取ＨＰＬＣ精製は以下の条件により行った。
機器：ギルソン社ハイスループット精製システム
カラム：CombiPrep ProC18RS S-5 μm、５０×２０ｍｍ(YMC)
溶媒：Ａ液；０．１％TFA含有水、Ｂ液；０．１％TFA含有アセトニトリル
グラジェントサイクル：０．００分(Ａ液/Ｂ液＝９８/２)、１．１０分(Ａ液/Ｂ液＝９８/２)、５．００分(Ａ液/Ｂ液＝０/１００)、６．４０分(Ａ液/Ｂ液＝０/１００)、６．５０分(Ａ液/Ｂ液＝９８/２)
流速：２０ｍＬ/ｍｉｎ、検出法：ＵＶ２２０、２５４ｎｍ The LC / MS analysis in Examples 118 to 667 below was measured under the following conditions.
Measuring instrument: Waters MUX4-ch LC / MS system HPLC part: Waters 1525μ
MS Department: Micromass ZQ
Column: CAPCELL PAK C18UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: A solution; 5 mM ammonium acetate aqueous solution, B solution; 5 mM ammonium acetate acetonitrile solution Gradient cycle: 0.00 min (A solution / B solution = 100/0), 2.00 min (A solution / B solution) = 0/100), 3.00 minutes (A liquid / B liquid = 0/100), 3.01 minutes (A liquid / B liquid = 100/0), 3.30 minutes (A liquid / B liquid = 100) / 0)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm, MS conditions Ionization method: ESI
Further, preparative HPLC purification in the following Example 118 was performed under the following conditions.
Instrument: Gilson High Throughput Purification System Column: CombiPrep ProC18RS S-5 μm, 50 x 20 mm (YMC)
Solvent: A solution; 0.1% TFA-containing water, B solution; 0.1% TFA-containing acetonitrile gradient cycle: 0.00 minutes (A solution / B solution = 98/2), 1.10 minutes (A solution) / B liquid = 98/2), 5.00 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B (Liquid = 98/2)
Flow rate: 20 mL / min, detection method: UV220, 254 nm
実施例１１８
N-シクロプロピル-2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセトアミド Example 118
N-cyclopropyl-2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetamide
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149
　シクロヘキシルアミン(9 mg, 0.16 mmol)に4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル酢酸(29 mg, 0.08 mmol)のDMF(0.5 mL)溶液、EDCI塩酸塩(38 mg, 0.2 mmol)とHOBt(27 mg, 0.2 mmol)のDMF(0.5 mL)溶液、およびトリエチルアミン(0.028 mL, 0.2 mmol)を加え室温で15時間攪拌した。反応液に、飽和重曹水(2 mL)および酢酸エチル(2 mL)を加え攪拌、その後、フェーズ分離フィルターを用い分液後、有機層を加温しながら空気で吹き飛ばした。残渣をDMSO(1 mL)に溶解させ分取HPLCにより分離後、目的物を含有するフラクションを加温しながら空気で吹き飛ばし題記化合物を得た。
収量：３．７ｍｇ
ＬＣ／ＭＳ分析：純度　１００％
ＭＳ(ＥＳＩ＋)：３９９(Ｍ+Ｈ) Cyclohexylamine (9 mg, 0.16 mmol) to 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl Acetic acid (29 mg, 0.08 mmol) in DMF (0.5 mL), EDCI hydrochloride (38 mg, 0.2 mmol) and HOBt (27 mg, 0.2 mmol) in DMF (0.5 mL), and triethylamine (0.028 mL, 0.2 mmol) was added and stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate (2 mL) and ethyl acetate (2 mL) were added to the reaction mixture, and the mixture was stirred and then separated using a phase separation filter. The organic layer was blown off with air while warming. The residue was dissolved in DMSO (1 mL) and separated by preparative HPLC, and the fraction containing the desired product was blown off with air while warming to give the title compound.
Yield: 3.7mg
LC / MS analysis: 100% purity
MS (ESI +): 399 (M + H)
　実施例１１８と同様にして表１～１３に記載の化合物(実施例１１９～１８８)を得た。 The compounds described in Tables 1 to 13 (Examples 119 to 188) were obtained in the same manner as Example 118.
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
実施例１８９
１-(ビフェニル-４-イルカルボニル)-４-[４-(２-メチル-１，３-オキサゾール-５-イル)フェニル]ピペラジン　トリフルオロ酢酸塩 Example 189
1- (biphenyl-4-ylcarbonyl) -4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine trifluoroacetate
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
　１-[４-(２-メチル-１，３-オキサゾール-５-イル)フェニル]ピペラジン・塩酸塩とトリエチルアミンを混合した(０．１６Ｍ)ＤＭＦ溶液(５００μＬ；８０μｍｏｌ)、および４-フェニル安息香酸の(０．１９２Ｍ)ＤＭＦ溶液(５００μＬ；９６μｍｏｌ)を室温で混合し、次いでＨＯＢｔとＷＳＣを混合した(０．１９２Ｍ)ＤＭＦ溶液(５００μＬ；９６μｍｏｌ)を加えて１６時間攪拌した。反応液に、水(１ｍＬ)を加え、酢酸エチル(３．５ｍＬ)で抽出した。酢酸エチル溶媒を減圧下留去し、残渣をＤＭＳＯ(１ｍＬ)に溶解し、分取ＨＰＬＣにより精製して題記化合物を得た。
収量：１．３ｍｇ
ＬＣ／ＭＳ分析：純度　７６％
ＭＳ(ＥＳＩ＋)：３７０(Ｍ+Ｈ) 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine hydrochloride and triethylamine mixed in (0.16M) DMF solution (500 μL; 80 μmol), and 4-phenylbenzoic acid (0.192 M) DMF solution (500 μL; 96 μmol) was mixed at room temperature, and then (0.192 M) DMF solution (500 μL; 96 μmol) mixed with HOBt and WSC was added and stirred for 16 hours. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3.5 mL). The ethyl acetate solvent was removed under reduced pressure, and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC to give the title compound.
Yield: 1.3mg
LC / MS analysis: purity 76%
MS (ESI +): 370 (M + H)
　実施例１８９と同様にして表１４～２２に記載の化合物(実施例１９０～実施例２３６)を得た。 In the same manner as in Example 189, the compounds described in Tables 14 to 22 (Example 190 to Example 236) were obtained.
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
実施例２３７
Ｎ-ベンジル-４-[３-メトキシ-４-(２-メチル-１，３-オキサゾール-５-イル)フェニル]ピペラジン-１-カルボキサミド　トリフルオロ酢酸塩 Example 237
N-benzyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide trifluoroacetate
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
　Ｎ-ベンジルアミンの(０．１７６Ｍ)ＤＭＦ溶液(５００μＬ；８８μｍｏｌ)にＣＤＩの(０．１６Ｍ)ＤＭＦ溶液(５００μＬ；８０μｍｏｌ)を室温で加え、そのまま1時間攪拌した。次いで１-[３-メトキシ-４-(２-メチル-１，３-オキサゾール-５-イル)フェニル]ピペラジン(０．２０Ｍ)の(０．１６Ｍ)ＤＭＦ溶液(５００μＬ；８０μｍｏｌ)を室温で加え、１６時間攪拌した。反応液に、水(１ｍＬ)を加え、酢酸エチル(３．５ｍＬ)で抽出した。酢酸エチル溶媒を減圧下留去し、残渣をＤＭＳＯ(１ｍＬ)に溶解し、分取ＨＰＬＣにより精製して題記化合物を得た。
収量：１０．５ｍｇ
ＬＣ／ＭＳ分析：純度　９４％
ＭＳ(ＥＳＩ＋)：４０７(Ｍ+Ｈ) To a (0.176M) DMF solution (500 μL; 88 μmol) of N-benzylamine, a (0.16M) DMF solution (500 μL; 80 μmol) of CDI was added at room temperature, and the mixture was stirred for 1 hour. 1- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine (0.20M) in (0.16M) DMF (500 μL; 80 μmol) was then added at room temperature. And stirred for 16 hours. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3.5 mL). The ethyl acetate solvent was removed under reduced pressure, and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC to give the title compound.
Yield: 10.5mg
LC / MS analysis: 94% purity
MS (ESI +): 407 (M + H)
　実施例２３７と同様にして表２３～９６に記載の化合物(実施例２３８～実施例６６７)を得た。 In the same manner as in Example 237, the compounds described in Tables 23 to 96 (Example 238 to Example 667) were obtained.
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000247
実施例668
4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 668
4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000248
Figure JPOXMLDOC01-appb-C000248
　tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(150 mg, 0.43 mmol)の酢酸エチル(4.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で2時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(4.0 mL)に懸濁し、N-エチルジイソプロピルアミン(150 μL, 0.86 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(110 μL, 0.64 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ～メタノール/酢酸エチル=1/9)で精製した。得られた固形物をメタノール/酢酸エチルより再結晶して、題記化合物を無色固体(130 mg, 69%(2 steps))として得た。
LC/MS 441 
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz) 2.48 (3 H, s) 3.14 - 3.28 (4 H, m) 3.46 - 3.61 (4 H, m) 4.71 (1 H, d, J=6.8 Hz) 5.76 - 5.94 (1 H, m) 6.89 - 7.02 (2 H, m) 7.41 - 7.63 (6 H, m) 7.81 (1 H, d, J=7.9 Hz) 7.85 - 7.91 (1 H, m) 8.17 (1 H, d, J=7.9 Hz) 8.30 (1 H, s).  tert-Butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (150 mg, 0.43 mmol) in ethyl acetate (4.0 mL) 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 2 hr. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (4.0 mL), and N-ethyldiisopropylamine (150 μL, 0.86 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (110 μL, 0.64 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone to methanol / ethyl acetate = 1/9). The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (130 mg, 69% (2 steps)).
LC / MS 441
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz) 2.48 (3 H, s) 3.14-3.28 (4 H, m) 3.46-3.61 (4 H, m) 4.71 (1 H, d , J = 6.8 Hz) 5.76-5.94 (1 H, m) 6.89-7.02 (2 H, m) 7.41-7.63 (6 H, m) 7.81 (1 H, d, J = 7.9 Hz) 7.85-7.91 (1 H, m) 8.17 (1 H, d, J = 7.9 Hz) 8.30 (1 H, s).
実施例669 
4-[2-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 669
4- [2-Fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000249
Figure JPOXMLDOC01-appb-C000249
　tert-ブチル 4-[2-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(160 mg, 0.45 mmol)の酢酸エチル(4.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で2.5時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(230 μL, 1.3 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(120 μL, 0.67 mmol)を加え、室温で5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/4～酢酸エチルのみ～メタノール/酢酸エチル=3/47)で精製した。得られた固形物をメタノール/酢酸エチルより再結晶して、題記化合物を無色固体(130 mg, 64%(2 steps))として得た。
LC/MS 459 
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.4 Hz) 2.48 (3 H, s) 3.00 - 3.16 (4 H, m) 3.43 - 3.64 (4 H, m) 4.71 (1 H, d, J=7.2 Hz) 5.77 - 5.94 (1 H, m) 6.97 (1 H, t, J=8.9 Hz) 7.29 - 7.61 (6 H, m) 7.80 (1 H, d, J=8.0 Hz) 7.85 - 7.92 (1 H, m) 8.17 (1 H, d, J=8.3 Hz) 8.33 (1 H, s). tert-Butyl 4- [2-fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (160 mg, 0.45 mmol) in ethyl acetate ( 4.0 mL) To the suspension was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (230 μL, 1.3 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (120 μL, 0.67 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to ethyl acetate alone to methanol / ethyl acetate = 3/47). The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (130 mg, 64% (2 steps)).
LC / MS 459
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.4 Hz) 2.48 (3 H, s) 3.00-3.16 (4 H, m) 3.43-3.64 (4 H, m) 4.71 (1 H, d , J = 7.2 Hz) 5.77-5.94 (1 H, m) 6.97 (1 H, t, J = 8.9 Hz) 7.29-7.61 (6 H, m) 7.80 (1 H, d, J = 8.0 Hz) 7.85- 7.92 (1 H, m) 8.17 (1 H, d, J = 8.3 Hz) 8.33 (1 H, s).
実施例670 
N-(3,4-ジクロロベンジル)-4-[2-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキサミド Example 670
N- (3,4-dichlorobenzyl) -4- [2-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000250
Figure JPOXMLDOC01-appb-C000250
　tert-ブチル 4-[2-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(320 mg, 0.85 mmol)の酢酸エチル(2.5 mL)懸濁液に4N塩酸酢酸エチル溶液(5.0 mL)を加え、室温で4時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(220 μL, 1.3 mmol)と3,4-ジクロロベンジルイソシアナート(94 μL, 0.64 mmol)を加え、室温で4時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル=3/47)で精製した。得られた残留物をヘキサンで洗浄して、題記化合物を無色非定形固体(120 mg, 59%(2 steps))として得た。
LC/MS 475 
NMR (CDCl3) δ: 2.49 (3 H, s) 3.02 - 3.16 (4 H, m) 3.50 - 3.66 (4 H, m) 3.96 (3 H, s) 4.42 (2 H, d, J=5.7 Hz) 4.84 (1 H, t, J=6.1 Hz) 6.95 (1 H, d, J=8.3 Hz) 7.10 (1 H, dd, J=8.3, 2.3 Hz) 7.18 (1 H, dd, J=8.3, 2.3 Hz) 7.22 (1 H, d, J=2.3 Hz) 7.38 - 7.44 (2 H, m) 8.36 (1 H, s). tert-Butyl 4- [2-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (320 mg, 0.85 mmol) in ethyl acetate ( 2.5 mL) To the suspension was added 4N hydrochloric acid ethyl acetate solution (5.0 mL), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and 1/2 of the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (220 μL, 1.3 mmol) and 3,4-dichlorobenzyl isocyanate (94 μL, 0.64 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate only to methanol / ethyl acetate = 3/47). The obtained residue was washed with hexane to give the title compound as a colorless amorphous solid (120 mg, 59% (2 steps)).
LC / MS 475
NMR (CDCl 3 ) δ: 2.49 (3 H, s) 3.02-3.16 (4 H, m) 3.50-3.66 (4 H, m) 3.96 (3 H, s) 4.42 (2 H, d, J = 5.7 Hz ) 4.84 (1 H, t, J = 6.1 Hz) 6.95 (1 H, d, J = 8.3 Hz) 7.10 (1 H, dd, J = 8.3, 2.3 Hz) 7.18 (1 H, dd, J = 8.3, 2.3 Hz) 7.22 (1 H, d, J = 2.3 Hz) 7.38-7.44 (2 H, m) 8.36 (1 H, s).
実施例671 
4-[2-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 671
4- [2-Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000251
Figure JPOXMLDOC01-appb-C000251
　tert-ブチル 4-[2-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(320 mg, 0.85 mmol)の酢酸エチル(2.5 mL)懸濁液に4N塩酸酢酸エチル溶液(5.0 mL)を加え、室温で4時間攪拌した。溶媒を減圧留去し、得られた残渣の1/2をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(220 μL, 1.3 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(110 μL, 0.64 mmol)を加え、室温で4時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル=7/93)で精製した。得られた残留物をヘキサンで洗浄して、題記化合物を無色非定形固体(130 mg, 63%(2 steps))として得た。
LC/MS 471 
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz) 2.49 (3 H, s) 3.04 (4 H, t, J=5.1 Hz) 3.46 - 3.64 (4 H, m) 3.93 (3 H, s) 4.71 (1 H, d, J=7.2 Hz) 5.77 - 5.98 (1 H, m) 6.92 (1 H, d, J=8.7 Hz) 7.09 (1 H, dd, J=8.7, 2.3 Hz) 7.19 (1 H, d, J=2.3 Hz) 7.38 - 7.65 (4 H, m) 7.80 (1 H, d, J=8.0 Hz) 7.84 - 7.92 (1 H, m) 8.18 (1 H, d, J=8.3 Hz) 8.34 (1 H, s). tert-Butyl 4- [2-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (320 mg, 0.85 mmol) in ethyl acetate ( 2.5 mL) To the suspension was added 4N hydrochloric acid ethyl acetate solution (5.0 mL), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and 1/2 of the obtained residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (220 μL, 1.3 mmol) and (S)-(+)-1- (1 -Naphthyl) -ethyl isocyanate (110 μL, 0.64 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate only to methanol / ethyl acetate = 7/93). The obtained residue was washed with hexane to give the title compound as a colorless amorphous solid (130 mg, 63% (2 steps)).
LC / MS 471
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz) 2.49 (3 H, s) 3.04 (4 H, t, J = 5.1 Hz) 3.46-3.64 (4 H, m) 3.93 (3 H, s) 4.71 (1 H, d, J = 7.2 Hz) 5.77-5.98 (1 H, m) 6.92 (1 H, d, J = 8.7 Hz) 7.09 (1 H, dd, J = 8.7, 2.3 Hz ) 7.19 (1 H, d, J = 2.3 Hz) 7.38-7.65 (4 H, m) 7.80 (1 H, d, J = 8.0 Hz) 7.84-7.92 (1 H, m) 8.18 (1 H, d, J = 8.3 Hz) 8.34 (1 H, s).
実施例672 
4-[3-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 672
4- [3-Fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000252
Figure JPOXMLDOC01-appb-C000252
　tert-ブチル 4-[3-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(240 mg, 0.66 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で2時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(340 μL, 2.0 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(170 μL, 0.99 mmol)を加え、室温で6時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル=1/19)で精製した。得られた固形物をメタノール/酢酸エチルより再結晶して、題記化合物を無色固体(150 mg, 50%(2 steps))として得た。
LC/MS 459 
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.4 Hz) 2.48 (3 H, s) 3.13 - 3.35 (4 H, m) 3.45 - 3.64 (4 H, m) 4.71 (1 H, d, J=7.2 Hz) 5.86 (1 H, quin, J=6.9 Hz) 6.61 - 6.76 (2 H, m) 7.42 - 7.66 (5 H, m) 7.81 (1 H, d, J=8.3 Hz) 7.84 - 7.91 (1 H, m) 8.16 (1 H, d, J=8.3 Hz) 8.36 (1 H, d, J=2.3 Hz). tert-Butyl 4- [3-fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (240 mg, 0.66 mmol) in ethyl acetate ( 1.0 mL) 4N hydrochloric acid ethyl acetate solution (4.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (340 μL, 2.0 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (170 μL, 0.99 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate only-methanol / ethyl acetate = 1/19). The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (150 mg, 50% (2 steps)).
LC / MS 459
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.4 Hz) 2.48 (3 H, s) 3.13-3.35 (4 H, m) 3.45-3.64 (4 H, m) 4.71 (1 H, d , J = 7.2 Hz) 5.86 (1 H, quin, J = 6.9 Hz) 6.61-6.76 (2 H, m) 7.42-7.66 (5 H, m) 7.81 (1 H, d, J = 8.3 Hz) 7.84- 7.91 (1 H, m) 8.16 (1 H, d, J = 8.3 Hz) 8.36 (1 H, d, J = 2.3 Hz).
実施例673 
4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-プロポキシフェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 673
4- [4- (3-Methyl-1H-1,2,4-triazol-1-yl) -3-propoxyphenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1- Carboxamide
Figure JPOXMLDOC01-appb-C000253
Figure JPOXMLDOC01-appb-C000253
　tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-プロポキシフェニル]ピペラジン-1-カルボキシラート(200 mg, 0.50 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(260 μL, 1.5 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(130 μL, 0.75 mmol)を加え、室温で3.5時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/9～酢酸エチルのみ)で精製して、題記化合物を無色非定形固体(240 mg, 97%(2 steps))として得た。
LC/MS 499 
NMR (CDCl3) δ: 0.99 (3 H, t, J=7.4 Hz) 1.70 (3 H, d, J=6.8 Hz) 1.73 - 1.89 (2 H, m) 2.47 (3 H, s) 3.11 - 3.27 (4 H, m) 3.44 - 3.64 (4 H, m) 3.97 (2 H, t, J=6.4 Hz) 4.72 (1 H, d, J=7.2 Hz) 5.85 (1 H, quin, J=6.8 Hz) 6.43 - 6.63 (2 H, m) 7.40 - 7.64 (5 H, m) 7.81 (1 H, d, J=7.9 Hz) 7.84 - 7.92 (1 H, m) 8.16 (1 H, d, J=8.3 Hz) 8.50 (1 H, s). tert-Butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3-propoxyphenyl] piperazine-1-carboxylate (200 mg, 0.50 mmol) in ethyl acetate ( 1.0 mL) To the suspension was added 4N hydrochloric acid ethyl acetate solution (4.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (260 μL, 1.5 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (130 μL, 0.75 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to ethyl acetate only) to give the title compound as a colorless amorphous solid (240 mg, 97% (2 steps)). .
LC / MS 499
NMR (CDCl 3 ) δ: 0.99 (3 H, t, J = 7.4 Hz) 1.70 (3 H, d, J = 6.8 Hz) 1.73-1.89 (2 H, m) 2.47 (3 H, s) 3.11-3.27 (4 H, m) 3.44-3.64 (4 H, m) 3.97 (2 H, t, J = 6.4 Hz) 4.72 (1 H, d, J = 7.2 Hz) 5.85 (1 H, quin, J = 6.8 Hz ) 6.43-6.63 (2 H, m) 7.40-7.64 (5 H, m) 7.81 (1 H, d, J = 7.9 Hz) 7.84-7.92 (1 H, m) 8.16 (1 H, d, J = 8.3 Hz) 8.50 (1 H, s).
実施例674 
4-[3-エトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 674
4- [3-Ethoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000254
Figure JPOXMLDOC01-appb-C000254
　tert-ブチル 4-[3-エトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(220 mg, 0.58 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で4.5時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(300 μL, 2.0 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(130 μL, 0.99 mmol)を加え、室温で6時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/4～9/1)で精製して、題記化合物を淡黄色非定形固体(270 mg, 97%(2 steps))として得た。
LC/MS 485 
NMR (CDCl3) δ: 1.52 (3 H, t, J=6.8 Hz) 1.70 (3 H, d, J=6.8 Hz) 2.49 (3 H, s) 3.17 - 3.26 (4 H, m) 3.41 - 3.65 (4 H, m) 4.12 (2 H, q, J=6.8 Hz) 4.71 (1 H, d, J=7.2 Hz) 5.85 (1 H, quin, J=6.8 Hz) 6.44 (1 H, d, J=2.3 Hz) 6.51 (1 H, dd, J=8.7, 2.3 Hz) 7.28 (1 H, s) 7.41 - 7.67 (5 H, m) 7.80 (1 H, d, J=8.3 Hz) 7.84 - 7.91 (1 H, m) 8.17 (1 H, d, J=8.3 Hz). tert-butyl 4- [3-ethoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (220 mg, 0.58 mmol) in ethyl acetate (1.0 mL) 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the suspension, and the mixture was stirred at room temperature for 4.5 hr. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (300 μL, 2.0 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (130 μL, 0.99 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 4-9 / 1) to give the title compound as a pale yellow amorphous solid (270 mg, 97% (2 steps)). It was.
LC / MS 485
NMR (CDCl 3 ) δ: 1.52 (3 H, t, J = 6.8 Hz) 1.70 (3 H, d, J = 6.8 Hz) 2.49 (3 H, s) 3.17-3.26 (4 H, m) 3.41-3.65 (4 H, m) 4.12 (2 H, q, J = 6.8 Hz) 4.71 (1 H, d, J = 7.2 Hz) 5.85 (1 H, quin, J = 6.8 Hz) 6.44 (1 H, d, J = 2.3 Hz) 6.51 (1 H, dd, J = 8.7, 2.3 Hz) 7.28 (1 H, s) 7.41-7.67 (5 H, m) 7.80 (1 H, d, J = 8.3 Hz) 7.84-7.91 ( 1 H, m) 8.17 (1 H, d, J = 8.3 Hz).
実施例675 
4-[3-(1-メチルエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 675
4- [3- (1-Methylethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl ] Piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000255
Figure JPOXMLDOC01-appb-C000255
　tert-ブチル 4-[3-(1-メチルエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(120 mg, 0.30 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で2.5時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(2.0 mL)に懸濁し、N-エチルジイソプロピルアミン(150 μL, 0.90 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(68 μL, 0.39 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/4～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(140 mg, 93%(2 steps))として得た。
LC/MS 499 
NMR (CDCl3) δ: 1.31 (6 H, d, J=6.0 Hz) 1.70 (3 H, d, J=6.7 Hz) 2.47 (3 H, s) 3.13 - 3.25 (4 H, m) 3.44 - 3.65 (4 H, m) 4.53 (1 H, quin, J=6.0 Hz) 4.71 (1 H, d, J=7.2 Hz) 5.86 (1 H, quin, J=6.7 Hz) 6.50 - 6.59 (2 H, m) 7.41 - 7.61 (5 H, m) 7.81 (1 H, d, J=7.9 Hz) 7.84 - 7.91 (1 H, m) 8.17 (1 H, d, J=8.3 Hz) 8.52 (1 H, s). tert-Butyl 4- [3- (1-methylethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (120 mg, 0.30 mmol ) In ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (2.0 mL), and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (2.0 mL), and N-ethyldiisopropylamine (150 μL, 0.90 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (68 μL, 0.39 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to ethyl acetate alone) to give the title compound as a colorless amorphous solid (140 mg, 93% (2 steps)).
LC / MS 499
NMR (CDCl 3 ) δ: 1.31 (6 H, d, J = 6.0 Hz) 1.70 (3 H, d, J = 6.7 Hz) 2.47 (3 H, s) 3.13-3.25 (4 H, m) 3.44-3.65 (4 H, m) 4.53 (1 H, quin, J = 6.0 Hz) 4.71 (1 H, d, J = 7.2 Hz) 5.86 (1 H, quin, J = 6.7 Hz) 6.50-6.59 (2 H, m 7.41-7.61 (5 H, m) 7.81 (1 H, d, J = 7.9 Hz) 7.84-7.91 (1 H, m) 8.17 (1 H, d, J = 8.3 Hz) 8.52 (1 H, s) .
実施例676
4-[4-(2-メチル-1,3-オキサゾール-5-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 676
4- [4- (2-Methyl-1,3-oxazol-5-yl) -3- (2,2,2-trifluoroethoxy) phenyl] -N-[(1S) -1-naphthalene-1- Ylethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000256
Figure JPOXMLDOC01-appb-C000256
　tert-ブチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート(150 mg, 0.34 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(2.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(180 μL, 1.0 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(78 μL, 0.45 mmol)を加え、室温で6時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=3/7～7/3)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(91 mg, 49%(2 steps))として得た。
LC/MS 539 
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz) 2.50 (3 H, s) 3.15 - 3.30 (4 H, m) 3.44 - 3.65 (4 H, m) 4.42 (2 H, q, J=8.0 Hz) 4.70 (1 H, d, J=6.8 Hz) 5.78 - 5.96 (1 H, m) 6.36 (1 H, d, J=1.9 Hz) 6.61 (1 H, dd, J=8.7, 1.9 Hz) 7.25 (1 H, s) 7.42 - 7.66 (5 H, m) 7.81 (1 H, d, J=8.3 Hz) 7.85 - 7.90 (1 H, m) 8.16 (1 H, d, J=8.3 Hz). tert-Butyl 4- [4- (2-methyl-1,3-oxazol-5-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxylate (150 mg, 0.34 mmol) in ethyl acetate (1.0 mL) was added 4N hydrochloric acid ethyl acetate solution (2.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (180 μL, 1.0 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (78 μL, 0.45 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to 7/3). The residue was washed with hexane to give the title compound as a colorless amorphous solid (91 mg, 49% (2 steps)).
LC / MS 539
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz) 2.50 (3 H, s) 3.15-3.30 (4 H, m) 3.44-3.65 (4 H, m) 4.42 (2 H, q , J = 8.0 Hz) 4.70 (1 H, d, J = 6.8 Hz) 5.78-5.96 (1 H, m) 6.36 (1 H, d, J = 1.9 Hz) 6.61 (1 H, dd, J = 8.7, 1.9 Hz) 7.25 (1 H, s) 7.42-7.66 (5 H, m) 7.81 (1 H, d, J = 8.3 Hz) 7.85-7.90 (1 H, m) 8.16 (1 H, d, J = 8.3 Hz).
実施例677 
4-[2,3-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 677
4- [2,3-Difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalen-1-ylethyl] piperazine- 1-carboxamide
Figure JPOXMLDOC01-appb-C000257
Figure JPOXMLDOC01-appb-C000257
　tert-ブチル 4-[2,3-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(240 mg, 0.63 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(3.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(330 μL, 1.9 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(220 μL, 0.82 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/4～9/1)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(220 mg, 74%(2 steps))として得た。
LC/MS 477 
NMR (CDCl3) δ: 1.70 (3 H, d, J=6.8 Hz) 2.49 (3 H, s) 3.01 - 3.17 (4 H, m) 3.43 - 3.65 (4 H, m) 4.72 (1 H, d, J=6.8 Hz) 5.86 (1 H, quin, J=7.0 Hz) 6.65 - 6.86 (1 H, m) 7.42 - 7.63 (5 H, m) 7.81 (1 H, d, J=8.0 Hz) 7.85 - 7.91 (1 H, m) 8.17 (1 H, d, J=8.3 Hz) 8.42 (1 H, d, J=2.7 Hz). Acetic acid of tert-butyl 4- [2,3-difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (240 mg, 0.63 mmol) 4N Hydrochloric acid ethyl acetate solution (3.0 mL) was added to the ethyl (1.0 mL) suspension, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (330 μL, 1.9 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (220 μL, 0.82 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to 9/1). The residue was washed with hexane to give the title compound as a colorless amorphous solid (220 mg, 74% (2 steps)).
LC / MS 477
NMR (CDCl 3 ) δ: 1.70 (3 H, d, J = 6.8 Hz) 2.49 (3 H, s) 3.01-3.17 (4 H, m) 3.43-3.65 (4 H, m) 4.72 (1 H, d , J = 6.8 Hz) 5.86 (1 H, quin, J = 7.0 Hz) 6.65-6.86 (1 H, m) 7.42-7.63 (5 H, m) 7.81 (1 H, d, J = 8.0 Hz) 7.85- 7.91 (1 H, m) 8.17 (1 H, d, J = 8.3 Hz) 8.42 (1 H, d, J = 2.7 Hz).
実施例678 
4-[3-(2,2-ジフルオロエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Example 678
4- [3- (2,2-difluoroethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -N-[(1S) -1-naphthalene-1 -Ilethyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000258
Figure JPOXMLDOC01-appb-C000258
　tert-ブチル 4-[3-(2,2-ジフルオロエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート(230 mg, 0.53 mmol)の酢酸エチル(1.0 mL)懸濁液に4N塩酸酢酸エチル溶液(3.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣をTHF(3.0 mL)に懸濁し、N-エチルジイソプロピルアミン(270 μL, 1.6 mmol)と(S)-(+)-1-(1-ナフチル)-エチルイソシアナート(120 μL, 0.69 mmol)を加え、室温で3時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=3/7～9/1)で精製した。残留物をヘキサンで洗浄し、題記化合物を無色非定形固体(200 mg, 72%(2 steps))として得た。
LC/MS 521 
NMR (CDCl3) δ: 1.71 (3 H, d, J=6.4 Hz) 2.47 (3 H, s) 3.14 - 3.29 (4 H, m) 3.39 - 3.66 (4 H, m) 4.21 (2 H, td, J=13.0, 4.0 Hz) 4.71 (1 H, d, J=7.2 Hz) 5.77 - 6.25 (2 H, m) 6.47 (1 H, d, J=2.7 Hz) 6.61 (1 H, dd, J=8.9, 2.7 Hz) 7.41 - 7.64 (5 H, m) 7.81 (1 H, d, J=8.0 Hz) 7.85 - 7.94 (1 H, m) 8.16 (1 H, d, J=8.3 Hz) 8.39 (1 H, s). tert-butyl 4- [3- (2,2-difluoroethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (230 mg, A 4N hydrochloric acid ethyl acetate solution (3.0 mL) was added to a suspension of 0.53 mmol) in ethyl acetate (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in THF (3.0 mL), and N-ethyldiisopropylamine (270 μL, 1.6 mmol) and (S)-(+)-1- (1-naphthyl)- Ethyl isocyanate (120 μL, 0.69 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3/7 to 9/1). The residue was washed with hexane to give the title compound as a colorless amorphous solid (200 mg, 72% (2 steps)).
LC / MS 521
NMR (CDCl 3 ) δ: 1.71 (3 H, d, J = 6.4 Hz) 2.47 (3 H, s) 3.14-3.29 (4 H, m) 3.39-3.66 (4 H, m) 4.21 (2 H, td , J = 13.0, 4.0 Hz) 4.71 (1 H, d, J = 7.2 Hz) 5.77-6.25 (2 H, m) 6.47 (1 H, d, J = 2.7 Hz) 6.61 (1 H, dd, J = 8.9, 2.7 Hz) 7.41-7.64 (5 H, m) 7.81 (1 H, d, J = 8.0 Hz) 7.85-7.94 (1 H, m) 8.16 (1 H, d, J = 8.3 Hz) 8.39 (1 H, s).
実施例679 
1-(2-{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-イル}-1-メチル-2-オキソエチル)-1H-ベンゾイミダゾール Example 679
1- (2- {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-1-yl} -1-methyl-2- Oxoethyl) -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000259
Figure JPOXMLDOC01-appb-C000259
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート(600 mg, 1.5 mmol)の酢酸エチル(1.0 mL)溶液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残渣の1/4をDMF(2.0 mL)に懸濁し、2-(1H-ベンゾイミダゾール-1-イル)プロパン酸(89 mg, 0.47 mmol)とシアノホスホン酸ジエチル(70 μL, 0.47 mmol)を加えた。室温で30分攪拌した後、トリエチルアミン(220 μL, 1.6 mmol)を加え、室温で2時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ)で精製した。得られた固形物をメタノール/酢酸エチルより再結晶して、題記化合物を無色固体(95 mg, 53% (2 steps))として得た。
LC/MS 460 
NMR (CDCl3) δ: 1.19 - 1.29 (1/2 H, m) 1.63 - 1.74 (3 H, m) 1.77 - 2.13 (3/2 H, m) 2.49 - 2.50 (3 H, m) 2.72 - 3.14 (1 H, m) 3.25 - 3.37 (3/2 H, m) 3.49 - 3.77 (5 H, m) 3.86 - 3.87 (3 H, m) 4.05 - 4.14 (1/2 H, m) 5.19 - 5.38 (1 H, m) 6.07 - 6.17 (1 H, m) 6.23 - 6.30 (1 H, m) 7.11 - 7.24 (3 H, m) 7.29 - 7.33 (1 H, m) 7.49 - 7.55 (1 H, m) 7.77 - 7.82 (1 H, m) 8.01 - 8.07 (1 H, m). tert-Butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate (600 mg, 1.5 mmol) in ethyl acetate 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the (1.0 mL) solution, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and 1/4 of the obtained residue was suspended in DMF (2.0 mL), and 2- (1H-benzoimidazol-1-yl) propanoic acid (89 mg, 0.47 mmol) and cyanophosphonic acid were suspended. Diethyl (70 μL, 0.47 mmol) was added. After stirring at room temperature for 30 minutes, triethylamine (220 μL, 1.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate only). The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (95 mg, 53% (2 steps)).
LC / MS 460
NMR (CDCl 3 ) δ: 1.19-1.29 (1/2 H, m) 1.63-1.74 (3 H, m) 1.77-2.13 (3/2 H, m) 2.49-2.50 (3 H, m) 2.72-3.14 (1 H, m) 3.25-3.37 (3/2 H, m) 3.49-3.77 (5 H, m) 3.86-3.87 (3 H, m) 4.05-4.14 (1/2 H, m) 5.19-5.38 ( 1 H, m) 6.07-6.17 (1 H, m) 6.23-6.30 (1 H, m) 7.11-7.24 (3 H, m) 7.29-7.33 (1 H, m) 7.49-7.55 (1 H, m) 7.77-7.82 (1 H, m) 8.01-8.07 (1 H, m).
実施例680 
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-[4-(トリフルオロメチル)ベンジル]-1,4-ジアゼパン-1-カルボキサミド Example 680
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- [4- (trifluoromethyl) benzyl] -1,4-diazepan-1-carboxamide
Figure JPOXMLDOC01-appb-C000260
Figure JPOXMLDOC01-appb-C000260
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート(600 mg, 1.5 mmol)の酢酸エチル(1.0 mL)溶液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去した。CDI(69 mg, 0.43 mmol)のDMF(1 mL)溶液に4-(トリフルオロメチル)ベンジルアミン(61 μL, 0.43 mmol)のDMF(1 mL)溶液を0 ℃で加えた。0 ℃で30分、室温で30分攪拌した後に、反応溶液に得られた残渣の1/4とN-エチルジイソプロピルアミン(130 μL, 0.78 mmol)のDMF(1 mL)溶液を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ～メタノール/酢酸エチル=1/19)で精製し、題記化合物を無色非定形固体(75 mg, 40% (2 steps))として得た。
LC/MS 489 
NMR (CDCl3) δ: 1.97 - 2.05 (2 H, m) 2.49 (3 H, s) 2.84 - 2.99 (1 H, m) 3.35 (2 H, t, J=6.0 Hz) 3.64 (2 H, t, J=6.0 Hz) 3.69 (3 H, s) 3.90 (3 H, s) 4.46 (2 H, d, J=5.3 Hz) 4.83 (1 H, br. s.) 6.27 (1 H, d, J=2.3 Hz) 6.37 (1 H, dd, J=8.7, 2.3 Hz) 7.19 (1 H, s) 7.29 (2 H, d, J=7.9 Hz) 7.51 (2 H, d, J=7.9 Hz) 7.55 (1 H, d, J=8.7 Hz). tert-Butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate (600 mg, 1.5 mmol) in ethyl acetate 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the (1.0 mL) solution, and the mixture was stirred at room temperature for 3 hr. The solvent was removed under reduced pressure. To a DMF (1 mL) solution of CDI (69 mg, 0.43 mmol), a DMF (1 mL) solution of 4- (trifluoromethyl) benzylamine (61 μL, 0.43 mmol) was added at 0 ° C. After stirring at 0 ° C. for 30 minutes and at room temperature for 30 minutes, 1/4 of the obtained residue and N-ethyldiisopropylamine (130 μL, 0.78 mmol) in DMF (1 mL) were added to the reaction solution, and Stir for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate only to methanol / ethyl acetate = 1/19) to give the title compound as a colorless amorphous solid (75 mg, 40% (2 steps)).
LC / MS 489
NMR (CDCl 3 ) δ: 1.97-2.05 (2 H, m) 2.49 (3 H, s) 2.84-2.99 (1 H, m) 3.35 (2 H, t, J = 6.0 Hz) 3.64 (2 H, t , J = 6.0 Hz) 3.69 (3 H, s) 3.90 (3 H, s) 4.46 (2 H, d, J = 5.3 Hz) 4.83 (1 H, br. S.) 6.27 (1 H, d, J = 2.3 Hz) 6.37 (1 H, dd, J = 8.7, 2.3 Hz) 7.19 (1 H, s) 7.29 (2 H, d, J = 7.9 Hz) 7.51 (2 H, d, J = 7.9 Hz) 7.55 (1 H, d, J = 8.7 Hz).
実施例681 
N-[(5-クロロチオフェン-2-イル)メチル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキサミド Example 681
N-[(5-chlorothiophen-2-yl) methyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-1 -Carboxamide
Figure JPOXMLDOC01-appb-C000261
Figure JPOXMLDOC01-appb-C000261
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート(600 mg, 1.5 mmol)の酢酸エチル(1.0 mL)溶液に4N塩酸酢酸エチル溶液(4.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去した。CDI(69 mg, 0.43 mmol)のDMF(1.0 mL)溶液に1-(5-クロロチオフェン-2-イル)メタンアミン　1塩酸塩(79 mg, 0.43 mmol)とN-エチルジイソプロピルアミン(73μL, 0.85 mmol)のDMF(1.0 mL)溶液を0 ℃で加えた。0 ℃で15分、室温で30分攪拌した後に、反応溶液に得られた残渣の1/4とN-エチルジイソプロピルアミン(130 μL, 0.78 mmol)のDMF(1.0 mL)溶液を加え、室温で14時間攪拌した。反応溶液を水とトルエンで希釈し、激しく攪拌した。分離し、得られた有機層ををシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=7/3～酢酸エチルのみ～メタノール/酢酸エチル=1/19)で精製し、題記化合物を無色非定形固体(52 mg, 29% (2 steps))として得た。
LC/MS 461
NMR (CDCl3) δ: 1.95 - 2.11 (2 H, m) 2.49 (3 H, s) 3.21 - 3.39 (2 H, m) 3.56 - 3.75 (6 H, m) 3.91 (3 H, s) 4.48 (2 H, d, J=5.7 Hz) 4.62 - 4.79 (1 H, m) 6.26 (1 H, d, J=2.3 Hz) 6.36 (1 H, dd, J=8.7, 2.3 Hz) 6.60 - 6.75 (2 H, m) 7.18 (1 H, s) 7.54 (1 H, d, J=8.7 Hz).  tert-Butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate (600 mg, 1.5 mmol) in ethyl acetate 4N Hydrochloric acid ethyl acetate solution (4.0 mL) was added to the (1.0 mL) solution, and the mixture was stirred at room temperature for 3 hr. The solvent was removed under reduced pressure. 1- (5-Chlorothiophen-2-yl) methanamine monohydrochloride (79 mg, 0.43 mmol) and N-ethyldiisopropylamine (73 μL, 0.85 mmol) in DMF (1.0 mL) solution of CDI (69 mg, 0.43 mmol) ) In DMF (1.0 mL) was added at 0 ° C. After stirring at 0 ° C for 15 minutes and at room temperature for 30 minutes, 1/4 of the obtained residue and N-ethyldiisopropylamine (130 μL, 0.78 mmol) in DMF (1.0 mL) were added to the reaction solution, and Stir for 14 hours. The reaction solution was diluted with water and toluene and stirred vigorously. The organic layer obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 7 / 3-ethyl acetate only-methanol / ethyl acetate = 1/19) to give the title compound as a colorless amorphous solid (52 mg, 29% (2 steps)).
LC / MS 461
NMR (CDCl 3 ) δ: 1.95-2.11 (2 H, m) 2.49 (3 H, s) 3.21-3.39 (2 H, m) 3.56-3.75 (6 H, m) 3.91 (3 H, s) 4.48 ( 2 H, d, J = 5.7 Hz) 4.62-4.79 (1 H, m) 6.26 (1 H, d, J = 2.3 Hz) 6.36 (1 H, dd, J = 8.7, 2.3 Hz) 6.60-6.75 (2 H, m) 7.18 (1 H, s) 7.54 (1 H, d, J = 8.7 Hz).
実施例682
N-(2-メトキシベンジル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキサミド Example 682
N- (2-methoxybenzyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-1-carboxamide
Figure JPOXMLDOC01-appb-C000262
Figure JPOXMLDOC01-appb-C000262
　CDI(71 mg, 0.44 mmol)のDMF(1.0 mL)溶液にo-メトキシベンジルアミン(39 μL, 0.44 mmol)のDMF(1.0 mL)溶液を0 ℃で加えた。0 ℃で30分攪拌した後に、反応溶液に1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.0 mL)溶液を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ～メタノール/酢酸エチル=3/97)で精製した。得られた固形物をメタノール/酢酸エチルより再結晶して、題記化合物を無色固体(89 mg, 50%)として得た。
LC/MS 451 
NMR (CDCl3) δ: 1.93 - 2.11 (2 H, m) 2.49 (3 H, s) 3.25 (2 H, t, J=6.2 Hz) 3.54 - 3.68 (6 H, m) 3.85 (3 H, s) 3.91 (3 H, s) 4.42 (2 H, d, J=5.7 Hz) 4.98 (1 H, t, J=5.7 Hz) 6.25 (1 H, d, J=2.3 Hz) 6.35 (1 H, dd, J=8.7, 2.3 Hz) 6.87 (1 H, d, J=7.5 Hz) 6.89 - 6.94 (1 H, m) 7.17 (1 H, s) 7.21 - 7.26 (1 H, m) 7.27 - 7.30 (1 H, m) 7.53 (1 H, d, J=8.7 Hz). To a DMF (1.0 mL) solution of CDI (71 mg, 0.44 mmol), a DMF (1.0 mL) solution of o-methoxybenzylamine (39 μL, 0.44 mmol) was added at 0 ° C. After stirring at 0 ° C. for 30 minutes, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) was added to the reaction solution. ) In DMF (1.0 mL) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone to methanol / ethyl acetate = 3/97). The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as a colorless solid (89 mg, 50%).
LC / MS 451
NMR (CDCl 3 ) δ: 1.93-2.11 (2 H, m) 2.49 (3 H, s) 3.25 (2 H, t, J = 6.2 Hz) 3.54-3.68 (6 H, m) 3.85 (3 H, s ) 3.91 (3 H, s) 4.42 (2 H, d, J = 5.7 Hz) 4.98 (1 H, t, J = 5.7 Hz) 6.25 (1 H, d, J = 2.3 Hz) 6.35 (1 H, dd , J = 8.7, 2.3 Hz) 6.87 (1 H, d, J = 7.5 Hz) 6.89-6.94 (1 H, m) 7.17 (1 H, s) 7.21-7.26 (1 H, m) 7.27-7.30 (1 H, m) 7.53 (1 H, d, J = 8.7 Hz).
実施例683
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-{2-[3-(トリフルオロメチル)フェニル]エチル}-1,4-ジアゼパン-1-カルボキサミド Example 683
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- {2- [3- (trifluoromethyl) phenyl] ethyl} -1,4-diazepan -1-carboxamide
Figure JPOXMLDOC01-appb-C000263
Figure JPOXMLDOC01-appb-C000263
　CDI(71 mg, 0.44 mmol)のDMF(1.0 mL)溶液に3-(トリフルオロメチル)フェネチルアミン(83 mg, 0.44 mmol)のDMF(1.0 mL)溶液を0 ℃で加えた。室温で30分攪拌した後に、反応溶液に1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.0 mL)溶液を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ～メタノール/酢酸エチル=1/19)で精製した。得られた固形物を酢酸エチル/ヘキサンより再結晶して、題記化合物を無色固体(110 mg, 53%)として得た。
LC/MS 503 
NMR (CDCl3) δ: 1.83 - 1.98 (2 H, m) 2.49 (3 H, s) 2.89 (2 H, t, J=6.8 Hz) 3.20 (2 H, t, J=6.8 Hz) 3.48 - 3.58 (4 H, m) 3.61 (4 H, s) 3.91 (3 H, s) 4.27 - 4.43 (1 H, m) 6.25 (1 H, d, J=2.6 Hz) 6.34 (1 H, dd, J=8.7, 2.6 Hz) 7.17 (1 H, s) 7.33 - 7.51 (4 H, m) 7.54 (1 H, d, J=8.7 Hz). A solution of 3- (trifluoromethyl) phenethylamine (83 mg, 0.44 mmol) in DMF (1.0 mL) was added to a solution of CDI (71 mg, 0.44 mmol) in DMF (1.0 mL) at 0 ° C. After stirring at room temperature for 30 minutes, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) was added to the reaction solution. Of DMF (1.0 mL) was added and stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone to methanol / ethyl acetate = 1/19). The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as a colorless solid (110 mg, 53%).
LC / MS 503
NMR (CDCl 3 ) δ: 1.83-1.98 (2 H, m) 2.49 (3 H, s) 2.89 (2 H, t, J = 6.8 Hz) 3.20 (2 H, t, J = 6.8 Hz) 3.48-3.58 (4 H, m) 3.61 (4 H, s) 3.91 (3 H, s) 4.27-4.43 (1 H, m) 6.25 (1 H, d, J = 2.6 Hz) 6.34 (1 H, dd, J = (8.7, 2.6 Hz) 7.17 (1 H, s) 7.33-7.51 (4 H, m) 7.54 (1 H, d, J = 8.7 Hz).
実施例684
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N-{[5-(トリフルオロメチル)フラン-2-イル]メチル}-1,4-ジアゼパン-1-カルボキサミド Example 684
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N-{[5- (trifluoromethyl) furan-2-yl] methyl} -1,4 -Diazepan-1-carboxamide
Figure JPOXMLDOC01-appb-C000264
Figure JPOXMLDOC01-appb-C000264
　CDI(71 mg, 0.44 mmol)のDMF(1.0 mL)溶液に1-[5-(トリフルオロメチル)フラン-2-イル]メタンアミン(73 mg, 0.44 mmol)のDMF(1.0 mL)溶液を0 ℃で加えた。室温で30分攪拌した後に、反応溶液に1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.0 mL)溶液を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ～メタノール/酢酸エチル=3/97)で精製した。得られた固形物をヘキサンで洗浄して、題記化合物を淡黄色非定形固体(120 mg, 61%)として得た。
LC/MS 479 
NMR (CDCl3) δ: 2.04 (2 H, quin, J=6.2 Hz) 2.49 (3 H, s) 3.31 (2 H, t, J=6.2 Hz) 3.61 (2 H, t, J=6.2 Hz) 3.66 (4 H, s) 3.91 (3 H, s) 4.44 (2 H, d, J=5.7 Hz) 4.79 (1 H, t, J=5.7 Hz) 6.22 (1 H, d, J=3.4 Hz) 6.26 (1 H, d, J=2.3 Hz) 6.36 (1 H, dd, J=8.7, 2.3 Hz) 6.67 (1 H, dd, J=3.4, 1.5 Hz) 7.18 (1 H, s) 7.54 (1 H, d, J=8.7 Hz). To a solution of CDI (71 mg, 0.44 mmol) in DMF (1.0 mL) was added 1- [5- (trifluoromethyl) furan-2-yl] methanamine (73 mg, 0.44 mmol) in DMF (1.0 mL) at 0 ° C. Added in. After stirring at room temperature for 30 minutes, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) was added to the reaction solution. Of DMF (1.0 mL) was added and stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone to methanol / ethyl acetate = 3/97). The obtained solid was washed with hexane to give the title compound as a pale yellow amorphous solid (120 mg, 61%).
LC / MS 479
NMR (CDCl 3 ) δ: 2.04 (2 H, quin, J = 6.2 Hz) 2.49 (3 H, s) 3.31 (2 H, t, J = 6.2 Hz) 3.61 (2 H, t, J = 6.2 Hz) 3.66 (4 H, s) 3.91 (3 H, s) 4.44 (2 H, d, J = 5.7 Hz) 4.79 (1 H, t, J = 5.7 Hz) 6.22 (1 H, d, J = 3.4 Hz) 6.26 (1 H, d, J = 2.3 Hz) 6.36 (1 H, dd, J = 8.7, 2.3 Hz) 6.67 (1 H, dd, J = 3.4, 1.5 Hz) 7.18 (1 H, s) 7.54 (1 (H, d, J = 8.7 Hz).
実施例685
N-(1H-インドール-2-イルメチル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキサミド Example 685
N- (1H-Indol-2-ylmethyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-1-carboxamide
Figure JPOXMLDOC01-appb-C000265
Figure JPOXMLDOC01-appb-C000265
　CDI(71 mg, 0.44 mmol)のDMF(1.0 mL)溶液に1-(1H-インドール-2-イル)メタンアミン(64 mg, 0.44 mmol)のDMF(1.0 mL)溶液を0 ℃で加えた。室温で30分攪拌した後に、反応溶液に1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン(120 mg, 0.40 mmol)のDMF(1.0 mL)溶液を加え、室温で15時間攪拌した。反応溶液を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ)で精製した。得られた固形物をヘキサンで洗浄して、題記化合物を無色非定形固体(78 mg, 42%)として得た。
LC/MS 460 
NMR (CDCl3) δ: 1.95 - 2.11 (2 H, m) 2.49 (3 H, s) 3.30 (2 H, t, J=6.0 Hz) 3.59 (2 H, t, J=6.0 Hz) 3.67 (4 H, s) 3.90 (3 H, s) 4.46 (2 H, d, J=6.0 Hz) 4.90 (1 H, t, J=6.0 Hz) 6.25 (1 H, d, J=2.3 Hz) 6.27 - 6.30 (1 H, m) 6.35 (1 H, dd, J=8.7, 2.3 Hz) 7.02 - 7.09 (1 H, m) 7.10 - 7.17 (1 H, m) 7.17 (1 H, s) 7.28 - 7.34 (1 H, m) 7.53 (2 H, d, J=8.7 Hz) 9.24 (1 H, br. s.). To a DMF (1.0 mL) solution of CDI (71 mg, 0.44 mmol), a DMF (1.0 mL) solution of 1- (1H-indol-2-yl) methanamine (64 mg, 0.44 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, 1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane (120 mg, 0.40 mmol) was added to the reaction solution. Of DMF (1.0 mL) was added and stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate only). The obtained solid was washed with hexane to give the title compound as a colorless amorphous solid (78 mg, 42%).
LC / MS 460
NMR (CDCl 3 ) δ: 1.95-2.11 (2 H, m) 2.49 (3 H, s) 3.30 (2 H, t, J = 6.0 Hz) 3.59 (2 H, t, J = 6.0 Hz) 3.67 (4 H, s) 3.90 (3 H, s) 4.46 (2 H, d, J = 6.0 Hz) 4.90 (1 H, t, J = 6.0 Hz) 6.25 (1 H, d, J = 2.3 Hz) 6.27-6.30 (1 H, m) 6.35 (1 H, dd, J = 8.7, 2.3 Hz) 7.02-7.09 (1 H, m) 7.10-7.17 (1 H, m) 7.17 (1 H, s) 7.28-7.34 (1 H, m) 7.53 (2 H, d, J = 8.7 Hz) 9.24 (1 H, br.s.).
実施例686
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1-(3,4,5-トリフルオロベンジル)ピペラジン-2-オン Example 686
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1- (3,4,5-trifluorobenzyl) piperazin-2-one
Figure JPOXMLDOC01-appb-C000266
Figure JPOXMLDOC01-appb-C000266
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(0.44 g, 1.6 mmol)、1-(3,4,5-トリフルオロベンジル)ピペラジン-2-オン(0.40 g, 1.6 mmol)、DavePhos(65 mg, 0.16 mmol)及びナトリウム tert-ブトキシド(0.24 g, 2.5 mmol)のトルエン(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(75 mg, 0.082 mmol)を加え、90℃で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラム(ヘキサン/酢酸エチル=1/1～0/1)で精製した。残留物を酢酸エチル－ヘキサンより再結晶し、題記化合物を白色固体(0.16 g, 23%)として得た。
LC/MS 432.0
NMR (CDCl3) δ: 2.52 (3 H, s), 3.44 (2 H, t, J=4.8 Hz), 3.55 (2 H, t, J=4.8 Hz), 3.95 (3 H, s), 4.05 (2 H, s), 4.61 (2 H, s), 6.44 (1 H, d, J=2.1 Hz), 6.53 (1 H, dd, J= 2.1 Hz, 8.4 Hz), 6.95 (2 H, m), 7.26 (1 H, s), 7.63 (1 H, d, J=8.4 Hz).  5- (4-Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole (0.44 g, 1.6 mmol), 1- (3,4,5-trifluorobenzyl) piperazin-2-one (0.40 g, 1.6 mmol), DavePhos (65 mg, 0.16 mmol) and sodium tert-butoxide (0.24 g, 2.5 mmol) in toluene (4 mL) under a nitrogen atmosphere, Pd 2 (dba) 3 (75 mg, 0.082 mmol) ) Was added and stirred at 90 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified with a silica gel column (hexane / ethyl acetate = 1/1 to 0/1). The residue was recrystallized from ethyl acetate-hexane to give the title compound as a white solid (0.16 g, 23%).
LC / MS 432.0
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 3.44 (2 H, t, J = 4.8 Hz), 3.55 (2 H, t, J = 4.8 Hz), 3.95 (3 H, s), 4.05 (2 H, s), 4.61 (2 H, s), 6.44 (1 H, d, J = 2.1 Hz), 6.53 (1 H, dd, J = 2.1 Hz, 8.4 Hz), 6.95 (2 H, m ), 7.26 (1 H, s), 7.63 (1 H, d, J = 8.4 Hz).
実施例687
4-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1-(3,4,5-トリフルオロベンジル)ピペラジン-2-オン Example 687
4- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1- (3,4,5-trifluorobenzyl) piperazin-2-one
Figure JPOXMLDOC01-appb-C000267
Figure JPOXMLDOC01-appb-C000267
　4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピラゾール(0.33 g, 1.5 mmol)、1-(3,4,5-トリフルオロベンジル)ピペラジン-2-オン(0.36 g, 1.5 mmol)、DavePhos(58 mg, 0.15 mmol)及びナトリウム tert-ブトキシド(0.21 g, 2.2 mmol)のトルエン(3 mL)溶液に窒素雰囲気下、Pd2(dba)3(68 mg, 0.074 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラム(ヘキサン/酢酸エチル=1/1～0/1)で精製した。残留物を酢酸エチル－ヘキサンより再結晶し、題記化合物を白色固体(97 mg, 15%)として得た。
LC/MS 431.0
NMR (CDCl3) δ: 3.43 (2 H, t, J=5.4 Hz), 3.51 (2 H, t, J=5.4 Hz), 3.91 (3 H, s), 3.95 (3 H, s), 4.01 (2 H, s), 4.61 (2 H, s), 6.48 (1 H, d, J=2.1 Hz), 6.52 (1 H, dd, J= 2.1 Hz, 8.1 Hz), 6.95 (2 H, m), 7.43 (1 H, d, J=8.1 Hz), 7.76 (1 H, s), 7.80 (1 H, s). 4- (4-Chloro-2-methoxyphenyl) -1-methyl-1H-pyrazole (0.33 g, 1.5 mmol), 1- (3,4,5-trifluorobenzyl) piperazin-2-one (0.36 g, 1.5 mmol), DavePhos (58 mg, 0.15 mmol) and sodium tert-butoxide (0.21 g, 2.2 mmol) in toluene (3 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (68 mg, 0.074 mmol) In addition, the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified with a silica gel column (hexane / ethyl acetate = 1/1 to 0/1). The residue was recrystallized from ethyl acetate-hexane to give the title compound as a white solid (97 mg, 15%).
LC / MS 431.0
NMR (CDCl 3 ) δ: 3.43 (2 H, t, J = 5.4 Hz), 3.51 (2 H, t, J = 5.4 Hz), 3.91 (3 H, s), 3.95 (3 H, s), 4.01 (2 H, s), 4.61 (2 H, s), 6.48 (1 H, d, J = 2.1 Hz), 6.52 (1 H, dd, J = 2.1 Hz, 8.1 Hz), 6.95 (2 H, m ), 7.43 (1 H, d, J = 8.1 Hz), 7.76 (1 H, s), 7.80 (1 H, s).
実施例688
N-(3-クロロ-4-フルオロフェニル)-2-{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}アセトアミド Example 688
N- (3-Chloro-4-fluorophenyl) -2- {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxo Piperazin-1-yl} acetamide
Figure JPOXMLDOC01-appb-C000268
Figure JPOXMLDOC01-appb-C000268
　tert-ブチル {4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート(0.44 g, 1.1 mmol)にトリフルオロ酢酸(2 mL)を加え、50℃で1時間攪拌した。減圧下に濃縮し、残留物にDMF(6 mL)を加え、氷冷でトリエチルアミン(0.33 g, 3.3 mmol)を加え、0℃で10分攪拌した。同温で3-クロロ-4-フルオロアニリン(0.16 g, 1.1 mmol)、HOBt(0.17 g, 1.1 mmol)、WSC(0.21 g, 1.1 mmol)を加え、50℃で3時間攪拌した。室温とし、酢酸エチル－飽和食塩水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。シリカゲルカラム(酢酸エチル/MeOH=1/0～9/1)で精製、残留物を酢酸エチルより再結晶し、題記化合物を淡黄白色固体(23 mg, 4%)として得た。
LC/MS 473.1
NMR (CDCl3) δ: 2.49 (3 H, s), 3.62 (2 H, t, J=5.1 Hz), 3.75 (2 H, t, J=5.4 Hz), 3.90 (3 H, s), 4.05 (2 H, s), 4.20 (2 H, s), 6.50 (1 H, d, J=2.1 Hz), 6.55 (1 H, dd, J=2.1 Hz, 8.7 Hz), 7.08 (1 H, dd, J=8.4 Hz, 8.7 Hz), 7.29 - 7.32 (1 H, m), 7.59 (1 H, d, J=8.7 Hz), 7.72 (1 H, dd, J=2.4 Hz, 6.6 Hz), 8.46 (1 H, s), 8.64 (1 H, s).
m.p. 201 - 205℃ tert-butyl {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxopiperazin-1-yl} acetate (0.44 g, 1.1 To (mmol), trifluoroacetic acid (2 mL) was added and stirred at 50 ° C. for 1 hour. The mixture was concentrated under reduced pressure, DMF (6 mL) was added to the residue, triethylamine (0.33 g, 3.3 mmol) was added with ice cooling, and the mixture was stirred at 0 ° C. for 10 min. 3-Chloro-4-fluoroaniline (0.16 g, 1.1 mmol), HOBt (0.17 g, 1.1 mmol) and WSC (0.21 g, 1.1 mmol) were added at the same temperature, and the mixture was stirred at 50 ° C. for 3 hours. The mixture was brought to room temperature, ethyl acetate-saturated brine was added, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / MeOH = 1 / 0-9 / 1), and the residue was recrystallized from ethyl acetate to give the title compound as a pale yellowish white solid (23 mg, 4%).
LC / MS 473.1
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 3.62 (2 H, t, J = 5.1 Hz), 3.75 (2 H, t, J = 5.4 Hz), 3.90 (3 H, s), 4.05 (2 H, s), 4.20 (2 H, s), 6.50 (1 H, d, J = 2.1 Hz), 6.55 (1 H, dd, J = 2.1 Hz, 8.7 Hz), 7.08 (1 H, dd , J = 8.4 Hz, 8.7 Hz), 7.29-7.32 (1 H, m), 7.59 (1 H, d, J = 8.7 Hz), 7.72 (1 H, dd, J = 2.4 Hz, 6.6 Hz), 8.46 (1 H, s), 8.64 (1 H, s).
mp 201-205 ℃
実施例689
2-{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}-N-[4-(トリフルオロメチル)フェニル]アセトアミド Example 689
2- {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxopiperazin-1-yl} -N- [4- ( Trifluoromethyl) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000269
Figure JPOXMLDOC01-appb-C000269
　tert-ブチル {4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート(3.4 g, 8.4 mmol)にトリフルオロ酢酸(15 mL)を加え、50℃で1時間攪拌した。減圧下に濃縮し、残留物のDMF(30 mL)溶液に氷冷下でトリエチルアミン(2.6 g, 25 mmol)を加え、同温で10分攪拌した。反応液を5等分した溶液にp-トリフルオロメチルアニリン(0.27 g, 1.7 mmol)、HOBt(0.26 g, 1.7 mmol)、WSC(0.32 g, 1.7 mmol)を加え、室温で6時間攪拌し、さらに70℃で16時間攪拌した。酢酸エチル－飽和食塩水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。シリカゲルカラム(ヘキサン/酢酸エチル/MeOH=1/1/0～0/9/1)で精製、残留物を酢酸エチル－MeOHより再結晶し、題記化合物を淡黄白色固体(16 mg, 2%)として得た。
LC/MS 489.1
NMR (CDCl3) δ: 2.49 (3 H, s), 3.63 (2 H, t, J=4.5 Hz), 3.76 (2 H, t, J=5.1 Hz), 3.90 (3 H, s), 4.06 (2 H, s), 4.23 (2 H, s), 6.50 (1 H, d, J=2.4 Hz), 6.56 (1 H, dd, J=2.4 Hz, 8.7 Hz), 7.56 - 7.65 (5 H, m), 8.46 (1 H, s), 8.79 (1 H, s). tert-butyl {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxopiperazin-1-yl} acetate (3.4 g, 8.4 trifluoroacetic acid (15 mL) was added to (mmol), and the mixture was stirred at 50 ° C. for 1 hour. The mixture was concentrated under reduced pressure, triethylamine (2.6 g, 25 mmol) was added to a DMF (30 mL) solution of the residue under ice-cooling, and the mixture was stirred at the same temperature for 10 min. P-Trifluoromethylaniline (0.27 g, 1.7 mmol), HOBt (0.26 g, 1.7 mmol), WSC (0.32 g, 1.7 mmol) were added to the solution divided into 5 equal parts, and the mixture was stirred at room temperature for 6 hours. The mixture was further stirred at 70 ° C. for 16 hours. Ethyl acetate-saturated brine was added, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column (hexane / ethyl acetate / MeOH = 1/1 / 0-0 / 9/1), the residue was recrystallized from ethyl acetate-MeOH, and the title compound was pale yellowish white solid (16 mg, 2% ).
LC / MS 489.1
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 3.63 (2 H, t, J = 4.5 Hz), 3.76 (2 H, t, J = 5.1 Hz), 3.90 (3 H, s), 4.06 (2 H, s), 4.23 (2 H, s), 6.50 (1 H, d, J = 2.4 Hz), 6.56 (1 H, dd, J = 2.4 Hz, 8.7 Hz), 7.56-7.65 (5 H m), 8.46 (1 H, s), 8.79 (1 H, s).
実施例690
2-{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}-N-[3-(トリフルオロメチル)フェニル]アセトアミド Example 690
2- {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxopiperazin-1-yl} -N- [3- ( Trifluoromethyl) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000270
Figure JPOXMLDOC01-appb-C000270
　tert-ブチル {4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート(3.4 g, 8.4 mmol)にトリフルオロ酢酸(15 mL)を加え、50℃で1時間攪拌した。減圧下に濃縮し、残留物のDMF(30 mL)溶液に氷冷下でトリエチルアミン(2.6 g, 25 mmol)を加え、同温で10分攪拌した。反応液を5等分した溶液にm-トリフルオロメチルアニリン(0.27 g, 1.7 mmol)、HOBt(0.26 g, 1.7 mmol)、WSC(0.32 g, 1.7 mmol)を加え、室温で6時間攪拌し、さらに70℃で16時間攪拌した。酢酸エチル－飽和食塩水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。シリカゲルカラム(酢酸エチル/MeOH=1/0～9/1)で精製、残留物を酢酸エチルより再結晶し、題記化合物を淡黄白色固体(15 mg, 2%)として得た。
LC/MS 489.1
NMR (CDCl3) δ: 2.54 (3 H, s), 3.68 (2 H, t, J=4.8 Hz), 3.81 (2 H, t, J=5.7 Hz), 3.95 (3 H, s), 4.11 (2 H, s), 4.28 (2 H, s), 6.55 (1 H, d, J=2.1 Hz), 6.61 (1 H, dd, J=2.4 Hz, 8.7 Hz), 7.42 - 7.52 (1 H, m), 7.64 (1 H, d, J=8.7 Hz), 7.74 (1 H, d, J=7.8 Hz), 7.90 (1 H, s), 8.50 (1 H, s), 8.76 (1 H, s). tert-butyl {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxopiperazin-1-yl} acetate (3.4 g, 8.4 trifluoroacetic acid (15 mL) was added to (mmol), and the mixture was stirred at 50 ° C. for 1 hour. The mixture was concentrated under reduced pressure, triethylamine (2.6 g, 25 mmol) was added to a DMF (30 mL) solution of the residue under ice-cooling, and the mixture was stirred at the same temperature for 10 min. M-Trifluoromethylaniline (0.27 g, 1.7 mmol), HOBt (0.26 g, 1.7 mmol), WSC (0.32 g, 1.7 mmol) were added to the solution divided into 5 equal parts, and the mixture was stirred at room temperature for 6 hours. The mixture was further stirred at 70 ° C. for 16 hours. Ethyl acetate-saturated brine was added, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate / MeOH = 1 / 0-9 / 1), and the residue was recrystallized from ethyl acetate to give the title compound as a pale yellowish white solid (15 mg, 2%).
LC / MS 489.1
NMR (CDCl 3 ) δ: 2.54 (3 H, s), 3.68 (2 H, t, J = 4.8 Hz), 3.81 (2 H, t, J = 5.7 Hz), 3.95 (3 H, s), 4.11 (2 H, s), 4.28 (2 H, s), 6.55 (1 H, d, J = 2.1 Hz), 6.61 (1 H, dd, J = 2.4 Hz, 8.7 Hz), 7.42-7.52 (1 H , m), 7.64 (1 H, d, J = 8.7 Hz), 7.74 (1 H, d, J = 7.8 Hz), 7.90 (1 H, s), 8.50 (1 H, s), 8.76 (1 H , s).
実施例691
N-{2-ヒドロキシ-2-メチル-1-[4-(トリフルオロメチル)フェニル]プロピル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド Example 691
N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) Phenyl] piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000271
Figure JPOXMLDOC01-appb-C000271
　メチル [({4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}カルボニル)アミノ][4-(トリフルオロメチル)フェニル]アセタート(1.0 g, 1.88 mmol)のTHF(20 mL)溶液に臭化メチルマグネシウムのTHF溶液(約1.0 M, 6.58 mL)を氷冷下で滴下した。室温で6時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。その抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去させた。得られた残留物をシリカゲルカラム(ヘキサン/酢酸エチル=3/7～酢酸エチルのみ～酢酸エチル/メタノール =9/1)で精製した後、ヘキサン－酢酸エチルから再結晶し、題記化合物を白色固体(0.23 g)として得た。ろ液の溶媒を減圧留去した後、分取HPLCで精製し、題記化合物を白色固体(93 mg, 合計32%)として得た。
LC/MS 533.3
NMR (CDCl3) δ: 1.07 (3 H, s), 1.42 (3 H, s), 1.67 (1 H, s), 2.50 (3 H, s), 3.18 - 3.34 (4 H, m), 3.49 - 3.66 (4 H, m), 3.93 (3 H, s), 4.77 (1 H, d, J=7.7 Hz), 5.68 (1 H, d, J=7.7 Hz), 6.47 (1 H, d, J=2.2 Hz), 6.55 (1 H, dd, J=8.7, 2.3 Hz), 7.24 (1 H, s), 7.46 (2 H, d, J=8.0 Hz), 7.60 (3 H, d, J=8.5 Hz). Methyl [({4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} carbonyl) amino] [4- (trifluoromethyl) phenyl] To a solution of acetate (1.0 g, 1.88 mmol) in THF (20 mL) was added dropwise a solution of methylmagnesium bromide in THF (about 1.0 M, 6.58 mL) under ice cooling. After stirring at room temperature for 6 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 3 / 7-ethyl acetate only-ethyl acetate / methanol = 9/1) and recrystallized from hexane-ethyl acetate to give the title compound as a white solid Obtained as (0.23 g). After evaporating the solvent of the filtrate under reduced pressure, the residue was purified by preparative HPLC to give the title compound as a white solid (93 mg, total 32%).
LC / MS 533.3
NMR (CDCl 3 ) δ: 1.07 (3 H, s), 1.42 (3 H, s), 1.67 (1 H, s), 2.50 (3 H, s), 3.18-3.34 (4 H, m), 3.49 -3.66 (4 H, m), 3.93 (3 H, s), 4.77 (1 H, d, J = 7.7 Hz), 5.68 (1 H, d, J = 7.7 Hz), 6.47 (1 H, d, J = 2.2 Hz), 6.55 (1 H, dd, J = 8.7, 2.3 Hz), 7.24 (1 H, s), 7.46 (2 H, d, J = 8.0 Hz), 7.60 (3 H, d, J = 8.5 Hz).
実施例692、693
N-{2-ヒドロキシ-2-メチル-1-[4-(トリフルオロメチル)フェニル]プロピル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド(保持時間小)
N-{2-ヒドロキシ-2-メチル-1-[4-(トリフルオロメチル)フェニル]プロピル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド(保持時間大)
　実施例691で得られたN-{2-ヒドロキシ-2-メチル-1-[4-(トリフルオロメチル)フェニル]プロピル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド(0.24 g)を超臨界流体クロマトグラフィー(機器：MULTIGRAM II(メトラー・トレド製)、カラム：CHIRALPAK　AD-H(20 mmID×250 mmL ダイセル化学工業製)、移動相：A)二酸化炭素=100%、B)2－プロパノール=100%、混合比：A／B=700／300、流速：50mL／min、カラム温度:35℃、試料濃度：20 mg／mL(2－プロパノール)、注入量：3.0mL)を用いて分画した。上記の超臨界流体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮した後、ヘキサン－酢酸エチルから再結晶し、N-{2-ヒドロキシ-2-メチル-1-[4-(トリフルオロメチル)フェニル]プロピル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド(保持時間小)(91mg、>99.9%ee)を得た。
LC/MS 533.5
NMR (CDCl3) δ: 1.07 (3 H, s), 1.42 (3 H, s), 2.51 (3 H, s), 3.17 - 3.31 (4 H, m), 3.50 - 3.65 (4 H, m), 3.93 (3 H, s), 4.77 (1 H, d, J=8.0 Hz), 5.68 (1 H, d, J=8.0 Hz), 6.48 (1 H, d, J=1.9 Hz), 6.55 (1 H, dd, J=8.5, 2.2 Hz), 7.24 (1 H, s), 7.46 (2 H, d, J=8.2 Hz), 7.59 (3 H, d, J=8.8 Hz).
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮した後、ヘキサン－酢酸エチルから再結晶し、N-{2-ヒドロキシ-2-メチル-1-[4-(トリフルオロメチル)フェニル]プロピル}-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキサミド (保持時間大)(94mg、>99.9%ee)を得た。
LC/MS 533.3
NMR (CDCl3) δ: 1.07 (3 H, s), 1.42 (3 H, s), 2.51 (3 H, s), 3.17 - 3.32 (4 H, m), 3.50 - 3.66 (4 H, m), 3.93 (3 H, s), 4.77 (1 H, d, J=8.0 Hz), 5.68 (1 H, d, J=7.4 Hz), 6.48 (1 H, d, J=2.2 Hz), 6.55 (1 H, dd, J=8.5, 2.2 Hz), 7.25 (1 H, s), 7.46 (2 H, d, J=8.0 Hz), 7.60 (3 H, d, J=8.8 Hz).
　ここで、上記の鏡像体過剰率(ee)は超臨界流体クロマトグラフィー(カラム：CHIRALPAK　AD－H(4.6mmID×150mmL ダイセル化学工業製)、移動相：A)二酸化炭素100%、B)2－プロパノール=100%、混合比：A／B=700／300、流速：2．0 mL／min、カラム温度：35℃、試料濃度：1．0 mg／mL(2－プロパノール)、注入量：5μL)を用いて測定した。 Examples 692, 693
N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) Phenyl] piperazine-1-carboxamide (low retention time)
N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) Phenyl] piperazine-1-carboxamide (large retention time)
N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3) obtained in Example 691 -Oxazol-5-yl) phenyl] piperazine-1-carboxamide (0.24 g) with supercritical fluid chromatography (instrument: MULTIGRAM II (manufactured by METTLER TOLEDO), column: CHIRALPAK AD-H (20 mmID × 250 mmL) (Manufactured by Kogyo), mobile phase: A) carbon dioxide = 100%, B) 2-propanol = 100%, mixing ratio: A / B = 700/300, flow rate: 50 mL / min, column temperature: 35 ° C., sample concentration: Fractionation was carried out using 20 mg / mL (2-propanol), injection volume: 3.0 mL). After concentrating the fraction containing the optically active substance having a shorter retention time under the above supercritical fluid chromatography conditions, the fraction was recrystallized from hexane-ethyl acetate, and N- {2-hydroxy-2-methyl- 1- [4- (Trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide (low retention time) ) (91 mg,> 99.9% ee).
LC / MS 533.5
NMR (CDCl 3 ) δ: 1.07 (3 H, s), 1.42 (3 H, s), 2.51 (3 H, s), 3.17-3.31 (4 H, m), 3.50-3.65 (4 H, m) , 3.93 (3 H, s), 4.77 (1 H, d, J = 8.0 Hz), 5.68 (1 H, d, J = 8.0 Hz), 6.48 (1 H, d, J = 1.9 Hz), 6.55 ( 1 H, dd, J = 8.5, 2.2 Hz), 7.24 (1 H, s), 7.46 (2 H, d, J = 8.2 Hz), 7.59 (3 H, d, J = 8.8 Hz).
In addition, after concentrating the fraction containing the optically active substance having the longer retention time, it was recrystallized from hexane-ethyl acetate to give N- {2-hydroxy-2-methyl-1- [4- (trifluoro Methyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxamide (long retention time) (94 mg,> 99.9% ee )
LC / MS 533.3
NMR (CDCl 3 ) δ: 1.07 (3 H, s), 1.42 (3 H, s), 2.51 (3 H, s), 3.17-3.32 (4 H, m), 3.50-3.66 (4 H, m) , 3.93 (3 H, s), 4.77 (1 H, d, J = 8.0 Hz), 5.68 (1 H, d, J = 7.4 Hz), 6.48 (1 H, d, J = 2.2 Hz), 6.55 ( 1 H, dd, J = 8.5, 2.2 Hz), 7.25 (1 H, s), 7.46 (2 H, d, J = 8.0 Hz), 7.60 (3 H, d, J = 8.8 Hz).
Here, the enantiomeric excess (ee) is determined by supercritical fluid chromatography (column: CHIRALPAK AD-H (4.6 mm ID × 150 mmL, manufactured by Daicel Chemical Industries), mobile phase: A) carbon dioxide 100%, B) 2- Propanol = 100%, mixing ratio: A / B = 700/300, flow rate: 2.0 mL / min, column temperature: 35 ° C., sample concentration: 1.0 mg / mL (2-propanol), injection volume: 5 μL ).
　上記実施例１～６９３に記載の方法、または、それらに準じた方法に従って製造した実例化合物を以下の表９７～１４７に示す。 Example compounds prepared according to the methods described in Examples 1 to 693 or a method analogous thereto are shown in Tables 97 to 147 below.
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000322
参考例１
5-(4-ブロモフェニル)-1,3-オキサゾール
　4-ブロモベンズアルデヒド (10g, 54 mmol)と炭酸カリウム (11 g, 81 mmol)のメタノール(100 mL)溶液に、1-[(イソシアノメチル)スルホニル]-4-メチルベンゼン(11 g, 56 mmol)を加え、70 ℃で終夜撹拌した。溶媒を減圧留去した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。合わせた有機層を水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をヘキサンから再結晶して、題記化合物を黄色固体(10 g, 83%)として得た。
LC/MS 224
NMR (CDCl3) δ: 7.36 (1 H, s), 7.48 - 7.60 (4 H, m), 7.92 (1 H, s). Reference example 1
To a solution of 5- (4-bromophenyl) -1,3-oxazole 4-bromobenzaldehyde (10 g, 54 mmol) and potassium carbonate (11 g, 81 mmol) in methanol (100 mL), add 1-[(isocyanomethyl ) Sulfonyl] -4-methylbenzene (11 g, 56 mmol) was added and stirred at 70 ° C. overnight. The solvent was distilled off under reduced pressure, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from hexane to give the title compound as a yellow solid (10 g, 83%).
LC / MS 224
NMR (CDCl 3 ) δ: 7.36 (1 H, s), 7.48-7.60 (4 H, m), 7.92 (1 H, s).
参考例２
5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール
　ヨードベンゼンジアセテート (38 g, 0.12 mol)のアセトニトリル (100 mL) 溶液にトリフルオロメタンスルホン酸 (35 g, 0.23 mol)を滴下し、室温で30分間攪拌した。反応混合物に4-ブロモアセトフェノン (16 g, 78 mmol)のアセトニトリル(150 mL)溶液を加え、還流下で終夜攪拌した。溶媒を減圧留去し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝19/1～ヘキサン/酢酸エチル＝７/3)で精製し、題記化合物を淡黄色固体(14 g, 75%)として得た。
LC/MS 238
NMR (CDCl3) δ: 2.53 (3 H, s), 7.21 (1 H, s), 7.40 - 7.60 (4 H, m). Reference example 2
Trifluoromethanesulfonic acid (35 g, 0.23 mol) was added dropwise to a solution of 5- (4-bromophenyl) -2-methyl-1,3-oxazole iodobenzene diacetate (38 g, 0.12 mol) in acetonitrile (100 mL). And stirred at room temperature for 30 minutes. A solution of 4-bromoacetophenone (16 g, 78 mmol) in acetonitrile (150 mL) was added to the reaction mixture, and the mixture was stirred overnight under reflux. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19/1 to hexane / ethyl acetate = 7/3) to give the title compound as a pale yellow solid (14 g, 75%).
LC / MS 238
NMR (CDCl 3 ) δ: 2.53 (3 H, s), 7.21 (1 H, s), 7.40-7.60 (4 H, m).
参考例３
5-(4-ブロモ-2-フルオロフェニル)-2-メチル-1,3-オキサゾール Reference example 3
5- (4-Bromo-2-fluorophenyl) -2-methyl-1,3-oxazole
3a)4-ブロモ-2-フルオロ-N-メトキシ-N-メチルベンズアミド
　4-ブロモ-2-フルオロ安息香酸 (10 g, 46 mmol)のDMF(4.0 mL)溶液にN,O-ジメトキシヒドロキシルアミン　1塩酸塩(5.3 g, 55 mmol)、HOBt(8.0 g, 59 mmol)、N-エチルジイソプロピルアミン(23 mL, 137 mmol)、WSC(11 g, 59 mmol)を加え、室温で9時間、続いて40℃で38時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。得られた抽出液を1N水酸化ナトリウム水溶液、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を減圧留去して、題記化合物を淡黄色油状物(13 g, quant.)として得た。
LC/MS 262
NMR (CDCl3) δ: 3.35 (3 H, s), 3.55 (3 H, brs), 7.29 - 7.40 (3 H, m). 3a) 4-Bromo-2-fluoro-N-methoxy-N-methylbenzamide To a solution of 4-bromo-2-fluorobenzoic acid (10 g, 46 mmol) in DMF (4.0 mL), N, O-dimethoxyhydroxylamine 1 Add hydrochloride (5.3 g, 55 mmol), HOBt (8.0 g, 59 mmol), N-ethyldiisopropylamine (23 mL, 137 mmol), WSC (11 g, 59 mmol), then at room temperature for 9 hours, followed by The mixture was stirred at 40 ° C. for 38 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (13 g, quant.). Obtained.
LC / MS 262
NMR (CDCl 3 ) δ: 3.35 (3 H, s), 3.55 (3 H, brs), 7.29-7.40 (3 H, m).
3b) 1-(4-ブロモ-2-フルオロフェニル)エタノン
　4-ブロモ-2-フルオロ-N-メトキシ-N-メチルベンズアミド (13 g, 46 mmol)のTHF(4.0 mL)溶液にメチルマグネシウムブロマイド 3Mエチルエーテル溶液(30 mL, 91 mmol)を0 ℃で滴下し、室温で3時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を淡黄色油状物(10 g, quant.)として得た。
NMR (CDCl3) δ: 2.63 (3 H, d, J=5.3 Hz), 7.31 - 7.44 (2 H, m), 7.77 (1 H, t, J=8.0 Hz). 3b) 1- (4-Bromo-2-fluorophenyl) ethanone 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (13 g, 46 mmol) in THF (4.0 mL) in methylmagnesium bromide 3M Ethyl ether solution (30 mL, 91 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow oil (10 g, quant.).
NMR (CDCl 3 ) δ: 2.63 (3 H, d, J = 5.3 Hz), 7.31-7.44 (2 H, m), 7.77 (1 H, t, J = 8.0 Hz).
3c) 5-(4-ブロモ-2-フルオロフェニル)-2-メチル-1,3-オキサゾール
　ヨードベンゼンジアセテート(6.7 g, 21 mmol)のアセトニトリル(100 mL) 懸濁液にトリフルオロメタンスルホン酸 (3.7 mL, 42 mmol)を滴下し、室温で30分間攪拌した。反応混合物に1-(4-ブロモ-2-フルオロフェニル)エタノン (6.7 g, 21 mmol)のアセトニトリル(20 mL)を加え、加熱還流下2時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で中和した後、溶媒を減圧留去した。残留物を酢酸エチルで抽出し、得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/3)で精製し、題記化合物を淡黄色固体(2.6 g,75%)として得た。
LC/MS 256
NMR (CDCl3) δ: 2.54 (3 H, s), 7.31 - 7.40 (3 H, m), 7.52 - 7.65 (1 H, m). 3c) 5- (4-Bromo-2-fluorophenyl) -2-methyl-1,3-oxazole iodobenzene diacetate (6.7 g, 21 mmol) in acetonitrile (100 mL) suspension in trifluoromethanesulfonic acid ( 3.7 mL, 42 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1- (4-bromo-2-fluorophenyl) ethanone (6.7 g, 21 mmol) in acetonitrile (20 mL), and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/3) to give the title compound as a pale yellow solid (2.6 g, 75%).
LC / MS 256
NMR (CDCl 3 ) δ: 2.54 (3 H, s), 7.31-7.40 (3 H, m), 7.52-7.65 (1 H, m).
参考例４
5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール
　5-(4-ブロモ-2-フルオロフェニル)-2-メチル-1,3-オキサゾール(400 mg, 1.6 mmol)のDMF(10 mL)溶液に28%ナトリウムメトキシドMeOH溶液(900 μL, 4.7 mmol)を加え、80 ℃で2時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(370 mg, 88%)として得た。
LC/MS 268
NMR (CDCl3) δ: 2.52 (3 H, s), 3.95 (3 H, s), 7.10 (1 H, d, J=1.9 Hz), 7.17 (1 H, dd, J=8.3, 1.9 Hz), 7.39 (1 H, s), 7.59 (1 H, d, J=8.3 Hz). Reference example 4
5- (4-Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole 5- (4-Bromo-2-fluorophenyl) -2-methyl-1,3-oxazole (400 mg, 1.6 mmol ) In DMF (10 mL) was added 28% sodium methoxide MeOH solution (900 μL, 4.7 mmol), and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (370 mg, 88%).
LC / MS 268
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 3.95 (3 H, s), 7.10 (1 H, d, J = 1.9 Hz), 7.17 (1 H, dd, J = 8.3, 1.9 Hz) , 7.39 (1 H, s), 7.59 (1 H, d, J = 8.3 Hz).
参考例５
1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン Reference Example 5
1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine
5a) tert-ブチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(7.0 g, 29 mmol)、tert-ブチル ピペラジン-1-カルボキシラート (7.1 g, 38 mmol)、DavePhos (1.2 g, 2.9 mmol)及びナトリウム tert-ブトキシド (4.2 g, 44 mmol)のトルエン(50 mL)溶液に窒素雰囲気下、Pd2(dba)3 (1.4 g, 1.5 mmol)を加え、110 ℃で終夜攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。得られた抽出液を無水硫酸マグネシウムで乾燥、セライトろ過をし、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄し、題記化合物を淡黄色固体(5.7 g, 57%)として得た。
LC/MS 344
NMR (CDCl3) δ: 1.49 (9 H, s), 2.51 (3 H, s), 3.10 - 3.26 (4 H, m), 3.52 - 3.68 (4 H, m), 6.93 (2 H, d, J=9.1 Hz), 7.06 (1 H, s), 7.50 (2 H, d, J=8.8 Hz). 5a) tert-butyl 4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -2-methyl-1,3- Oxazole (7.0 g, 29 mmol), tert-butyl piperazine-1-carboxylate (7.1 g, 38 mmol), DavePhos (1.2 g, 2.9 mmol) and sodium tert-butoxide (4.2 g, 44 mmol) in toluene (50 Under a nitrogen atmosphere, Pd 2 (dba) 3 (1.4 g, 1.5 mmol) was added to the solution, and the mixture was stirred at 110 ° C. overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound as a pale-yellow solid (5.7 g, 57%).
LC / MS 344
NMR (CDCl 3 ) δ:   1.49 (9 H, s), 2.51 (3 H, s), 3.10-3.26 (4 H, m), 3.52-3.68 (4 H, m), 6.93 (2 H, d, J = 9.1 Hz), 7.06 (1 H, s), 7.50 (2 H, d, J = 8.8 Hz).
5b) 1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン
　tert-ブチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート (5.7 g, 17 mmol)の酢酸エチル (20 mL)溶液に4N塩酸メタノール溶液(20 mL)を加え、室温で2時間撹拌した。溶媒を減圧留去した後、得られた残留物を酢酸エチルで洗浄した。得られた残留物をさらに4N塩酸メタノール溶液(20 mL)に加え、室温で２時間撹拌した後、溶媒を減圧留去した。得られた残留物(5.0 g)のうち2.4 gを水に溶解させた後、8M水酸化ナトリウム水溶液で塩基性にし、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、題記化合物を淡黄色固体 (1.6 g, 83%)として得た。
LC/MS 244
NMR (CDCl3) δ: 2.50 (3 H, s), 2.99 - 3.14 (4 H, m), 3.15 - 3.30 (4 H, m), 6.93 (2 H, d, J=8.8 Hz), 7.04 (1 H, s), 7.49 (2 H, d, J=8.8 Hz). 5b) 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine tert-butyl 4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] To a solution of piperazine-1-carboxylate (5.7 g, 17 mmol) in ethyl acetate (20 mL) was added 4N hydrochloric acid methanol solution (20 mL), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the obtained residue was washed with ethyl acetate. The obtained residue was further added to 4N hydrochloric acid methanol solution (20 mL) and stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. 2.4 g of the obtained residue (5.0 g) was dissolved in water, basified with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (1.6 g, 83%).
LC / MS 244
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 2.99-3.14 (4 H, m), 3.15-3.30 (4 H, m), 6.93 (2 H, d, J = 8.8 Hz), 7.04 ( 1 H, s), 7.49 (2 H, d, J = 8.8 Hz).
参考例６
1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　１塩酸塩
　tert-ブチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.27 g, 0.8 mmol)の酢酸エチル(5 mL)溶液に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を淡黄色固体(0.23 g, 100%)として得た。
LC/MS 244
NMR (DMSO-d6) δ: 2.45 (3 H, s), 3.14 - 3.30 (4 H, m), 3.32 - 3.54 (4 H, m), 7.06 (2 H, d, J=9.0 Hz), 7.34 (1 H, s), 7.54 (2 H, d, J=8.7 Hz), 9.08 (2 H, brs). Reference Example 6
1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine monohydrochloride tert-butyl 4- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl ] To a solution of piperazine-1-carboxylate (0.27 g, 0.8 mmol) in ethyl acetate (5 mL) was added 4N hydrochloric acid ethyl acetate solution (10 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a pale yellow solid (0.23 g, 100%).
LC / MS 244
NMR (DMSO-d 6 ) δ: 2.45 (3 H, s), 3.14-3.30 (4 H, m), 3.32-3.54 (4 H, m), 7.06 (2 H, d, J = 9.0 Hz), 7.34 (1 H, s), 7.54 (2 H, d, J = 8.7 Hz), 9.08 (2 H, brs).
参考例７
tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシラート
　1-ブロモ-4-ヨードベンゼン(8.5 g, 30 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(5.6 g, 30 mmol)、(rac)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル(1.9 g, 3 mmol)、及びカリウム tert-ブトキシド(5.1 g, 45 mmol)のトルエン(90 mL)溶液にPd2(dba)3(1.4 g, 1.5 mmol)を加え、窒素雰囲気下90 ℃にて23時間攪拌した。反応混合物を室温まで冷却し、溶媒の2/3を減圧留去した。得られたトルエン懸濁物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、得られた固体を酢酸エチル－ヘキサンより再結晶して、題記化合物を白色固体(3.6 g, 35%)として得た。
LC/MS 244
NMR (DMSO-d6) δ: 1.41 (9 H, s), 2.93 - 3.14 (4 H, m), 3.38 - 3.57 (4 H, m), 6.91 (2 H, d, J=9.0 Hz), 7.36 (2 H, d, J=9.0 Hz). Reference Example 7
tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate 1-bromo-4-iodobenzene (8.5 g, 30 mmol), tert-butyl piperazine-1-carboxylate (5.6 g, 30 mmol), To a solution of (rac) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (1.9 g, 3 mmol) and potassium tert-butoxide (5.1 g, 45 mmol) in toluene (90 mL) Pd 2 (dba) 3 (1.4 g, 1.5 mmol) was added, and the mixture was stirred at 90 ° C. for 23 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and 2/3 of the solvent was distilled off under reduced pressure. The resulting toluene suspension was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1), and the resulting solid was recrystallized from ethyl acetate-hexane to give the title compound as a white solid ( 3.6 g, 35%).
LC / MS 244
NMR (DMSO-d 6 ) δ: 1.41 (9 H, s), 2.93-3.14 (4 H, m), 3.38-3.57 (4 H, m), 6.91 (2 H, d, J = 9.0 Hz), 7.36 (2 H, d, J = 9.0 Hz).
参考例８
1-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン　1塩酸塩 Reference Example 8
1- [4- (1-Methyl-1H-pyrazol-4-yl) phenyl] piperazine monohydrochloride
8a) tert-ブチル 4-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート
　tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシラート(0.21 g, 0.6 mmol)、(1-メチル-1H-ピラゾール-4-イル)ボロン酸　1塩酸塩(0.20 g, 1.2 mmol)、Pd(PPh3)4(69 mg, 0.06 mmol)、2M炭酸セシウム水溶液(1.5 mL, 3 mmol)及びDME(2.5 mL)の混合物を窒素雰囲気下、マイクロウェーブ照射下160℃で5分間攪拌した。反応混合物を室温まで冷却した後、水層を除去した。有機層をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製し、題記化合物を白色固体(50 mg, 24%)として得た。
LC/MS 342
NMR (DMSO-d6) δ: 1.42 (9 H, s), 3.03 - 3.16 (4 H, m), 3.40 - 3.53 (4 H, m), 3.83 (3 H, s), 6.94 (2 H, d, J=8.7 Hz), 7.40 (2 H, d, J=8.7 Hz), 7.73 (1 H, s), 7.98 (1 H, s). 8a) tert-butyl 4- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine-1-carboxylate tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate (0.21 g, 0.6 mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid monohydrochloride (0.20 g, 1.2 mmol), Pd (PPh 3 ) 4 (69 mg, 0.06 mmol), 2M aqueous cesium carbonate solution A mixture of (1.5 mL, 3 mmol) and DME (2.5 mL) was stirred at 160 ° C. for 5 minutes under microwave irradiation in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the aqueous layer was removed. The organic layer was purified by NH silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a white solid (50 mg, 24%).
LC / MS 342
NMR (DMSO-d 6 ) δ: 1.42 (9 H, s), 3.03-3.16 (4 H, m), 3.40-3.53 (4 H, m), 3.83 (3 H, s), 6.94 (2 H, d, J = 8.7 Hz), 7.40 (2 H, d, J = 8.7 Hz), 7.73 (1 H, s), 7.98 (1 H, s).
8b)1-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン　1塩酸塩
　tert-ブチル 4-[4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート(50 mg, 0.15 mmol)の酢酸エチル(3 mL)溶液に4N塩酸酢酸エチル溶液(3 mL)を加え、室温で2時間攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を白色固体(42 mg, 100%)として得た。
NMR (DMSO-d6) δ: 3.14 - 3.27 (4 H, m), 3.29 - 3.45 (4 H, m), 3.84 (3 H, s), 6.98 (2 H, d, J=8.7 Hz), 7.44 (2 H, d, J=8.7 Hz), 7.76 (1 H, s), 8.01 (1 H, s), 8.97 (2 H, brs). 8b) 1- [4- (1-Methyl-1H-pyrazol-4-yl) phenyl] piperazine monohydrochloride tert-butyl 4- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine To a solution of -1-carboxylate (50 mg, 0.15 mmol) in ethyl acetate (3 mL) was added 4N hydrochloric acid ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound as a white solid (42 mg, 100%).
NMR (DMSO-d 6 ) δ: 3.14-3.27 (4 H, m), 3.29-3.45 (4 H, m), 3.84 (3 H, s), 6.98 (2 H, d, J = 8.7 Hz), 7.44 (2 H, d, J = 8.7 Hz), 7.76 (1 H, s), 8.01 (1 H, s), 8.97 (2 H, brs).
参考例９
1-[4-(5-メチルチオフェン-2-イル)フェニル]ピペラジンン　2塩酸塩 Reference Example 9
1- [4- (5-Methylthiophen-2-yl) phenyl] piperazine dihydrochloride
9a) tert-ブチル 4-[4-(5-メチルチオフェン-2-イル)フェニル]ピペラジン-1-カルボキシラート
　tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシラート(0.21 g, 0.6 mmol)、(5-メチルチオフェン-2-イル)ボロン酸(0.17 g, 1.2 mmol)、Pd(PPh3)4(69 mg, 0.06 mmol)、2M炭酸セシウム水溶液(1.5 mL, 3 mmol)及びDME(2.5 mL)の混合物をマイクロウェーブ照射下160℃で5分間攪拌した。反応混合物を室温まで冷却した後、水層を除去した。有機層をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を白色固体(35 mg, 15%)として得た。
LC/MS 358
NMR (DMSO-d6) δ: 1.42 (9 H, s), 2.43 (3 H, s), 3.02 - 3.19 (4 H, m), 3.39 - 3.56 (4 H, m), 6.75 (1 H, dd, J=3.4, 1.1 Hz), 6.96 (2 H, d, J=8.7 Hz), 7.11 (1 H, d, J=3.8 Hz), 7.42 (2 H, d, J=8.7 Hz). 9a) tert-butyl 4- [4- (5-methylthiophen-2-yl) phenyl] piperazine-1-carboxylate tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate (0.21 g, 0.6 mmol), (5-methylthiophen-2-yl) boronic acid (0.17 g, 1.2 mmol), Pd (PPh 3 ) 4 (69 mg, 0.06 mmol), 2M aqueous cesium carbonate (1.5 mL, 3 mmol) and DME (2.5 mL) of the mixture was stirred at 160 ° C. for 5 minutes under microwave irradiation. After the reaction mixture was cooled to room temperature, the aqueous layer was removed. The organic layer was purified by NH silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to obtain the title compound as a white solid (35 mg, 15%).
LC / MS 358
NMR (DMSO-d 6 ) δ: 1.42 (9 H, s), 2.43 (3 H, s), 3.02-3.19 (4 H, m), 3.39-3.56 (4 H, m), 6.75 (1 H, dd, J = 3.4, 1.1 Hz), 6.96 (2 H, d, J = 8.7 Hz), 7.11 (1 H, d, J = 3.8 Hz), 7.42 (2 H, d, J = 8.7 Hz).
9b) 1-[4-(5-メチルチオフェン-2-イル)フェニル]ピペラジンン　2塩酸塩
　tert-ブチル 4-[4-(5-メチルチオフェン-2-イル)フェニル]ピペラジン-1-カルボキシラート(35 mg, 0.1 mmol)の酢酸エチル(4 mL)溶液に4N塩酸酢酸エチル溶液(4 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を白色固体(33 mg, 100%)として得た。
LC/MS 259
NMR (DMSO-d6) δ: 2.44 (3 H, s), 3.10 - 3.30 (4 H, m), 3.30 - 3.49 (4 H, m), 6.76 (1 H, dd, J=3.6, 0.9 Hz), 7.00 (2 H, d, J=9.0 Hz), 7.14 (1 H, d, J=3.8 Hz), 7.46 (2 H, d, J=8.7 Hz), 9.09 (3 H, brs.). 9b) 1- [4- (5-Methylthiophen-2-yl) phenyl] piperazine dihydrochloride tert-butyl 4- [4- (5-methylthiophen-2-yl) phenyl] piperazine-1-carboxylate ( To a solution of 35 mg, 0.1 mmol) in ethyl acetate (4 mL) was added 4N hydrochloric acid ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a white solid (33 mg, 100%).
LC / MS 259
NMR (DMSO-d 6 ) δ: 2.44 (3 H, s), 3.10-3.30 (4 H, m), 3.30-3.49 (4 H, m), 6.76 (1 H, dd, J = 3.6, 0.9 Hz ), 7.00 (2 H, d, J = 9.0 Hz), 7.14 (1 H, d, J = 3.8 Hz), 7.46 (2 H, d, J = 8.7 Hz), 9.09 (3 H, brs.).
参考例１０
1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン　２臭化水素酸塩 Reference Example 10
1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan dihydrobromide
10a) ベンジル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.48 g, 2 mmol)、ベンジル 1,4-ジアゼパン-1-カルボキシラート(0.56 g, 2.4 mmol)、DavePhos(79 mg, 0.2 mmol)、Pd2(dba)3(92 mg, 0.1 mmol)、カリウム tert-ブトキシド(0.34 g, 3 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、90℃で20時間攪拌した。反応混合物を室温まで冷却後、NHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製し、題記化合物を茶色非定形固体(0.50 g, 64%)として得た。
LC/MS 391
NMR (DMSO-d6) δ: 1.70 - 1.90 (2 H, m), 2.43 (3 H, s), 2.58 - 2.79 (1 H, m), 3.37 - 3.73 (7 H, m), 4.85 - 5.15 (2 H, m), 6.80 (2 H, d, J=9.1 Hz), 7.04 - 7.50 (8 H, m). 10a) Benzyl 4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate 5- (4-bromophenyl) -2-methyl-1 , 3-oxazole (0.48 g, 2 mmol), benzyl 1,4-diazepane-1-carboxylate (0.56 g, 2.4 mmol), DavePhos (79 mg, 0.2 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), potassium tert-butoxide (0.34 g, 3 mmol) and toluene (5 mL) were stirred at 90 ° C. for 20 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by NH silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a brown amorphous solid (0.50 g, 64%).
LC / MS 391
NMR (DMSO-d 6 ) δ: 1.70-1.90 (2 H, m), 2.43 (3 H, s), 2.58-2.79 (1 H, m), 3.37-3.73 (7 H, m), 4.85-5.15 (2 H, m), 6.80 (2 H, d, J = 9.1 Hz), 7.04-7.50 (8 H, m).
10b) 1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン　２臭化水素酸塩
　ベンジル4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート(0.50 g, 1.3 mmol)に33%臭化水素酸酢酸溶液(10 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を茶色非定形固体(0.45 g, 84%)として得た。
LC/MS 258
NMR (DMSO-d6) δ: 2.00 - 2.20 (2 H, m), 2.44 - 2.51 (3 H, m), 2.99 - 3.39 (3 H, m), 3.40 - 3.67 (3 H, m), 3.67 - 3.95 (2 H, m), 6.78 - 7.03 (2 H, m), 7.31 - 7.74 (3 H, m), 8.47 - 9.36 (3 H, m). 10b) 1- [4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan dihydrobromide benzyl 4- [4- (2-methyl-1,3 -Oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate (0.50 g, 1.3 mmol) was added with 33% hydrobromic acid acetic acid solution (10 mL) and stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a brown amorphous solid (0.45 g, 84%).
LC / MS 258
NMR (DMSO-d 6 ) δ: 2.00-2.20 (2 H, m), 2.44-2.51 (3 H, m), 2.99-3.39 (3 H, m), 3.40-3.67 (3 H, m), 3.67 -3.95 (2 H, m), 6.78-7.03 (2 H, m), 7.31-7.74 (3 H, m), 8.47-9.36 (3 H, m).
参考例１１
6,6-ジメチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン Reference Example 11
6,6-Dimethyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan
11a) tert-ブチル 6,6-ジメチル-3-オキソ-1,4-ジアゼパン-1-カルボキシラート
　6,6-ジメチル-1,4-ジアゼパン-2-オン(公知文献: Polish Journal of Chemistry, 52, 1023-1028 (1978))(7.26 g)のEtOH(100 mL)溶液にジtert-ブチル ジカルボネート(11.7 mL)を加え、室温にて終夜攪拌した。溶媒を減圧留去し、残留物を酢酸エチル－ジイソプロピルエーテルより再結晶して、題記化合物を白色結晶(10.1 g, 81%)として得た。
LC/MS 243
NMR (DMSO-d6) δ: 0.76 - 0.88 (6 H, m), 1.38 (9 H, s), 2.81 - 2.91 (2 H, m), 3.21 (2 H, brs), 3.87 (2 H, s), 7.45 (1 H, brs). 11a) tert-butyl 6,6-dimethyl-3-oxo-1,4-diazepan-1-carboxylate 6,6-dimethyl-1,4-diazepan-2-one (publicly known: Polish Journal of Chemistry, 52 , 1023-1028 (1978)) (7.26 g) in EtOH (100 mL) was added ditert-butyl dicarbonate (11.7 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (10.1 g, 81%).
LC / MS 243
NMR (DMSO-d 6 ) δ: 0.76-0.88 (6 H, m), 1.38 (9 H, s), 2.81-2.91 (2 H, m), 3.21 (2 H, brs), 3.87 (2 H, s), 7.45 (1 H, brs).
11b) tert-ブチル 6,6-ジメチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3-オキソ-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 6,6-ジメチル-3-オキソ-1,4-ジアゼパン-1-カルボキシラート(0.49 g, 2 mmol)、5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.48 g, 2 mmol)、Xantphos(0.12 g, 0.2 mmol)、Pd2(dba)3(92 mg, 0.1mmol)および炭酸セシウム(0.98 g, 3 mmol)のトルエン(5 mL)懸濁液を窒素雰囲気下、90℃で20時間攪拌した。反応混合物を室温まで冷却後、シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=1/1)で精製し、題記化合物を無色非定形固体(0.63 g, 79%)として得た。
LC/MS 400
NMR (DMSO-d6) δ: 0.73 - 0.94 (6 H, m), 1.30 - 1.51 (9 H, m), 2.47 (3 H, s), 2.77 - 3.26 (2 H, m), 3.46 - 3.91 (2 H, m), 4.17 (2 H, s), 7.21 (2 H, d, J=8.7 Hz), 7.49 (1 H, s), 7.66 (2 H, d, J=8.3 Hz). 11b) tert-butyl 6,6-dimethyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3-oxo-1,4-diazepane-1-carboxylate tert- Butyl 6,6-dimethyl-3-oxo-1,4-diazepane-1-carboxylate (0.49 g, 2 mmol), 5- (4-bromophenyl) -2-methyl-1,3-oxazole (0.48 g , 2 mmol), Xantphos (0.12 g, 0.2 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol) and cesium carbonate (0.98 g, 3 mmol) in toluene (5 mL) under a nitrogen atmosphere. And stirred at 90 ° C. for 20 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous solid (0.63 g, 79%).
LC / MS 400
NMR (DMSO-d 6 ) δ: 0.73-0.94 (6 H, m), 1.30-1.51 (9 H, m), 2.47 (3 H, s), 2.77-3.26 (2 H, m), 3.46-3.91 (2 H, m), 4.17 (2 H, s), 7.21 (2 H, d, J = 8.7 Hz), 7.49 (1 H, s), 7.66 (2 H, d, J = 8.3 Hz).
11c) 6,6-ジメチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-2-オン　1塩酸塩
　tert-ブチル 6,6-ジメチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3-オキソ-1,4-ジアゼパン-1-カルボキシラート(0.63 g, 1.6 mmol)の酢酸エチル‐メタノール(1:1)(10 mL)溶液に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた固体をジイソプロピルエーテルで洗浄して題記化合物を淡茶色固体(0.49 g, 91%)として得た。
LC/MS 300
NMR (DMSO-d6) δ: 0.98 - 1.10 (6 H, m), 2.48 (3 H, s), 2.83 - 3.22 (2 H, m), 3.66 - 3.84 (2 H, m), 4.03 (2 H, brs.), 7.35 (2 H, d, J=8.7 Hz), 7.53 (1 H, s), 7.69 (2 H, d, J=8.7 Hz), 9.93 (2 H, brs). 11c) 6,6-Dimethyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-2-one monohydrochloride tert-butyl 6,6- Dimethyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3-oxo-1,4-diazepane-1-carboxylate (0.63 g, 1.6 mmol) in ethyl acetate To a methanol (1: 1) (10 mL) solution was added 4N hydrochloric acid ethyl acetate solution (10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound as a pale brown solid (0.49 g, 91%).
LC / MS 300
NMR (DMSO-d 6 ) δ: 0.98-1.10 (6 H, m), 2.48 (3 H, s), 2.83-3.22 (2 H, m), 3.66-3.84 (2 H, m), 4.03 (2 H, brs.), 7.35 (2 H, d, J = 8.7 Hz), 7.53 (1 H, s), 7.69 (2 H, d, J = 8.7 Hz), 9.93 (2 H, brs).
11d) 6,6-ジメチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン
　水素化アルミニウムリチウム(0.11 g, 2.9 mmol)のTHF(5 mL)懸濁液に、0℃にて6,6-ジメチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-2-オン　1塩酸塩(0.24 g, 0.7 mmol)を加え、0.5時間攪拌した。反応混合物に、水(0.5 mL)、1N 水酸化ナトリウム水溶液(0.5 mL)、および水(0.5 mL)を加え、セライト濾過した。濾液を減圧下濃縮し、得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～メタノール/酢酸エチル=1/10)で精製し、題記化合物を黄色油状物(90 mg, 44%)として得た。
LC/MS 286
NMR (DMSO-d6) δ: 0.87 (6 H, s), 2.37 - 2.43 (4 H, m), 2.86 - 2.98 (2 H, m), 3.22 - 3.43 (6 H, m), 6.81 (2 H, d, J=9.0 Hz), 7.15 (1 H, s), 7.39 (2 H, d, J=8.7 Hz). 11d) THF of 6,6-dimethyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan lithium aluminum hydride (0.11 g, 2.9 mmol) ( 5 mL) 6,6-Dimethyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan-2-one at 0 ° C. Monohydrochloride (0.24 g, 0.7 mmol) was added and stirred for 0.5 hour. Water (0.5 mL), 1N aqueous sodium hydroxide solution (0.5 mL), and water (0.5 mL) were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (hexane only to methanol / ethyl acetate = 1/10) to give the title compound as a yellow oil (90 mg, 44%). It was.
LC / MS 286
NMR (DMSO-d 6 ) δ: 0.87 (6 H, s), 2.37-2.43 (4 H, m), 2.86-2.98 (2 H, m), 3.22-3.43 (6 H, m), 6.81 (2 H, d, J = 9.0 Hz), 7.15 (1 H, s), 7.39 (2 H, d, J = 8.7 Hz).
参考例１２
1-[4-(2,4-ジメチル-1,3-チアゾール-5-イル)フェニル]ピペラジン　2塩酸塩 Reference Example 12
1- [4- (2,4-Dimethyl-1,3-thiazol-5-yl) phenyl] piperazine dihydrochloride
12a) tert-ブチル 4-[4-(2,4-ジメチル-1,3-チアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシラート(0.29 g, 0.9 mmol)、2,4-ジメチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1,3-チアゾール(0.41 g, 1.7 mmol)、Pd(PPh3)4(99 mg, 0.09 mmol)、2M炭酸セシウム水溶液(0.86 mL, 1.7 mmol)及びDME(3.5 mL)の混合物を、マイクロウェーブ照射下160℃で15分間攪拌した。反応混合物を室温まで冷却した後、水層を除去した。有機層をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/2)で精製し、題記化合物を無色非定形固体(0.21 g, 65%)として得た。
LC/MS 374
NMR (DMSO-d6) δ: 1.42 (9 H, s), 2.34 (3 H, s), 2.58 (3 H, s), 3.04 - 3.24 (4 H, m), 3.38 - 3.57 (4 H, m), 7.01 (2 H, d, J=8.7 Hz), 7.28 (2 H, d, J=8.7 Hz). 12a) tert-butyl 4- [4- (2,4-dimethyl-1,3-thiazol-5-yl) phenyl] piperazine-1-carboxylate tert-butyl 4- (4-bromophenyl) piperazine-1- Carboxylate (0.29 g, 0.9 mmol), 2,4-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-thiazole (0.41 g, 1.7 mmol), Pd (PPh 3 ) 4 (99 mg, 0.09 mmol), 2M aqueous cesium carbonate solution (0.86 mL, 1.7 mmol) and DME (3.5 mL) were mixed at 160 ° C. for 15 minutes under microwave irradiation. Stir. After the reaction mixture was cooled to room temperature, the aqueous layer was removed. The organic layer was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a colorless amorphous solid (0.21 g, 65%).
LC / MS 374
NMR (DMSO-d 6 ) δ: 1.42 (9 H, s), 2.34 (3 H, s), 2.58 (3 H, s), 3.04-3.24 (4 H, m), 3.38-3.57 (4 H, m), 7.01 (2 H, d, J = 8.7 Hz), 7.28 (2 H, d, J = 8.7 Hz).
12b) 1-[4-(2,4-ジメチル-1,3-チアゾール-5-イル)フェニル]ピペラジン　2塩酸塩
　tert-ブチル 4-[4-(2,4-ジメチル-1,3-チアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.21 g, 0.6 mmol)の酢酸エチル(4 mL)溶液に4N塩酸酢酸エチル溶液(4 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を白色固体(0.19 g, 100%)として得た。
LC/MS 274
NMR (DMSO-d6) δ: 2.36 (3 H, s), 2.64 (3 H, s), 3.22 (4 H, brs.), 3.35 - 3.56 (4 H, m), 7.07 (2 H, d, J=8.7 Hz), 7.34 (2 H, d, J=8.7 Hz), 9.14 (3 H, brs). 12b) 1- [4- (2,4-Dimethyl-1,3-thiazol-5-yl) phenyl] piperazine dihydrochloride tert-butyl 4- [4- (2,4-dimethyl-1,3-thiazole To a solution of -5-yl) phenyl] piperazine-1-carboxylate (0.21 g, 0.6 mmol) in ethyl acetate (4 mL) was added 4N hydrochloric acid ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound as a white solid (0.19 g, 100%).
LC / MS 274
NMR (DMSO-d 6 ) δ: 2.36 (3 H, s), 2.64 (3 H, s), 3.22 (4 H, brs.), 3.35-3.56 (4 H, m), 7.07 (2 H, d , J = 8.7 Hz), 7.34 (2 H, d, J = 8.7 Hz), 9.14 (3 H, brs).
参考例１３
1-[4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル]ピペラジン　2トリフルオロ酢酸塩 Reference Example 13
1- [4- (3,5-Dimethylisoxazol-4-yl) phenyl] piperazine 2 trifluoroacetate
13a) tert-ブチル 4-[4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート
　tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシラート(0.29 g, 0.9 mmol)、(3,5-ジメチルイソオキサゾール-4-イル)ボロン酸(0.24 g, 1.7 mmol)、Pd(PPh3)4(99 mg, 0.09 mmol)、2M炭酸セシウム水溶液(0.86 mL, 1.7 mmol)及びDME(3.5 mL)の混合物を、マイクロウェーブ照射下160℃で15分間攪拌した。反応混合物を室温まで冷却した後、水層を除去した。有機層をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/2)で精製し、題記化合物を無色非定形固体(0.18 g, 59%)として得た。
LC/MS 302
NMR (DMSO-d6) δ: 1.42 (9 H, s), 2.19 (3 H, s), 2.36 (3 H, s), 3.00 - 3.25 (4 H, m), 3.38 - 3.61 (4 H, m), 7.03 (2 H, d, J=8.7 Hz), 7.22 (2 H, d, J=8.7 Hz). 13a) tert-butyl 4- [4- (3,5-dimethylisoxazol-4-yl) phenyl] piperazine-1-carboxylate tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate (0.29 g, 0.9 mmol), (3,5-dimethylisoxazol-4-yl) boronic acid (0.24 g, 1.7 mmol), Pd (PPh 3 ) 4 (99 mg, 0.09 mmol), 2M aqueous cesium carbonate (0.86 mL) , 1.7 mmol) and DME (3.5 mL) were stirred at 160 ° C. for 15 minutes under microwave irradiation. After the reaction mixture was cooled to room temperature, the aqueous layer was removed. The organic layer was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a colorless amorphous solid (0.18 g, 59%).
LC / MS 302
NMR (DMSO-d 6 ) δ: 1.42 (9 H, s), 2.19 (3 H, s), 2.36 (3 H, s), 3.00-3.25 (4 H, m), 3.38-3.61 (4 H, m), 7.03 (2 H, d, J = 8.7 Hz), 7.22 (2 H, d, J = 8.7 Hz).
13b) 1-[4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル]ピペラジン　2トリフルオロ酢酸塩
　tert-ブチル 4-[4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート(0.18 g, 0.5 mmol)の酢酸エチル(3 mL)溶液に4N塩酸酢酸エチル溶液(3 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を白色固体(0.23 g, 100%)として得た。
LC/MS 258
NMR (DMSO-d6) δ: 2.20 (3 H, s), 2.37 (3 H, s), 3.14 - 3.31 (4 H, m), 3.32 - 3.53 (4 H, m), 7.08 (2 H, d, J=8.7 Hz), 7.27 (2 H, d, J=8.7 Hz), 8.73 (3 H, brs). 13b) 1- [4- (3,5-Dimethylisoxazol-4-yl) phenyl] piperazine 2 trifluoroacetate tert-butyl 4- [4- (3,5-dimethylisoxazol-4-yl) phenyl ] To a solution of piperazine-1-carboxylate (0.18 g, 0.5 mmol) in ethyl acetate (3 mL) was added 4N hydrochloric acid ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound as a white solid (0.23 g, 100%).
LC / MS 258
NMR (DMSO-d 6 ) δ: 2.20 (3 H, s), 2.37 (3 H, s), 3.14-3.31 (4 H, m), 3.32-3.53 (4 H, m), 7.08 (2 H, d, J = 8.7 Hz), 7.27 (2 H, d, J = 8.7 Hz), 8.73 (3 H, brs).
参考例１４
2-メチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　2塩酸塩 Reference Example 14
2-Methyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrochloride
14a) tert-ブチル 3-メチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.48 g, 2 mmol)、tert-ブチル 3-メチルピペラジン-1-カルボキシラート(0.44 g, 2.2 mmol)、DavePhos(79 mg, 0.2 mmol)、Pd2(dba)3(92 mg, 0.1 mmol)、カリウム tert-ブトキシド(0.34 g, 3 mmol)及びトルエン(10 mL)の混合物を窒素雰囲気下、90℃で終夜攪拌した。反応混合物を室温まで冷却後、NHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/2)で精製し、題記化合物を黄色固体(0.51 g, 71%)として得た。
LC/MS 357
NMR (DMSO-d6) δ: 0.83 - 1.03 (3 H, m), 1.29 - 1.53 (9 H, m), 2.43 (3 H, s), 2.66 - 3.28 (2 H, m), 3.34 - 3.43 (1 H, m), 3.57 - 4.18 (4 H, m), 6.95 (2 H, d, J=9.0 Hz), 7.28 (1 H, s), 7.40 - 7.57 (2 H, m). 14a) tert-butyl 3-methyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -2-methyl- 1,3-oxazole (0.48 g, 2 mmol), tert-butyl 3-methylpiperazine-1-carboxylate (0.44 g, 2.2 mmol), DavePhos (79 mg, 0.2 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), potassium tert-butoxide (0.34 g, 3 mmol) and toluene (10 mL) were stirred at 90 ° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by NH silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a yellow solid (0.51 g, 71%).
LC / MS 357
NMR (DMSO-d 6 ) δ: 0.83-1.03 (3 H, m), 1.29-1.53 (9 H, m), 2.43 (3 H, s), 2.66-3.28 (2 H, m), 3.34-3.43 (1 H, m), 3.57-4.18 (4 H, m), 6.95 (2 H, d, J = 9.0 Hz), 7.28 (1 H, s), 7.40-7.57 (2 H, m).
14b) 2-メチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　2塩酸塩
　tert-ブチル 3-メチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.51 g, 1.4 mmol)の酢酸エチル(5 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、減圧下乾燥して題記化合物を無色非定形固体(0.47 g, 100%)として得た。
LC/MS 258
NMR (DMSO-d6) δ: 1.06 - 1.14 (3 H, m), 2.45 (3 H, s), 2.80 - 3.69 (6 H, m), 4.14 - 4.37 (1 H, m), 7.05 (2 H, d, J=9.0 Hz), 7.36 (1 H, s), 7.51 - 7.64 (2 H, m), 8.70 - 10.13 (3 H, m). 14b) 2-Methyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrochloride tert-butyl 3-methyl-4- [4- (2-methyl-1 , 3-Oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.51 g, 1.4 mmol) in ethyl acetate (5 mL) was added 4N hydrochloric acid ethyl acetate solution (5 mL) and stirred at room temperature overnight. . The solvent was removed under reduced pressure and dried under reduced pressure to give the title compound as a colorless amorphous solid (0.47 g, 100%).
LC / MS 258
NMR (DMSO-d 6 ) δ: 1.06-1.14 (3 H, m), 2.45 (3 H, s), 2.80-3.69 (6 H, m), 4.14-4.37 (1 H, m), 7.05 (2 H, d, J = 9.0 Hz), 7.36 (1 H, s), 7.51-7.64 (2 H, m), 8.70-10.13 (3 H, m).
参考例１５
メチル4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-2-カルボキシラート　2塩酸塩 Reference Example 15
Methyl 4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-2-carboxylate dihydrochloride
15a) 1-tert-ブチル 2-メチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1,2-ジカルボキシラート
　5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.48 g, 2 mmol)、1-tert-ブチル 2-メチル ピペラジン-1,2-ジカルボキシラート(0.54 g, 2.2 mmol)、DavePhos(79 mg, 0.2 mmol)、Pd2(dba)3(92 mg, 0.1 mmol)、カリウム tert-ブトキシド(0.34 g, 3 mmol)及びトルエン(10 mL)の混合物を窒素雰囲気下、90℃で終夜攪拌した。反応混合物を室温まで冷却後、NHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/2)で精製し、題記化合物を黄色非定形固体(0.24 g, 30%)として得た。
LC/MS 401
NMR (DMSO-d6) δ: 1.28 - 1.50 (9 H, m), 2.44 (3 H, s), 2.64 - 3.27 (3 H, m), 3.54 - 4.20 (6 H, m), 4.61 - 4.85 (1 H, m), 6.97 (2 H, d, J = 9.0 Hz), 7.31 (1 H, s), 7.52 (2 H, d, J = 8.7). 15a) 1-tert-butyl 2-methyl 4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1,2-dicarboxylate 5- (4-bromophenyl)- 2-Methyl-1,3-oxazole (0.48 g, 2 mmol), 1-tert-butyl 2-methylpiperazine-1,2-dicarboxylate (0.54 g, 2.2 mmol), DavePhos (79 mg, 0.2 mmol) , Pd 2 (dba) 3 (92 mg, 0.1 mmol), potassium tert-butoxide (0.34 g, 3 mmol) and toluene (10 mL) were stirred at 90 ° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by NH silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a yellow amorphous solid (0.24 g, 30%).
LC / MS 401
NMR (DMSO-d 6 ) δ: 1.28-1.50 (9 H, m), 2.44 (3 H, s), 2.64-3.27 (3 H, m), 3.54-4.20 (6 H, m), 4.61-4.85 (1 H, m), 6.97 (2 H, d, J = 9.0 Hz), 7.31 (1 H, s), 7.52 (2 H, d, J = 8.7).
15b) メチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-2-カルボキシラート　2塩酸塩
　1-tert-ブチル 2-メチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1,2-ジカルボキシラート(0.24 g, 0.6 mmol)の酢酸エチル(5 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた固体をジイソプロピルエーテルで洗浄して題記化合物を白色固体(0.22 g, 100%)として得た。
LC/MS 302
NMR (DMSO-d6) δ: 1.91 (3 H, s), 2.45 (3 H, s), 3.10 - 3.93 (7 H, m), 4.34 - 4.64 (1 H, m), 7.08 (2 H, d, J=9.0 Hz), 7.37 (1 H, s), 7.56 (2 H, d, J=8.7 Hz), 9.51 - 10.21 (2 H, m). 15b) Methyl 4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-2-carboxylate dihydrochloride 1-tert-butyl 2-methyl 4- [4- (2- Methyl-1,3-oxazol-5-yl) phenyl] piperazine-1,2-dicarboxylate (0.24 g, 0.6 mmol) in ethyl acetate (5 mL) was added 4N hydrochloric acid ethyl acetate solution (5 mL). And stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound as a white solid (0.22 g, 100%).
LC / MS 302
NMR (DMSO-d 6 ) δ: 1.91 (3 H, s), 2.45 (3 H, s), 3.10-3.93 (7 H, m), 4.34-4.64 (1 H, m), 7.08 (2 H, d, J = 9.0 Hz), 7.37 (1 H, s), 7.56 (2 H, d, J = 8.7 Hz), 9.51-10.21 (2 H, m).
参考例１６
3-メチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　2臭化水素酸塩 Reference Example 16
3-Methyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrobromide
16a) ベンジル 2-メチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-メチル-1,3-オキサゾール(0.48 g, 2 mmol)、ベンジル 2-メチルピペラジン-1-カルボキシラート(公知文献: EP1548010)(0.52 g, 2.2 mmol)、DavePhos(79 mg, 0.2 mmol)、Pd2(dba)3(92 mg, 0.1 mmol)、カリウム tert-ブトキシド(0.34 g, 3 mmol)及びトルエン(10 mL)の混合物を窒素雰囲気下、90℃で終夜攪拌した。反応混合物を室温まで冷却後、NHシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/2)で精製し、題記化合物を黄色固体(0.43 g, 55%)として得た。
LC/MS 391
NMR (DMSO-d6) δ: 1.21 (3 H, d, J=6.8 Hz), 2.44 (3 H, s), 2.60 - 3.08 (3 H, m), 3.42 - 3.97 (3 H, m), 4.21 - 4.40 (1 H, m), 5.11 (2 H, d, J=3.0 Hz), 6.98 (2 H, d, J=9.0 Hz), 7.23 - 7.43 (6 H, m), 7.50 (2 H, d, J=8.7 Hz). 16a) Benzyl 2-methyl-4- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -2-methyl-1, 3-oxazole (0.48 g, 2 mmol), benzyl 2-methylpiperazine-1-carboxylate (known literature: EP1548010) (0.52 g, 2.2 mmol), DavePhos (79 mg, 0.2 mmol), Pd 2 (dba) 3 A mixture of (92 mg, 0.1 mmol), potassium tert-butoxide (0.34 g, 3 mmol) and toluene (10 mL) was stirred at 90 ° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then purified by NH silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a yellow solid (0.43 g, 55%).
LC / MS 391
NMR (DMSO-d 6 ) δ: 1.21 (3 H, d, J = 6.8 Hz), 2.44 (3 H, s), 2.60-3.08 (3 H, m), 3.42-3.97 (3 H, m), 4.21-4.40 (1 H, m), 5.11 (2 H, d, J = 3.0 Hz), 6.98 (2 H, d, J = 9.0 Hz), 7.23-7.43 (6 H, m), 7.50 (2 H , d, J = 8.7 Hz).
16b) 3-メチル-1-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン　2臭化水素酸塩
　ベンジル2-メチル-4-[4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.43 g, 1.1 mmol)に33%臭化水素酸酢酸溶液(10 mL)を加え、室温で5時間攪拌した。溶媒を減圧留去し得られた固体をジイソプロピルエーテルで洗浄して、題記化合物を白色固体(0.46 g, 100%)として得た。
LC/MS 258
NMR (DMSO-d6) δ: 1.28 (3 H, d, J=6.4 Hz), 2.45 (3 H, s), 2.76 (1 H, dd, J=13.4, 10.7 Hz), 2.89 - 3.26 (3 H, m), 3.30 - 3.54 (1 H, m), 3.74 - 3.95 (2 H, m), 7.08 (2 H, d, J=8.7 Hz), 7.35 (1 H, s), 7.54 (2 H, d, J=8.7 Hz), 8.61 (1 H, brs), 8.92 (2 H, brs). 16b) 3-methyl-1- [4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine dihydrobromide benzyl 2-methyl-4- [4- (2-methyl- 33% Hydrobromic acid acetic acid solution (10 mL) was added to 1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.43 g, 1.1 mmol), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diisopropyl ether to give the title compound as a white solid (0.46 g, 100%).
LC / MS 258
NMR (DMSO-d 6 ) δ: 1.28 (3 H, d, J = 6.4 Hz), 2.45 (3 H, s), 2.76 (1 H, dd, J = 13.4, 10.7 Hz), 2.89-3.26 (3 H, m), 3.30-3.54 (1 H, m), 3.74-3.95 (2 H, m), 7.08 (2 H, d, J = 8.7 Hz), 7.35 (1 H, s), 7.54 (2 H , d, J = 8.7 Hz), 8.61 (1 H, brs), 8.92 (2 H, brs).
参考例１７
9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3,9-ジアザビシクロ[3.3.1]ノナン Reference Example 17
9- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,9-diazabicyclo [3.3.1] nonane
17a) 3-ベンジル-9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3,9-ジアザビシクロ[3.3.1]ノナン
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(0.74 g, 2.8 mmol)、3-ベンジル-3,9-ジアザビシクロ[3.3.1]ノナン(公知文献；Farmaco, 55, 553 (2000))(0.60 g, 2.8 mmol)、DavePhos(0.11 g, 0.28 mmol)、Pd2(dba)3(0.13 g, 0.14 mmol)、カリウム tert-ブトキシド(0.47 g, 4.2 mmol)及びトルエン(27 mL)の混合物を窒素雰囲気下、90℃で終夜攪拌した。反応混合物を室温まで冷却後、シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を黄色油状物(0.64 g, 57%)として得た。
LC/MS 403
NMR (DMSO-d6) δ: 1.36 - 1.96 (3 H, m), 2.26 - 2.48 (7 H, m), 2.72 - 3.00 (1 H, m), 3.32 (1 H, s), 3.41 (1 H, s), 3.78 - 4.16 (7 H, m), 6.44 - 6.61 (1 H, m), 6.95 - 7.48 (7 H, m), 7.48 - 7.73 (1 H, m). 17a) 3-Benzyl-9- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,9-diazabicyclo [3.3.1] nonane 5- (4-bromo -2-methoxyphenyl) -2-methyl-1,3-oxazole (0.74 g, 2.8 mmol), 3-benzyl-3,9-diazabicyclo [3.3.1] nonane (public literature; Farmaco, 55, 553 (2000 )) (0.60 g, 2.8 mmol), DavePhos (0.11 g, 0.28 mmol), Pd 2 (dba) 3 (0.13 g, 0.14 mmol), potassium tert-butoxide (0.47 g, 4.2 mmol) and toluene (27 mL) The mixture was stirred at 90 ° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a yellow oil (0.64 g, 57%).
LC / MS 403
NMR (DMSO-d 6 ) δ: 1.36-1.96 (3 H, m), 2.26-2.48 (7 H, m), 2.72-3.00 (1 H, m), 3.32 (1 H, s), 3.41 (1 H, s), 3.78-4.16 (7 H, m), 6.44-6.61 (1 H, m), 6.95-7.48 (7 H, m), 7.48-7.73 (1 H, m).
17b) 9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3,9-ジアザビシクロ[3.3.1]ノナン
　3-ベンジル-9-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-3,9-ジアザビシクロ[3.3.1]ノナン(0.64 g, 1.6 mmol)のメタノール(5 mL)溶液に20%水酸化パラジウムカーボン(0.13g)を加え、水素雰囲気下室温にて終夜攪拌した。反応混合物をセライト濾過し、濾液を減圧下濃縮した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝1/4)で精製し、題記化合物を淡茶色固体(0.12 g, 20%)として得た。
LC/MS 313
NMR (DMSO-d6) δ: 1.34 - 1.55 (1 H, m), 1.55 - 1.73 (2 H, m), 1.74 - 1.98 (2 H, m), 2.42 (3 H, s), 2.57 - 2.88 (2 H, m), 2.91 - 3.18 (4 H, m), 3.87 (3 H, s), 3.94 (2 H, brs), 6.22 - 6.67 (2 H, m), 7.08 (1 H, s), 7.41 (1 H, d, J=8.7 Hz). 17b) 9- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -3,9-diazabicyclo [3.3.1] nonane 3-benzyl-9- [3-methoxy -4- (2-Methyl-1,3-oxazol-5-yl) phenyl] -3,9-diazabicyclo [3.3.1] nonane (0.64 g, 1.6 mmol) in methanol (5 mL) in 20% water Palladium oxide carbon (0.13 g) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 1/4) to obtain the title compound as a light brown solid (0.12 g, 20%).
LC / MS 313
NMR (DMSO-d 6 ) δ: 1.34-1.55 (1 H, m), 1.55-1.73 (2 H, m), 1.74-1.98 (2 H, m), 2.42 (3 H, s), 2.57-2.88 (2 H, m), 2.91-3.18 (4 H, m), 3.87 (3 H, s), 3.94 (2 H, brs), 6.22-6.67 (2 H, m), 7.08 (1 H, s) , 7.41 (1 H, d, J = 8.7 Hz).
参考例１８
ベンジル4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2,2-ジメチルピペラジン-1-カルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(0.22 g, 0.8 mmol)、ベンジル 2,2-ジメチルピペラジン-1-カルボキシラート(0.20 g, 0.8 mmol)、(rac)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル(0.10 g, 0.16 mmol)、酢酸パラジウム(II)(18 mg, 0.08 mmol)、炭酸セシウム(0.53 g, 1.6 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、90℃で終夜攪拌した。反応混合物を室温まで冷却後、シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を白色固体(0.14 g, 39%)として得た。
LC/MS 436
NMR (DMSO-d6) δ: 1.38 (6 H, s), 2.42 (3 H, s), 3.36 - 3.46 (2 H, m), 3.52 (2 H, s), 3.83 (2 H, t, J=5.7 Hz), 3.90 (3 H, s), 5.09 (2 H, s), 6.27 - 6.60 (2 H, m), 7.08 (1 H, s), 7.23 - 7.55 (6 H, m). Reference Example 18
Benzyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2,2-dimethylpiperazine-1-carboxylate 5- (4-bromo-2-methoxyphenyl) ) -2-Methyl-1,3-oxazole (0.22 g, 0.8 mmol), benzyl 2,2-dimethylpiperazine-1-carboxylate (0.20 g, 0.8 mmol), (rac) -2,2'-bis ( Diphenylphosphino) -1,1'-binaphthyl (0.10 g, 0.16 mmol), palladium (II) acetate (18 mg, 0.08 mmol), cesium carbonate (0.53 g, 1.6 mmol) and toluene (5 mL) The mixture was stirred at 90 ° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a white solid (0.14 g, 39%).
LC / MS 436
NMR (DMSO-d 6 ) δ: 1.38 (6 H, s), 2.42 (3 H, s), 3.36-3.46 (2 H, m), 3.52 (2 H, s), 3.83 (2 H, t, J = 5.7 Hz), 3.90 (3 H, s), 5.09 (2 H, s), 6.27-6.60 (2 H, m), 7.08 (1 H, s), 7.23-7.55 (6 H, m).
参考例１９
ベンジル2-エチル-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(0.18 g, 0.68 mmol)、ベンジル 2-エチルピペラジン-1-カルボキシラート(0.17 g, 0.68 mmol)、(rac)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル(0.085 g, 0.14 mmol)、酢酸パラジウム(II)(15 mg, 0.07 mmol)、炭酸セシウム(0.44 g, 1.4 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、90℃で終夜攪拌した。反応混合物を室温まで冷却後、シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を黄色油状物(0.17 g, 59%)として得た。
LC/MS 436
NMR (DMSO-d6) δ: 0.83 (3 H, t, J=7.4 Hz), 1.48 - 1.83 (2 H, m), 2.43 (3 H, s), 2.62 - 2.84 (1 H, m), 2.91 (1 H, dd, J=12.9, 3.8 Hz), 3.07 - 3.28 (1 H, m), 3.63 - 3.79 (2 H, m), 3.85 - 4.17 (5 H, m), 5.00 - 5.21 (2 H, m), 6.48 - 6.66 (2 H, m), 7.15 (1 H, s), 7.28 - 7.52 (6 H, m). Reference Example 19
Benzyl 2-ethyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromo-2-methoxyphenyl)- 2-Methyl-1,3-oxazole (0.18 g, 0.68 mmol), benzyl 2-ethylpiperazine-1-carboxylate (0.17 g, 0.68 mmol), (rac) -2,2'-bis (diphenylphosphino) A mixture of -1,1'-binaphthyl (0.085 g, 0.14 mmol), palladium (II) acetate (15 mg, 0.07 mmol), cesium carbonate (0.44 g, 1.4 mmol) and toluene (5 mL) under a nitrogen atmosphere Stir at 90 ° C. overnight. The reaction mixture was cooled to room temperature, and purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a yellow oil (0.17 g, 59%).
LC / MS 436
NMR (DMSO-d 6 ) δ: 0.83 (3 H, t, J = 7.4 Hz), 1.48-1.83 (2 H, m), 2.43 (3 H, s), 2.62-2.84 (1 H, m), 2.91 (1 H, dd, J = 12.9, 3.8 Hz), 3.07-3.28 (1 H, m), 3.63-3.79 (2 H, m), 3.85-4.17 (5 H, m), 5.00-5.21 (2 H, m), 6.48-6.66 (2 H, m), 7.15 (1 H, s), 7.28-7.52 (6 H, m).
参考例２０
tert-ブチル 3-エチル-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(0.27 g, 1 mmol)、tert-ブチル 3-エチルピペラジン-1-カルボキシラート(0.21 g, 1 mmol)、(rac)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル(0.13 g, 0.20 mmol)、酢酸パラジウム(II)(23 mg, 0.10 mmol)、炭酸セシウム(0.65 g, 2 mmol)及びトルエン(10 mL)の混合物を窒素雰囲気下、90℃で60時間攪拌した。反応混合物を室温まで冷却後、シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を黄色油状物(0.10 g, 25%)として得た。
LC/MS 402
NMR (DMSO-d6) δ: 0.75 - 0.99 (3 H, m), 1.42 (9 H, s), 2.43 (3 H, s), 2.62 - 3.23 (4 H, m), 3.37 - 4.13 (8 H, m), 6.39 - 6.71 (2 H, m), 7.06 - 7.19 (1 H, m), 7.44 (1 H, dd, J=9.3, 2.8 Hz). Reference Example 20
tert-butyl 3-ethyl-4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromo-2-methoxyphenyl) ) -2-methyl-1,3-oxazole (0.27 g, 1 mmol), tert-butyl 3-ethylpiperazine-1-carboxylate (0.21 g, 1 mmol), (rac) -2,2'-bis ( Diphenylphosphino) -1,1'-binaphthyl (0.13 g, 0.20 mmol), palladium (II) acetate (23 mg, 0.10 mmol), cesium carbonate (0.65 g, 2 mmol) and toluene (10 mL) The mixture was stirred at 90 ° C. for 60 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a yellow oil (0.10 g, 25%).
LC / MS 402
NMR (DMSO-d 6 ) δ: 0.75-0.99 (3 H, m), 1.42 (9 H, s), 2.43 (3 H, s), 2.62-3.23 (4 H, m), 3.37-4.13 (8 H, m), 6.39-6.71 (2 H, m), 7.06-7.19 (1 H, m), 7.44 (1 H, dd, J = 9.3, 2.8 Hz).
参考例２１
tert-ブチル 4-[3-フルオロ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモ-2-フルオロフェニル)-2-メチル-1,3-オキサゾール(500 mg, 2.0 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(360 mg, 2.0 mmol)、DavePhos(77 mg, 0.20 mmol)及びナトリウム tert-ブトキシド(280 mg, 2.9 mmol)のトルエン(5.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(89 mg, 0.10 mmol)を加え、90 ℃で6時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を淡黄色固体(500 mg, 71%)として得た。
LC/MS 362
NMR (CDCl3) δ: 1.49 (9 H, s), 2.52 (3 H, s), 3.05 - 3.28 (4 H, m), 3.50 - 3.64 (4 H, m), 6.65 (1 H, dd, J=14.0, 2.3 Hz), 6.72 (1 H, dd, J=8.5, 2.3 Hz), 7.18 (1 H, d, J=4.2 Hz), 7.57 (1 H, t, J=8.5 Hz). Reference Example 21
tert-butyl 4- [3-fluoro-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromo-2-fluorophenyl) -2- Methyl-1,3-oxazole (500 mg, 2.0 mmol), tert-butyl piperazine-1-carboxylate (360 mg, 2.0 mmol), DavePhos (77 mg, 0.20 mmol) and sodium tert-butoxide (280 mg, 2.9 mmol) in toluene (5.0 mL) was added Pd 2 (dba) 3 (89 mg, 0.10 mmol) under a nitrogen atmosphere and stirred at 90 ° C. for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a pale yellow solid (500 mg, 71%).
LC / MS 362
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.52 (3 H, s), 3.05-3.28 (4 H, m), 3.50-3.64 (4 H, m), 6.65 (1 H, dd, J = 14.0, 2.3 Hz), 6.72 (1 H, dd, J = 8.5, 2.3 Hz), 7.18 (1 H, d, J = 4.2 Hz), 7.57 (1 H, t, J = 8.5 Hz).
参考例２２
tert-ブチル 4-[5-(1-メチル-1H-ピラゾール-4-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート Reference Example 22
tert-butyl 4- [5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl] piperazine-1-carboxylate
22a) 1-(5-ブロモピリジン-2-イル)エタノン
　5-ブロモピリジン-2-カルボニトリル (3.0 g, 16 mmol)のTHF(70 mL)溶液にメチルマグネシウムブロマイド 3Mエチルエーテル溶液(16 mL, 49 mmol)を-10 ℃で滴下し、徐々に昇温し室温で16時間攪拌した。反応混合物に１N塩酸を加え、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝3/1)で精製し、題記化合物を黄色固体(1.2 g, 36％)として得た。
NMR (CDCl3) δ: 2.62 (3 H, s), 7.83 (1 H, d, J=8.3 Hz), 8.19 (1 H, dd, J=8.3, 2.3 Hz), 8.93 (1 H, d, J=2.3 Hz). 22a) 1- (5-Bromopyridin-2-yl) ethanone 5-Bromopyridine-2-carbonitrile (3.0 g, 16 mmol) in THF (70 mL) and methylmagnesium bromide in 3M ethyl ether solution (16 mL, 49 mmol) was added dropwise at -10 ° C, the temperature was gradually raised, and the mixture was stirred at room temperature for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 3/1) to give the title compound as a yellow solid (1.2 g, 36%).
NMR (CDCl 3 ) δ: 2.62 (3 H, s), 7.83 (1 H, d, J = 8.3 Hz), 8.19 (1 H, dd, J = 8.3, 2.3 Hz), 8.93 (1 H, d, J = 2.3 Hz).
22b) 5-ブロモ-2-(2-メチル-1,3-オキサゾール-5-イル)ピリジン
　ヨードベンゼンジアセテート(1.5 g, 4.5 mmol)のアセトニトリル(20 mL)懸濁液にトリフルオロメタンスルホン酸 (800 μL, 9.0 mmol)を滴下し、室温で30分間攪拌した。反応混合物に1-(5-ブロモピリジン-2-イル)エタノン (600 mg, 3.0 mmol)のアセトニトリル(10 mL)を加え、加熱還流下2時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で中和した後、溶媒を減圧留去した。残留物を酢酸エチルで抽出し、得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を淡黄色固体(520 mg,73%)として得た。
LC/MS 239
NMR (CDCl3) δ: 2.56 (3 H, s), 7.32 (1 H, s), 7.53 (1 H, d, J=8.3 Hz), 7.74 (1 H, dd, J=8.3, 3.0 Hz), 8.63 (1 H, d, J=3.0 Hz). 22b) A suspension of 5-bromo-2- (2-methyl-1,3-oxazol-5-yl) pyridine iodobenzene diacetate (1.5 g, 4.5 mmol) in acetonitrile (20 mL) with trifluoromethanesulfonic acid ( 800 μL, 9.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1- (5-bromopyridin-2-yl) ethanone (600 mg, 3.0 mmol) in acetonitrile (10 mL), and the mixture was stirred with heating under reflux for 2 hr. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a pale yellow solid (520 mg, 73%).
LC / MS 239
NMR (CDCl 3 ) δ: 2.56 (3 H, s), 7.32 (1 H, s), 7.53 (1 H, d, J = 8.3 Hz), 7.74 (1 H, dd, J = 8.3, 3.0 Hz) , 8.63 (1 H, d, J = 3.0 Hz).
22c) tert-ブチル 4-[5-(1-メチル-1H-ピラゾール-4-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート
　5-ブロモ-2-(2-メチル-1,3-オキサゾール-5-イル)ピリジン(260 mg, 0.75 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(140 mg, 0.75 mmol)、DavePhos(30 mg, 0.075 mmol)及びナトリウム tert-ブトキシド(110 mg, 1.1 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(35 mg, 0.038 mmol)を加え、90 ℃で8時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/4～4/1)で精製し、題記化合物を黄色固体(153 mg, 59%)として得た。
LC/MS 345
NMR (CDCl3) δ: 1.49 (9 H, s), 2.51 (3 H, s), 3.45 - 3.68 (8 H, m), 6.67 (1 H, d, J=8.7 Hz), 7.06 (1 H, s), 7.68 (1 H, dd, J=8.7, 2.3 Hz), 8.45 (1 H, d, J=2.3 Hz). 22c) tert-butyl 4- [5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl] piperazine-1-carboxylate 5-bromo-2- (2-methyl-1,3- Oxazol-5-yl) pyridine (260 mg, 0.75 mmol), tert-butyl piperazine-1-carboxylate (140 mg, 0.75 mmol), DavePhos (30 mg, 0.075 mmol) and sodium tert-butoxide (110 mg, 1.1 Pd 2 (dba) 3 (35 mg, 0.038 mmol) was added to a toluene (2.0 mL) solution of mmol) under a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to 4/1) to give the title compound as a yellow solid (153 mg, 59%).
LC / MS 345
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.51 (3 H, s), 3.45-3.68 (8 H, m), 6.67 (1 H, d, J = 8.7 Hz), 7.06 (1 H , s), 7.68 (1 H, dd, J = 8.7, 2.3 Hz), 8.45 (1 H, d, J = 2.3 Hz).
参考例２３
tert-ブチル 4-[5-(1-メチル-1H-ピラゾール-4-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート Reference Example 23
tert-butyl 4- [5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl] piperazine-1-carboxylate
23a) tert-ブチル 4-(5-ブロモピリミジン-2-イル)ピペラジン-1-カルボキシラート
　5-ブロモ-2-クロロピリミジン (2.0 g, 10 mmol)のDMF(30 mL)溶液にtert-ブチル ピペラジン-1-カルボキシラート(2.3 g, 12 mmol)、炭酸カリウム(2.1 g, 16 mmol)を加え、80 ℃で6時間攪拌した。反応混合物を室温まで冷却し、水で希釈した。生じた析出物をろ取、水洗して、題記化合物を白色固体(3.5 g, 98％)として得た。
LC/MS 243
NMR (CDCl3) δ: 1.49 (9 H, s), 3.42 - 3.57 (4 H, m), 3.68 - 3.84 (4 H, m), 8.30 (2 H, s). 23a) tert-Butyl 4- (5-bromopyrimidin-2-yl) piperazine-1-carboxylate 5-Bromo-2-chloropyrimidine (2.0 g, 10 mmol) in DMF (30 mL) solution in tert-butyl piperazine -1-carboxylate (2.3 g, 12 mmol) and potassium carbonate (2.1 g, 16 mmol) were added, and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration and washed with water to give the title compound as a white solid (3.5 g, 98%).
LC / MS 243
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 3.42-3.57 (4 H, m), 3.68-3.84 (4 H, m), 8.30 (2 H, s).
23b) tert-ブチル 4-[5-(1-メチル-1H-ピラゾール-4-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート
　tert-ブチル 4-(5-ブロモピリミジン-2-イル)ピペラジン-1-カルボキシラート(500 mg, 1.5 mmol)、2M炭酸ナトリウム水溶液(2.9 mL, 5.8 mmol)、1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン)-2-イル-1H-ピラゾール(360 mg, 1.8 mmol)のDME(2.0 mL)溶液に窒素雰囲気下、Pd(PPh3)4(35 mg, 0.038 mmol)を加え、90 ℃で2.5時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～7/3)で精製し、題記化合物を無色固体(160 mg, 33%)として得た。
LC/MS 345
NMR (CDCl3) δ: 1.49 (9 H, s), 3.43 - 3.56 (4 H, m), 3.74 - 3.86 (4 H, m), 3.95 (3 H, s), 7.52 (1 H, s), 7.65 (1 H, s), 8.43 (2 H, s). 23b) tert-butyl 4- [5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl] piperazine-1-carboxylate tert-butyl 4- (5-bromopyrimidin-2-yl) Piperazine-1-carboxylate (500 mg, 1.5 mmol), 2 M aqueous sodium carbonate (2.9 mL, 5.8 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2- Pd (PPh 3 ) 4 (35 mg, 0.038 mmol) was added to a solution of dioxaborane) -2-yl-1H-pyrazole (360 mg, 1.8 mmol) in DME (2.0 mL) under a nitrogen atmosphere at 90 ° C. for 2.5 hours. Stir. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-7 / 3) to give the title compound as a colorless solid (160 mg, 33%).
LC / MS 345
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 3.43-3.56 (4 H, m), 3.74-3.86 (4 H, m), 3.95 (3 H, s), 7.52 (1 H, s) , 7.65 (1 H, s), 8.43 (2 H, s).
参考例２４
tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 24
tert-butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(370 mg, 1.4 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(260 mg, 1.4 mmol)、DavePhos(54 mg, 0.14 mmol)及びナトリウム tert-ブトキシド(200 mg, 2.1 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(63 mg, 0.070 mmol)を加え、90 ℃で15時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～7/3)で精製し、題記化合物を淡橙色固体(380 mg, 73%)として得た。
LC/MS 374
NMR (CDCl3) δ: 1.49 (9 H, s), 2.50 (3 H, s), 3.14 - 3.27 (4 H, m), 3.53 - 3.66 (4 H, m), 3.93 (3 H, s), 6.50 (1 H, d, J=2.3 Hz), 6.57 (1 H, dd, J=8.7, 2.3 Hz), 7.25 (1 H, s), 7.60 (1 H, d, J=8.7 Hz). 5- (4-Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole (370 mg, 1.4 mmol), tert-butyl piperazine-1-carboxylate (260 mg, 1.4 mmol), DavePhos (54 Pd 2 (dba) 3 (63 mg, 0.070 mmol) was added to a toluene (2.0 mL) solution of sodium tert-butoxide (200 mg, 2.1 mmol) in a nitrogen atmosphere at 90 ° C. for 15 hours. Stir. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 9-7 / 3) to give the title compound as a pale orange solid (380 mg, 73%).
LC / MS 374
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.50 (3 H, s), 3.14-3.27 (4 H, m), 3.53-3.66 (4 H, m), 3.93 (3 H, s) , 6.50 (1 H, d, J = 2.3 Hz), 6.57 (1 H, dd, J = 8.7, 2.3 Hz), 7.25 (1 H, s), 7.60 (1 H, d, J = 8.7 Hz).
参考例２５
tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメチル)フェニル]ピペラジン-1-カルボキシラート Reference Example 25
tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethyl) phenyl] piperazine-1-carboxylate
25a) [4-ブロモ-2-(トリフルオロメチル)フェニル]ヒドラジン
　2-アミノ-5-ブロモベンゾトリフルオリド(4.6 g, 19 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(1.4 g, 20 mmol)の水(5.0 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(13 g, 71 mmol)の濃塩酸(20 mL)溶液中に－20 ℃で滴下し、室温で2時間攪拌した。反応混合物を0 ℃に冷却し、生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物を10％炭酸カリウム水溶液で中和し、酢酸エチルを加えた。不溶物を除去後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色固体(2.3 g, 47%)として得た。
NMR (CDCl3) δ: 3.62 (2 H, brs), 5.83 (1 H, brs), 7.21 - 7.32 (1 H, m), 7.46 - 7.59 (2 H, m). 25a) [4-Bromo-2- (trifluoromethyl) phenyl] hydrazine 2-amino-5-bromobenzotrifluoride (4.6 g, 19 mmol) in concentrated hydrochloric acid (20 mL) was added to sodium nitrite (1.4 g, 20 mmol) in water (5.0 mL) was added at −20 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (13 g, 71 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C., and the resulting precipitate was collected by filtration and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.3 g, 47%).
NMR (CDCl 3 ) δ: 3.62 (2 H, brs), 5.83 (1 H, brs), 7.21-7.32 (1 H, m), 7.46-7.59 (2 H, m).
25b) 1-[4-ブロモ-2-(トリフルオロメチル)フェニル]-3-メチル-1H-1,2,4-トリアゾール
　[4-ブロモ-2-(トリフルオロメチル)フェニル]ヒドラジン (2.3 g, 8.9 mmol)のMeOH(20 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(公知文献；Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry，21，272(1982))(1.9 g, 8.9 mmol)を加え、室温で1.5時間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(15 mL)溶液にオルトギ酸トリメチル(8.0 mL)、ピリジン(11 mL)を加え、100 ℃で5時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(1.8 g, 66%)として得た。
LC/MS 306
NMR (CDCl3) δ: 2.49 (3 H, s), 7.42 (1 H, d, J=8.3 Hz), 7.84 (1 H, dd, J=8.3, 2.3 Hz), 7.97 (1 H, d, J=2.3 Hz), 8.19 (1 H, s). 25b) 1- [4-Bromo-2- (trifluoromethyl) phenyl] -3-methyl-1H-1,2,4-triazole [4-Bromo-2- (trifluoromethyl) phenyl] hydrazine (2.3 g , 8.9 mmol) in MeOH (20 mL) in methyl ethaneimidothioate hydroiodide (known literature; Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 21, 272 (1982)) (1.9 g, (8.9 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours, and the solvent was distilled off under reduced pressure. Trimethyl orthoformate (8.0 mL) and pyridine (11 mL) were added to a toluene (15 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (1.8 g, 66%).
LC / MS 306
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 7.42 (1 H, d, J = 8.3 Hz), 7.84 (1 H, dd, J = 8.3, 2.3 Hz), 7.97 (1 H, d, J = 2.3 Hz), 8.19 (1 H, s).
25c) tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメチル)フェニル]ピペラジン-1-カルボキシラート
　1-[4-ブロモ-2-(トリフルオロメチル)フェニル]-3-メチル-1H-1,2,4-トリアゾール(400 mg, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(240 mg, 1.3 mmol)、DavePhos(51 mg, 0.13 mmol)及びナトリウム tert-ブトキシド(190 mg, 2.0 mmol)のトルエン(4.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(60 mg, 0.065 mmol)を加え、90 ℃で15時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ)で精製し、題記化合物を淡黄色固体(300 mg, 56%)として得た。
LC/MS 412
NMR (CDCl3) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.21 - 3.37 (4 H, m), 3.53 - 3.70 (4 H, m), 7.08 (1 H, dd, J=8.7, 2.8 Hz), 7.21 (1 H, d, J=2.8 Hz), 7.35 (1 H, d, J=8.7 Hz), 8.10 (1 H, s). 25c) tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethyl) phenyl] piperazine-1-carboxylate 1- [4- Bromo-2- (trifluoromethyl) phenyl] -3-methyl-1H-1,2,4-triazole (400 mg, 1.3 mmol), tert-butyl piperazine-1-carboxylate (240 mg, 1.3 mmol), Pd 2 (dba) 3 (60 mg, 0.065 mmol) was added to a toluene (4.0 mL) solution of DavePhos (51 mg, 0.13 mmol) and sodium tert-butoxide (190 mg, 2.0 mmol) in a nitrogen atmosphere at 90 ° C. For 15 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone) to give the title compound as a pale yellow solid (300 mg, 56%).
LC / MS 412
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.21-3.37 (4 H, m), 3.53-3.70 (4 H, m), 7.08 (1 H, dd, J = 8.7, 2.8 Hz), 7.21 (1 H, d, J = 2.8 Hz), 7.35 (1 H, d, J = 8.7 Hz), 8.10 (1 H, s).
参考例２６
tert-ブチル 4-[3-エトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 26
tert-butyl 4- [3-ethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
26a) (4-ブロモ-2-フルオロフェニル)ヒドラジン
　4-ブロモ-2-フルオロアニリン(5.0 g, 26 mmol)の濃塩酸(25 mL)溶液に亜硝酸ナトリウム(1.9 g, 28 mmol)の水(2.5 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(19 g, 99 mmol)の濃塩酸(25 mL)溶液中に－20 ℃で滴下し、室温で1時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物を10％炭酸カリウム水溶液で中和し、酢酸エチルを加えた。不溶物を除去後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色固体(3.4 g, 63%)として得た。
NMR (CDCl3) δ: 3.56 (2 H, brs), 5.41 (1 H, brs), 7.02 (1 H, t, J=9.0 Hz), 7.12 (1 H, dd, J=10.9, 2.3 Hz), 7.16 - 7.23 (1 H, m). 26a) (4-Bromo-2-fluorophenyl) hydrazine 4-Bromo-2-fluoroaniline (5.0 g, 26 mmol) in concentrated hydrochloric acid (25 mL) was added to sodium nitrite (1.9 g, 28 mmol) in water ( 2.5 mL) solution was added at −20 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (19 g, 99 mmol) in concentrated hydrochloric acid (25 mL) at −20 ° C. and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (3.4 g, 63%).
NMR (CDCl 3 ) δ: 3.56 (2 H, brs), 5.41 (1 H, brs), 7.02 (1 H, t, J = 9.0 Hz), 7.12 (1 H, dd, J = 10.9, 2.3 Hz) , 7.16-7.23 (1 H, m).
26b) 1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-2-フルオロフェニル)ヒドラジン(3.4 g, 17 mmol)のMeOH(25 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(3.6 g, 17 mmol)を加え、室温で40分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸トリメチル(15 mL)、ピリジン(15 mL)を加え、100 ℃で9時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(3.7 g, 87%)として得た。
LC/MS 256
NMR (CDCl3) δ: 2.50 (3 H, s), 7.40 - 7.51 (2 H, m), 7.68 - 7.85 (1 H, m), 8.52 (1 H, d, J=3.0 Hz). 26b) 1- (4-Bromo-2-fluorophenyl) -3-methyl-1H-1,2,4-triazole (4-bromo-2-fluorophenyl) hydrazine (3.4 g, 17 mmol) in MeOH (25 To the solution was added methyl ethaneimidothioate hydroiodide (3.6 g, 17 mmol), and the mixture was stirred at room temperature for 40 minutes, and the solvent was distilled off under reduced pressure. Trimethyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 9 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (3.7 g, 87%).
LC / MS 256
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 7.40-7.51 (2 H, m), 7.68-7.85 (1 H, m), 8.52 (1 H, d, J = 3.0 Hz).
26c) 1-(4-ブロモ-2-エトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.2 mmol)のDMF(8.0 mL)溶液にナトリウムエトキシド 20%EtOH溶液(1.2 mL, 3.5 mmol)を加え、80 ℃で13時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を淡黄色固体(300 mg, 91%)として得た。
LC/MS 282
NMR (CDCl3) δ: 1.47 (3 H, t, J=7.0 Hz), 2.48 (3 H, s), 4.15 (2 H, q, J=7.0 Hz), 7.15 - 7.24 (2 H, m), 7.68 (1 H, d, J=8.3 Hz), 8.68 (1 H, s). 26c) 1- (4-Bromo-2-ethoxyphenyl) -3-methyl-1H-1,2,4-triazole 1- (4-Bromo-2-fluorophenyl) -3-methyl-1H-1,2 1,4-triazole (300 mg, 1.2 mmol) in DMF (8.0 mL) was added sodium ethoxide 20% EtOH solution (1.2 mL, 3.5 mmol), and the mixture was stirred at 80 ° C. for 13 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a pale yellow solid (300 mg, 91%).
LC / MS 282
NMR (CDCl 3 ) δ: 1.47 (3 H, t, J = 7.0 Hz), 2.48 (3 H, s), 4.15 (2 H, q, J = 7.0 Hz), 7.15-7.24 (2 H, m) , 7.68 (1 H, d, J = 8.3 Hz), 8.68 (1 H, s).
26d) tert-ブチル 4-[3-エトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-エトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.1 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(200 mg, 1.1 mmol)、DavePhos(41 mg, 0.11 mmol)及びナトリウム tert-ブトキシド(150 mg, 1.6 mmol)のトルエン(3.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(48 mg, 0.053 mmol)を加え、90 ℃で7.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～3/2)で精製し、題記化合物を淡黄色固体(280 mg, 68%)として得た。
LC/MS 388
NMR (CDCl3) δ: 1.42 (3 H, t, J=6.8 Hz), 1.49 (9 H, s), 2.48 (3 H, s), 3.09 - 3.23 (4 H, m), 3.54 - 3.67 (4 H, m), 4.10 (2 H, q, J=6.8 Hz), 6.48 - 6.64 (2 H, m), 7.58 (1 H, d, J=8.7 Hz), 8.53 (1 H, s). 26d) tert-butyl 4- [3-ethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-2- Ethoxyphenyl) -3-methyl-1H-1,2,4-triazole (300 mg, 1.1 mmol), tert-butyl piperazine-1-carboxylate (200 mg, 1.1 mmol), DavePhos (41 mg, 0.11 mmol) Pd 2 (dba) 3 (48 mg, 0.053 mmol) was added to a toluene (3.0 mL) solution of sodium tert-butoxide (150 mg, 1.6 mmol) in a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 7.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 3/2) to give the title compound as a pale yellow solid (280 mg, 68%).
LC / MS 388
NMR (CDCl 3 ) δ: 1.42 (3 H, t, J = 6.8 Hz), 1.49 (9 H, s), 2.48 (3 H, s), 3.09-3.23 (4 H, m), 3.54-3.67 ( 4 H, m), 4.10 (2 H, q, J = 6.8 Hz), 6.48-6.64 (2 H, m), 7.58 (1 H, d, J = 8.7 Hz), 8.53 (1 H, s).
参考例２７
tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート Reference Example 27
tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxylate
27a) 1-[4-ブロモ-2-(2,2,2-トリフルオロエトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール
　1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.2 mmol)のDMF(6.0 mL)溶液に炭酸カリウム(320 mg, 2.3 mmol)及び2,2,2-トリフルオロエタノール(140 μL, 2.0 mmol)を加え、80 ℃で5.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝3/2)で精製し、題記化合物を無色固体(450 mg, 97%)として得た。
LC/MS 336
NMR (CDCl3) δ: 2.49 (3 H, s), 4.46 (2 H, q, J=7.6 Hz), 7.18 (1 H, d, J=1.9 Hz), 7.35 (1 H, dd, J=8.7, 1.9 Hz), 7.75 (1 H, d, J=8.7 Hz), 8.58 (1 H, s). 27a) 1- [4-Bromo-2- (2,2,2-trifluoroethoxy) phenyl] -3-methyl-1H-1,2,4-triazole 1- (4-bromo-2-fluorophenyl) -3-Methyl-1H-1,2,4-triazole (300 mg, 1.2 mmol) in DMF (6.0 mL) was added to potassium carbonate (320 mg, 2.3 mmol) and 2,2,2-trifluoroethanol (140 μL, 2.0 mmol) was added, and the mixture was stirred at 80 ° C. for 5.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 3/2) to give the title compound as a colorless solid (450 mg, 97%).
LC / MS 336
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 4.46 (2 H, q, J = 7.6 Hz), 7.18 (1 H, d, J = 1.9 Hz), 7.35 (1 H, dd, J = 8.7, 1.9 Hz), 7.75 (1 H, d, J = 8.7 Hz), 8.58 (1 H, s).
27b) tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート
　1-[4-ブロモ-2-(2,2,2-トリフルオロエトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール(450 mg, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(250 mg, 1.3 mmol)、DavePhos(52 mg, 0.13 mmol)及びナトリウム tert-ブトキシド(190 mg, 2.0 mmol)のトルエン(4.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(61 mg, 0.066 mmol)を加え、90 ℃で14時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を淡黄色固体(390 mg, 67%)として得た。
LC/MS 442
NMR (CDCl3) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.09 - 3.27 (4 H, m), 3.54 - 3.66 (4 H, m), 4.37 (2 H, q, J=7.9 Hz), 6.51 (1 H, d, J=2.6 Hz), 6.69 (1 H, dd, J=9.0, 2.6 Hz), 7.60 (1 H, d, J=9.0 Hz), 8.42 (1 H, s). 27b) tert-Butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxy 1- [4-Bromo-2- (2,2,2-trifluoroethoxy) phenyl] -3-methyl-1H-1,2,4-triazole (450 mg, 1.3 mmol), tert-butyl piperazine A solution of 1-carboxylate (250 mg, 1.3 mmol), DavePhos (52 mg, 0.13 mmol) and sodium tert-butoxide (190 mg, 2.0 mmol) in toluene (4.0 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (61 mg, 0.066 mmol) was added, and the mixture was stirred at 90 ° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a pale yellow solid (390 mg, 67%).
LC / MS 442
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.09-3.27 (4 H, m), 3.54-3.66 (4 H, m), 4.37 (2 H, q, J = 7.9 Hz), 6.51 (1 H, d, J = 2.6 Hz), 6.69 (1 H, dd, J = 9.0, 2.6 Hz), 7.60 (1 H, d, J = 9.0 Hz), 8.42 (1 H, s).
参考例２８
tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメトキシ)フェニル]ピペラジン-1-カルボキシラート Reference Example 28
tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethoxy) phenyl] piperazine-1-carboxylate
28a) 1-[4-ブロモ-2-(トリフルオロメトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール
　4-ブロモ-2-(トリフルオロメトキシ)アニリン(5.0 g, 21 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(1.5 g, 22 mmol)の水(2.5 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(15 g, 78 mmol)の濃塩酸(20 mL)溶液中に－20 ℃で滴下し、室温で1時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物を10％炭酸カリウム水溶液で中和し、酢酸エチルを加えた。不溶物を除去後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物のMeOH(25 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(3.2 g, 15 mmol)を加え、室温で30分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸トリメチル(15 mL)、ピリジン(15 mL)を加え、100 ℃で15時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝3/7)で精製し、題記化合物を無色固体(2.7 g, 40%(2 steps))として得た。
LC/MS 322
NMR (CDCl3) δ: 2.49 (3 H, s), 7.54 - 7.63 (2 H, m), 7.72 (1 H, d, J=9.1 Hz), 8.45 (1 H, s). 28a) 1- [4-Bromo-2- (trifluoromethoxy) phenyl] -3-methyl-1H-1,2,4-triazole 4-bromo-2- (trifluoromethoxy) aniline (5.0 g, 21 mmol ) In concentrated hydrochloric acid (20 mL) was added a solution of sodium nitrite (1.5 g, 22 mmol) in water (2.5 mL) at −20 ° C., and the mixture was stirred at 0 ° C. for 30 min. The reaction mixture was added dropwise to a solution of tin chloride (15 g, 78 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Methylethaneimidothioate hydroiodide (3.2 g, 15 mmol) was added to a solution of the obtained residue in MeOH (25 mL), and the mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. Trimethyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 3/7) to give the title compound as a colorless solid (2.7 g, 40% (2 steps)).
LC / MS 322
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 7.54-7.63 (2 H, m), 7.72 (1 H, d, J = 9.1 Hz), 8.45 (1 H, s).
28b) tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-(トリフルオロメトキシ)フェニル]ピペラジン-1-カルボキシラート
　1-[4-ブロモ-2-(トリフルオロメトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール(400 mg, 1.2 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(230 mg, 1.2 mmol)、DavePhos(49 mg, 0.12 mmol)及びナトリウム tert-ブトキシド(180 mg, 1.9 mmol)のトルエン(4.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(57 mg, 0.062 mmol)を加え、90 ℃で7時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～3/2)で精製し、題記化合物を淡茶色固体(410 mg, 77%)として得た。
LC/MS 428
NMR (CDCl3) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.14 - 3.29 (4 H, m), 3.55 - 3.68 (4 H, m), 6.82 - 6.87 (1 H, m), 6.90 (1 H, dd, J=9.0, 2.6 Hz), 7.56 (1 H, d, J=9.0 Hz), 8.29 (1 H, s). 28b) tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3- (trifluoromethoxy) phenyl] piperazine-1-carboxylate 1- [4- Bromo-2- (trifluoromethoxy) phenyl] -3-methyl-1H-1,2,4-triazole (400 mg, 1.2 mmol), tert-butyl piperazine-1-carboxylate (230 mg, 1.2 mmol), Pd 2 (dba) 3 (57 mg, 0.062 mmol) was added to a toluene (4.0 mL) solution of DavePhos (49 mg, 0.12 mmol) and sodium tert-butoxide (180 mg, 1.9 mmol) in a nitrogen atmosphere at 90 ° C. For 7 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 3/2) to give the title compound as a pale brown solid (410 mg, 77%).
LC / MS 428
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.14-3.29 (4 H, m), 3.55-3.68 (4 H, m), 6.82-6.87 (1 H, m), 6.90 (1 H, dd, J = 9.0, 2.6 Hz), 7.56 (1 H, d, J = 9.0 Hz), 8.29 (1 H, s).
参考例２９
tert-ブチル 4-[2-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 29
tert-butyl 4- [2-fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
29a) (4-ブロモ-5-フルオロ-2-メトキシフェニル)ヒドラジン
　4-ブロモ-5-フルオロ-2-メトキシアニリン(5.0 g, 23 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(1.7 g, 24 mmol)の水(2.5 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(16 g, 85 mmol)の濃塩酸(20 mL)溶液中に－20 ℃で滴下し、室温で1時間攪拌した。反応混合物を0 ℃に冷却し、生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物を10％炭酸カリウム水溶液で中和し、酢酸エチルを加えた。不溶物を除去後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色固体(3.6 g, 68%)として得た。
NMR (CDCl3) δ: 3.50 (2 H, brs), 3.80 (3 H, s), 5.68 (1 H, brs), 6.74 - 6.90 (2 H, m). 29a) (4-Bromo-5-fluoro-2-methoxyphenyl) hydrazine 4-Bromo-5-fluoro-2-methoxyaniline (5.0 g, 23 mmol) in concentrated hydrochloric acid (20 mL) was added to sodium nitrite (1.7 ml). g, 24 mmol) in water (2.5 mL) was added at −20 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (16 g, 85 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C., and the resulting precipitate was collected by filtration and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (3.6 g, 68%).
NMR (CDCl 3 ) δ: 3.50 (2 H, brs), 3.80 (3 H, s), 5.68 (1 H, brs), 6.74-6.90 (2 H, m).
29b) 1-(4-ブロモ-5-フルオロ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-5-フルオロ-2-メトキシフェニル)ヒドラジン(3.6 g, 15 mmol)のMeOH(25 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(3.3 g, 15 mmol)を加え、室温で30分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸トリメチル(15 mL)、ピリジン(15 mL)を加え、100 ℃で13時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を無色固体(4.0 g, 91%)として得た。
LC/MS 286
NMR (CDCl3) δ: 2.48 (3 H, s), 3.94 (3 H, s), 7.22 (1 H, d, J=6.0 Hz), 7.71 (1 H, d, J=8.7 Hz), 8.72 (1 H, s). 29b) 1- (4-Bromo-5-fluoro-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (4-bromo-5-fluoro-2-methoxyphenyl) hydrazine (3.6 g , 15 mmol) in MeOH (25 mL) was added methylethaneimidothioate hydroiodide (3.3 g, 15 mmol), stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. Trimethyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 13 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless solid (4.0 g, 91%).
LC / MS 286
NMR (CDCl 3 ) δ: 2.48 (3 H, s), 3.94 (3 H, s), 7.22 (1 H, d, J = 6.0 Hz), 7.71 (1 H, d, J = 8.7 Hz), 8.72 (1 H, s).
29c) tert-ブチル 4-[2-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-5-フルオロ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(400 mg, 1.4 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(260 mg, 1.4 mmol)、DavePhos(55 mg, 0.14 mmol)及びナトリウム tert-ブトキシド(200 mg, 2.1 mmol)のトルエン(4.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(64 mg, 0.070 mmol)を加え、90 ℃で15.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～4/1)で精製し、題記化合物を淡茶色固体(320 mg, 59%)として得た。
LC/MS 392
NMR (CDCl3) δ: 1.49 (9 H, s), 2.47 (3 H, s), 2.96 - 3.15 (4 H, m), 3.51 - 3.68 (4 H, m), 3.88 (3 H, s), 6.58 (1 H, d, J=7.2 Hz), 7.52 (1 H, d, J=12.8 Hz), 8.58 (1 H, s). 29c) tert-butyl 4- [2-fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4- Bromo-5-fluoro-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (400 mg, 1.4 mmol), tert-butyl piperazine-1-carboxylate (260 mg, 1.4 mmol), Pd 2 (dba) 3 (64 mg, 0.070 mmol) was added to a toluene (4.0 mL) solution of DavePhos (55 mg, 0.14 mmol) and sodium tert-butoxide (200 mg, 2.1 mmol) in a nitrogen atmosphere at 90 ° C. For 15.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-4 / 1) to give the title compound as a pale brown solid (320 mg, 59%).
LC / MS 392
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.47 (3 H, s), 2.96-3.15 (4 H, m), 3.51-3.68 (4 H, m), 3.88 (3 H, s) , 6.58 (1 H, d, J = 7.2 Hz), 7.52 (1 H, d, J = 12.8 Hz), 8.58 (1 H, s).
参考例３０
tert-ブチル 4-[3-メチル-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 30
tert-butyl 4- [3-methyl-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
30a) (4-ブロモ-2-メチルフェニル)ヒドラジン　1塩酸塩
　4-ブロモ-2-メチルアニリン(5.0 g, 27 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(2.0 g, 28 mmol)の水(2.5 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(16 g, 85 mmol)の濃塩酸(20 mL)溶液中に－20 ℃で滴下し、室温で1時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄し、題記化合物を無色固体(4.7 g, 73%)として得た。
NMR (DMSO-d6) δ: 2.18 (3 H, s), 6.88 (1 H, d, J=8.3 Hz), 7.27 - 7.41 (2 H, m), 8.00 (1 H, brs), 10.30 (3 H, brs). 30a) (4-Bromo-2-methylphenyl) hydrazine monohydrochloride 4-bromo-2-methylaniline (5.0 g, 27 mmol) in concentrated hydrochloric acid (20 mL) with sodium nitrite (2.0 g, 28 mmol) Of water (2.5 mL) was added at −20 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (16 g, 85 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound as a colorless solid (4.7 g, 73%).
NMR (DMSO-d 6 ) δ: 2.18 (3 H, s), 6.88 (1 H, d, J = 8.3 Hz), 7.27-7.41 (2 H, m), 8.00 (1 H, brs), 10.30 ( 3 H, brs).
30b) 1-(4-ブロモ-2-メチル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-2-メチルフェニル)ヒドラジン　1塩酸塩(4.7 g, 20 mmol)、メチル エタンイミドチオアート　ヨウ化水素酸塩(3.3 g, 15 mmol) のMeOH(25 mL)溶液にトリエチルアミン(4.0 mL, 30 mmol)を0 ℃で滴下し、室温で45分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸トリメチル(15 mL)、ピリジン(15 mL)を加え、100 ℃で14.5時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(2.8 g, 56%)として得た。
LC/MS 252
NMR (CDCl3) δ: 2.24 (3 H, s), 2.49 (3 H, s), 7.18 (1 H, d, J=8.3 Hz), 7.44 (1 H, dd, J=8.3, 2.3 Hz), 7.51 (1 H, d, J=2.3 Hz), 8.11 (1 H, s). 30b) 1- (4-Bromo-2-methyl) -3-methyl-1H-1,2,4-triazole (4-bromo-2-methylphenyl) hydrazine monohydrochloride (4.7 g, 20 mmol), methyl Triethylamine (4.0 mL, 30 mmol) was added dropwise to a solution of ethaneimidothioate hydroiodide (3.3 g, 15 mmol) in MeOH (25 mL) at 0 ° C and stirred at room temperature for 45 minutes. Left. Trimethyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 14.5 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (2.8 g, 56%).
LC / MS 252
NMR (CDCl 3 ) δ: 2.24 (3 H, s), 2.49 (3 H, s), 7.18 (1 H, d, J = 8.3 Hz), 7.44 (1 H, dd, J = 8.3, 2.3 Hz) , 7.51 (1 H, d, J = 2.3 Hz), 8.11 (1 H, s).
30c) tert-ブチル 4-[3-メチル-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-メチル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.2 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(220 mg, 1.2 mmol)、DavePhos(47 mg, 0.12 mmol)及びナトリウム tert-ブトキシド(170 mg, 1.8 mmol)のトルエン(3.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(55 mg, 0.060 mmol)を加え、90 ℃で15.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～7/3)で精製し、題記化合物を淡茶色固体(220 mg, 51%)として得た。
LC/MS 358
NMR (CDCl3) δ: 1.49 (9 H, s), 2.18 (3 H, s), 2.48 (3 H, s), 3.12 - 3.26 (4 H, m), 3.53 - 3.64 (4 H, m), 6.69 - 6.86 (2 H, m), 7.17 (1 H, d, J=8.3 Hz), 8.05 (1 H, s). 30c) tert-Butyl 4- [3-methyl-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-Bromo-2- Methyl) -3-methyl-1H-1,2,4-triazole (300 mg, 1.2 mmol), tert-butyl piperazine-1-carboxylate (220 mg, 1.2 mmol), DavePhos (47 mg, 0.12 mmol) and Under a nitrogen atmosphere, Pd 2 (dba) 3 (55 mg, 0.060 mmol) was added to a toluene (3.0 mL) solution of sodium tert-butoxide (170 mg, 1.8 mmol), and the mixture was stirred at 90 ° C. for 15.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-7 / 3) to give the title compound as a pale brown solid (220 mg, 51%).
LC / MS 358
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.18 (3 H, s), 2.48 (3 H, s), 3.12-3.26 (4 H, m), 3.53-3.64 (4 H, m) , 6.69-6.86 (2 H, m), 7.17 (1 H, d, J = 8.3 Hz), 8.05 (1 H, s).
参考例３１
tert-ブチル 4-[3,5-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 31
tert-butyl 4- [3,5-difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
31a) (4-ブロモ-2,6-ジフルオロフェニル)ヒドラジン　1塩酸塩
　4-ブロモ-2,6-ジフルオロアニリン(5.0 g, 24 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(1.7 g, 25 mmol)の水(2.5 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(17 g, 90 mmol)の濃塩酸(20 mL)溶液中に－20 ℃で滴下し、室温で2時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄し、題記化合物を無色固体(5.5 g, 89%)として得た。
NMR (DMSO-d6) δ: 7.38 - 7.70 (2 H, m), 8.03 (1 H, brs), 10.15 (3 H, brs). 31a) (4-Bromo-2,6-difluorophenyl) hydrazine monohydrochloride To a solution of 4-bromo-2,6-difluoroaniline (5.0 g, 24 mmol) in concentrated hydrochloric acid (20 mL), sodium nitrite (1.7 g , 25 mmol) in water (2.5 mL) was added at −20 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (17 g, 90 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound as a colorless solid (5.5 g, 89%).
NMR (DMSO-d 6 ) δ: 7.38-7.70 (2 H, m), 8.03 (1 H, brs), 10.15 (3 H, brs).
31b) 1-(4-ブロモ-2,6-ジフルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-2,6-ジフルオロフェニル)ヒドラジン　1塩酸塩(5.5 g, 21 mmol)、メチル エタンイミドチオアート　ヨウ化水素酸塩(4.6 g, 21 mmol) のMeOH(25 mL)溶液にトリエチルアミン(3.0 mL, 21 mmol)を0 ℃で滴下し、室温で45分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸トリメチル(15 mL)、ピリジン(15 mL)を加え、100 ℃で14.5時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝3/7)で精製し、題記化合物を無色固体(3.5 g, 60%)として得た。
LC/MS 274
NMR (CDCl3) δ: 2.51 (3 H, s), 7.28 - 7.37 (2 H, m), 8.20 (1 H, s). 31b) 1- (4-Bromo-2,6-difluorophenyl) -3-methyl-1H-1,2,4-triazole (4-bromo-2,6-difluorophenyl) hydrazine monohydrochloride (5.5 g, 21 mL), triethylamine (3.0 mL, 21 mmol) was added dropwise to a solution of methyl ethaneimidothioate hydroiodide (4.6 g, 21 mmol) in MeOH (25 mL) at 0 ° C and stirred at room temperature for 45 minutes. The solvent was distilled off under reduced pressure. Trimethyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 14.5 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 3/7) to give the title compound as a colorless solid (3.5 g, 60%).
LC / MS 274
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 7.28-7.37 (2 H, m), 8.20 (1 H, s).
31c) tert-ブチル 4-[3,5-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2,6-ジフルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.1 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(200 mg, 1.1 mmol)、DavePhos(43 mg, 0.11 mmol)及びナトリウム tert-ブトキシド(160 mg, 1.6 mmol)のトルエン(3.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(50 mg, 0.055 mmol)を加え、90 ℃で9時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を淡茶色固体(290 mg, 70%)として得た。
LC/MS 380
NMR (CDCl3) δ: 1.49 (9 H, s), 2.50 (3 H, s), 3.13 - 3.34 (4 H, m), 3.52 - 3.70 (4 H, m), 6.41 - 6.61 (2 H, m), 8.11 (1 H, s). 31c) tert-butyl 4- [3,5-difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-Bromo- 2,6-difluorophenyl) -3-methyl-1H-1,2,4-triazole (300 mg, 1.1 mmol), tert-butyl piperazine-1-carboxylate (200 mg, 1.1 mmol), DavePhos (43 mg , 0.11 mmol) and sodium tert-butoxide (160 mg, 1.6 mmol) in toluene (3.0 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (50 mg, 0.055 mmol) was added and stirred at 90 ° C. for 9 hours did. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a pale-brown solid (290 mg, 70%).
LC / MS 380
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.50 (3 H, s), 3.13-3.34 (4 H, m), 3.52-3.70 (4 H, m), 6.41-6.61 (2 H, m), 8.11 (1 H, s).
参考例３２
2-(4-ブロモフェニル)-5-メチル-1,3,4-オキサジアゾール
　4-ブロモベンゾヒドラジド(1.4 g, 6.3 mmol)の2-プロパノール(8 mL)溶液に無水酢酸(0.60 mL, 6.3 mmol)を加え、室温で2時間攪拌した。反応生成物をろ取し、2-プロパノールで洗浄した。ろ取物にオキシ塩化りん(4 mL)を加え、100℃で1時間攪拌した。氷冷水に反応混合物を加え、飽和炭酸水素ナトリウム水で中和し、酢酸エチルで抽出した。有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をヘキサンで洗浄し、題記化合物を白色固体(0.69 g, 46%)として得た。
LC/MS 239
NMR (CDCl3) δ: 2.63 (3 H, s), 7.65 (2 H, d, J=8.7 Hz), 7.90 (2 H, d, J=8.7 Hz). Reference Example 32
2- (4-Bromophenyl) -5-methyl-1,3,4-oxadiazole 4-bromobenzohydrazide (1.4 g, 6.3 mmol) in 2-propanol (8 mL) with acetic anhydride (0.60 mL, 6.3 mmol) was added and stirred at room temperature for 2 hours. The reaction product was collected by filtration and washed with 2-propanol. Phosphorous oxychloride (4 mL) was added to the filtered product, and the mixture was stirred at 100 ° C. for 1 hr. The reaction mixture was added to ice-cold water, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with hexane to give the title compound as a white solid (0.69 g, 46%).
LC / MS 239
NMR (CDCl 3 ) δ: 2.63 (3 H, s), 7.65 (2 H, d, J = 8.7 Hz), 7.90 (2 H, d, J = 8.7 Hz).
参考例３３
tert-ブチル 4-[4-(5-メチル-1,3,4-オキサジアゾール-2-イル)フェニル]ピペラジン-1-カルボキシラート
　2-(4-ブロモフェニル)-5-メチル-1,3,4-オキサジアゾール(0.30 g, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.30 g, 1.6 mmol)、DavePhos(99 mg, 0.26 mmol)及びナトリウム tert-ブトキシド(0.18 g, 1.9 mmol)のトルエン(2 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.12 g, 0.13 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をＮＨシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1～1/1)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を白色固体(0.12 g, 28%)として得た。
LC/MS 345
NMR (CDCl3) δ: 1.51 (9 H, s), 2.60 (3 H, s), 3.31 (4 H, t, J=4.8 Hz), 3.61 (4 H, t, J=5.1 Hz), 6.96 (2 H, d, J=8.7 Hz), 7.91 (2 H, d, J=9.0 Hz). Reference Example 33
tert-butyl 4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] piperazine-1-carboxylate 2- (4-bromophenyl) -5-methyl-1, 3,4-oxadiazole (0.30 g, 1.3 mmol), tert-butyl piperazine-1-carboxylate (0.30 g, 1.6 mmol), DavePhos (99 mg, 0.26 mmol) and sodium tert-butoxide (0.18 g, 1.9 mmol) in toluene (2 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (0.12 g, 0.13 mmol) was added and stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/1). The residue was recrystallized from ethyl acetate to give the title compound as a white solid (0.12 g, 28%).
LC / MS 345
NMR (CDCl 3 ) δ: 1.51 (9 H, s), 2.60 (3 H, s), 3.31 (4 H, t, J = 4.8 Hz), 3.61 (4 H, t, J = 5.1 Hz), 6.96 (2 H, d, J = 8.7 Hz), 7.91 (2 H, d, J = 9.0 Hz).
参考例３４
4-(4-ブロモフェニル)-2-メチル-2H-1,2,3-トリアゾール
　2,4'-ジブロモアセトフェノン(1.4 g, 5.0 mmol)の酢酸(2 mL)溶液にメチルヒドラジン(1.3 mL, 25 mmol)を加え、100℃で3時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/0～4/1)で精製し、題記化合物を黄色固体(0.10 g, 8%)として得た。
LC/MS 238
NMR (CDCl3) δ: 4.25 (3 H, s), 7.56 (2 H, d, J=8.4 Hz), 7.65 (2 H, d, J=8.4 Hz), 7.81 (1 H, s). Reference Example 34
4- (4-Bromophenyl) -2-methyl-2H-1,2,3-triazole 2,4'-dibromoacetophenone (1.4 g, 5.0 mmol) in acetic acid (2 mL) was added to methyl hydrazine (1.3 mL, 25 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-4 / 1) to give the title compound as a yellow solid (0.10 g, 8%).
LC / MS 238
NMR (CDCl 3 ) δ: 4.25 (3 H, s), 7.56 (2 H, d, J = 8.4 Hz), 7.65 (2 H, d, J = 8.4 Hz), 7.81 (1 H, s).
参考例３５
tert-ブチル 4-[4-(2-メチル-2H-1,2,3-トリアゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート
　4-(4-ブロモフェニル)-2-メチル-2H-1,2,3-トリアゾール(0.10 g, 0.42 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.10 g, 0.55 mmol)、DavePhos(33 mg, 0.084 mmol)及びナトリウム tert-ブトキシド(61 mg, 0.63 mmol)のトルエン(1 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.12 g, 0.13 mmol)を加え、100℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を黄色固体(59 mg, 41%)として得た。
LC/MS 343
NMR (CDCl3) δ: 1.51 (9 H, s), 3.21 (4 H, t, J=4.8 Hz), 3.61 (4 H, t, J=5.1 Hz), 4.23 (3 H, s), 6.97 (2 H, d, J=8.7 Hz), 7.74 (1 H, s), 7.98 (2 H, d, J=8.4 Hz). Reference Example 35
tert-butyl 4- [4- (2-methyl-2H-1,2,3-triazol-4-yl) phenyl] piperazine-1-carboxylate 4- (4-bromophenyl) -2-methyl-2H- 1,2,3-triazole (0.10 g, 0.42 mmol), tert-butyl piperazine-1-carboxylate (0.10 g, 0.55 mmol), DavePhos (33 mg, 0.084 mmol) and sodium tert-butoxide (61 mg, 0.63 mmol) in toluene (1 mL) was added Pd 2 (dba) 3 (0.12 g, 0.13 mmol) under a nitrogen atmosphere and stirred at 100 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (59 mg, 41%).
LC / MS 343
NMR (CDCl 3 ) δ: 1.51 (9 H, s), 3.21 (4 H, t, J = 4.8 Hz), 3.61 (4 H, t, J = 5.1 Hz), 4.23 (3 H, s), 6.97 (2 H, d, J = 8.7 Hz), 7.74 (1 H, s), 7.98 (2 H, d, J = 8.4 Hz).
参考例３６
5-(4-ブロモフェニル)-2-エチル-1,3-オキサゾール
　2-アミノ-4'-ブロモアセトフェノン 1塩酸塩(2.0 g, 8.0 mmol)のオルトプロピオン酸トリエチル(25 mL)の溶液にp-トルエンスルホン酸・1水和物(0.15 g, 0.80 mmol)を加え、加熱還流下16時間攪拌した。反応混合物を酢酸エチル－飽和炭酸水素ナトリウム水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1)で精製し、題記化合物を橙色固体(1.9 g, 92%)として得た。
LC/MS 252
NMR (CDCl3) δ: 1.39 (3 H, t, J=7.8 Hz), 2.85 (2 H, q, J=7.5 Hz), 7.26 (1 H, s), 7.46 (2 H, d, J=8.7 Hz), 7.52 (2 H, d, J=8.7 Hz). Reference Example 36
To a solution of 5- (4-bromophenyl) -2-ethyl-1,3-oxazole 2-amino-4'-bromoacetophenone monohydrochloride (2.0 g, 8.0 mmol) in triethyl orthopropionate (25 mL) -Toluenesulfonic acid monohydrate (0.15 g, 0.80 mmol) was added, and the mixture was stirred for 16 hours with heating under reflux. The reaction mixture was diluted with ethyl acetate-saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound as an orange solid (1.9 g, 92%).
LC / MS 252
NMR (CDCl 3 ) δ: 1.39 (3 H, t, J = 7.8 Hz), 2.85 (2 H, q, J = 7.5 Hz), 7.26 (1 H, s), 7.46 (2 H, d, J = 8.7 Hz), 7.52 (2 H, d, J = 8.7 Hz).
参考例３７
tert-ブチル 4-[4-(2-エチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-エチル-1,3-オキサゾール(0.50 g, 2.0 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.37 g, 2.0 mmol)、DavePhos(78 mg, 0.20 mmol)及びナトリウム tert-ブトキシド(0.29 g, 3.0 mmol)のトルエン(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(91 mg, 0.10 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を黄色固体(59 mg, 41%)として得た。
LC/MS 358
NMR (CDCl3) δ: 1.39 (3 H, t, J=7.5 Hz), 1.51 (9 H, s), 2.85 (2 H, q, J=7.8 Hz), 3.20 (4 H, t, J=4.8 Hz), 3.60 (4 H, t, J=5.1 Hz), 6.94 (2 H, d, J=9.0 Hz), 7.08 (1 H, s), 7.52 (2 H, d, J=9.0 Hz). Reference Example 37
tert-butyl 4- [4- (2-ethyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -2-ethyl-1,3-oxazole ( 0.50 g, 2.0 mmol), tert-butyl piperazine-1-carboxylate (0.37 g, 2.0 mmol), DavePhos (78 mg, 0.20 mmol) and sodium tert-butoxide (0.29 g, 3.0 mmol) in toluene (4 mL) Under a nitrogen atmosphere, Pd 2 (dba) 3 (91 mg, 0.10 mmol) was added to the solution, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (59 mg, 41%).
LC / MS 358
NMR (CDCl 3 ) δ: 1.39 (3 H, t, J = 7.5 Hz), 1.51 (9 H, s), 2.85 (2 H, q, J = 7.8 Hz), 3.20 (4 H, t, J = 4.8 Hz), 3.60 (4 H, t, J = 5.1 Hz), 6.94 (2 H, d, J = 9.0 Hz), 7.08 (1 H, s), 7.52 (2 H, d, J = 9.0 Hz) .
参考例３８
5-(4-ブロモフェニル)-2-プロピル-1,3-オキサゾール
　2-アミノ-4'-ブロモアセトフェノン 1塩酸塩(2.0 g, 8.0 mmol)のオルト酪酸トリエチル(25 mL)の溶液にp-トルエンスルホン酸・1水和物(0.15 g, 0.80 mmol)を加え、加熱還流下16時間攪拌した。反応混合物を酢酸エチル－飽和炭酸水素ナトリウム水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1)で精製し、題記化合物を橙色固体(0.38 g, 18%)として得た。
LC/MS 266
NMR (CDCl3) δ: 1.03 (3H, t, J=7.2 Hz), 1.85 (2 H, m), 2.80 (2 H, t, J=7.8 Hz), 7.22 (1 H, s), 7.46 (2 H, d, J=8.7 Hz), 7.52 (2 H, d, J=8.7 Hz). Reference Example 38
5- (4-Bromophenyl) -2-propyl-1,3-oxazole 2-amino-4'-bromoacetophenone monohydrochloride (2.0 g, 8.0 mmol) in triethyl orthobutyrate (25 mL) was added p- Toluenesulfonic acid monohydrate (0.15 g, 0.80 mmol) was added, and the mixture was stirred for 16 hours with heating under reflux. The reaction mixture was diluted with ethyl acetate-saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound as an orange solid (0.38 g, 18%).
LC / MS 266
NMR (CDCl 3 ) δ: 1.03 (3H, t, J = 7.2 Hz), 1.85 (2 H, m), 2.80 (2 H, t, J = 7.8 Hz), 7.22 (1 H, s), 7.46 ( 2 H, d, J = 8.7 Hz), 7.52 (2 H, d, J = 8.7 Hz).
参考例３９
tert-ブチル 4-[4-(2-プロピル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-プロピル-1,3-オキサゾール(0.30 g, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.25 g, 1.3 mmol)、DavePhos(52 mg, 0.13 mmol)及びナトリウム tert-ブトキシド(0.19 g, 2.0 mmol)のトルエン(2 mL)溶液に窒素雰囲気下、Pd2(dba)3(60 mg, 0.066 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～7/3)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を黄色固体(0.32 g, 76%)として得た。
LC/MS 372
NMR (CDCl3) δ: 1.05 (3 H, t, J=7.5 Hz), 1.51 (9 H, s), 1.86 (2 H, tt, J=7.5 Hz, 7.5 Hz), 2.80 (2 H, t, J=7.5 Hz), 3.20 (4 H, t, J=5.1 Hz), 3.61 (4 H, t, J=5.4 Hz), 6.94 (2 H, d, J=8.7 Hz), 7.08 (1 H, s), 7.52 (2 H, d, J=8.7 Hz). Reference Example 39
tert-butyl 4- [4- (2-propyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -2-propyl-1,3-oxazole ( 0.30 g, 1.3 mmol), tert-butyl piperazine-1-carboxylate (0.25 g, 1.3 mmol), DavePhos (52 mg, 0.13 mmol) and sodium tert-butoxide (0.19 g, 2.0 mmol) in toluene (2 mL) Under a nitrogen atmosphere, Pd 2 (dba) 3 (60 mg, 0.066 mmol) was added to the solution, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-7 / 3). The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (0.32 g, 76%).
LC / MS 372
NMR (CDCl 3 ) δ: 1.05 (3 H, t, J = 7.5 Hz), 1.51 (9 H, s), 1.86 (2 H, tt, J = 7.5 Hz, 7.5 Hz), 2.80 (2 H, t , J = 7.5 Hz), 3.20 (4 H, t, J = 5.1 Hz), 3.61 (4 H, t, J = 5.4 Hz), 6.94 (2 H, d, J = 8.7 Hz), 7.08 (1 H , s), 7.52 (2 H, d, J = 8.7 Hz).
参考例４０
5-(4-ブロモフェニル)-2-(1-メチルエチル)-1,3-オキサゾール
　2-アミノ-4'-ブロモアセトフェノン 1塩酸塩(2.0 g, 8.0 mmol)のオルトイソ酪酸トリメチル(25 mL)の溶液にp-トルエンスルホン酸・1水和物(0.15 g, 0.80 mmol)を加え、加熱還流下16時間攪拌した。反応混合物を酢酸エチル－飽和炭酸水素ナトリウム水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1)で精製し、題記化合物を橙色固体(1.69 g, 80%)として得た。
LC/MS 266
NMR (CDCl3) δ: 1.40 (6 H, d, J=6.9 Hz), 3.14 (1 H, m), 7.21 (1 H, s), 7.46 (2 H, d, J=8.7 Hz), 7.52 (2 H, d, J=8.7 Hz). Reference Example 40
5- (4-Bromophenyl) -2- (1-methylethyl) -1,3-oxazole 2-amino-4'-bromoacetophenone monohydrochloride (2.0 g, 8.0 mmol) trimethyl orthoisobutyrate (25 mL) To the solution was added p-toluenesulfonic acid monohydrate (0.15 g, 0.80 mmol), and the mixture was stirred for 16 hours with heating under reflux. The reaction mixture was diluted with ethyl acetate-saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound as an orange solid (1.69 g, 80%).
LC / MS 266
NMR (CDCl 3 ) δ: 1.40 (6 H, d, J = 6.9 Hz), 3.14 (1 H, m), 7.21 (1 H, s), 7.46 (2 H, d, J = 8.7 Hz), 7.52 (2 H, d, J = 8.7 Hz).
参考例４１
tert-ブチル 4-{4-[2-(1-メチルエチル)-1,3-オキサゾール-5-イル]フェニル}ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-2-(1-メチルエチル)-1,3-オキサゾール(0.30 g, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.25 g, 1.3 mmol)、DavePhos(52 mg, 0.13 mmol)及びナトリウム tert-ブトキシド(0.19 g, 2.0 mmol)のトルエン(2 mL)溶液に窒素雰囲気下、Pd2(dba)3(60 mg, 0.066 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を黄色固体(0.25 g, 60%)として得た。
LC/MS 372
NMR (CDCl3) δ: 1.41 (6 H, t, J=6.9 Hz), 1.51 (9 H, s), 3.12 - 3.22 (5 H, m), 3.61 (4 H, t, J=5.4 Hz), 6.94 (2 H, d, J=8.4 Hz), 7.08 (1 H, s), 7.52 (2 H, d, J=8.7 Hz). Reference Example 41
tert-butyl 4- {4- [2- (1-methylethyl) -1,3-oxazol-5-yl] phenyl} piperazine-1-carboxylate 5- (4-bromophenyl) -2- (1- Methylethyl) -1,3-oxazole (0.30 g, 1.3 mmol), tert-butyl piperazine-1-carboxylate (0.25 g, 1.3 mmol), DavePhos (52 mg, 0.13 mmol) and sodium tert-butoxide (0.19 g , 2.0 mmol) in toluene (2 mL) was added Pd 2 (dba) 3 (60 mg, 0.066 mmol) in a nitrogen atmosphere and stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2). The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (0.25 g, 60%).
LC / MS 372
NMR (CDCl 3 ) δ: 1.41 (6 H, t, J = 6.9 Hz), 1.51 (9 H, s), 3.12-3.22 (5 H, m), 3.61 (4 H, t, J = 5.4 Hz) , 6.94 (2 H, d, J = 8.4 Hz), 7.08 (1 H, s), 7.52 (2 H, d, J = 8.7 Hz).
参考例４２
5-(4-ブロモフェニル)-3-メチル-1,2,4-オキサジアゾール
　N-ヒドロキシアセトアミジン(0.41 g, 5.5 mmol)のピリジン(35 mL)溶液に4-ブロモベンゾイル クロリド(1.1 g, 5.0 mmol)のTHF(15 mL)溶液を加え、加熱還流下1.5時間攪拌した。反応混合物を水で希釈し、1Ｎ－水酸化ナトリウム水でｐＨ＝１０とした。水層を酢酸エチルで抽出し、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製し、題記化合物を白色固体(0.73 g, 61%)として得た。
LC/MS 239
NMR (CDCl3) δ: 2.49 (3 H, s), 7.68 (2 H, d, J=8.4 Hz), 7.99 (2 H, d, J=8.7 Hz). Reference Example 42
4-Bromobenzoyl chloride (1.1 g) was added to a solution of 5- (4-bromophenyl) -3-methyl-1,2,4-oxadiazole N-hydroxyacetamidine (0.41 g, 5.5 mmol) in pyridine (35 mL). , 5.0 mmol) in THF (15 mL) was added, and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was diluted with water and adjusted to pH = 10 with 1N aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2) to give the title compound as a white solid (0.73 g, 61%).
LC / MS 239
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 7.68 (2 H, d, J = 8.4 Hz), 7.99 (2 H, d, J = 8.7 Hz).
参考例４３
tert-ブチル 4-[4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-3-メチル-1,2,4-オキサジアゾール(0.30 g, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.23 g, 1.3 mmol)、DavePhos(49 mg, 0.13 mmol)及びナトリウム tert-ブトキシド(0.18 g, 1.9 mmol)のトルエン(2 mL)溶液に窒素雰囲気下、Pd2(dba)3(58 mg, 0.063 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を黄色固体(0.28 g, 32%)として得た。
LC/MS 345
NMR (CDCl3) δ: 1.50 (9 H, s), 2.45 (3 H, s), 3.35 (4 H, t, J=4.8 Hz), 3.61 (4 H, t, J=5.4 Hz), 6.95 (2 H, d, J=8.7 Hz), 7.99 (2 H, d, J=9.0 Hz). Reference Example 43
tert-butyl 4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -3-methyl-1, 2,4-oxadiazole (0.30 g, 1.3 mmol), tert-butyl piperazine-1-carboxylate (0.23 g, 1.3 mmol), DavePhos (49 mg, 0.13 mmol) and sodium tert-butoxide (0.18 g, 1.9 Pd 2 (dba) 3 (58 mg, 0.063 mmol) was added to a toluene (2 mL) solution of mmol) under a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2). The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (0.28 g, 32%).
LC / MS 345
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 2.45 (3 H, s), 3.35 (4 H, t, J = 4.8 Hz), 3.61 (4 H, t, J = 5.4 Hz), 6.95 (2 H, d, J = 8.7 Hz), 7.99 (2 H, d, J = 9.0 Hz).
参考例４４
3-(4-ブロモフェニル)-5-メチル-1,2,4-オキサジアゾール Reference Example 44
3- (4-Bromophenyl) -5-methyl-1,2,4-oxadiazole
44a) 4-ブロモ-N'-ヒドロキシベンゼンカルボキシミドアミド
　ヒドロキシルアミン・1塩酸塩(0.38 g, 55 mmol)のＤＭＳＯ(20 mL)溶液にナトリウム tert-ブトキシド(6.2 g, 55 mmol)を加え、室温で1時間攪拌した。さらに、反応混合物に4-ブロモベンゾニトリル(1.0 g, 5.5 mmol)を加え、室温で16時間攪拌した。氷冷水に反応混合物を加え、析出物をろ取、水洗して、題記化合物を白色固体(0.73 g, 62%)として得た。
NMR (CDCl3) δ: 4.86 (2 H, br), 7.49 - 7.57 (4 H, m), 7.81 (1 H, br). 44a) 4-Bromo-N'-hydroxybenzenecarboximidamide To a solution of hydroxylamine monohydrochloride (0.38 g, 55 mmol) in DMSO (20 mL) was added sodium tert-butoxide (6.2 g, 55 mmol) at room temperature. For 1 hour. Furthermore, 4-bromobenzonitrile (1.0 g, 5.5 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to ice-cold water, and the precipitate was collected by filtration and washed with water to give the title compound as a white solid (0.73 g, 62%).
NMR (CDCl 3 ) δ: 4.86 (2 H, br), 7.49-7.57 (4 H, m), 7.81 (1 H, br).
44b) 3-(4-ブロモフェニル)-5-メチル-1,2,4-オキサジアゾール
　4-ブロモ-N'-ヒドロキシベンゼンカルボキシミドアミド(0.73 g, 3.4 mmol)のピリジン(25 mL)溶液に塩化アセチル(0.27 g, 3.7 mol)を加え、加熱還流下1.5時間攪拌した。反応混合物を水で希釈し、1Ｎ－水酸化ナトリウム水でｐＨ＝１０とした。水層を酢酸エチルで抽出し、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製し、題記化合物を白色固体(0.46 g, 57%)として得た。
LC/MS 239
NMR (CDCl3) δ: 2.49 (3 H, s), 7.68 (2 H, d, J=8.4 Hz), 7.99 (2 H, d, J=8.7 Hz). 44b) 3- (4-Bromophenyl) -5-methyl-1,2,4-oxadiazole 4-bromo-N'-hydroxybenzenecarboximidamide (0.73 g, 3.4 mmol) in pyridine (25 mL) To the mixture was added acetyl chloride (0.27 g, 3.7 mol), and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was diluted with water and adjusted to pH = 10 with 1N aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2) to give the title compound as a white solid (0.46 g, 57%).
LC / MS 239
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 7.68 (2 H, d, J = 8.4 Hz), 7.99 (2 H, d, J = 8.7 Hz).
参考例４５
tert-ブチル 4-[4-(5-メチル-1,2,4-オキサジアゾール-3-イル)フェニル]ピペラジン-1-カルボキシラート
　3-(4-ブロモフェニル)-5-メチル-1,2,4-オキサジアゾール(0.46 g, 1.9 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.36 g, 1.9 mmol)、DavePhos(76 mg, 0.19 mmol)及びナトリウム tert-ブトキシド(0.28 g, 2.9 mmol)のトルエン(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(88 mg, 0.096 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製した。残留物を酢酸エチルより再結晶し、題記化合物を淡黄色固体(0.28 g, 42%)として得た。
LC/MS 345
NMR (CDCl3) δ: 1.50 (9 H, s), 2.64 (3 H, s), 3.28 (4 H, t, J=4.8 Hz), 3.61 (4 H, t, J=5.1 Hz), 6.97 (2 H, d, J=9.0 Hz), 7.96 (2 H, d, J=9.0 Hz). Reference Example 45
tert-butyl 4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] piperazine-1-carboxylate 3- (4-bromophenyl) -5-methyl-1, 2,4-oxadiazole (0.46 g, 1.9 mmol), tert-butyl piperazine-1-carboxylate (0.36 g, 1.9 mmol), DavePhos (76 mg, 0.19 mmol) and sodium tert-butoxide (0.28 g, 2.9 mmol) in toluene (4 mL) was added Pd 2 (dba) 3 (88 mg, 0.096 mmol) under a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2). The residue was recrystallized from ethyl acetate to give the title compound as a pale yellow solid (0.28 g, 42%).
LC / MS 345
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 2.64 (3 H, s), 3.28 (4 H, t, J = 4.8 Hz), 3.61 (4 H, t, J = 5.1 Hz), 6.97 (2 H, d, J = 9.0 Hz), 7.96 (2 H, d, J = 9.0 Hz).
参考例４６
1-(4-ブロモフェニル)-4-メチル-1H-1,2,3-トリアゾール Reference Example 46
1- (4-Bromophenyl) -4-methyl-1H-1,2,3-triazole
46a) N'-[2,2-ジクロロ-1-メチルエチリデン]-4-メチルベンゼンスルホノヒドラジド
　p-トシルヒドラジン(6.7 g , 36 mmol)のプロピオン酸(30 mL)の溶液に1,1-ジクロロアセトン(3.8 mL)を加え、室温で4時間攪拌した。反応混合物にヘキサンを加え、析出物をろ取、ヘキサンで洗浄し、題記化合物を白色固体(9.9 g, 93%)として得た。
NMR (CDCl3) δ: 2.01 (3 H, s), 2.46 (3 H, s), 6.20 (1 H, s), 7.35 (2 H, d, J=8.1 Hz), 7.73 (1 H, s), 7.83 (2 H, d, J=8.4 Hz). 46a) N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonohydrazide p-tosylhydrazine (6.7 g, 36 mmol) in a solution of propionic acid (30 mL) Dichloroacetone (3.8 mL) was added and stirred at room temperature for 4 hours. Hexane was added to the reaction mixture, and the precipitate was collected by filtration and washed with hexane to give the title compound as a white solid (9.9 g, 93%).
NMR (CDCl 3 ) δ: 2.01 (3 H, s), 2.46 (3 H, s), 6.20 (1 H, s), 7.35 (2 H, d, J = 8.1 Hz), 7.73 (1 H, s ), 7.83 (2 H, d, J = 8.4 Hz).
46b) 1-(4-ブロモフェニル)-4-メチル-1H-1,2,3-トリアゾール
　N'-[2,2-ジクロロ-1-メチルエチリデン]-4-メチルベンゼンスルホノヒドラジド(3.0 g, 10 mmol)のMeOH(10 mL)溶液にp-ブロモアニリン(8.6 g, 50 mmol)のMeOH(10 mL)溶液を氷冷下に加え、0℃で2時間攪拌した。反応混合物を減圧下濃縮し、残留物にトルエン(50 mL)を加え、固体をろ去した。ろ液を１Ｎ－水酸化ナトリウム水で洗浄し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1～1/1)で精製し、題記化合物を黄色固体(0.78 g, 32%)として得た。
LC/MS 238
NMR (CDCl3) δ: 2.45 (3 H, s), 7.60 - 7.67 (4 H, m), 7.71 (1 H, s). 46b) 1- (4-Bromophenyl) -4-methyl-1H-1,2,3-triazole N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonohydrazide (3.0 g , 10 mmol) in MeOH (10 mL) was added p-bromoaniline (8.6 g, 50 mmol) in MeOH (10 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, toluene (50 mL) was added to the residue, and the solid was removed by filtration. The filtrate was washed with 1N sodium hydroxide aqueous solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/1) to give the title compound as a yellow solid (0.78 g, 32%).
LC / MS 238
NMR (CDCl 3 ) δ: 2.45 (3 H, s), 7.60-7.67 (4 H, m), 7.71 (1 H, s).
参考例４７
tert-ブチル 4-[4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモフェニル)-4-メチル-1H-1,2,3-トリアゾール(0.72 g, 3.0 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.56 g, 3.0 mmol)、DavePhos(0.12 g, 0.30 mmol)及びナトリウム tert-ブトキシド(0.44 g, 4.5 mmol)のトルエン(6 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.14 g, 0.15 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1)で精製し、題記化合物を淡橙色固体(0.72 g, 69%)として得た。
LC/MS 344
NMR (CDCl3) δ: 1.51 (9 H, s), 2.44 (3 H, s), 3.22 (4 H, t, J=4.5 Hz), 3.62 (4 H, t, J=5.4 Hz), 7.00 (2 H, d, J=9.0 Hz), 7.58 (2 H, d, J=8.7 Hz), 7.64 (1 H, s). Reference Example 47
tert-butyl 4- [4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromophenyl) -4-methyl-1H- 1,2,3-triazole (0.72 g, 3.0 mmol), tert-butyl piperazine-1-carboxylate (0.56 g, 3.0 mmol), DavePhos (0.12 g, 0.30 mmol) and sodium tert-butoxide (0.44 g, 4.5 Pd 2 (dba) 3 (0.14 g, 0.15 mmol) was added to a toluene (6 mL) solution of mmol) under a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound as a pale orange solid (0.72 g, 69%).
LC / MS 344
NMR (CDCl 3 ) δ: 1.51 (9 H, s), 2.44 (3 H, s), 3.22 (4 H, t, J = 4.5 Hz), 3.62 (4 H, t, J = 5.4 Hz), 7.00 (2 H, d, J = 9.0 Hz), 7.58 (2 H, d, J = 8.7 Hz), 7.64 (1 H, s).
参考例４８
tert-ブチル 4-[2-クロロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-3-クロロフェニル)-3-メチル-1H-1,2,4-トリアゾール(0.50 g, 1.8 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.34 g, 1.8 mmol)、DavePhos(72 mg, 0.18 mmol)及びナトリウム tert-ブトキシド(0.26 g, 2.8 mmol)のトルエン(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(84 mg, 0.092 mmol)を加え、90℃で1.5時間攪拌した。さらに、Pd2(dba)3(84 mg, 0.092 mmol)を加え、90℃で1時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～3/7)で精製し、題記化合物を淡黄色固体(0.33 g, 48%)として得た。
LC/MS 378
NMR (CDCl3) δ: 1.51 (9 H, s), 2.50 (3 H, s), 3.04 (4 H, t, J=4.5 Hz), 3.64 (4 H, t, J=4.8 Hz), 7.10 (2 H, d, J=8.4 Hz), 7.49 (1 H, dd, J=2.4 Hz, 8.4 Hz), 7.72 (1 H, d, J=2.4 Hz), 8.36 (1 H, s). Reference Example 48
tert-butyl 4- [2-chloro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-3-chlorophenyl) -3-Methyl-1H-1,2,4-triazole (0.50 g, 1.8 mmol), tert-butyl piperazine-1-carboxylate (0.34 g, 1.8 mmol), DavePhos (72 mg, 0.18 mmol) and sodium tert To a solution of -butoxide (0.26 g, 2.8 mmol) in toluene (4 mL) was added Pd 2 (dba) 3 (84 mg, 0.092 mmol) in a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 1.5 hr. Further, Pd 2 (dba) 3 ( 84 mg, 0.092 mmol) and the mixture was stirred for 1 hour at 90 ° C.. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 2-3 / 7) to give the title compound as a pale yellow solid (0.33 g, 48%).
LC / MS 378
NMR (CDCl 3 ) δ: 1.51 (9 H, s), 2.50 (3 H, s), 3.04 (4 H, t, J = 4.5 Hz), 3.64 (4 H, t, J = 4.8 Hz), 7.10 (2 H, d, J = 8.4 Hz), 7.49 (1 H, dd, J = 2.4 Hz, 8.4 Hz), 7.72 (1 H, d, J = 2.4 Hz), 8.36 (1 H, s).
参考例４９
1-(4-ブロモ-2-クロロフェニル)-3-メチル-1H-1,2,4-トリアゾール Reference Example 49
1- (4-Bromo-2-chlorophenyl) -3-methyl-1H-1,2,4-triazole
49a) (4-ブロモ-2-クロロフェニル)ヒドラジン
　4-ブロモ-2-クロロアニリン(5.0 g, 24 mmol)の濃塩酸(50 mL)溶液に0～3℃を保持しながら亜硝酸ナトリウム(1.8 g, 25 mmol)、水(3 mL)溶液を25分かけて滴下し、同温で20分攪拌した。さらに、塩化スズ(17 g, 91 mmol)の濃塩酸(180 mL)溶液に0～3℃を保持しながら反応混合物を30分かけて滴下し、同温で10分攪拌した後、室温で40分攪拌した。析出物をろ取し、水(25 mL)、ジエチルエーテル(50 mL)で洗浄した。ろ取した物に酢酸エチル－10％炭酸カリウム水を加え、不溶物をろ去した。ろ液の水層を酢酸エチルで抽出し、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、題記化合物を淡黄色固体(2.5 g, 47%)として得た。
NMR (CDCl3) δ: 3.58 (2 H, br), 5.70 (1 H, br), 7.03 (1 H, d, J=8.7 Hz), 7.25 - 7.35 (2 H, m). 49a) (4-Bromo-2-chlorophenyl) hydrazine Sodium nitrite (1.8 g) while maintaining 0-3 ° C in a solution of 4-bromo-2-chloroaniline (5.0 g, 24 mmol) in concentrated hydrochloric acid (50 mL) , 25 mmol) and water (3 mL) were added dropwise over 25 minutes, and the mixture was stirred at the same temperature for 20 minutes. Further, the reaction mixture was added dropwise to a concentrated hydrochloric acid (180 mL) solution of tin chloride (17 g, 91 mmol) over 30 minutes while maintaining 0 to 3 ° C., stirred at the same temperature for 10 minutes, and then stirred at room temperature for 40 minutes. Stir for minutes. The precipitate was collected by filtration and washed with water (25 mL) and diethyl ether (50 mL). Ethyl acetate-10% aqueous potassium carbonate was added to the filtered product, and the insoluble material was removed by filtration. The aqueous layer of the filtrate was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (2.5 g, 47%).
NMR (CDCl 3 ) δ: 3.58 (2 H, br), 5.70 (1 H, br), 7.03 (1 H, d, J = 8.7 Hz), 7.25-7.35 (2 H, m).
49b) 1-(4-ブロモ-2-クロロフェニル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-2-クロロフェニル)ヒドラジン(2.5 g, 11 mmol)のMeOH(25 mL)溶液にメチルエタンイミドチオアート　ヨウ化水素酸塩(2.6 g, 12 mmol)を添加し、室温で30分攪拌した。反応混合物を減圧下に濃縮し、残留物にオルトギ酸トリメチル(5 mL)、トルエン(10 mL)を加え、さらにピリジン(10 mL)を加え、100℃で3時間攪拌した。室温とし、反応混合物に減圧下に濃縮した。残留物に酢酸エチル－10%炭酸カリウム水を加え、水層を酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製し、題記化合物を淡黄色固体(1.7 g, 56%)として得た。
LC/MS 274
NMR (CDCl3) δ: 2.51 (3 H, s), 7.47 (1 H, d, 8.4 Hz), 7.55 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.73 (1 H, d, J=2.1 Hz), 8.43 (1 H, s). 49b) 1- (4-Bromo-2-chlorophenyl) -3-methyl-1H-1,2,4-triazole (4-bromo-2-chlorophenyl) hydrazine (2.5 g, 11 mmol) in MeOH (25 mL) Methylethaneimidothioate hydroiodide (2.6 g, 12 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, trimethyl orthoformate (5 mL) and toluene (10 mL) were added to the residue, pyridine (10 mL) was further added, and the mixture was stirred at 100 ° C. for 3 hr. Room temperature was achieved and the reaction mixture was concentrated under reduced pressure. Ethyl acetate-10% aqueous potassium carbonate was added to the residue, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2) to give the title compound as a pale yellow solid (1.7 g, 56%).
LC / MS 274
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 7.47 (1 H, d, 8.4 Hz), 7.55 (1H, dd, J = 2.1 Hz, 8.4 Hz), 7.73 (1 H, d, J = 2.1 Hz), 8.43 (1 H, s).
参考例５０
tert-ブチル 4-[3-クロロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-クロロフェニル)-3-メチル-1H-1,2,4-トリアゾール(1.1 g, 4.00 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.74 g, 4.00 mmol)、DavePhos(0.16 g, 0.40 mmol)及びナトリウム tert-ブトキシド(0.58 g, 6.0 mmol)のトルエン(8 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.18 g, 0.20 mmol)を加え、90℃で1.5時間攪拌した。さらに、Pd2(dba)3(0.18 g, 0.20 mmol)を加え、90℃で1.75時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～0/1)で精製し、題記化合物を淡黄色固体(0.81 g, 54%)として得た。
LC/MS 378
NMR (CDCl3) δ: 1.51 (9 H, s), 2.50 (3 H, s), 3.24 (4 H, t, J=5.1 Hz), 3.61 (4 H, t, J=5.1 Hz), 6.87 (1 H, dd, J=3.0 Hz, 9.3 Hz), 6.99 (1 H, d, J=2.4 Hz), 7.49 (1 H, d, J=8.7 Hz), 8.27 (1 H, s). Reference Example 50
tert-butyl 4- [3-chloro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-2-chlorophenyl) -3-methyl-1H-1,2,4-triazole (1.1 g, 4.00 mmol), tert-butyl piperazine-1-carboxylate (0.74 g, 4.00 mmol), DavePhos (0.16 g, 0.40 mmol) and sodium tert To a solution of -butoxide (0.58 g, 6.0 mmol) in toluene (8 mL) was added Pd 2 (dba) 3 (0.18 g, 0.20 mmol) under a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 1.5 hours. Furthermore, Pd 2 (dba) 3 (0.18 g, 0.20 mmol) was added, and the mixture was stirred at 90 ° C. for 1.75 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 2-0 / 1) to give the title compound as a pale yellow solid (0.81 g, 54%).
LC / MS 378
NMR (CDCl 3 ) δ: 1.51 (9 H, s), 2.50 (3 H, s), 3.24 (4 H, t, J = 5.1 Hz), 3.61 (4 H, t, J = 5.1 Hz), 6.87 (1 H, dd, J = 3.0 Hz, 9.3 Hz), 6.99 (1 H, d, J = 2.4 Hz), 7.49 (1 H, d, J = 8.7 Hz), 8.27 (1 H, s).
参考例５１
1-(4-ブロモ-2-フルオロフェニル)-4-メチル-1H-1,2,3-トリアゾール
　N'-[2,2-ジクロロ-1-メチルエチリデン]-4-メチルベンゼンスルホノヒドラジド(9.7 g, 51 mmol)のMeOH(20 mL)溶液に氷冷で4-ブロモ-2-フルオロアニリン(3.0 g, 10 mmol)を加え、室温で2時間攪拌した。反応混合物を減圧下に濃縮し、残留物にトルエン(50 mL)を加え、不溶物をろ去した。ろ液を１Ｎ－水酸化ナトリウム水、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製し、題記化合物を茶色固体(0.27 g, 10%)として得た。
LC/MS 256
NMR (CDCl3) δ: 2.47 (3 H, s), 7.47 - 7.51 (2 H, m), 7.82 (1 H, d, J=2.7 Hz), 7.89 (1 H, dd, J=8.4 Hz, 8.7 Hz). Reference Example 51
1- (4-Bromo-2-fluorophenyl) -4-methyl-1H-1,2,3-triazole N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonohydrazide ( To a solution of 9.7 g, 51 mmol) in MeOH (20 mL) was added 4-bromo-2-fluoroaniline (3.0 g, 10 mmol) with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, toluene (50 mL) was added to the residue, and the insoluble material was removed by filtration. The filtrate was washed with 1N aqueous sodium hydroxide and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2) to give the title compound as a brown solid (0.27 g, 10%).
LC / MS 256
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 7.47-7.51 (2 H, m), 7.82 (1 H, d, J = 2.7 Hz), 7.89 (1 H, dd, J = 8.4 Hz, 8.7 Hz).
参考例５２
tert-ブチル 4-[3-フルオロ-4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-フルオロフェニル)-4-メチル-1H-1,2,3-トリアゾール(0.25 g, 0.98 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.18 g, 0.98 mmol)、DavePhos(38 mg, 0.10 mmol)及びナトリウム tert-ブトキシド(0.14 g, 1.5 mmol)のトルエン(2 mL)溶液に窒素雰囲気下、Pd2(dba)3(45 mg, 0.05 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～6/4)で精製し、題記化合物を淡黄色固体(0.26 g, 74%)として得た。
LC/MS 362
NMR (CDCl3) δ: 1.50 (9 H, s), 2.45 (3 H, s), 3.24 (4 H, t, J=5.1 Hz), 3.61 (4 H, t, J=5.1 Hz), 6.70 - 6.80 (2 H, m), 7.70 - 7.76 (1 H, m). Reference Example 52
tert-butyl 4- [3-fluoro-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-2-fluorophenyl ) -4-Methyl-1H-1,2,3-triazole (0.25 g, 0.98 mmol), tert-butyl piperazine-1-carboxylate (0.18 g, 0.98 mmol), DavePhos (38 mg, 0.10 mmol) and sodium Pd 2 (dba) 3 (45 mg, 0.05 mmol) was added to a toluene (2 mL) solution of tert-butoxide (0.14 g, 1.5 mmol) in a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 4) to give the title compound as a pale yellow solid (0.26 g, 74%).
LC / MS 362
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 2.45 (3 H, s), 3.24 (4 H, t, J = 5.1 Hz), 3.61 (4 H, t, J = 5.1 Hz), 6.70 -6.80 (2 H, m), 7.70-7.76 (1 H, m).
参考例５３
tert-ブチル 4-[3-tert-ブトキシ-4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 53
tert-butyl 4- [3-tert-butoxy-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazine-1-carboxylate
53a) 4-ブロモ-2-フルオロ-N-[(1E)-N-ヒドロキシエタンイミドイル]ベンズアミド
　4-ブロモ-2-フルオロ安息香酸(10 g, 46 mmol)、N-ヒドロキシアセトアミジン(3.4 g, 46 mmol)のDMF溶液に氷冷でＷＳＣ(11 g, 55 mmol)を加え、室温で16時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝2/1)で精製し、題記化合物を白色固体(2.3 g, 19%)として得た。
LC/MS 275
NMR (CDCl3) δ: 2.07 (3 H, s), 4.96 (2 H, br), 7.37 (1 H, dd, J=1.8 Hz, 10.5 Hz), 7.42 (1 H, dd, J=1.8 Hz, 8.4 Hz), 7.95 (1 H, dd, J=7.8 Hz, 8.1 Hz). 53a) 4-Bromo-2-fluoro-N-[(1E) -N-hydroxyethaneimidoyl] benzamide 4-bromo-2-fluorobenzoic acid (10 g, 46 mmol), N-hydroxyacetamidine (3.4 g , 46 mmol) in a DMF solution was added WSC (11 g, 55 mmol) with ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound as a white solid (2.3 g, 19%).
LC / MS 275
NMR (CDCl 3 ) δ: 2.07 (3 H, s), 4.96 (2 H, br), 7.37 (1 H, dd, J = 1.8 Hz, 10.5 Hz), 7.42 (1 H, dd, J = 1.8 Hz , 8.4 Hz), 7.95 (1 H, dd, J = 7.8 Hz, 8.1 Hz).
53b) 5-(4-ブロモ-2-フルオロフェニル)-3-メチル-1,2,4-オキサジアゾール
　4-ブロモ-2-フルオロ-N-[(1E)-N-ヒドロキシエタンイミドイル]ベンズアミド(2.3 g, 8.5 mmol)のトルエン(25 mL)溶液にパラトルエンスルホン酸・1水和物(0.16 g, 0.85 mmol)を加え、120℃で3時間攪拌した。室温とし、反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、題記化合物を白色固体(2.0 g, 91%)として得た。
LC/MS 257
NMR (CDCl3) δ: 2.51 (3 H, s), 7.47 - 7.50 (2 H, m), 7.98 (1 H, dd, J=7.8 Hz, 8.1 Hz). 53b) 5- (4-Bromo-2-fluorophenyl) -3-methyl-1,2,4-oxadiazole 4-bromo-2-fluoro-N-[(1E) -N-hydroxyethaneimidoyl] Paratoluenesulfonic acid monohydrate (0.16 g, 0.85 mmol) was added to a solution of benzamide (2.3 g, 8.5 mmol) in toluene (25 mL), and the mixture was stirred at 120 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound as a white solid (2.0 g, 91%).
LC / MS 257
NMR (CDCl 3 ) δ: 2.51 (3 H, s), 7.47-7.50 (2 H, m), 7.98 (1 H, dd, J = 7.8 Hz, 8.1 Hz).
53c) tert-ブチル 4-[3-tert-ブトキシ-4-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモ-2-フルオロフェニル)-3-メチル-1,2,4-オキサジアゾール(0.51 g, 2.0 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.37 g, 2.0 mmol)、DavePhos(79 mg, 0.20 mmol)及びナトリウム tert-ブトキシド(0.29 g, 3.0 mmol)のトルエン(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(92 mg, 0.10 mmol)を加え、90℃で1.5時間攪拌した。さらに、Pd2(dba)3(92 mg, 0.10 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、題記化合物を黄色固体(0.14 g, 19%)として得た。
LC/MS 417
NMR (CDCl3) δ: 1.42 (9 H, s), 1.50 (9 H, s), 2.45 (3 H, s), 3.30 (4 H, t, J=4.8 Hz), 3.61 (4 H, t, J=5.4 Hz), 6.62 (1 H, d, J=2.1 Hz), 6.69 (1 H, dd, J=2.1 Hz, 8.7 Hz), 7.93 (1 H, d, J=8.7 Hz). 53c) tert-butyl 4- [3-tert-butoxy-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromo- 2-Fluorophenyl) -3-methyl-1,2,4-oxadiazole (0.51 g, 2.0 mmol), tert-butyl piperazine-1-carboxylate (0.37 g, 2.0 mmol), DavePhos (79 mg, 0.20 mmol) and sodium tert-butoxide (0.29 g, 3.0 mmol) in toluene (4 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (92 mg, 0.10 mmol) was added and stirred at 90 ° C. for 1.5 hours. Furthermore, Pd 2 (dba) 3 (92 mg, 0.10 mmol) was added, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound as a yellow solid (0.14 g, 19%).
LC / MS 417
NMR (CDCl 3 ) δ: 1.42 (9 H, s), 1.50 (9 H, s), 2.45 (3 H, s), 3.30 (4 H, t, J = 4.8 Hz), 3.61 (4 H, t , J = 5.4 Hz), 6.62 (1 H, d, J = 2.1 Hz), 6.69 (1 H, dd, J = 2.1 Hz, 8.7 Hz), 7.93 (1 H, d, J = 8.7 Hz).
参考例５４
1-(4-ブロモ-2-メトキシフェニル)-4-メチル-1H-1,2,3-トリアゾール
　1-(4-ブロモ-2-フルオロフェニル)-4-メチル-1H-1,2,3-トリアゾール(0.50 g, 2.0 mmol)のDMF(10 mL)溶液に28%ナトリウムメトキシドMeOH溶液(1.1 mL, 5.9 mmol)を加え、100℃で1時間攪拌した。室温とし、反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を茶色油状物(0.95 g, 95%)として得た。
LC/MS 268
NMR (CDCl3) δ: 2.45 (3 H, s), 3.91 (3 H, s), 7.22 - 7.26 (2 H, m), 7.66 (1 H, d, J=8.1 Hz), 7.82 (1 H, s). Reference Example 54
1- (4-Bromo-2-methoxyphenyl) -4-methyl-1H-1,2,3-triazole 1- (4-Bromo-2-fluorophenyl) -4-methyl-1H-1,2,3 To a DMF (10 mL) solution of -triazole (0.50 g, 2.0 mmol) was added 28% sodium methoxide MeOH solution (1.1 mL, 5.9 mmol), and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (0.95 g, 95%).
LC / MS 268
NMR (CDCl 3 ) δ: 2.45 (3 H, s), 3.91 (3 H, s), 7.22-7.26 (2 H, m), 7.66 (1 H, d, J = 8.1 Hz), 7.82 (1 H , s).
参考例５５
tert-ブチル 4-[3-メトキシ-4-(4-メチル-1H-1,2,3-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-メトキシフェニル)-4-メチル-1H-1,2,3-トリアゾール(0.50 g, 1.9 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.35 g, 1.9 mmol)、DavePhos(73 mg, 0.18 mmol)及びナトリウム tert-ブトキシド(0.27 g, 2.8 mmol)のトルエン(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(85 mg, 0.093 mmol)を加え、90℃で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、題記化合物を黄色固体(0.43 g, 62%)として得た。
LC/MS 374
NMR (CDCl3) δ: 1.51 (9 H, s), 2.44 (3 H, s), 3.23 (4 H, t, J=5.1 Hz), 3.62 (4 H, t, J=5.4 Hz), 3.86 (3 H, s), 6.55 - 6.61 (2 H, m), 7.58 (1 H, d, J=9.0 Hz), 7.72 (1 H, s). Reference Example 55
tert-butyl 4- [3-methoxy-4- (4-methyl-1H-1,2,3-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-2-methoxyphenyl) ) -4-Methyl-1H-1,2,3-triazole (0.50 g, 1.9 mmol), tert-butyl piperazine-1-carboxylate (0.35 g, 1.9 mmol), DavePhos (73 mg, 0.18 mmol) and sodium Under a nitrogen atmosphere, Pd 2 (dba) 3 (85 mg, 0.093 mmol) was added to a toluene (4 mL) solution of tert-butoxide (0.27 g, 2.8 mmol), and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound as a yellow solid (0.43 g, 62%).
LC / MS 374
NMR (CDCl 3 ) δ: 1.51 (9 H, s), 2.44 (3 H, s), 3.23 (4 H, t, J = 5.1 Hz), 3.62 (4 H, t, J = 5.4 Hz), 3.86 (3 H, s), 6.55-6.61 (2 H, m), 7.58 (1 H, d, J = 9.0 Hz), 7.72 (1 H, s).
参考例５６
4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピラゾール Reference Example 56
4- (4-Chloro-2-methoxyphenyl) -1-methyl-1H-pyrazole
56a) 4-(4-クロロ-2-フルオロフェニル)-1-メチル-1H-ピラゾール
　1-ブロモ-4-クロロ-2-フルオロベンゼン(1.1 g, 5.0 mmol)、1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(1.0 g, 5.0 mmol)のトルエン(5 mL)－エタノール(5 mL)－２Ｍ－炭酸ナトリウム水(5 mL)溶液に窒素雰囲気下Pd(PPh3)4(0.29 g, 0.25 mmol)を加え、80℃で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～1/1)で精製し、題記化合物を無色油状物(0.65 g, 62%)として得た。
LC/MS 211
NMR (CDCl3) δ: 3.97 (3 H, s), 7.13 - 7.16 (2 H, m), 7.47 (1 H, dd, J=8.1 Hz, 8.7 Hz), 7.75 (1 H, d, J=2.7 Hz), 7.82 (1 H, s). 56a) 4- (4-Chloro-2-fluorophenyl) -1-methyl-1H-pyrazole 1-bromo-4-chloro-2-fluorobenzene (1.1 g, 5.0 mmol), 1-methyl-4- (4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.0 g, 5.0 mmol) in toluene (5 mL) -ethanol (5 mL) -2M-sodium carbonate Pd (PPh 3 ) 4 (0.29 g, 0.25 mmol) was added to a water (5 mL) solution under a nitrogen atmosphere, and the mixture was stirred at 80 ° C. for 2 hr. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/2 to 1/1) to give the title compound as a colorless oil (0.65 g, 62%).
LC / MS 211
NMR (CDCl 3 ) δ: 3.97 (3 H, s), 7.13-7.16 (2 H, m), 7.47 (1 H, dd, J = 8.1 Hz, 8.7 Hz), 7.75 (1 H, d, J = 2.7 Hz), 7.82 (1 H, s).
56b) 4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピラゾール
　4-(4-クロロ-2-フルオロフェニル)-1-メチル-1H-ピラゾール(0.65 g, 3.1 mmol)のDMF(10 mL)溶液に28%ナトリウムメトキシドMeOH溶液(1.8 mL, 9.3 mmol)を加え、100℃で1時間攪拌した。室温とし、反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色油状物(0.70 g, 100%)として得た。
LC/MS 223
NMR (CDCl3) δ: 3.92 (3 H, s), 3.95 (3 H, s), 6.93 - 6.98 (2 H, m), 7.43 (1 H, d, J=8.1 Hz), 7.81 (1 H,s), 7.83 (1 H, s). 56b) 4- (4-Chloro-2-methoxyphenyl) -1-methyl-1H-pyrazole 4- (4-Chloro-2-fluorophenyl) -1-methyl-1H-pyrazole (0.65 g, 3.1 mmol) To a DMF (10 mL) solution was added 28% sodium methoxide MeOH solution (1.8 mL, 9.3 mmol), and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.70 g, 100%).
LC / MS 223
NMR (CDCl 3 ) δ: 3.92 (3 H, s), 3.95 (3 H, s), 6.93-6.98 (2 H, m), 7.43 (1 H, d, J = 8.1 Hz), 7.81 (1 H , s), 7.83 (1 H, s).
参考例５７
tert-ブチル 4-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペラジン-1-カルボキシラート
　4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピラゾール(0.30 g, 1.4 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.25 g, 1.4 mmol)、DavePhos(53 mg, 0.14 mmol)及びナトリウム tert-ブトキシド(0.19 g, 2.0 mmol)のトルエン(2 mL)溶液に窒素雰囲気下、Pd2(dba)3(62 mg, 0.069 mmol)を加え、90℃で2時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝7/3～4/6)で精製し、題記化合物を淡黄色固体(0.32 g, 64%)として得た。
LC/MS 373
NMR (CDCl3) δ: 1.51 (9 H, s), 3.17 (4 H, t, J=5.1 Hz), 3.61 (4 H, t, J=5.4 Hz), 3.91 (3 H, s), 3.94 (3 H, s), 6.54 - 6.58 (2 H, m), 7.41 (1 H, d, J=8.7 Hz), 7.75 (1 H, s), 7.80 (1 H,s). Reference Example 57
tert-butyl 4- [3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperazine-1-carboxylate 4- (4-chloro-2-methoxyphenyl) -1-methyl- 1H-pyrazole (0.30 g, 1.4 mmol), tert-butyl piperazine-1-carboxylate (0.25 g, 1.4 mmol), DavePhos (53 mg, 0.14 mmol) and sodium tert-butoxide (0.19 g, 2.0 mmol) in toluene Under a nitrogen atmosphere, Pd 2 (dba) 3 (62 mg, 0.069 mmol) was added to the (2 mL) solution, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7 / 3-4 / 6) to give the title compound as a pale yellow solid (0.32 g, 64%).
LC / MS 373
NMR (CDCl 3) δ: 1.51 (9 H, s), 3.17 (4 H, t, J = 5.1 Hz), 3.61 (4 H, t, J = 5.4 Hz), 3.91 (3 H, s), 3.94 (3 H, s), 6.54-6.58 (2 H, m), 7.41 (1 H, d, J = 8.7 Hz), 7.75 (1 H, s), 7.80 (1 H, s).
参考例５８
3-(4-ブロモフェニル)-5-メチル-4H-1,2,4-トリアゾール Reference Example 58
3- (4-Bromophenyl) -5-methyl-4H-1,2,4-triazole
58a) 4-ブロモ-N-[1-(ジメチルアミノ)エチリデン]ベンズアミド
　4-ブロモベンズアミド(5.0 g, 25 mmol)にN,N-ジメチルアセトアミドジメチルアセタール(10 mL)を加え、120℃で1.5時間攪拌した。室温とし、析出物をろ取し、ヘキサンで洗浄、題記化合物を黄色固体(4.6 g, 68%)として得た。
NMR (CDCl3) δ: 3.21 - 3.23 (6 H, m), 7.55 (2 H, d, J=8.4 Hz), 8.15 (2 H, d, J=8.4 Hz), 8.64 (1 H,s). 58a) 4-Bromo-N- [1- (dimethylamino) ethylidene] benzamide To 4-bromobenzamide (5.0 g, 25 mmol), N, N-dimethylacetamide dimethyl acetal (10 mL) was added and the mixture was heated at 120 ° C. for 1.5 hours. Stir. The precipitate was collected by filtration and washed with hexane to give the title compound as a yellow solid (4.6 g, 68%).
NMR (CDCl 3 ) δ: 3.21-3.23 (6 H, m), 7.55 (2 H, d, J = 8.4 Hz), 8.15 (2 H, d, J = 8.4 Hz), 8.64 (1 H, s) .
58b) 3-(4-ブロモフェニル)-5-メチル-4H-1,2,4-トリアゾール
　ヒドラジン・1水和物(0.57 mL, 12 mmol)の酢酸(30 mL)溶液に4-ブロモ-N-[1-(ジメチルアミノ)エチリデン]ベンズアミド(3.0 g, 11 mmol)を加え、90℃で1.5時間攪拌した。室温とし、減圧下に濃縮し、残留物にジエチルエーテルを加え、さらに減圧下に濃縮した。残留物に酢酸エチル－飽和炭酸水素ナトリウム水を加え、水層を酢酸エチルで抽出し、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、題記化合物を淡茶色固体(2.3 g, 87%)として得た。
LC/MS 238
NMR (CDCl3) δ: 2.56 (3 H, s),7.57 (2 H, d, J=8.4 Hz), 7.92 (2 H, d, J=8.4 Hz). 58b) 4-Bromo-N in 3- (4-bromophenyl) -5-methyl-4H-1,2,4-triazole hydrazine monohydrate (0.57 mL, 12 mmol) in acetic acid (30 mL) -[1- (Dimethylamino) ethylidene] benzamide (3.0 g, 11 mmol) was added and stirred at 90 ° C. for 1.5 hours. The mixture was brought to room temperature, concentrated under reduced pressure, diethyl ether was added to the residue, and the mixture was further concentrated under reduced pressure. Ethyl acetate-saturated aqueous sodium bicarbonate was added to the residue, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a light brown solid (2.3 g, 87%).
LC / MS 238
NMR (CDCl 3 ) δ: 2.56 (3 H, s), 7.57 (2 H, d, J = 8.4 Hz), 7.92 (2 H, d, J = 8.4 Hz).
参考例５９
4-[4-(5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール-3-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド Reference Example 59
4- [4- (5-Methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazol-3-yl) phenyl] -N-[(1S) -1- Naphthalen-1-ylethyl] piperazine-1-carboxamide
59a) 3-(4-ブロモフェニル)-5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール
　3-(4-ブロモフェニル)-5-メチル-4H-1,2,4-トリアゾール(0.44 g, 1.9 mmol)のDMF(5 mL)溶液にナトリウム tert-ブトキシド(0.20 g, 2.0 mmol)を加え、室温で30分攪拌し、さらに2-(クロロメトキシ)エチルトリメチルシラン(0.36 mL, 2.0 mmol)を加え、室温で16時間攪拌した。反応混合物を酢酸エチル－MeOH－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～8/2)で精製し、題記化合物を白色固体(0.44 g, 65%)として得た。
NMR (CDCl3) δ: 0.02 - 0.03 (9 H, m), 0.91 - 1.02 (2 H, m), 2.45 and 2.58 (3 H, s), 3.67 and 3.81 (2 H, t, J=8.4 Hz), 5.41 and 5.47 (2 H, s), 7.56 and 7.64 (2 H, d, J=8.7 Hz), 7.81 and 7.95 (2 H, d, J=8.7 Hz). 59a) 3- (4-Bromophenyl) -5-methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazole 3- (4-Bromophenyl) -5-methyl Sodium tert-butoxide (0.20 g, 2.0 mmol) was added to a solution of -4H-1,2,4-triazole (0.44 g, 1.9 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 30 minutes, and further 2- ( Chloromethoxy) ethyltrimethylsilane (0.36 mL, 2.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate-MeOH-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-8 / 2) to give the title compound as a white solid (0.44 g, 65%).
NMR (CDCl 3 ) δ: 0.02-0.03 (9 H, m), 0.91-1.02 (2 H, m), 2.45 and 2.58 (3 H, s), 3.67 and 3.81 (2 H, t, J = 8.4 Hz ), 5.41 and 5.47 (2 H, s), 7.56 and 7.64 (2 H, d, J = 8.7 Hz), 7.81 and 7.95 (2 H, d, J = 8.7 Hz).
59b) tert-ブチル 4-[4-(5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール-3-イル)フェニル]ピペラジン-1-カルボキシラート
　3-(4-ブロモフェニル)-5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール(1.18 g, 3.2 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(0.60 g, 3.2 mmol)、DavePhos(76 mg, 0.19 mmol)及びナトリウム tert-ブトキシド(0.46 g, 4.8 mmol)のトルエン(6 mL)溶液に窒素雰囲気下、Pd2(dba)3(88 mg, 0.10 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝7/3～1/9)で精製し、題記化合物を白色固体(0.44 g, 77%)として得た。
LC/MS 474
NMR (CDCl3) δ: 0.02 - 0.03 (9 H, m), 0.91 - 1.02 (2 H, m), 1.50 (9 H, s), 2.44 and 2.57 (3 H, s), 3.21 - 3.27 (4 H, m), 3.59 - 3.81 (6 H, m), 5.41 and 5.45 (2 H, s), 6.95 - 7.00 (2 H, m), 7.82 and 7.98 (2 H, d, J=9.0 Hz). 59b) tert-butyl 4- [4- (5-methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazol-3-yl) phenyl] piperazine-1-carboxy 3- (4-Bromophenyl) -5-methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazole (1.18 g, 3.2 mmol), tert-butyl piperazine- To a solution of 1-carboxylate (0.60 g, 3.2 mmol), DavePhos (76 mg, 0.19 mmol) and sodium tert-butoxide (0.46 g, 4.8 mmol) in toluene (6 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (88 mg, 0.10 mmol) was added and stirred at 90 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7 / 3-1 / 9) to give the title compound as a white solid (0.44 g, 77%).
LC / MS 474
NMR (CDCl 3 ) δ: 0.02-0.03 (9 H, m), 0.91-1.02 (2 H, m), 1.50 (9 H, s), 2.44 and 2.57 (3 H, s), 3.21-3.27 (4 H, m), 3.59-3.81 (6 H, m), 5.41 and 5.45 (2 H, s), 6.95-7.00 (2 H, m), 7.82 and 7.98 (2 H, d, J = 9.0 Hz).
59c) 4-[4-(5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール-3-イル)フェニル]-N-[(1S)-1-ナフタレン-1-イルエチル]ピペラジン-1-カルボキサミド
　tert-ブチル 4-[4-(5-メチル-4-{[2-(トリメチルシリル)エトキシ]メチル}-4H-1,2,4-トリアゾール-3-イル)フェニル]ピペラジン-1-カルボキシラート(0.60 g, 1.3 mmol)の酢酸エチル(2 mL)溶液に4N塩酸酢酸エチル溶液(10 mL)を加え、室温で1時間攪拌した。反応混合物を減圧下に濃縮し、DMF(10 mL)を加え、さらにトリエチルアミン(0.89 mL, 6.3 mmol)を加え、室温で1時間攪拌した。イソシアン酸 (S)-(+)-1-(1-ナフチル)エチル(0.22 mL, 1.3 mmol)を加え、室温で1時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝7/3～0/1)で精製し、題記化合物を無色油状物(0.25 g, 35%)として得た。
LC/MS 571
NMR (CDCl3) δ: 0.02 (9 H, s), 0.94 (2 H, t, J=8.4 Hz), 1.73 (3 H, d, J=6.6 Hz), 2.57 (3 H, s), 3.26 (4 H, t, J=5.1 Hz), 3.53 - 3.55 (4 H, m), 3.67 (2 H, t, J=8.4 Hz), 4.74 (1 H, d, J=7.2 Hz), 5.45 (2 H, s), 5.85 - 5.89 (1 H, m), 6.93 (2 H, d, J=9.0 Hz), 7.45 - 7.57 (4 H, m), 7.81 (1 H, d, J=8.4 Hz), 7.88 (1 H, d, J=7.2 Hz), 7.97 (2 H, d, J=8.7 Hz), 8.19 (1 H, d, J=8.1 Hz). 59c) 4- [4- (5-Methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazol-3-yl) phenyl] -N-[(1S)- 1-naphthalen-1-ylethyl] piperazine-1-carboxamide tert-butyl 4- [4- (5-methyl-4-{[2- (trimethylsilyl) ethoxy] methyl} -4H-1,2,4-triazole- To a solution of 3-yl) phenyl] piperazine-1-carboxylate (0.60 g, 1.3 mmol) in ethyl acetate (2 mL) was added 4N hydrochloric acid ethyl acetate solution (10 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, DMF (10 mL) was added, triethylamine (0.89 mL, 6.3 mmol) was further added, and the mixture was stirred at room temperature for 1 hr. Isocyanic acid (S)-(+)-1- (1-naphthyl) ethyl (0.22 mL, 1.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7 / 3-0 / 1) to give the title compound as a colorless oil (0.25 g, 35%).
LC / MS 571
NMR (CDCl 3 ) δ: 0.02 (9 H, s), 0.94 (2 H, t, J = 8.4 Hz), 1.73 (3 H, d, J = 6.6 Hz), 2.57 (3 H, s), 3.26 (4 H, t, J = 5.1 Hz), 3.53-3.55 (4 H, m), 3.67 (2 H, t, J = 8.4 Hz), 4.74 (1 H, d, J = 7.2 Hz), 5.45 ( 2 H, s), 5.85-5.89 (1 H, m), 6.93 (2 H, d, J = 9.0 Hz), 7.45-7.57 (4 H, m), 7.81 (1 H, d, J = 8.4 Hz ), 7.88 (1 H, d, J = 7.2 Hz), 7.97 (2 H, d, J = 8.7 Hz), 8.19 (1 H, d, J = 8.1 Hz).
参考例６０
1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール Reference Example 60
1- (4-Bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole
60a) (4-ブロモ-2-メトキシフェニル)ヒドラジン
　4-ブロモ-2-メトキシアニリン(4.0 g, 20 mmol)の濃塩酸(40 mL)溶液に-20℃を保持しながら亜硝酸ナトリウム(1.4 g, 21 mmol)水(2 mL)溶液を滴下し、同温で15分攪拌した。0℃とし、同温で20分攪拌し、さらに、塩化スズ・2水和物(17 g, 74 mmol)の濃塩酸(140 mL)溶液を-20℃を保持しながら反応混合物に滴下し、同温で10分攪拌した後、室温で40分攪拌した。析出物をろ取し、氷水、ジエチルエーテルで洗浄した。ろ取した物に酢酸エチル－10％炭酸カリウム水を加え、不溶物をろ去した。ろ液の水層を酢酸エチルで抽出し、有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、題記化合物を淡黄色固体(3.4 g, 78%)として得た。
NMR (CDCl3) δ: 3.49 (2 H, br), 3.84 (3 H, s), 5.61 (1 H, br), 6.85 - 6.88(2 H, m), 7.06 (1 H, dd, J=2.1, 8.7 Hz). 60a) (4-Bromo-2-methoxyphenyl) hydrazine Sodium nitrite (1.4 g) while maintaining -20 ° C in a solution of 4-bromo-2-methoxyaniline (4.0 g, 20 mmol) in concentrated hydrochloric acid (40 mL) , 21 mmol) water (2 mL) solution was added dropwise and stirred at the same temperature for 15 minutes. The mixture was stirred at the same temperature for 20 minutes, and a solution of tin chloride dihydrate (17 g, 74 mmol) in concentrated hydrochloric acid (140 mL) was added dropwise to the reaction mixture while maintaining -20 ° C. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 40 minutes. The precipitate was collected by filtration and washed with ice water and diethyl ether. Ethyl acetate-10% aqueous potassium carbonate was added to the filtered product, and the insoluble material was removed by filtration. The aqueous layer of the filtrate was extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (3.4 g, 78%).
NMR (CDCl 3 ) δ: 3.49 (2 H, br), 3.84 (3 H, s), 5.61 (1 H, br), 6.85-6.88 (2 H, m), 7.06 (1 H, dd, J = 2.1, 8.7 Hz).
60b) 1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-2-メトキシフェニル)ヒドラジン(2.8 g, 13 mmol)のMeOH(25 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(2.8 g, 13 mmol)を添加し、室温で30分攪拌した。反応混合物を減圧下に濃縮し、残留物にオルトギ酸トリメチル(13 mL)、トルエン(25 mL)を加え、さらにピリジン(25 mL)を加え、100℃で16時間攪拌した。反応混合物を室温まで冷却し、減圧下濃縮した。残留物に酢酸エチル－飽和炭酸水素ナトリウム水－水を加え、水層を酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～6/4)で精製し、題記化合物を淡黄色固体(2.6 g, 74%)として得た。
LC/MS 268
NMR (CDCl3) δ: 2.47 (3 H, s), 3.93 (3 H, s), 7.19 - 7.22 (2 H, m), 7.64 (1 H, d, J=8.1 Hz), 8.59 (1 H, br). 60b) 1- (4-Bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (4-bromo-2-methoxyphenyl) hydrazine (2.8 g, 13 mmol) in MeOH (25 To the solution was added methyl ethaneimidothioate hydroiodide (2.8 g, 13 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, trimethyl orthoformate (13 mL) and toluene (25 mL) were added to the residue, pyridine (25 mL) was further added, and the mixture was stirred at 100 ° C. for 16 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate-saturated aqueous sodium hydrogen carbonate-water was added to the residue, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 2-6 / 4) to give the title compound as a pale yellow solid (2.6 g, 74%).
LC / MS 268
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 3.93 (3 H, s), 7.19-7.22 (2 H, m), 7.64 (1 H, d, J = 8.1 Hz), 8.59 (1 H , br).
参考例６１
tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(4.0 g, 15 mmol)、tert-ブチル 1,4-ジアゼパン-1-カルボキシラート(2.9 mL, 15 mmol)、DavePhos(590 mg, 1.5 mmol)及びナトリウム tert-ブトキシド(2.2 g, 22 mmol)のトルエン(40 mL)溶液に窒素雰囲気下、Pd2(dba)3(680 mg, 0.75 mmol)を加え、90 ℃で14時間攪拌した。反応混合物を室温まで冷却し、セライトろ過し、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～3/2)で精製し、題記化合物を茶色非定形固体(5.1 g, 88%)として得た。
LC/MS 388
NMR (CDCl3) δ: 1.35 - 1.48 (9 H, m), 1.93 - 2.04 (2 H, m), 2.49 (3 H, s), 3.18 - 3.28 (1 H, m), 3.28 - 3.38 (1 H, m), 3.52 - 3.66 (6 H, m), 3.92 (3 H, s), 6.26 (1 H, d, J=2.3 Hz), 6.36 (1 H, d, J=8.7 Hz), 7.17 (1 H, s), 7.53 (1 H, d, J=8.7 Hz). Reference Example 61
tert-butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate 5- (4-bromo-2-methoxy Phenyl) -2-methyl-1,3-oxazole (4.0 g, 15 mmol), tert-butyl 1,4-diazepane-1-carboxylate (2.9 mL, 15 mmol), DavePhos (590 mg, 1.5 mmol) and Under a nitrogen atmosphere, Pd 2 (dba) 3 (680 mg, 0.75 mmol) was added to a toluene (40 mL) solution of sodium tert-butoxide (2.2 g, 22 mmol), and the mixture was stirred at 90 ° C. for 14 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 3/2) to give the title compound as a brown amorphous solid (5.1 g, 88%).
LC / MS 388
NMR (CDCl 3 ) δ: 1.35-1.48 (9 H, m), 1.93-2.04 (2 H, m), 2.49 (3 H, s), 3.18-3.28 (1 H, m), 3.28-3.38 (1 H, m), 3.52-3.66 (6 H, m), 3.92 (3 H, s), 6.26 (1 H, d, J = 2.3 Hz), 6.36 (1 H, d, J = 8.7 Hz), 7.17 (1 H, s), 7.53 (1 H, d, J = 8.7 Hz).
参考例６２
tert-ブチル 4-[3-(メチルスルファニル)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 62
tert-butyl 4- [3- (methylsulfanyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
62a) 1-[4-ブロモ-2-(メチルスルファニル)フェニル]-3-メチル-1H-1,2,4-トリアゾール
　1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(200 mg, 0.78 mmol)のDMF(3.0 mL)溶液にナトリウム メタンチオラート(110 mg, 1.6 mmol)を加え、80 ℃で2時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。
得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(220 mg, 78%)として得た。
LC/MS 284
NMR (CDCl3) δ: 2.43 (3 H, s), 2.50 (3 H, s), 7.23 (1 H, d, J=8.3 Hz), 7.39 (1 H, dd, J=8.3, 1.9 Hz), 7.44 (1 H, d, J=1.9 Hz), 8.27 (1 H, s). 62a) 1- [4-Bromo-2- (methylsulfanyl) phenyl] -3-methyl-1H-1,2,4-triazole 1- (4-Bromo-2-fluorophenyl) -3-methyl-1H- Sodium methanethiolate (110 mg, 1.6 mmol) was added to a solution of 1,2,4-triazole (200 mg, 0.78 mmol) in DMF (3.0 mL), and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate.
The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (220 mg, 78%).
LC / MS 284
NMR (CDCl 3 ) δ: 2.43 (3 H, s), 2.50 (3 H, s), 7.23 (1 H, d, J = 8.3 Hz), 7.39 (1 H, dd, J = 8.3, 1.9 Hz) , 7.44 (1 H, d, J = 1.9 Hz), 8.27 (1 H, s).
62b) tert-ブチル 4-[3-(メチルスルファニル)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-[4-ブロモ-2-(メチルスルファニル)フェニル]-3-メチル-1H-1,2,4-トリアゾール(220 mg, 0.77 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(140 mg, 0.77 mmol)、DavePhos(30 mg, 0.077 mmol)及びナトリウム tert-ブトキシド(110 mg, 1.1 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(35 mg, 0.038 mmol)を加え、90 ℃で15時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～4/1)で精製し、題記化合物を淡黄色固体(210 mg, 72%)として得た。
LC/MS 390
NMR (CDCl3) δ: 1.49 (9 H, s), 2.36 (3 H, s), 2.49 (3 H, s), 3.13 - 3.30 (4 H, m), 3.52 - 3.66 (4 H, m), 6.76 (1 H, dd, J=8.5, 2.8 Hz), 6.83 (1 H, d, J=2.8 Hz), 7.24 (1 H, d, J=8.5 Hz), 8.20 (1 H, s). 62b) tert-butyl 4- [3- (methylsulfanyl) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- [4-bromo -2- (methylsulfanyl) phenyl] -3-methyl-1H-1,2,4-triazole (220 mg, 0.77 mmol), tert-butyl piperazine-1-carboxylate (140 mg, 0.77 mmol), DavePhos ( 30 mg, 0.077 mmol) and sodium tert- butoxide (110 mg, under an atmosphere of nitrogen in toluene (2.0 mL) solution of 1.1 mmol), Pd 2 (dba ) 3 (35 mg, 0.038 mmol) was added, 15 at 90 ° C. Stir for hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 4/1) to give the title compound as a pale yellow solid (210 mg, 72%).
LC / MS 390
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.36 (3 H, s), 2.49 (3 H, s), 3.13-3.30 (4 H, m), 3.52-3.66 (4 H, m) , 6.76 (1 H, dd, J = 8.5, 2.8 Hz), 6.83 (1 H, d, J = 2.8 Hz), 7.24 (1 H, d, J = 8.5 Hz), 8.20 (1 H, s).
参考例６３
tert-ブチル 4-[3-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 63
tert-butyl 4- [3-fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
63a) 1-(4-ブロモ-2-フルオロ-6-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　1-(4-ブロモ-2,6-ジフルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(250 mg, 0.92 mmol)のDMF(3.0 mL)溶液に28%ナトリウムメトキシドMeOH溶液(110 mg, 1.8 mmol)を加え、80 ℃で13時間攪拌した。さらに、反応混合物に28%ナトリウムメトキシドMeOH溶液(55 mg, 0.90 mmol)を加え、80℃で20時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～4/1)で精製した。残留物を分取HPLCにて精製し、分取したフラクションを濃縮した。残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色固体(120 mg, 45%)として得た。
LC/MS 286
NMR (CDCl3) δ: 2.50 (3 H, s), 3.84 (3 H, s), 6.99 (1 H, t, J=1.9 Hz), 7.08 (1 H, dd, J=8.5, 1.9 Hz), 8.10 (1 H, s). 63a) 1- (4-Bromo-2-fluoro-6-methoxyphenyl) -3-methyl-1H-1,2,4-triazole 1- (4-bromo-2,6-difluorophenyl) -3-methyl 28% sodium methoxide MeOH solution (110 mg, 1.8 mmol) was added to a DMF (3.0 mL) solution of -1H-1,2,4-triazole (250 mg, 0.92 mmol), and the mixture was stirred at 80 ° C. for 13 hours. Furthermore, 28% sodium methoxide MeOH solution (55 mg, 0.90 mmol) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 4/1). The residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (120 mg, 45%).
LC / MS 286
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 3.84 (3 H, s), 6.99 (1 H, t, J = 1.9 Hz), 7.08 (1 H, dd, J = 8.5, 1.9 Hz) , 8.10 (1 H, s).
63b) tert-ブチル 4-[3-フルオロ-5-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-フルオロ-6-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(120 mg, 0.41 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(76 mg, 0.41 mmol)、DavePhos(16 mg, 0.041 mmol)及びナトリウム tert-ブトキシド(59 mg, 0.62 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(19 mg, 0.021 mmol)を加え、90 ℃で15時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～9/1)で精製し、題記化合物を淡黄色固体(140 mg, 87%)として得た。
LC/MS 392
NMR (CDCl3) δ: 1.49 (9 H, s), 2.49 (3 H, s), 3.12 - 3.33 (4 H, m), 3.45 - 3.66 (4 H, m), 3.78 (3 H, s), 6.25 (1 H, s), 6.27 - 6.36 (1 H, m), 8.04 (1 H, s). 63b) tert-butyl 4- [3-fluoro-5-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4- Bromo-2-fluoro-6-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (120 mg, 0.41 mmol), tert-butyl piperazine-1-carboxylate (76 mg, 0.41 mmol), Pd 2 (dba) 3 (19 mg, 0.021 mmol) was added to a toluene (2.0 mL) solution of DavePhos (16 mg, 0.041 mmol) and sodium tert-butoxide (59 mg, 0.62 mmol) in a nitrogen atmosphere at 90 ° C. For 15 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-9 / 1) to give the title compound as a pale yellow solid (140 mg, 87%).
LC / MS 392
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.49 (3 H, s), 3.12-3.33 (4 H, m), 3.45-3.66 (4 H, m), 3.78 (3 H, s) , 6.25 (1 H, s), 6.27-6.36 (1 H, m), 8.04 (1 H, s).
参考例６４
tert-ブチル 4-[3,5-ジメトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 64
tert-butyl 4- [3,5-dimethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
64a) 1-(4-ブロモ-2,6-ジメトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　1-(4-ブロモ-2,6-ジフルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(260 mg, 0.94 mmol)のDMF(2.5 mL)溶液に28%ナトリウムメトキシドMeOH溶液(1.4 mL, 7.5 mmol)を加え、100 ℃でマイクロ波を15分間照射した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/4～4/1)で精製し、題記化合物を無色固体(210 mg, 74%)として得た。
LC/MS 298
NMR (CDCl3) δ: 2.49 (3 H, s), 3.77 (6 H, s), 6.81 (2 H, s), 7.98 (1 H, s). 64a) 1- (4-Bromo-2,6-dimethoxyphenyl) -3-methyl-1H-1,2,4-triazole 1- (4-bromo-2,6-difluorophenyl) -3-methyl-1H To a solution of -1,2,4-triazole (260 mg, 0.94 mmol) in DMF (2.5 mL) was added 28% sodium methoxide MeOH solution (1.4 mL, 7.5 mmol) and irradiated with microwaves at 100 ° C. for 15 minutes. . The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to 4/1) to give the title compound as a colorless solid (210 mg, 74%).
LC / MS 298
NMR (CDCl 3 ) δ: 2.49 (3 H, s), 3.77 (6 H, s), 6.81 (2 H, s), 7.98 (1 H, s).
64b) tert-ブチル 4-[3,5-ジメトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2,6-ジメトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(200 mg, 0.69 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(130 mg, 0.69 mmol)、DavePhos(27 mg, 0.069 mmol)及びナトリウム tert-ブトキシド(99 mg, 1.0 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(31 mg, 0.034 mmol)を加え、90 ℃で14時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～酢酸エチルのみ)で精製し、題記化合物を淡黄色固体(230 mg, 83%)として得た。
LC/MS 404
NMR (CDCl3) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.16 - 3.30 (4 H, m), 3.53 - 3.69 (4 H, m), 3.74 (6 H, s), 6.12 (2 H, s), 7.95 (1 H, s). 64b) tert-butyl 4- [3,5-dimethoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo- 2,6-dimethoxyphenyl) -3-methyl-1H-1,2,4-triazole (200 mg, 0.69 mmol), tert-butyl piperazine-1-carboxylate (130 mg, 0.69 mmol), DavePhos (27 mg , 0.069 mmol) and sodium tert-butoxide (99 mg, 1.0 mmol) in toluene (2.0 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (31 mg, 0.034 mmol) was added and stirred at 90 ° C. for 14 hours. did. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-ethyl acetate alone) to give the title compound as a pale yellow solid (230 mg, 83%).
LC / MS 404
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.48 (3 H, s), 3.16-3.30 (4 H, m), 3.53-3.69 (4 H, m), 3.74 (6 H, s) , 6.12 (2 H, s), 7.95 (1 H, s).
参考例６５
tert-ブチル 4-[6-メトキシ-5-(3-メチル-1H-1,2,4-トリアゾール-1-イル)ピリジン-2-イル]ピペラジン-1-カルボキシラート Reference Example 65
tert-Butyl 4- [6-methoxy-5- (3-methyl-1H-1,2,4-triazol-1-yl) pyridin-2-yl] piperazine-1-carboxylate
65a) 6-クロロ-2-メトキシ-3-ニトロピリジン
　水素化ナトリウム(2.3 g, 57 mmol)のキシレン (100 mL) 懸濁液にメタノール(2.1 mL)のキシレン(30 mL)溶液を0 ℃で加え、0 ℃で20分間攪拌した。反応溶液に2,6-ジクロロ-3-ニトロピリジン(10 g, 52 mmol)のキシレン(150 mL)溶液を0 ℃で加え、室温で15時間攪拌した。反応混合物を水で希釈し、有機層を分離した。得られた有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/9)で精製し、題記化合物を無色固体(7.9 g, 80%)として得た。
NMR (CDCl3) δ: 4.14 (3 H, s), 7.05 (1 H, d, J=8.3 Hz), 8.28 (1 H, d, J=8.3 Hz). 65a) 6-Chloro-2-methoxy-3-nitropyridine Sodium hydride (2.3 g, 57 mmol) in xylene (100 mL) suspension of methanol (2.1 mL) in xylene (30 mL) at 0 ° C In addition, the mixture was stirred at 0 ° C. for 20 minutes. To the reaction solution, a solution of 2,6-dichloro-3-nitropyridine (10 g, 52 mmol) in xylene (150 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and the organic layer was separated. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/9) to give the title compound as a colorless solid (7.9 g, 80%).
NMR (CDCl 3 ) δ: 4.14 (3 H, s), 7.05 (1 H, d, J = 8.3 Hz), 8.28 (1 H, d, J = 8.3 Hz).
65b) 6-クロロ-2-メトキシピリジン-3-アミン
　6-クロロ-2-メトキシ-3-ニトロピリジン(8.6 g, 46 mmol)のEtOH(100 mL)懸濁液に鉄(7.6 g, 140 mmol)及び酢酸 (20 mL)を滴下し、室温で1.5時間攪拌した。反応溶液をセライトろ過後、ろ液を飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を淡黄色固体(5.9 g, 82%)として得た。
LC/MS 159
NMR (CDCl3) δ: 3.75 (2 H, brs), 3.99 (3 H, s), 6.72 (1 H, d, J=7.9 Hz), 6.84 (1H, d, J=7.9 Hz). 65b) 6-chloro-2-methoxypyridin-3-amine 6-chloro-2-methoxy-3-nitropyridine (8.6 g, 46 mmol) in EtOH (100 mL) suspension in iron (7.6 g, 140 mmol) ) And acetic acid (20 mL) were added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was filtered through celite, and the filtrate was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to ethyl acetate / hexane = 2/3) to give the title compound as a pale yellow solid (5.9 g, 82%).
LC / MS 159
NMR (CDCl 3 ) δ: 3.75 (2 H, brs), 3.99 (3 H, s), 6.72 (1 H, d, J = 7.9 Hz), 6.84 (1H, d, J = 7.9 Hz).
65c) 6-クロロ-2-メトキシ-3-(3-メチル-1H-1,2,4-トリアゾール-1-イル)ピリジン
　6-クロロ-2-メトキシピリジン-3-アミン(5.0 g, 32 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(2.3 g, 33 mmol)の水(3.0 mL)溶液を－20 ℃で加え、0 ℃で30分間攪拌した。反応混合物を塩化すず(22 g, 120 mmol)の濃塩酸(20 mL)溶液中に－20 ℃で滴下し、室温で1時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固体及びメチル エタンイミドチオアート　ヨウ化水素酸塩(6.8 g, 32 mmol) のMeOH(25 mL)溶液にトリエチルアミン(6.6 mL, 47 mmol)を0 ℃で滴下し、室温で10分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸トリメチル(15 mL)、ピリジン(15 mL)を加え、100 ℃で5時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(1.7 g, 24%(2 steps))として得た。
LC/MS 225
NMR (CDCl3) δ: 2.48 (3 H, s), 4.12 (3 H, s), 7.07 (1 H, d, J=8.3 Hz), 8.13 (1 H, d, J=8.3 Hz), 8.76 (1 H, s). 65c) 6-Chloro-2-methoxy-3- (3-methyl-1H-1,2,4-triazol-1-yl) pyridine 6-chloro-2-methoxypyridin-3-amine (5.0 g, 32 mmol ) In concentrated hydrochloric acid (20 mL) was added sodium nitrite (2.3 g, 33 mmol) in water (3.0 mL) at −20 ° C., and the mixture was stirred at 0 ° C. for 30 min. The reaction mixture was added dropwise to a solution of tin chloride (22 g, 120 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with diethyl ether. Triethylamine (6.6 mL, 47 mmol) was added dropwise at 0 ° C to a solution of the obtained solid and methyl ethaneimidothioate hydroiodide (6.8 g, 32 mmol) in MeOH (25 mL) and stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure. Trimethyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (1.7 g, 24% (2 steps)).
LC / MS 225
NMR (CDCl 3 ) δ: 2.48 (3 H, s), 4.12 (3 H, s), 7.07 (1 H, d, J = 8.3 Hz), 8.13 (1 H, d, J = 8.3 Hz), 8.76 (1 H, s).
65d) tert-ブチル 4-[6-メトキシ-5-(3-メチル-1H-1,2,4-トリアゾール-1-イル)ピリジン-2-イル]ピペラジン-1-カルボキシラート
　6-クロロ-2-メトキシ-3-(3-メチル-1H-1,2,4-トリアゾール-1-イル)ピリジン(300 mg, 1.3 mmol)の1-メチル-2-ピロリドン(3.0 mL)溶液に炭酸カリウム(220 mg, 1.6 mmol)及びtert-ブチル ピペラジン-1-カルボキシラート(250 mg, 1.3 mmol)を加え、100 ℃で16時間、続いて130 ℃で5.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～7/3)で精製し、題記化合物を黄色非定形固体(51 mg, 10%)として得た。
LC/MS 375
NMR (CDCl3) δ: 1.49 (9 H, s), 2.47 (3 H, s), 3.56 (8 H, s), 3.98 (3 H, s), 6.26 (1 H, d, J=8.7 Hz), 7.82 (1 H, d, J=8.7 Hz), 8.49 (1 H, s). 65d) tert-butyl 4- [6-methoxy-5- (3-methyl-1H-1,2,4-triazol-1-yl) pyridin-2-yl] piperazine-1-carboxylate 6-chloro-2 2-Methoxy-3- (3-methyl-1H-1,2,4-triazol-1-yl) pyridine (300 mg, 1.3 mmol) in 1-methyl-2-pyrrolidone (3.0 mL) was added to potassium carbonate (220 mg, 1.6 mmol) and tert-butyl piperazine-1-carboxylate (250 mg, 1.3 mmol) were added, and the mixture was stirred at 100 ° C. for 16 hours and subsequently at 130 ° C. for 5.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 9-7 / 3) to give the title compound as a yellow amorphous solid (51 mg, 10%).
LC / MS 375
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.47 (3 H, s), 3.56 (8 H, s), 3.98 (3 H, s), 6.26 (1 H, d, J = 8.7 Hz ), 7.82 (1 H, d, J = 8.7 Hz), 8.49 (1 H, s).
参考例６６
4-ベンジル-1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン Reference Example 66
4-Benzyl-1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepane
66a) 1-ベンジル-3-メチル-1,4-ジアゼパン
　1-ベンジル-3-メチルピペリジン-4-オン(4.7 g, 23 mmol)のクロロホルム(50 mL)溶液に0 ℃で濃硫酸(12 mL, 230 mmol)を滴下して加えた。この混合物にアジ化ナトリウム(3.0 g, 46 mmol)を少しずつ加えて、0 ℃で1時間攪拌し、次に50 ℃で４時間攪拌した。反応混合物を0 ℃に冷却し、氷水を加え、炭酸カリウムを加えて反応混合物を塩基性にし、室温で終夜攪拌した。有機層を分離し、水層を酢酸エチル、クロロホルムの順で抽出した。抽出液を合わせて無水硫酸マグネシウムで乾燥し、溶媒を留去して淡黄色固体(5.1 g)を得た。水素化リチウムアルミニウム(780 mg, 21 mmol)のTHF(30 mL)懸濁液に、先に得られた固体の一部(1.5 g)のTHF(30 mL)溶液を0 ℃で滴下し、室温で2日攪拌した。反応混合物に硫酸ナトリウム10水和物(7.8 g)を0 ℃で加え、室温で1時間攪拌した。反応混合物をセライトろ過後、ろ液を減圧留去し、題記化合物を無色油状物(1.4 g, quant.)として得た。
LC/MS 205
NMR (CDCl3) δ: 0.98 (3 H, d, J=6.4 Hz), 1.66 - 1.87 (2 H, m), 2.20 - 2.38 (1 H, m), 2.52 - 3.15 (7 H, m), 3.66 (2 H, s), 7.27 - 7.41 (5 H, m). 66a) 1-Benzyl-3-methyl-1,4-diazepan Concentrated sulfuric acid (12 mL) at 0 ° C in a solution of 1-benzyl-3-methylpiperidin-4-one (4.7 g, 23 mmol) in chloroform (50 mL) , 230 mmol) was added dropwise. To this mixture was added sodium azide (3.0 g, 46 mmol) little by little, and the mixture was stirred at 0 ° C for 1 hour, and then stirred at 50 ° C for 4 hours. The reaction mixture was cooled to 0 ° C., ice water was added, potassium carbonate was added to basify the reaction mixture and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was extracted in the order of ethyl acetate and chloroform. The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a pale yellow solid (5.1 g). To a suspension of lithium aluminum hydride (780 mg, 21 mmol) in THF (30 mL), a solution of a portion of the solid (1.5 g) obtained above in THF (30 mL) was added dropwise at 0 ° C, For 2 days. Sodium sulfate decahydrate (7.8 g) was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound as a colorless oil (1.4 g, quant.).
LC / MS 205
NMR (CDCl 3 ) δ: 0.98 (3 H, d, J = 6.4 Hz), 1.66-1.87 (2 H, m), 2.20-2.38 (1 H, m), 2.52-3.15 (7 H, m), 3.66 (2 H, s), 7.27-7.41 (5 H, m).
66b) 4-ベンジル-1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(270 mg, 1.0 mmol)、1-ベンジル-3-メチル-1,4-ジアゼパン(390 mg, 1.0 mmol)、DavePhos(39 mg, 0.10 mmol)及びナトリウム tert-ブトキシド(140 mg, 1.5 mmol)のトルエン(2.5 mL)溶液に窒素雰囲気下、Pd2(dba)3(46 mg, 0.05 mmol)を加え、90 ℃で17時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～4/1)で精製し、題記化合物を黄色油状物(77 mg, 20%)として得た。
LC/MS 392
NMR (CDCl3) δ: 1.04 (3 H, d, J=6.4 Hz), 2.50 (3 H, s), 2.54 - 2.72 (3 H, m), 2.93 - 3.11 (2 H, m), 3.23 - 3.46 (2 H, m), 3.47 - 3.73 (4 H, m), 3.79 - 4.02 (4 H, m), 6.26 (1 H, d, J=2.3 Hz), 6.38 (1 H, dd, J=8.9, 2.3 Hz), 7.16 (1 H, s), 7.21 - 7.25 (1 H, m), 7.27 - 7.31 (3 H, m), 7.56 (1 H, d, J=8.7 Hz). 66b) 4-Benzyl-1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepane 5- (4-bromo-2 -Methoxyphenyl) -2-methyl-1,3-oxazole (270 mg, 1.0 mmol), 1-benzyl-3-methyl-1,4-diazepane (390 mg, 1.0 mmol), DavePhos (39 mg, 0.10 mmol) ) And sodium tert-butoxide (140 mg, 1.5 mmol) in toluene (2.5 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (46 mg, 0.05 mmol) was added, and the mixture was stirred at 90 ° C. for 17 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 4/1) to give the title compound as a yellow oil (77 mg, 20%).
LC / MS 392
NMR (CDCl 3 ) δ: 1.04 (3 H, d, J = 6.4 Hz), 2.50 (3 H, s), 2.54-2.72 (3 H, m), 2.93-3.11 (2 H, m), 3.23- 3.46 (2 H, m), 3.47-3.73 (4 H, m), 3.79-4.02 (4 H, m), 6.26 (1 H, d, J = 2.3 Hz), 6.38 (1 H, dd, J = 8.9, 2.3 Hz), 7.16 (1 H, s), 7.21-7.25 (1 H, m), 7.27-7.31 (3 H, m), 7.56 (1 H, d, J = 8.7 Hz).
参考例６７
tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン-1-カルボキシラート Reference Example 67
tert-butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepane-1-carboxylate
67a) tert-ブチル 4-ベンジル-2-メチル-1,4-ジアゼパン-1-カルボキシラート
　1-ベンジル-3-メチル-1,4-ジアゼパン(410 mg, 2.0 mmol)のTHF(10 mL)溶液に0 ℃で炭酸カリウム(300 mg, 2.2 mmol)及びジtert-ブチル　ジカルボネート(510 μL, 2.2 mmol)を加え、室温で5時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/4)で精製し、題記化合物を無色油状物(530 mg, 87%)として得た。
LC/MS 305
NMR (CDCl3) δ: 0.88 - 0.99 (3 H, m), 1.45 - 1.48 (1 H, m), 1.47 - 1.54 (9 H, m), 1.72 - 2.03 (1 H, m), 2.31 - 2.45 (1 H, m), 2.44 - 2.61 (1 H, m), 2.76 - 3.03 (3 H, m), 3.54 - 3.97 (3 H, m), 4.02 - 4.42 (1 H, m), 7.21 - 7.44 (5 H, m). 67a) tert-butyl 4-benzyl-2-methyl-1,4-diazepane-1-carboxylate 1-benzyl-3-methyl-1,4-diazepane (410 mg, 2.0 mmol) in THF (10 mL) To the mixture were added potassium carbonate (300 mg, 2.2 mmol) and ditert-butyl dicarbonate (510 μL, 2.2 mmol) at 0 ° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/4) to give the title compound as a colorless oil (530 mg, 87%).
LC / MS 305
NMR (CDCl 3 ) δ: 0.88-0.99 (3 H, m), 1.45-1.48 (1 H, m), 1.47-1.54 (9 H, m), 1.72-2.03 (1 H, m), 2.31-2.45 (1 H, m), 2.44-2.61 (1 H, m), 2.76-3.03 (3 H, m), 3.54-3.97 (3 H, m), 4.02-4.42 (1 H, m), 7.21-7.44 (5 H, m).
67b) tert-ブチル 2-メチル-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 4-ベンジル-2-メチル-1,4-ジアゼパン-1-カルボキシラート(530 mg, 1.7 mmol)のMeOH(15 mL)溶液に10%パラジウムカーボン(53 mg)を加え、室温で水素雰囲気下、13時間攪拌した。反応混合物を濾過し、溶媒を減圧留去し、題記化合物を無色油状物(350mg, 94%)として得た。
LC/MS 215
NMR (CDCl3) δ: 1.01 (3 H, d, J=6.4 Hz), 1.43 - 1.52 (11 H, m), 1.65 - 1.71 (1 H, m), 2.25 - 2.65 (2 H, m), 2.71 - 2.96 (1 H, m), 3.01 - 3.39 (2 H, m), 3.62 - 3.98 (1 H, m), 3.98 - 4.37 (1 H, m). 67b) tert-butyl 2-methyl-1,4-diazepane-1-carboxylate tert-butyl 4-benzyl-2-methyl-1,4-diazepane-1-carboxylate (530 mg, 1.7 mmol) in MeOH ( 15%) 10% palladium carbon (53 mg) was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere for 13 hours. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (350 mg, 94%).
LC / MS 215
NMR (CDCl 3 ) δ: 1.01 (3 H, d, J = 6.4 Hz), 1.43-1.52 (11 H, m), 1.65-1.71 (1 H, m), 2.25-2.65 (2 H, m), 2.71-2.96 (1 H, m), 3.01-3.39 (2 H, m), 3.62-3.98 (1 H, m), 3.98-4.37 (1 H, m).
67c) tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-メチル-1,4-ジアゼパン-1-カルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(350 mg, 1.3 mmol)、tert-ブチル 2-メチル-1,4-ジアゼパン-1-カルボキシラート(280 mg, 1.3 mmol)、DavePhos(51 mg, 0.13 mmol)及びナトリウム tert-ブトキシド(190 mg, 1.9 mmol)のトルエン(3.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(60 mg, 0.065 mmol)を加え、90 ℃で15.5時間攪拌した。反応混合物を室温まで冷却後、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/9～7/3)で精製し、題記化合物を黄色非定形固体(340 mg, 66%)として得た。
LC/MS 402
NMR (CDCl3) δ: 0.99 - 1.18 (9 H, m), 1.28 (2 H, brs), 1.56 (5 H, s), 2.49 (3 H, s), 2.76 - 3.18 (3 H, m), 3.83 - 4.12 (5 H, m), 6.25 (1 H, d, J=2.3 Hz), 6.36 (1 H, dd, J=8.7, 2.3 Hz), 7.12 - 7.17 (1 H, m), 7.49 (1 H, d, J=8.7 Hz). 67c) tert-butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-methyl-1,4-diazepane-1-carboxylate 5- (4 -Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole (350 mg, 1.3 mmol), tert-butyl 2-methyl-1,4-diazepane-1-carboxylate (280 mg, 1.3 mmol) Pd 2 (dba) 3 (60 mg, 0.065 mmol) was added to a toluene (3.0 mL) solution of DavePhos (51 mg, 0.13 mmol) and sodium tert-butoxide (190 mg, 1.9 mmol) under a nitrogen atmosphere, and 90 The mixture was stirred at ° C for 15.5 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 9-7 / 3) to give the title compound as a yellow amorphous solid (340 mg, 66%).
LC / MS 402
NMR (CDCl 3 ) δ: 0.99-1.18 (9 H, m), 1.28 (2 H, brs), 1.56 (5 H, s), 2.49 (3 H, s), 2.76-3.18 (3 H, m) , 3.83-4.12 (5 H, m), 6.25 (1 H, d, J = 2.3 Hz), 6.36 (1 H, dd, J = 8.7, 2.3 Hz), 7.12-7.17 (1 H, m), 7.49 (1 H, d, J = 8.7 Hz).
参考例６８
tert-ブチル 4-[4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート Reference Example 68
tert-butyl 4- [4-methoxy-5- (2-methyl-1,3-oxazol-5-yl) pyrimidin-2-yl] piperazine-1-carboxylate
68a) N,4-ジメトキシ-N-メチル-2-(メチルスルファニル)ピリミジン-5-カルボキサミド
　エチル4-クロロ-2-(メチルスルファニル)ピリミジン-5-カルボキシラート(9.3 g, 40 mmol)のMeOH(100 mL)溶液に28%ナトリウムメトキシドMeOH溶液(7.7 g, 40 mmol) のMeOH(20 mL)溶液を0 ℃で加え、室温で3時間攪拌した。さらに、反応溶液に28%ナトリウムメトキシドMeOH溶液(9.2 g, 48 mmol)のMeOH(25 mL)溶液を0 ℃で加え、室温で20時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物のDMF(35 mL)溶液にN,O-ジメトキシヒドロキシルアミン　1塩酸塩(2.5 g, 26 mmol)、HOBt(3.5 g, 26 mmol)、N-エチルジイソプロピルアミン(13 mL, 78 mmol)、およびWSC(5.0 g, 26 mmol)を加え、室温で15時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色油状物(1.8 g,18%(2 steps))として得た。
LC/MS 244
NMR (CDCl3) δ: 2.58 (3 H, s), 3.33 (3 H, s), 3.57 (3 H, s), 4.04 (3 H, s), 8.31 (1 H, s). 68a) N, 4-Dimethoxy-N-methyl-2- (methylsulfanyl) pyrimidine-5-carboxamide Ethyl 4-chloro-2- (methylsulfanyl) pyrimidine-5-carboxylate (9.3 g, 40 mmol) in MeOH ( 100 mL) solution was added 28% sodium methoxide MeOH solution (7.7 g, 40 mmol) in MeOH (20 mL) at 0 ° C. and stirred at room temperature for 3 hours. Further, a 28% sodium methoxide MeOH solution (9.2 g, 48 mmol) in MeOH (25 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (35 mL), N, O-dimethoxyhydroxylamine monohydrochloride (2.5 g, 26 mmol), HOBt (3.5 g, 26 mmol), N-ethyldiisopropylamine (13 mL, 78 mmol) and WSC (5.0 g, 26 mmol) were added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless oil (1.8 g, 18% (2 steps)).
LC / MS 244
NMR (CDCl 3 ) δ: 2.58 (3 H, s), 3.33 (3 H, s), 3.57 (3 H, s), 4.04 (3 H, s), 8.31 (1 H, s).
68b) 1-[4-メトキシ-2-(メチルスルファニル)ピリミジン-5-イル]エタノン
　N,4-ジメトキシ-N-メチル-2-(メチルスルファニル)ピリミジン-5-カルボキサミド(1.7 g, 11 mmol)のTHF(20 mL)溶液に1Mメチルマグネシウムブロマイド THF溶液(11 mL, 91 mmol)を0 ℃で滴下し、室温で5時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝7/3)で精製し、題記化合物を無色固体(1.3 g, 93%)として得た。
LC/MS 199
NMR (CDCl3) δ: 2.58 (3 H, s), 2.60 (3 H, s), 4.11 (3 H, s), 8.77 (1 H, s). 68b) 1- [4-Methoxy-2- (methylsulfanyl) pyrimidin-5-yl] ethanone N, 4-dimethoxy-N-methyl-2- (methylsulfanyl) pyrimidine-5-carboxamide (1.7 g, 11 mmol) 1M methylmagnesium bromide THF solution (11 mL, 91 mmol) was added dropwise to a THF (20 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate / hexane = 7/3) to give the title compound as a colorless solid (1.3 g, 93%).
LC / MS 199
NMR (CDCl 3 ) δ: 2.58 (3 H, s), 2.60 (3 H, s), 4.11 (3 H, s), 8.77 (1 H, s).
68c) 4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)-2-(メチルスルファニル)ピリミジン
　ヨードベンゼンジアセテート(1.7 g, 5.3 mmol)のアセトニトリル(25 mL) 懸濁液にトリフルオロメタンスルホン酸 (0.94 mL, 11 mmol)を滴下し、室温で30分間攪拌した。反応混合物に1-[4-メトキシ-2-(メチルスルファニル)ピリミジン-5-イル]エタノン(700 mg, 3.5 mmol)のアセトニトリル(10 mL)溶液を加え、加熱還流下4時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で中和した後、溶媒を減圧留去した。残留物を酢酸エチルで抽出し、得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を淡黄色固体(550 mg, 65%)として得た。
LC/MS 238
NMR (CDCl3) δ: 2.54 (3 H, s), 2.60 (3 H, s), 4.14 (3 H, s), 7.33 (1 H, s), 8.63 (1 H, s). 68c) Suspension of 4-methoxy-5- (2-methyl-1,3-oxazol-5-yl) -2- (methylsulfanyl) pyrimidine iodobenzene diacetate (1.7 g, 5.3 mmol) in acetonitrile (25 mL) Trifluoromethanesulfonic acid (0.94 mL, 11 mmol) was added dropwise to the solution, and the mixture was stirred at room temperature for 30 minutes. A solution of 1- [4-methoxy-2- (methylsulfanyl) pyrimidin-5-yl] ethanone (700 mg, 3.5 mmol) in acetonitrile (10 mL) was added to the reaction mixture, and the mixture was stirred with heating under reflux for 4 hours. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a pale yellow solid (550 mg, 65%).
LC / MS 238
NMR (CDCl 3 ) δ: 2.54 (3 H, s), 2.60 (3 H, s), 4.14 (3 H, s), 7.33 (1 H, s), 8.63 (1 H, s).
68d) 4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)-2-(メチルスルホニル)ピリミジン
　4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)-2-(メチルスルファニル)ピリミジン(420 mg, 1.8 mmol)のアセトニトリル(8.0 mL)溶液にm-クロロ過安息香酸(1.3 g, 5.3 mmol)を0 ℃加え、室温で2時間攪拌した。反応混合物を飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～9/1)で精製し、題記化合物を無色固体(190 mg, 39%)として得た。
LC/MS 270
NMR (CDCl3) δ: 2.60 (3 H, s), 3.37 (3 H, s), 4.29 (3 H, s), 7.60 (1 H, s), 8.92 (1 H, s). 68d) 4-Methoxy-5- (2-methyl-1,3-oxazol-5-yl) -2- (methylsulfonyl) pyrimidine 4-methoxy-5- (2-methyl-1,3-oxazole-5- To a solution of yl) -2- (methylsulfanyl) pyrimidine (420 mg, 1.8 mmol) in acetonitrile (8.0 mL) was added m-chloroperbenzoic acid (1.3 g, 5.3 mmol) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-9 / 1) to give the title compound as a colorless solid (190 mg, 39%).
LC / MS 270
NMR (CDCl 3 ) δ: 2.60 (3 H, s), 3.37 (3 H, s), 4.29 (3 H, s), 7.60 (1 H, s), 8.92 (1 H, s).
68e) tert-ブチル 4-[4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)ピリミジン-2-イル]ピペラジン-1-カルボキシラート
　4-メトキシ-5-(2-メチル-1,3-オキサゾール-5-イル)-2-(メチルスルホニル)ピリミジン(110 mg, 0.39 mmol)のDMF(3.0 mL)溶液に炭酸カリウム(82 mg, 0.59 mmol)及びtert-ブチル ピペラジン-1-カルボキシラート(88 mg, 0.47 mmol)を加え、80 ℃で5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝2/3)で精製し、題記化合物を無色固体(84 mg, 57%)として得た。
LC/MS 376
NMR (CDCl3) δ: 1.49 (9 H, s), 2.50 (3 H, s), 3.42 - 3.62 (4 H, m), 3.79 - 3.91 (4 H, m), 4.04 (3 H, s), 7.13 (1 H, s), 8.45 (1 H, s). 68e) tert-Butyl 4- [4-methoxy-5- (2-methyl-1,3-oxazol-5-yl) pyrimidin-2-yl] piperazine-1-carboxylate 4-methoxy-5- (2- To a solution of methyl-1,3-oxazol-5-yl) -2- (methylsulfonyl) pyrimidine (110 mg, 0.39 mmol) in DMF (3.0 mL) was added potassium carbonate (82 mg, 0.59 mmol) and tert-butyl piperazine- 1-Carboxylate (88 mg, 0.47 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (84 mg, 57%).
LC / MS 376
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 2.50 (3 H, s), 3.42-3.62 (4 H, m), 3.79-3.91 (4 H, m), 4.04 (3 H, s) , 7.13 (1 H, s), 8.45 (1 H, s).
参考例６９
1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン Reference Example 69
1- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepan
69a) ベンジル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール (5.0 g, 19 mmol)、ベンジル 1,4-ジアゼパン-1-カルボキシラート (4.6 mL, 22 mmol)、DavePhos (0.73 g, 1.9 mmol)及びカリウム tert-ブトキシド (3.1 g, 28 mmol)のトルエン (40 mL)溶液に窒素雰囲気下、Pd2(dba)3 (0.85 g, 0.93 mmol)を加え、100 ℃で終夜攪拌した。反応混合物をセライトろ過し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝3/2～3/7)で精製し、題記化合物を黄色固体(2.7 g, 34%)として得た。
LC/MS 422
NMR (CDCl3) δ: 1.90 - 2.09 (2 H, m), 2.50 (3 H, s), 3.34 (1 H, t, J=6.2 Hz), 3.41 (1 H, t, J=5.9 Hz), 3.50 - 3.77 (6 H, m), 3.81 - 3.96 (3 H, m), 5.03 - 5.17 (2 H, m), 6.23 (1 H, dd, J=5.4, 2.3 Hz), 6.29 - 6.41 (1 H, m), 7.12 - 7.21 (1 H, m), 7.26 - 7.42 (5 H, m), 7.53 (1 H, dd, J=8.7, 2.1 Hz). 69a) Benzyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate 5- (4-bromo-2-methoxy Phenyl) -2-methyl-1,3-oxazole (5.0 g, 19 mmol), benzyl 1,4-diazepane-1-carboxylate (4.6 mL, 22 mmol), DavePhos (0.73 g, 1.9 mmol) and potassium tert To a solution of -butoxide (3.1 g, 28 mmol) in toluene (40 mL) was added Pd 2 (dba) 3 (0.85 g, 0.93 mmol) in a nitrogen atmosphere, and the mixture was stirred at 100 ° C. overnight. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 2-3 / 7) to give the title compound as a yellow solid (2.7 g, 34%).
LC / MS 422
NMR (CDCl 3 ) δ: 1.90-2.09 (2 H, m), 2.50 (3 H, s), 3.34 (1 H, t, J = 6.2 Hz), 3.41 (1 H, t, J = 5.9 Hz) , 3.50-3.77 (6 H, m), 3.81-3.96 (3 H, m), 5.03-5.17 (2 H, m), 6.23 (1 H, dd, J = 5.4, 2.3 Hz), 6.29-6.41 ( 1 H, m), 7.12-7.21 (1 H, m), 7.26-7.42 (5 H, m), 7.53 (1 H, dd, J = 8.7, 2.1 Hz).
69b) 1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン
　ベンジル4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1,4-ジアゼパン-1-カルボキシラート (2.7 g, 6.3 mmol)のTHF (30 mL)溶液にPd/C (10%, 0.27 g)を加え、約1気圧の水素雰囲気下、室温で3時間撹拌した。反応混合物をろ過後、溶媒を減圧留去し、題記化合物を褐色油状物(1.7 g, 92%)として得た。
LC/MS 287
NMR (CDCl3) δ: 1.83 - 2.00 (2 H, m), 2.49 (3 H, s), 2.77 - 2.91 (2 H, m), 2.97 - 3.14 (2 H, m), 3.49 - 3.72 (4 H, m), 3.92 (3 H, s), 6.25 (1 H, d, J=2.5 Hz), 6.36 (1 H, dd, J=8.8, 2.5 Hz), 7.15 (1 H, s), 7.52 (1 H, d, J=8.8 Hz). 69b) 1- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1,4-diazepane benzyl 4- [3-methoxy-4- (2-methyl-1) , 3-Oxazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate (2.7 g, 6.3 mmol) in THF (30 mL) was added Pd / C (10%, 0.27 g), The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere of about 1 atm. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (1.7 g, 92%).
LC / MS 287
NMR (CDCl 3 ) δ: 1.83-2.00 (2 H, m), 2.49 (3 H, s), 2.77-2.91 (2 H, m), 2.97-3.14 (2 H, m), 3.49-3.72 (4 H, m), 3.92 (3 H, s), 6.25 (1 H, d, J = 2.5 Hz), 6.36 (1 H, dd, J = 8.8, 2.5 Hz), 7.15 (1 H, s), 7.52 (1 H, d, J = 8.8 Hz).
参考例７０
1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン
　tert-ブチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート (4.0 g, 11 mmol)の酢酸エチル (100 mL)溶液に4N塩酸酢酸エチル溶液(50 mL)を加え、室温で終夜撹拌した。溶媒を減圧留去した後、得られた残留物を酢酸エチルで洗浄した。得られた残留物を水に溶解させた後、8M水酸化ナトリウム水溶液を加え塩基性にし、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、題記化合物を淡黄色固体 (2.7 g, 93%)として得た。
NMR (CDCl3) δ: 2.50 (3 H, s), 2.98 - 3.09 (4 H, m), 3.14 - 3.25 (4 H, m), 3.93 (3 H, s), 6.49 (1 H, d, J=2.2 Hz), 6.56 (1 H, dd, J=8.7, 2.3 Hz), 7.23 (1 H, s), 7.58 (1 H, d, J=8.5 Hz). Reference Example 70
1- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine tert-butyl 4- [3-methoxy-4- (2-methyl-1,3-oxazole- To a solution of 5-yl) phenyl] piperazine-1-carboxylate (4.0 g, 11 mmol) in ethyl acetate (100 mL) was added 4N hydrochloric acid ethyl acetate solution (50 mL), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the obtained residue was washed with ethyl acetate. The obtained residue was dissolved in water, basified with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (2.7 g, 93%).
NMR (CDCl 3 ) δ: 2.50 (3 H, s), 2.98-3.09 (4 H, m), 3.14-3.25 (4 H, m), 3.93 (3 H, s), 6.49 (1 H, d, J = 2.2 Hz), 6.56 (1 H, dd, J = 8.7, 2.3 Hz), 7.23 (1 H, s), 7.58 (1 H, d, J = 8.5 Hz).
参考例７１
1-(2-エチルピラゾロ[1,5-a]ピリジン-3-イル)メタンアミン
　3-(アジドメチル)-2-エチルピラゾロ[1,5-a]ピリジン(210 mg, 1.04 mmol)、トリフェニルホスフィン(409 mg, 1.56 mmol)および水(500 μL)のTHF(5 mL)混合液を60℃で2時間攪拌後、酢酸エチルで希釈した。この混合液を1N塩酸で抽出した。抽出液をジエチルエーテルで洗浄し、飽和炭酸水素ナトリウム水溶液で中和した後に、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、題記化合物を無色液体(161 mg, 88%)として得た。
NMR (CDCl3) δ: 1.37 (3 H, t, J=7.6 Hz), 2.87 (2 H, q, J=7.6 Hz), 3.99 (2 H, s), 6.61 - 6.68 (1 H, m), 7.01 - 7.09 (1 H, m), 7.46 - 7.52 (1 H, m), 8.35 (1 H, d, J=6.9 Hz). Reference Example 71
1- (2-ethylpyrazolo [1,5-a] pyridin-3-yl) methanamine 3- (azidomethyl) -2-ethylpyrazolo [1,5-a] pyridine (210 mg, 1.04 mmol), triphenylphosphine (409 mg, 1.56 mmol) and water (500 μL) in THF (5 mL) were stirred at 60 ° C. for 2 hours, and then diluted with ethyl acetate. This mixture was extracted with 1N hydrochloric acid. The extract was washed with diethyl ether, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless liquid (161 mg, 88%).
NMR (CDCl 3 ) δ: 1.37 (3 H, t, J = 7.6 Hz), 2.87 (2 H, q, J = 7.6 Hz), 3.99 (2 H, s), 6.61-6.68 (1 H, m) , 7.01-7.09 (1 H, m), 7.46-7.52 (1 H, m), 8.35 (1 H, d, J = 6.9 Hz).
参考例７２
3-(アジドメチル)-2-エチルピラゾロ[1,5-a]ピリジン
　ボロントリフルオリドエチルエーテルコンプレックス(540 μL, 4.26 mmol)をトリメチルシリルアジド(754 μL, 5.68 mmol)のクロロベンゼン(7 mL)溶液に0℃で加えて、室温で15分間攪拌した。この反応液に、(2-エチルピラゾロ[1,5-a]ピリジン-3-イル)メタノール(250 mg, 1.42 mmol)のクロロベンゼン(1.5 mL)溶液を室温で滴下し、室温で20分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0/10～3/7)で精製し、題記化合物を無色液体(210 mg, 73%)として得た。
LC/MS 202
NMR (CDCl3) δ: 1.38 (3 H, t, J=7.7 Hz), 2.88 (2 H, q, J=7.7 Hz), 4.50 (2 H, s), 6.69 - 6.81 (1 H, m), 7.10 - 7.19 (1 H, m), 7.45 - 7.52 (1 H, m), 8.39 (1 H, d, J=6.9 Hz). Reference Example 72
3- (Azidomethyl) -2-ethylpyrazolo [1,5-a] pyridine Boron trifluoride ethyl ether complex (540 μL, 4.26 mmol) was added to a solution of trimethylsilyl azide (754 μL, 5.68 mmol) in chlorobenzene (7 mL) at 0 ° C. And stirred at room temperature for 15 minutes. To this reaction solution, a solution of (2-ethylpyrazolo [1,5-a] pyridin-3-yl) methanol (250 mg, 1.42 mmol) in chlorobenzene (1.5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 20 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 10-3 / 7) to give the title compound as a colorless liquid (210 mg, 73%).
LC / MS 202
NMR (CDCl 3 ) δ: 1.38 (3 H, t, J = 7.7 Hz), 2.88 (2 H, q, J = 7.7 Hz), 4.50 (2 H, s), 6.69-6.81 (1 H, m) , 7.10-7.19 (1 H, m), 7.45-7.52 (1 H, m), 8.39 (1 H, d, J = 6.9 Hz).
参考例７３
(2-エチルピラゾロ[1,5-a]ピリジン-3-イル)メタノール
　エチル2-エチルピラゾロ[1,5-a]ピリジン-3-カルボキシラート(900 mg, 4.13 mmol)のTHF(9 mL)溶液をリチウムアルミニウムヒドリド(627 mg, 16.5 mmol)のTHF(9 mL)懸濁液に0℃で滴下し、室温で20分間攪拌した。反応液に硫酸ナトリウム十水和物(6 g)を0℃で加え、生じた混合物をろ過し、溶媒を減圧留去し、題記化合物を黄色液体(730 mg, 100%)として得た。
LC/MS 177
NMR (CDCl3) δ: 1.37 (3 H, t, J=7.8 Hz), 2.89 (2 H, q, J=7.8 Hz), 4.83 (2 H, s), 6.66 - 6.73 (1 H, m), 7.07 - 7.15 (1 H, m), 7.49 - 7.56 (1 H, m), 8.34 - 8.40 (1 H, m). Reference Example 73
(2-ethylpyrazolo [1,5-a] pyridin-3-yl) methanol Ethyl 2-ethylpyrazolo [1,5-a] pyridine-3-carboxylate (900 mg, 4.13 mmol) in THF (9 mL) To a suspension of lithium aluminum hydride (627 mg, 16.5 mmol) in THF (9 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Sodium sulfate decahydrate (6 g) was added to the reaction mixture at 0 ° C., the resulting mixture was filtered, and the solvent was evaporated under reduced pressure to give the title compound as a yellow liquid (730 mg, 100%).
LC / MS 177
NMR (CDCl 3 ) δ: 1.37 (3 H, t, J = 7.8 Hz), 2.89 (2 H, q, J = 7.8 Hz), 4.83 (2 H, s), 6.66-6.73 (1 H, m) , 7.07-7.15 (1 H, m), 7.49-7.56 (1 H, m), 8.34-8.40 (1 H, m).
参考例７４
メチル2-(5,6-ジクロロ-2-エチル-1H-ベンゾイミダゾール-1-イル)プロパノアート
　5,6-ジクロロ-2-エチル-1H-ベンゾイミダゾール(500 mg, 2.32 mmol)、メチル 2-ブロモプロパノアート(311 μL, 2.79 mmol)および炭酸セシウム(2.27 g, 6.97 mmol)のDMF(5 mL)混合液を室温で2時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0/10～5/5)で精製し、題記化合物を褐色液体 (673 mg, 96%)として得た。
LC/MS 301
NMR (CDCl3) δ: 1.46 (3 H, t, J=7.6 Hz), 1.80 (3 H, d, J=7.1 Hz), 2.88 (2 H, q, J=7.6 Hz), 3.75 (3 H, s), 5.09 (1 H, q, J=7.1 Hz), 7.38 (1 H, s), 7.79 (1 H, s). Reference Example 74
Methyl 2- (5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl) propanoate 5,6-dichloro-2-ethyl-1H-benzimidazole (500 mg, 2.32 mmol), methyl 2-bromo A mixture of propanoate (311 μL, 2.79 mmol) and cesium carbonate (2.27 g, 6.97 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0 / 10-5 / 5) to give the title compound as a brown liquid (673 mg, 96%).
LC / MS 301
NMR (CDCl 3 ) δ: 1.46 (3 H, t, J = 7.6 Hz), 1.80 (3 H, d, J = 7.1 Hz), 2.88 (2 H, q, J = 7.6 Hz), 3.75 (3 H , s), 5.09 (1 H, q, J = 7.1 Hz), 7.38 (1 H, s), 7.79 (1 H, s).
参考例７５
5,6-ジクロロ-2-エチル-1H-ベンゾイミダゾール
　4,5-ジクロロベンゼン-1,2-ジアミン(2.00 g, 11.3 mmol)、プロピオン酸(843 μL, 11.3 mmol)およびポリリン酸(10 g)の混合物を110℃で1日間攪拌後、氷冷した水に注ぎ、炭酸カリウムで中和し、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をIPEで洗浄し、題記化合物を赤色固体 (1.92 g, 79%)として得た。
LC/MS 215
NMR (DMSO-d6) δ: 1.29 (3 H, t, J=7.7 Hz), 2.82 (2 H, q, J=7.7 Hz), 7.70 (2 H, s), 12.50 (1 H, brs). Reference Example 75
5,6-dichloro-2-ethyl-1H-benzimidazole 4,5-dichlorobenzene-1,2-diamine (2.00 g, 11.3 mmol), propionic acid (843 μL, 11.3 mmol) and polyphosphoric acid (10 g) The mixture was stirred at 110 ° C. for 1 day, poured into ice-cooled water, neutralized with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with IPE to give the title compound as a red solid (1.92 g, 79%).
LC / MS 215
NMR (DMSO-d 6) δ :   1.29 (3 H, t, J = 7.7 Hz), 2.82 (2 H, q, J = 7.7 Hz), 7.70 (2 H, s), 12.50 (1 H, brs).
参考例７６
エチルN-({4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-イル}カルボニル)グリシナート
　1-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン(150 mg, 0.549 mmol)およびイソシアナト酢酸エチル(67.7 μL, 0.604 mmol)のTHF(5 mL)混合液を室温で1時間攪拌後、シリカゲルカラムクロマトグラフィー(メタノール/酢酸エチル＝0/10～0.5/9.5)で精製し、題記化合物を無色固体 (212 mg, 96%)として得た。
LC/MS 403
NMR (CDCl3) δ: 1.30 (3 H, t, J=7.1 Hz), 2.50 (3H, s), 3.23 - 3.30 (4H, m), 3.57 - 3.64 (4H, m), 3.93 (3H, s), 4.04 (2H, d, J=4.9 Hz), 4.23 (2H, q, J=7.1 Hz), 5.02 (1H, t, J=4.9 Hz), 6.48 (1H, d, J=2.2 Hz), 6.55 (1H, dd, J=8.5, 2.2 Hz), 7.24 (1H, s), 7.59 (1H, d, J=8.5 Hz). Reference Example 76
Ethyl N-({4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazin-1-yl} carbonyl) glycinate 1- [3-methoxy-4- ( 2-Methyl-1,3-oxazol-5-yl) phenyl] piperazine (150 mg, 0.549 mmol) and ethyl isocyanatoacetate (67.7 μL, 0.604 mmol) in THF (5 mL) were stirred at room temperature for 1 hour. Purification by silica gel column chromatography (methanol / ethyl acetate = 0/10 to 0.5 / 9.5) gave the title compound as a colorless solid (212 mg, 96%).
LC / MS 403
NMR (CDCl 3 ) δ: 1.30 (3 H, t, J = 7.1 Hz), 2.50 (3H, s), 3.23-3.30 (4H, m), 3.57-3.64 (4H, m), 3.93 (3H, s ), 4.04 (2H, d, J = 4.9 Hz), 4.23 (2H, q, J = 7.1 Hz), 5.02 (1H, t, J = 4.9 Hz), 6.48 (1H, d, J = 2.2 Hz), 6.55 (1H, dd, J = 8.5, 2.2 Hz), 7.24 (1H, s), 7.59 (1H, d, J = 8.5 Hz).
参考例７７
エチル2-(1H-ベンゾイミダゾール-1-イル)ブタノアート
　ベンゾイミダゾール(1.00 g, 8.46 mmol)、エチル 2-ブロモブタノアート(1.50 mL, 10.2 mmol)および炭酸セシウム(8.67 g, 26.6 mmol)のDMF(10 mL)混合液を室温で2時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0/10～3/7)で精製し、題記化合物を無色液体(1.95 g, 99%)として得た。
LC/MS 233
NMR (CDCl3) δ: 0.95 (3 H, t, J=7.4 Hz), 1.24 (3 H, t, J=7.0 Hz), 2.14 - 2.47 (2 H, m), 4.21 (2 H, q, J=7.0 Hz), 4.88 (1 H, dd, J=9.3, 6.2 Hz), 7.28 - 7.45 (3 H, m), 7.79 - 7.86 (1 H, m), 8.09 (1 H, s). Reference Example 77
DMF of ethyl 2- (1H-benzimidazol-1-yl) butanoate benzimidazole (1.00 g, 8.46 mmol), ethyl 2-bromobutanoate (1.50 mL, 10.2 mmol) and cesium carbonate (8.67 g, 26.6 mmol) (10 mL) The mixture was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 0 / 10-3 / 7) to give the title compound as a colorless liquid (1.95 g, 99%).
LC / MS 233
NMR (CDCl 3 ) δ: 0.95 (3 H, t, J = 7.4 Hz), 1.24 (3 H, t, J = 7.0 Hz), 2.14-2.47 (2 H, m), 4.21 (2 H, q, J = 7.0 Hz), 4.88 (1 H, dd, J = 9.3, 6.2 Hz), 7.28-7.45 (3 H, m), 7.79-7.86 (1 H, m), 8.09 (1 H, s).
参考例７８
メチル2-(1H-インドール-1-イル)プロパノアート
　インドール(1.00 g, 8.54 mmol)、メチル 2-ブロモプロパノアート(1.14 mL, 10.2 mmol)および炭酸セシウム(8.21 g, 25.2 mmol)のDMF(10 mL)混合液を室温で3日間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0/10～1/9)およびシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0/10～1/9)で精製し、題記化合物を無色液体 (1.14 g, 66%)として得た。
LC/MS 204
NMR (CDCl3) δ: 1.83 (3 H, d, J=7.2 Hz), 3.70 (3 H, s), 5.16 (1 H, q, J=7.2 Hz), 6.58 (1 H, d, J=3.0 Hz), 7.09 - 7.16 (1 H, m), 7.18 - 7.28 (2 H, m), 7.32 (1 H, d, J=8.3 Hz), 7.61 - 7.65 (1 H, m).  Reference Example 78
Methyl 2- (1H-indol-1-yl) propanoate Indole (1.00 g, 8.54 mmol), methyl 2-bromopropanoate (1.14 mL, 10.2 mmol) and cesium carbonate (8.21 g, 25.2 mmol) in DMF (10 mL) The mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 0/10 to 1/9) and silica gel column chromatography (ethyl acetate / hexane = 0/10 to 1/9) to give the title compound As a colorless liquid (1.14 g, 66%).
LC / MS 204
NMR (CDCl 3 ) δ: 1.83 (3 H, d, J = 7.2 Hz), 3.70 (3 H, s), 5.16 (1 H, q, J = 7.2 Hz), 6.58 (1 H, d, J = 3.0 Hz), 7.09-7.16 (1 H, m), 7.18-7.28 (2 H, m), 7.32 (1 H, d, J = 8.3 Hz), 7.61-7.65 (1 H, m).
参考例７９
メチル2-(5,6-ジフルオロ-1H-ベンゾイミダゾール-1-イル)プロパノアート
　5,6-ジフルオロ-1H-ベンゾイミダゾール(1.00 g, 6.49 mmol)、メチル 2-ブロモプロパノアート(869 μL, 7.79 mmol)および炭酸セシウム(6.34 g, 19.5 mmol)のDMF(10 mL)混合液を室温で1時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝2/8～7/3)で精製し、題記化合物を褐色液体 (1.33 g, 85%)として得た。
LC/MS 241
NMR (CDCl3) δ: 1.90 (3 H, d, J=7.2 Hz), 3.76 (3 H, s), 5.04 (1 H, q, J=7.2 Hz), 7.15 (1 H, dd, J=9.8, 6.7 Hz), 7.58 (1 H, dd, J=10.4, 7.4 Hz), 8.04 (1 H, s). Reference Example 79
Methyl 2- (5,6-difluoro-1H-benzimidazol-1-yl) propanoate 5,6-difluoro-1H-benzimidazole (1.00 g, 6.49 mmol), methyl 2-bromopropanoate (869 μL, 7.79 mmol) and cesium carbonate (6.34 g, 19.5 mmol) in DMF (10 mL) were stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2 / 8-7 / 3) to give the title compound as a brown liquid (1.33 g, 85%).
LC / MS 241
NMR (CDCl 3 ) δ: 1.90 (3 H, d, J = 7.2 Hz), 3.76 (3 H, s), 5.04 (1 H, q, J = 7.2 Hz), 7.15 (1 H, dd, J = 9.8, 6.7 Hz), 7.58 (1 H, dd, J = 10.4, 7.4 Hz), 8.04 (1 H, s).
参考例８０
2-メチル-N-(2-ニトロフェニル)アラニン
　2-フルオロニトロベンゼン(1.00 g, 7.09 mmol)、2-メチルアラニン(574 mmg, 5.57 mmol)および炭酸カリウム(403 mg, 2.92 mmol)のアセトニトリル(5 mL)／水(5 mL)混合液を80℃で2日間攪拌した。この反応液を水で希釈し、酢酸エチルで洗浄した後、1N塩酸で酸性とし、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、題記化合物を黄色固体 (626 mg, 50%)として得た。
LC/MS 223
NMR (CDCl3) δ: 1.72 (6 H, s), 6.61 - 6.75 (2 H, m), 7.34 - 7.43 (1 H, m), 8.20 (1 H, dd, J=8.5, 1.6 Hz), 8.38 (1 H, brs). Reference Example 80
2-methyl-N- (2-nitrophenyl) alanine 2-fluoronitrobenzene (1.00 g, 7.09 mmol), 2-methylalanine (574 mmg, 5.57 mmol) and potassium carbonate (403 mg, 2.92 mmol) in acetonitrile (5 mL) / water (5 mL) mixture was stirred at 80 ° C. for 2 days. The reaction mixture was diluted with water, washed with ethyl acetate, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (626 mg, 50%).
LC / MS 223
NMR (CDCl 3 ) δ: 1.72 (6 H, s), 6.61-6.75 (2 H, m), 7.34-7.43 (1 H, m), 8.20 (1 H, dd, J = 8.5, 1.6 Hz), 8.38 (1 H, brs).
参考例８１
2-ピラゾロ[1,5-a]ピリジン-3-イルプロパン酸
　2-ピラゾロ[1,5-a]ピリジン-3-イルプロパンニトリル(81.5 mg, 0.476 mmol)および水酸化リチウム一水和物(99.9 mg, 2.38 mmol)の水(1 mL)混合液を100℃で3日間攪拌後、6N塩酸で中和した。生じた沈殿を濾取し、水で洗浄し、題記化合物を無色固体 (64.0 mg, 71%)として得た。
LC/MS 191
NMR (DMSO-d6) δ: 1.47 (3 H, d, J=7.1 Hz), 3.94 (1 H, q, J=7.1 Hz), 6.80 - 6.91 (1 H, m), 7.13 - 7.23 (1 H, m), 7.63 - 7.70 (1 H, m), 7.91 (1 H, s), 8.57 - 8.65 (1 H, m), 12.34 (1 H, brs). Reference Example 81
2-pyrazolo [1,5-a] pyridin-3-ylpropanoic acid 2-pyrazolo [1,5-a] pyridin-3-ylpropanenitrile (81.5 mg, 0.476 mmol) and lithium hydroxide monohydrate ( A mixture of 99.9 mg, 2.38 mmol) of water (1 mL) was stirred at 100 ° C. for 3 days, and then neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration, and washed with water to give the title compound as a colorless solid (64.0 mg, 71%).
LC / MS 191
NMR (DMSO-d 6 ) δ: 1.47 (3 H, d, J = 7.1 Hz), 3.94 (1 H, q, J = 7.1 Hz), 6.80-6.91 (1 H, m), 7.13-7.23 (1 H, m), 7.63-7.70 (1 H, m), 7.91 (1 H, s), 8.57-8.65 (1 H, m), 12.34 (1 H, brs).
参考例８２
2-ピラゾロ[1,5-a]ピリジン-3-イルプロパンニトリル
　ボロントリフルオリドエチルエーテルコンプレックス(1.17 mL, 9.23 mmol)をトリメチルシリルシアニド(1.64 mL, 12.3 mmol)のクロロベンゼン(12 mL)溶液に0℃で加え、0℃で30分間攪拌した。この反応液に、1-ピラゾロ[1,5-a]ピリジン-3-イルエタノール(500 mg, 3.08 mmol)のクロロベンゼン(3 mL)溶液を0℃で滴下し、室温で2時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0.5/9.5～4/6)で精製し、題記化合物を無色液体 (181 mg, 34%)として得た。
LC/MS 172
NMR (CDCl3) δ: 1.76 (3 H, d, J=7.4 Hz), 4.15 (1 H, q, J=7.4 Hz), 6.79 - 6.86 (1 H, m), 7.17 - 7.23 (1 H, m), 7.59 - 7.65 (1 H, m), 7.91 (1 H, s), 8.44 - 8.49 (1 H, m).  Reference Example 82
2-pyrazolo [1,5-a] pyridin-3-ylpropanenitrile Boron trifluoride ethyl ether complex (1.17 mL, 9.23 mmol) was added to a solution of trimethylsilylcyanide (1.64 mL, 12.3 mmol) in chlorobenzene (12 mL). The mixture was added at 0 ° C. and stirred at 0 ° C. for 30 minutes. To this reaction solution, a solution of 1-pyrazolo [1,5-a] pyridin-3-ylethanol (500 mg, 3.08 mmol) in chlorobenzene (3 mL) was added dropwise at 0 ° C. and stirred at room temperature for 2 hours, then saturated. Aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0.5 / 9.5-4 / 6) to give the title compound as a colorless liquid (181 mg, 34%).
LC / MS 172
NMR (CDCl 3 ) δ: 1.76 (3 H, d, J = 7.4 Hz), 4.15 (1 H, q, J = 7.4 Hz), 6.79-6.86 (1 H, m), 7.17-7.23 (1 H, m), 7.59-7.65 (1 H, m), 7.91 (1 H, s), 8.44-8.49 (1 H, m).
参考例８３
メチル1H-ピロロ[2,3-b]ピリジン-1-イルアセタート
　1H-ピロロ[2,3-b]ピリジン(1.00 g, 8.46 mmol)、ブロモ酢酸メチル(961μL, 10.2 mmol)および炭酸セシウム(8.67 g, 26.6 mmol)のDMF(10 mL)混合液を室温で2時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0.5/9.5～4/6)で精製し、題記化合物を無色液体 (756 mg, 47%)として得た。
LC/MS 191
NMR (CDCl3) δ: 3.76 (3 H, s), 5.08 (2 H, s), 6.53 (1 H, d, J=3.6 Hz), 7.08 (1 H, dd, J=7.8, 4.8 Hz), 7.22 (1 H, d, J=3.6 Hz), 7.91 (1 H, dd, J=7.8, 1.5 Hz), 8.30 (1 H, dd, J=4.8, 1.5 Hz). Reference Example 83
Methyl 1H-pyrrolo [2,3-b] pyridin-1-yl acetate 1H-pyrrolo [2,3-b] pyridine (1.00 g, 8.46 mmol), methyl bromoacetate (961 μL, 10.2 mmol) and cesium carbonate (8.67 g) , 26.6 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate / hexane = 0.5 / 9.5 to 4/6) to give the title compound as a colorless liquid (756 mg, 47%).
LC / MS 191
NMR (CDCl 3 ) δ: 3.76 (3 H, s), 5.08 (2 H, s), 6.53 (1 H, d, J = 3.6 Hz), 7.08 (1 H, dd, J = 7.8, 4.8 Hz) , 7.22 (1 H, d, J = 3.6 Hz), 7.91 (1 H, dd, J = 7.8, 1.5 Hz), 8.30 (1 H, dd, J = 4.8, 1.5 Hz).
参考例８４
メチル(5-クロロ-1H-ピロロ[2,3-b]ピリジン-1-イル)アセタート
　5-クロロ-1H-ピロロ[2,3-b]ピリジン(1.00 g, 6.55 mmol)、ブロモ酢酸メチル(773μL, 8.17 mmol)および炭酸セシウム(6.40 g, 19.6 mmol)のDMF(10 mL)混合液を室温で2時間攪拌した。反応液に水を加えて、生じた沈殿を濾取し、水で洗浄して題記化合物を白色固体 (1.25 g, 85%)として得た。
LC/MS 225
NMR (CDCl3) δ: 3.76 (3 H, s), 5.04 (2 H, s), 6.48 (1 H, d, J=3.6 Hz), 7.25 (1 H, d, J=3.6 Hz), 7.88 (1 H, d, J=2.2 Hz), 8.23 (1 H, d, J=2.2 Hz).  Reference Example 84
Methyl (5-chloro-1H-pyrrolo [2,3-b] pyridin-1-yl) acetate 5-chloro-1H-pyrrolo [2,3-b] pyridine (1.00 g, 6.55 mmol), methyl bromoacetate ( 773 μL, 8.17 mmol) and cesium carbonate (6.40 g, 19.6 mmol) in DMF (10 mL) were stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration, and washed with water to give the title compound as a white solid (1.25 g, 85%).
LC / MS 225
NMR (CDCl 3 ) δ: 3.76 (3 H, s), 5.04 (2 H, s), 6.48 (1 H, d, J = 3.6 Hz), 7.25 (1 H, d, J = 3.6 Hz), 7.88 (1 H, d, J = 2.2 Hz), 8.23 (1 H, d, J = 2.2 Hz).
参考例８５
メチル[5-(トリフルオロメチル)-1H-ピロロ[2,3-b]ピリジン-1-イル]アセタート
　5-(トリフルオロメチル)-1H-ピロロ[2,3-b]ピリジン(500 mg, 2.69 mmol)、ブロモ酢酸メチル(306μL, 3.23 mmol)および炭酸セシウム(2.63 g, 8.07 mmol)のDMF(5 mL)混合液を室温で2時間攪拌後、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝0.5/9.5～4/6)で精製し、題記化合物を無色液体 (599 mg, 86%)として得た。
LC/MS 259
NMR (CDCl3) δ: 3.77 (3 H, s), 5.11 (2 H, s), 6.63 (1 H, d, J=3.6 Hz), 7.34 (1 H, d, J=3.6 Hz), 8.17 (1 H, d, J=2.2 Hz), 8.56 (1 H, d, J=2.2 Hz). Reference Example 85
Methyl [5- (trifluoromethyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] acetate 5- (trifluoromethyl) -1H-pyrrolo [2,3-b] pyridine (500 mg, 2.69 mmol), methyl bromoacetate (306 μL, 3.23 mmol) and cesium carbonate (2.63 g, 8.07 mmol) in DMF (5 mL) were stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0.5 / 9.5-4 / 6) to give the title compound as a colorless liquid (599 mg, 86%).
LC / MS 259
NMR (CDCl 3 ) δ: 3.77 (3 H, s), 5.11 (2 H, s), 6.63 (1 H, d, J = 3.6 Hz), 7.34 (1 H, d, J = 3.6 Hz), 8.17 (1 H, d, J = 2.2 Hz), 8.56 (1 H, d, J = 2.2 Hz).
参考例８６
1-[1-(3,4-ジクロロフェニル)シクロプロピル]メタンアミン　１塩酸塩 Reference Example 86
1- [1- (3,4-Dichlorophenyl) cyclopropyl] methanamine monohydrochloride
86a)1-(3,4-ジクロロフェニル)シクロプロパンカルボニトリル
　水素化ナトリウム (4.8 g, 0.12 mol, 60%油状)のDMSO (100 mL)溶液に、(3,4-ジクロロフェニル)アセトニトリル(9.3 g, 50 mmol)のDMSO (30 mL)溶液を滴下し、窒素雰囲気下、室温で30分間攪拌した。反応混合物に1-ブロモ-2-クロロエタン (6.3 mL, 75 mmol)のDMSO (10 mL)溶液を加え、室温で1日撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をヘキサン－酢酸エチルで再結晶し、題記化合物を淡黄色固体 (8.5 g, 80%)として得た。
NMR (CDCl3) δ: 1.37 - 1.43 (2 H, m), 1.72 - 1.81 (2 H, m), 7.14 (1 H, dd, J=8.3 , 2.3 Hz), 7.36 (1 H, d, J=2.3 Hz), 7.42 (1 H, d, J=8.3 Hz). 86a) 1- (3,4-Dichlorophenyl) cyclopropanecarbonitrile Sodium hydride (4.8 g, 0.12 mol, 60% oil) in DMSO (100 mL) was added to (3,4-dichlorophenyl) acetonitrile (9.3 g, 50 mmol) in DMSO (30 mL) was added dropwise and stirred at room temperature for 30 minutes under a nitrogen atmosphere. A solution of 1-bromo-2-chloroethane (6.3 mL, 75 mmol) in DMSO (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give the title compound as a pale yellow solid (8.5 g, 80%).
NMR (CDCl 3 ) δ: 1.37-1.43 (2 H, m), 1.72-1.81 (2 H, m), 7.14 (1 H, dd, J = 8.3, 2.3 Hz), 7.36 (1 H, d, J = 2.3 Hz), 7.42 (1 H, d, J = 8.3 Hz).
86b)1-[1-(3,4-ジクロロフェニル)シクロプロピル]メタンアミン　１塩酸塩
　1-(3,4-ジクロロフェニル)シクロプロパンカルボニトリル(5.0 g, 24 mmol)のTHF (50 mL)溶液に THF－ボランのTHF溶液 (1.18 mol/L, 31 mL, 26 mmol)を氷冷下で滴下し、窒素雰囲気下、60 ℃で4時間攪拌した。0 ℃まで冷却した後、さらにTHF－ボランのTHF溶液(1.18 mol/L, 31 mL, 26 mmol)を氷冷下で加え、窒素雰囲気下、60 ℃で4時間攪拌した。反応混合物にメタノールを加え、減圧留去した。得られた残留物を酢酸エチル(20 mL)に溶解し、4N塩酸酢酸エチル溶液(30 mL)を加え、室温で終夜撹拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル－エタノールから再結晶し、題記化合物を白色固体 (5.1 g, 86%)として得た。
LC/MS 216
NMR (DMSO-d6) δ: 0.86 - 0.98 (2 H, m), 0.98 - 1.08 (2 H, m), 3.05 (2 H, s), 7.35 (1 H, dt, J=8.3, 2.2 Hz), 7.58 (1 H, d, J=8.5 Hz), 7.61 - 7.68 (1 H, m), 7.93 (3 H, brs). 86b) 1- [1- (3,4-Dichlorophenyl) cyclopropyl] methanamine monohydrochloride 1- (3,4-dichlorophenyl) cyclopropanecarbonitrile (5.0 g, 24 mmol) in THF (50 mL) in THF -A THF solution of borane (1.18 mol / L, 31 mL, 26 mmol) was added dropwise under ice-cooling, and the mixture was stirred at 60 ° C for 4 hours under a nitrogen atmosphere. After cooling to 0 ° C., THF-borane in THF (1.18 mol / L, 31 mL, 26 mmol) was further added under ice cooling, and the mixture was stirred at 60 ° C. for 4 hours under a nitrogen atmosphere. Methanol was added to the reaction mixture and evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (20 mL), 4N hydrochloric acid ethyl acetate solution (30 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (5.1 g, 86%).
LC / MS 216
NMR (DMSO-d 6 ) δ:   0.86-0.98 (2 H, m), 0.98-1.08 (2 H, m), 3.05 (2 H, s), 7.35 (1 H, dt, J = 8.3, 2.2 Hz), 7.58 (1 H, d, J = 8.5 Hz), 7.61-7.68 (1 H, m), 7.93 (3 H, brs).
参考例８７
tert-ブチル 4-[4-(1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモフェニル)-1,3-オキサゾール (3.0 g, 13 mmol)、tert-ブチル ピペラジン-1-カルボキシラート (3.2 g, 17 mmol)、DavePhos (0.53 g, 1.3 mmol)及びナトリウム tert-ブトキシド (1.9 g, 20 mmol)のトルエン(20 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.61 g, 0.67 mmol)を加え、90℃で終夜攪拌した。反応混合物をセライトろ過し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～1/1)で精製し、題記化合物を黄色固体(0.84 g, 19%)として得た。
LC/MS 329
NMR (CDCl3) δ: 1.50 (9 H, s), 3.13 - 3.31 (4 H, m), 3.48 - 3.70 (4 H, m), 6.95 (2 H, d, J=8.8 Hz), 7.21 (1 H, s), 7.55 (2 H, d, J=8.5 Hz), 7.85 (1 H, s). Reference Example 87
tert-butyl 4- [4- (1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromophenyl) -1,3-oxazole (3.0 g, 13 mmol), tert N-butyl piperazine-1-carboxylate (3.2 g, 17 mmol), DavePhos (0.53 g, 1.3 mmol) and sodium tert-butoxide (1.9 g, 20 mmol) in toluene (20 mL) under a nitrogen atmosphere under Pd 2 (dba) 3 (0.61 g, 0.67 mmol) was added, and the mixture was stirred at 90 ° C. overnight. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/2 to 1/1) to give the title compound as a yellow solid (0.84 g, 19%).
LC / MS 329
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 3.13-3.31 (4 H, m), 3.48-3.70 (4 H, m), 6.95 (2 H, d, J = 8.8 Hz), 7.21 ( 1 H, s), 7.55 (2 H, d, J = 8.5 Hz), 7.85 (1 H, s).
参考例８８
1-(3,4-ジクロロフェニル)シクロプロパンアミン　１塩酸塩 Reference Example 88
1- (3,4-Dichlorophenyl) cyclopropanamine monohydrochloride
88a) 1-(3,4-ジクロロフェニル)シクロプロパンカルボン酸
　1-(3,4-ジクロロフェニル)シクロプロパンカルボニトリル (5.0 g, 24 mmol)のエタノール (15 mL)溶液に水酸化カリウム (11 g, 0.19 mol)の水 (25 mL)溶液を加え、100℃で6時間撹拌した。溶媒を減圧留去した後に、得られた残留物を水に溶解させた。ジエチルエーテルで洗浄した後に、水層を6M塩酸で酸性とし、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、題記化合物を淡黄色固体 (5.1 g, 94%)として得た。
NMR (CDCl3) δ: 1.22 - 1.31 (2 H, m), 1.66 - 1.74 (2 H, m), 7.18 (1 H, dd, J=8.2, 2.2 Hz), 7.37 (1 H, d, J=8.2 Hz), 7.43 (1 H, d, J=1.9 Hz). 88a) 1- (3,4-dichlorophenyl) cyclopropanecarboxylic acid 1- (3,4-dichlorophenyl) cyclopropanecarbonitrile (5.0 g, 24 mmol) in ethanol (15 mL) in potassium hydroxide (11 g, A solution of 0.19 mol) in water (25 mL) was added, and the mixture was stirred at 100 ° C. for 6 hours. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in water. After washing with diethyl ether, the aqueous layer was acidified with 6M hydrochloric acid and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (5.1 g, 94%).
NMR (CDCl 3 ) δ: 1.22-1.31 (2 H, m), 1.66-1.74 (2 H, m), 7.18 (1 H, dd, J = 8.2, 2.2 Hz), 7.37 (1 H, d, J = 8.2 Hz), 7.43 (1 H, d, J = 1.9 Hz).
88b) tert-ブチル [1-(3,4-ジクロロフェニル)シクロプロピル]カルバマート
　1-(3,4-ジクロロフェニル)シクロプロパンカルボン酸 (3.5g, 15 mmol)とジフェニル アジドホスファート (3.3 mL, 15 mmol)、トリエチルアミン (3.2 mL, 23 mmol)のトルエン (100 mL)溶液を100 ℃で6時間撹拌した。反応混合物を室温まで冷却した後、t-ブチルアルコールを加え、100 ℃で終夜撹拌した。溶媒を減圧留去後、得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝7/3～3/7)で精製し、題記化合物を黄色固体(3.8 g, 83%)として得た。
LC/MS 246 ([M+H]+-tBu)
NMR (CDCl3) δ: 1.15 - 1.24 (2 H, m), 1.26 - 1.34 (2 H, m), 1.44 (9 H, s), 5.24 (1 H, brs), 7.03 (1 H, dd, J=8.5, 2.2 Hz), 7.29 (1 H, d, J=2.2 Hz), 7.34 (1 H, d, J=8.2 Hz). 88b) tert-Butyl [1- (3,4-dichlorophenyl) cyclopropyl] carbamate 1- (3,4-dichlorophenyl) cyclopropanecarboxylic acid (3.5 g, 15 mmol) and diphenyl azidophosphate (3.3 mL, 15 mmol ), A solution of triethylamine (3.2 mL, 23 mmol) in toluene (100 mL) was stirred at 100 ° C. for 6 hours. The reaction mixture was cooled to room temperature, t-butyl alcohol was added, and the mixture was stirred at 100 ° C. overnight. After evaporating the solvent under reduced pressure, the obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 7 / 3-3 / 7) to give the title compound as a yellow solid (3.8 g, 83%). It was.
LC / MS 246 ([M + H] + -tBu)
NMR (CDCl 3 ) δ: 1.15-1.24 (2 H, m), 1.26-1.34 (2 H, m), 1.44 (9 H, s), 5.24 (1 H, brs), 7.03 (1 H, dd, J = 8.5, 2.2 Hz), 7.29 (1 H, d, J = 2.2 Hz), 7.34 (1 H, d, J = 8.2 Hz).
88c) 1-(3,4-ジクロロフェニル)シクロプロパンアミン　１塩酸塩
　tert-ブチル [1-(3,4-ジクロロフェニル)シクロプロピル]カルバマート (3.8g, 13 mmol)の酢酸エチル (20 mL)溶液に4N塩酸酢酸エチル溶液を加え、室温で2時間撹拌した。溶媒を減圧留去した後、得られた残留物を酢酸エチルで洗浄して題記化合物を白色固体(2.4 g, 80%)として得た。
LC/MS 202
NMR (DMSO-d6) δ: 1.21 - 1.34 (2 H, m), 1.34 - 1.46 (2 H, m), 7.35 - 7.42 (1 H, m), 7.68 (1 H, d, J=8.5 Hz), 7.70 (1 H, d, J=2.2 Hz), 8.88 (3 H, brs). 88c) 1- (3,4-Dichlorophenyl) cyclopropanamine monohydrochloride tert-butyl [1- (3,4-dichlorophenyl) cyclopropyl] carbamate (3.8 g, 13 mmol) in ethyl acetate (20 mL) It was added 4N hydrochloric acid ethyl acetate solution and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was washed with ethyl acetate to give the title compound as a white solid (2.4 g, 80%).
LC / MS 202
NMR (DMSO-d 6 ) δ: 1.21-1.34 (2 H, m), 1.34-1.46 (2 H, m), 7.35-7.42 (1 H, m), 7.68 (1 H, d, J = 8.5 Hz ), 7.70 (1 H, d, J = 2.2 Hz), 8.88 (3 H, brs).
参考例８９
1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン Reference Example 89
1- [3-Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine
89a) tert-ブチル 4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール (0.40 g, 1.5 mmol)、tert-ブチル ピペラジン-1-カルボキシラート (0.31 g, 1.6 mmol)、DavePhos (59 mg, 0.15 mmol)及びナトリウム tert-ブトキシド (0.22 g, 2.2 mmol)のトルエン(3 mL)溶液に窒素雰囲気下、Pd2(dba)3 (68 mg, 75 μmol)を加え、90 ℃で終夜攪拌した。反応混合物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、題記化合物を無色油状物(0.46 g, 82%)として得た。
NMR (CDCl3) δ: 1.50 (9 H, s), 2.48 (3 H, s), 3.15 - 3.25 (4 H, m), 3.55 - 3.66 (4 H, m), 3.87 (3 H, s), 6.50 - 6.61 (2 H, m), 7.53 (1 H, d, J=8.5 Hz), 8.43 (1 H, s). 89a) tert-Butyl 4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-Bromo-2- Methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.40 g, 1.5 mmol), tert-butyl piperazine-1-carboxylate (0.31 g, 1.6 mmol), DavePhos (59 mg, 0.15 mmol) To a solution of sodium tert-butoxide (0.22 g, 2.2 mmol) in toluene (3 mL) was added Pd 2 (dba) 3 (68 mg, 75 μmol) under a nitrogen atmosphere, and the mixture was stirred at 90 ° C. overnight. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as a colorless oil (0.46 g, 82%).
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 2.48 (3 H, s), 3.15-3.25 (4 H, m), 3.55-3.66 (4 H, m), 3.87 (3 H, s) , 6.50-6.61 (2 H, m), 7.53 (1 H, d, J = 8.5 Hz), 8.43 (1 H, s).
89b) 1-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン
　tert-ブチル 4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート (0.46 g, 1.2 mmol)の酢酸エチル (5 mL)溶液に4N塩酸メタノール溶液(5 mL)を加え、室温で2時間撹拌した。溶媒を減圧留去した後、得られた残留物を水に溶解させ8M水酸化ナトリウム水溶液で塩基性にし、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、題記化合物を淡黄色固体 (0.28 g, 85%)として得た。
NMR (CDCl3) δ: 2.47 (3 H, s), 2.97 - 3.11 (4 H, m), 3.15 - 3.30 (4 H, m), 3.87 (3 H, s), 6.44 - 6.68 (2 H, m), 7.51 (1 H, d, J=8.5 Hz), 8.42 (1 H, s). 89b) 1- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine tert-butyl 4- [3-methoxy-4- (3-methyl- 1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate (0.46 g, 1.2 mmol) in ethyl acetate (5 mL) was added with 4N hydrochloric acid in methanol (5 mL) at room temperature. For 2 hours. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in water, basified with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (0.28 g, 85%).
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 2.97-3.11 (4 H, m), 3.15-3.30 (4 H, m), 3.87 (3 H, s), 6.44-6.68 (2 H, m), 7.51 (1 H, d, J = 8.5 Hz), 8.42 (1 H, s).
参考例９０
アミノ(3,4-ジクロロフェニル)アセトニトリル
　3,4-ジクロロベンズアルデヒド (5.0 g, 29 mmol)と4-ジメチルアミノピリジン (35 mg, 0.29 mmol)のアセトニトリル (60 mL)溶液に、トリメチルシリルシアニド (3.8 mL, 30 mmol)を氷冷下で滴下し、室温で1時間撹拌した。溶媒を減圧留去した後に、得られた残留物を8Mアンモニア MeOH溶液 (30 mL)に溶解し、封管中で40 ℃で３時間撹拌した。溶媒を減圧留去し、題記化合物を褐色油状物(5.7 g, 99%(粗収率))として得た。
NMR (CDCl3) δ: 2.19 (2 H, brs), 4.89 (1 H, s), 7.36 - 7.44 (1 H, m), 7.50 (1 H, d, J=8.2 Hz), 7.68 (1 H, d, J=2.2 Hz). Reference Example 90
Amino (3,4-dichlorophenyl) acetonitrile A solution of 3,4-dichlorobenzaldehyde (5.0 g, 29 mmol) and 4-dimethylaminopyridine (35 mg, 0.29 mmol) in acetonitrile (60 mL) was added to trimethylsilylcyanide (3.8 mL). , 30 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the obtained residue was dissolved in 8M ammonia MeOH solution (30 mL) and stirred in a sealed tube at 40 ° C. for 3 hours. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (5.7 g, 99% (crude yield)).
NMR (CDCl 3 ) δ: 2.19 (2 H, brs), 4.89 (1 H, s), 7.36-7.44 (1 H, m), 7.50 (1 H, d, J = 8.2 Hz), 7.68 (1 H , d, J = 2.2 Hz).
参考例９１
メチル アミノ(3,4-ジクロロフェニル)アセタート
　メタノール(6 mL)に塩化アセチル (3.5 mL)を-10 ℃で滴下し、同温度で30分間撹拌した。反応混合物にアミノ(3,4-ジクロロフェニル)アセトニトリル (0.50 g)のメタノール (1 mL)を加え、室温で終夜撹拌した。溶媒を減圧留去して得られた残留物に水を加え、飽和炭酸水素ナトリウム水溶液で塩基性にした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、題記化合物を褐色油状物(0.27 g, 46%)として得た。
LC/MS 234
NMR (CDCl3) δ: 1.89 (2 H, brs), 3.72 (3 H, s), 4.59 (1 H, s), 7.20 - 7.25 (1 H, m), 7.42 (1 H, d, J=8.2 Hz), 7.51 (1 H, d, J=2.2 Hz). Reference Example 91
Methylamino (3,4-dichlorophenyl) acetate Acetyl chloride (3.5 mL) was added dropwise to methanol (6 mL) at −10 ° C., and the mixture was stirred at the same temperature for 30 minutes. Amino (3,4-dichlorophenyl) acetonitrile (0.50 g) in methanol (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as a brown oil (0.27 g, 46%).
LC / MS 234
NMR (CDCl 3 ) δ: 1.89 (2 H, brs), 3.72 (3 H, s), 4.59 (1 H, s), 7.20-7.25 (1 H, m), 7.42 (1 H, d, J = 8.2 Hz), 7.51 (1 H, d, J = 2.2 Hz).
参考例９２
1-イミダゾ[1,2-a]ピリジン-3-イルエタンアミン Reference Example 92
1-Imidazo [1,2-a] pyridin-3-ylethanamine
92a) 1-イミダゾ[1,2-a]ピリジン-3-イルエタノン
　イミダゾ[1,2-a]ピリジン (5.0 g, 42 mmol)のクロロベンゼン (40 mL)溶液に、塩化アルミニウム (11 g, 85 mmol)を氷冷下で加えた。室温で30分間撹拌した後、無水酢酸 (2.9 mL, 30 mmol)を加え、60 ℃で4時間撹拌した。溶媒を減圧留去後、得られた残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～1/1)で精製し、題記化合物を淡黄色固体(1.7 g, 35%)として得た。
LC/MS 161
NMR (CDCl3) δ: 2.60 (3 H, s), 7.07 (1 H, t, J=6.9 Hz), 7.38 - 7.54 (1 H, m), 7.74 (1 H, d, J=9.1 Hz), 8.33 (1 H, s), 9.62 (1 H, d, J=6.9 Hz). 92a) 1-Imidazo [1,2-a] pyridin-3-ylethanone Imidazo [1,2-a] pyridine (5.0 g, 42 mmol) in chlorobenzene (40 mL) solution with aluminum chloride (11 g, 85 mmol) ) Was added under ice cooling. After stirring at room temperature for 30 minutes, acetic anhydride (2.9 mL, 30 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. After evaporating the solvent under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 8/2 to 1/1) to give the title compound as a pale yellow solid (1.7 g, 35%).
LC / MS 161
NMR (CDCl 3 ) δ: 2.60 (3 H, s), 7.07 (1 H, t, J = 6.9 Hz), 7.38-7.54 (1 H, m), 7.74 (1 H, d, J = 9.1 Hz) , 8.33 (1 H, s), 9.62 (1 H, d, J = 6.9 Hz).
92b) 1-イミダゾ[1,2-a]ピリジン-3-イルエタノール
　リチウムアルミニウムヒドリド (0.80 g, 21 mmol)のTHF (40 mL)溶液に1-イミダゾ[1,2-a]ピリジン-3-イルエタノン (1.7g, 11 mmol)のTHF (10 mL)溶液を氷冷下で滴下し、室温で１時間撹拌した。反応混合物に硫酸ナトリウム10水和物を加え、セライトろ過後、溶媒を減圧留去した。得られた残留物を酢酸エチル－メタノールから再結晶し、題記化合物を白色固体(1.1 g, 67%)として得た。
LC/MS 163
NMR (CDCl3) δ: 1.74 (3 H, d, J=6.6 Hz), 3.00 (1 H, brs), 5.15 (1 H, q, J=6.6 Hz), 6.82 (1 H, t, J=6.7 Hz), 7.10 - 7.23 (1 H, m), 7.28 (1 H, s), 7.53 (1 H, dd, J=9.1, 1.1 Hz), 8.36 (1 H, d, J=7.1 Hz). 92b) 1-imidazo [1,2-a] pyridin-3-ylethanol To a solution of lithium aluminum hydride (0.80 g, 21 mmol) in THF (40 mL), 1-imidazo [1,2-a] pyridin-3- A solution of iretanone (1.7 g, 11 mmol) in THF (10 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate was added to the reaction mixture. After filtration through celite, the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-methanol to give the title compound as a white solid (1.1 g, 67%).
LC / MS 163
NMR (CDCl 3 ) δ: 1.74 (3 H, d, J = 6.6 Hz), 3.00 (1 H, brs), 5.15 (1 H, q, J = 6.6 Hz), 6.82 (1 H, t, J = 6.7 Hz), 7.10-7.23 (1 H, m), 7.28 (1 H, s), 7.53 (1 H, dd, J = 9.1, 1.1 Hz), 8.36 (1 H, d, J = 7.1 Hz).
92c) 3-(1-アジドエチル)イミダゾ[1,2-a]ピリジン
　1-イミダゾ[1,2-a]ピリジン-3-イルエタノール (1.1 g, 7.0 mmol)のトルエン (40 mL)溶液にジフェニル アジドホスファート (4.6 mL, 21 mmol)と1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(3.2 mL, 21 mmol)を加え、室温で2時間撹拌した。反応混合液に飽和食塩水を加え、水層を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、題記化合物を黄色油状物(0.62 g, 47%)として得た。
LC/MS 188
NMR (CDCl3) δ: 1.87 (3 H, d, J=6.9 Hz), 4.75 (1 H, d, J=6.9 Hz), 6.84 - 6.95 (1 H, m), 7.23 - 7.31 (1 H, m), 7.60 - 7.71 (2 H, m), 8.16 (1 H, d, J=6.9 Hz). 92c) 3- (1-Azidoethyl) imidazo [1,2-a] pyridine 1-imidazo [1,2-a] pyridin-3-ylethanol (1.1 g, 7.0 mmol) in toluene (40 mL) in diphenyl Azidophosphate (4.6 mL, 21 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (3.2 mL, 21 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated brine was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate alone) to give the title compound as a yellow oil (0.62 g, 47%).
LC / MS 188
NMR (CDCl 3 ) δ:   1.87 (3 H, d, J = 6.9 Hz), 4.75 (1 H, d, J = 6.9 Hz), 6.84-6.95 (1 H, m), 7.23-7.31 (1 H, m), 7.60-7.71 ( 2 H, m), 8.16 (1 H, d, J = 6.9 Hz).
92d) 1-イミダゾ[1,2-a]ピリジン-3-イルエタンアミン
　3-(1-アジドエチル)イミダゾ[1,2-a]ピリジン(0.62 g, 3.3 mmol)とトリフェニルホスフィン (1.8 g, 6.7 mmol)、水 (0.30 mL, 17 mmol)のTHF (20 mL)溶液を50 ℃で3日間撹拌した。反応混合物にトリフェニルホスフィン (0.9 g, 3.3 mmol)と水 (0.30 mL, 17 mmol)を加え、還流下で4時間撹拌した。溶媒を減圧留去後、得られた残留物をNHシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～酢酸エチル/エタノール＝9/1)で精製し、題記化合物を無色油状物(0.42 g, 79%)として得た。
LC/MS 162
NMR (CDCl3) δ: 1.46 (2 H, brs), 1.65 (3 H, d, J=6.6 Hz), 4.42 (1 H, q, J=6.6 Hz), 6.81 (1 H, td, J=6.8, 1.2 Hz), 7.16 (1 H, ddd, J=9.1, 6.7, 1.2 Hz), 7.49 (1 H, s), 7.60 (1 H, dt, J=9.1, 1.2 Hz), 8.36 (1 H, dt, J=7.0, 1.2 Hz). 92d) 1-imidazo [1,2-a] pyridin-3-ylethanamine 3- (1-azidoethyl) imidazo [1,2-a] pyridine (0.62 g, 3.3 mmol) and triphenylphosphine (1.8 g, 6.7 mmol), a solution of water (0.30 mL, 17 mmol) in THF (20 mL) was stirred at 50 ° C. for 3 days. Triphenylphosphine (0.9 g, 3.3 mmol) and water (0.30 mL, 17 mmol) were added to the reaction mixture, and the mixture was stirred under reflux for 4 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate only to ethyl acetate / ethanol = 9/1) to give the title compound as a colorless oil (0.42 g, 79%). Obtained.
LC / MS 162
NMR (CDCl 3 ) δ: 1.46 (2 H, brs), 1.65 (3 H, d, J = 6.6 Hz), 4.42 (1 H, q, J = 6.6 Hz), 6.81 (1 H, td, J = 6.8, 1.2 Hz), 7.16 (1 H, ddd, J = 9.1, 6.7, 1.2 Hz), 7.49 (1 H, s), 7.60 (1 H, dt, J = 9.1, 1.2 Hz), 8.36 (1 H , dt, J = 7.0, 1.2 Hz).
参考例９３
1-(4-フルオロナフタレン-1-イル)エタンアミン　１塩酸塩 Reference Example 93
1- (4-Fluoronaphthalen-1-yl) ethanamine monohydrochloride
93a) 4-フルオロ-N-メトキシ-N-メチルナフタレン-1-カルボキサミド
　4-フルオロナフタレン-1-カルボン酸 (3.5 g, 19 mmol)、N,O-ジメトキシヒドロキシルアミン　1塩酸塩 (2.2 g, 22 mmol)、WSC (4.3 g, 22 mmol)、およびHOBt (3.0 g, 22 mmol)のDMF (30 mL)溶液にN-エチルジイソプロピルアミン (3.8 mL)を加え、室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1～酢酸エチルのみ)で精製し、題記化合物を黄色油状物(2.8 g, 65%)として得た。
LC/MS 234
NMR (CDCl3) δ: 3.40 (3 H, brs), 3.51 (3 H, brs), 7.16 (1 H, dd, J=10.0, 7.8 Hz), 7.48 (1 H, dd, J=7.8, 5.4 Hz), 7.53 - 7.66 (2 H, m), 7.83 - 7.98 (1 H, m), 8.05 - 8.20 (1 H, m). 93a) 4-Fluoro -N- methoxy -N- methyl-naphthalene-1-carboxamide 4-Fluoro-naphthalene-1-carboxylic acid (3.5 g, 19 mmol), N, O- dimethoxy hydroxylamine monohydrochloride (2.2 g, 22 mmol), WSC (4.3 g, 22 mmol), and HOBt (3.0 g, 22 mmol) DMF and (30 mL) was added N- ethyldiisopropylamine (3.8 mL) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate only), the title compound was obtained as a yellow oil (2.8 g, 65%).
LC / MS 234
NMR (CDCl 3) δ: 3.40 (3 H, brs), 3.51 (3 H, brs), 7.16 (1 H, dd, J = 10.0, 7.8 Hz), 7.48 (1 H, dd, J = 7.8, 5.4 Hz), 7.53-7.66 (2 H, m), 7.83-7.98 (1 H, m), 8.05-8.20 (1 H, m).
93b) 1-(4-フルオロナフタレン-1-イル)エタノン
　4-フルオロ-N-メトキシ-N-メチルナフタレン-1-カルボキサミド (2.8 g, 12 mmol)のTHF (20 mL)溶液にメチルマグネシウムブロマイドTHF溶液(ca.1.0M, 14 mL, ca.14 mmol)を0 ℃で滴下し、室温で2時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝97/3～酢酸エチル/ヘキサン＝17/3)で精製し、題記化合物を無色油状物 (1.8 g, 79%)として得た。
LC/MS 189
NMR (CDCl3) δ: 2.74 (3 H, s), 7.16 (1 H, dd, J=9.7, 8.1 Hz), 7.54 - 7.74 (2 H, m), 7.97 (1 H, dd, J=8.0, 5.5 Hz), 8.16 (1 H, d, J=7.7 Hz), 8.89 (1 H, d, J=8.5 Hz). 93b) 1- (4-Fluoronaphthalen-1-yl) ethanone 4-Fluoro-N-methoxy-N-methylnaphthalene-1-carboxamide (2.8 g, 12 mmol) in THF (20 mL) in methylmagnesium bromide THF The solution (ca.1.0M, 14 mL, ca.14 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 97/3 to ethyl acetate / hexane = 17/3) to give the title compound as a colorless oil (1.8 g, 79%).
LC / MS 189
NMR (CDCl 3 ) δ: 2.74 (3 H, s), 7.16 (1 H, dd, J = 9.7, 8.1 Hz), 7.54-7.74 (2 H, m), 7.97 (1 H, dd, J = 8.0 , 5.5 Hz), 8.16 (1 H, d, J = 7.7 Hz), 8.89 (1 H, d, J = 8.5 Hz).
93c) 1-(4-フルオロナフタレン-1-イル)エタノール
　リチウムアルミニウムヒドリド (0.54 g, 14 mmol)のTHF (30 mL)溶液に1-(4-フルオロナフタレン-1-イル)エタノン (1.8g, 9.5 mmol)のTHF (20 mL)溶液を氷冷下で滴下し、同温度で１時間撹拌した。反応混合物に硫酸ナトリウム10水和物を加え、セライトろ過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝17/3～酢酸エチル/ヘキサン＝1/1)で精製し、題記化合物を無色油状物 (1.8 g, 98%)として得た。
NMR (CDCl3) δ: 1.67 (3 H, d, J=6.3 Hz), 1.89 (1 H, dd, J=3.8, 1.9 Hz), 5.63 (1 H, qd, J=6.3, 3.8 Hz), 7.14 (1 H, dd, J=10.3, 8.1 Hz), 7.49 - 7.67 (3 H, m), 8.07 - 8.22 (2 H, m). 93c) 1- (4-Fluoronaphthalen-1-yl) ethanol Lithium aluminum hydride (0.54 g, 14 mmol) in THF (30 mL) in 1- (4-fluoronaphthalen-1-yl) ethanone (1.8 g, (9.5 mmol) in THF (20 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Sodium sulfate decahydrate was added to the reaction mixture. After filtration through celite, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 17/3 to ethyl acetate / hexane = 1/1) to give the title compound as a colorless oil (1.8 g, 98%).
NMR (CDCl 3 ) δ: 1.67 (3 H, d, J = 6.3 Hz), 1.89 (1 H, dd, J = 3.8, 1.9 Hz), 5.63 (1 H, qd, J = 6.3, 3.8 Hz), 7.14 (1 H, dd, J = 10.3, 8.1 Hz), 7.49-7.67 (3 H, m), 8.07-8.22 (2 H, m).
93d) 1-(1-アジドエチル)-4-フルオロナフタレン
　1-(4-フルオロナフタレン-1-イル)エタノール (1.8 g, 9.3 mmol)のトルエン (20 mL)溶液にジフェニル アジドホスファート (3.0 mL, 14 mmol)と1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(2.1 mL, 14 mmol)を加え、室温で1時間撹拌した。反応混合液に水を加え、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル＝9/1)で精製し、題記化合物を無色油状物(1.6 g, 80%)として得た。
NMR (CDCl3) δ: 1.73 (3 H, d, J=6.9 Hz), 5.28 (1 H, q, J=6.7 Hz), 7.15 (1 H, dd, J=10.0, 8.1 Hz), 7.51 (1 H, dd, J=8.1, 5.4 Hz), 7.54 - 7.69 (2 H, m), 8.03 - 8.23 (2 H, m). 93d) 1- (1-Azidoethyl) -4-fluoronaphthalene 1- (4-Fluoronaphthalen-1-yl) ethanol (1.8 g, 9.3 mmol) in toluene (20 mL) was added to diphenyl azidophosphate (3.0 mL, 14 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (2.1 mL, 14 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 9/1) to give the title compound as a colorless oil (1.6 g, 80%).
NMR (CDCl 3 ) δ: 1.73 (3 H, d, J = 6.9 Hz), 5.28 (1 H, q, J = 6.7 Hz), 7.15 (1 H, dd, J = 10.0, 8.1 Hz), 7.51 ( 1 H, dd, J = 8.1, 5.4 Hz), 7.54-7.69 (2 H, m), 8.03-8.23 (2 H, m).
93e) 1-(4-フルオロナフタレン-1-イル)エタンアミン　１塩酸塩
　1-(1-アジドエチル)-4-フルオロナフタレン (1.6 g, 7.4 mmol) とトリフェニルホスフィン (3.9 g, 15 mmol)、水 (0.67 mL, 37 mmol)のTHF (20 mL)溶液を50 ℃で3時間撹拌した。溶媒を減圧留去後、得られた残留物をNHシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝17/3～酢酸エチル/エタノール＝1/1)で精製した。得られた油状物の酢酸エチル (15 mL)溶液に4N塩酸酢酸エチル溶液(15 mL)を加え、室温で30分間撹拌した後、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄し、題記化合物を白色固体(1.3 g, 75%)として得た。
LC/MS 190
NMR (DMSO-d6) δ: 1.60 (3 H, d, J=6.6 Hz), 5.24 (1 H, q, J=6.6 Hz), 7.45 (1 H, dd, J=10.4, 8.2 Hz), 7.61 - 7.87 (3 H, m), 7.99 - 8.34 (2 H, m), 8.60 (3 H, brs). 93e) 1- (4-Fluoronaphthalen-1-yl) ethanamine monohydrochloride 1- (1-azidoethyl) -4-fluoronaphthalene (1.6 g, 7.4 mmol) and triphenylphosphine (3.9 g, 15 mmol), water A solution of (0.67 mL, 37 mmol) in THF (20 mL) was stirred at 50 ° C. for 3 hours. After the solvent was distilled off under reduced pressure, the obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 17/3 to ethyl acetate / ethanol = 1/1). To a solution of the obtained oily substance in ethyl acetate (15 mL) was added 4N hydrochloric acid ethyl acetate solution (15 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound as a white solid (1.3 g, 75%).
LC / MS 190
NMR (DMSO-d 6 ) δ:   1.60 (3 H, d, J = 6.6 Hz), 5.24 (1 H, q, J = 6.6 Hz), 7.45 (1 H, dd, J = 10.4, 8.2 Hz), 7.61-7.87 (3 H, m) , 7.99-8.34 (2 H, m), 8.60 (3 H, brs).
参考例９４
1-ベンジル 2-メチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1,2-ジカルボキシラート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(3.2 g, 12 mmol)、1-ベンジル 2-メチル ピペラジン-1,2-ジカルボキシラート(5.0 g, 18 mmol)、酢酸パラジウム(II)(27 mg, 0.12 mmol)、(rac)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル(0.11 g, 0.18 mmol)、炭酸セシウム(3.9 g, 12 mmol)、およびトルエン(240 mL)の混合物を、アルゴンガス雰囲気下100 ℃にて3日間攪拌した。反応混合物を室温まで冷却し、セライト濾過した。濾液を減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチル/ヘキサン＝1/2)で精製して、題記化合物を無色油状物(5.0 g, 90%)として得た。
LC/MS 466
NMR (DMSO-d6) δ: 2.50 (3 H, s), 2.81 - 2.90 (1 H, m), 3.03 (1 H, dd, J=12.4, 4.0 Hz), 3.32 - 3.59 (2 H, m), 3.72 - 3.78 (3 H, m), 3.93 (3 H, s), 4.05 - 4.26 (2 H, m), 4.90 (1 H, d, J=4.4 Hz), 5.15 - 5.25 (2 H, m), 6.50 (1 H, s), 6.55 (1 H, dd, J=8.4, 1.6 Hz), 7.25 (1 H, s), 7.32 - 7.40 (5 H, m), 7.59 (1 H, d, J=8.4 Hz). Reference Example 94
1-benzyl 2-methyl 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1,2-dicarboxylate 5- (4-bromo-2- (Methoxyphenyl) -2-methyl-1,3-oxazole (3.2 g, 12 mmol), 1-benzyl 2-methylpiperazine-1,2-dicarboxylate (5.0 g, 18 mmol), palladium (II) acetate ( 27 mg, 0.12 mmol), (rac) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (0.11 g, 0.18 mmol), cesium carbonate (3.9 g, 12 mmol), and toluene ( 240 mL) was stirred at 100 ° C. under an argon gas atmosphere for 3 days. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate / hexane = 1/2) to give the title compound as a colorless oil (5.0 g). , 90%).
LC / MS 466
NMR (DMSO-d 6 ) δ: 2.50 (3 H, s), 2.81-2.90 (1 H, m), 3.03 (1 H, dd, J = 12.4, 4.0 Hz), 3.32-3.59 (2 H, m ), 3.72-3.78 (3 H, m), 3.93 (3 H, s), 4.05-4.26 (2 H, m), 4.90 (1 H, d, J = 4.4 Hz), 5.15-5.25 (2 H, m), 6.50 (1 H, s), 6.55 (1 H, dd, J = 8.4, 1.6 Hz), 7.25 (1 H, s), 7.32-7.40 (5 H, m), 7.59 (1 H, d , J = 8.4 Hz).
参考例９５
1-[(ベンジルオキシ)カルボニル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-2-カルボン酸
　1-ベンジル 2-メチル 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1,2-ジカルボキシラート(1.0 g, 2.2mmol)のMeOH-THF-水(1:1:1)(11 mL)溶液に水酸化ナトリウム(0.43 g, 11 mmol)を加え、室温にて0.5時間攪拌した。溶媒を減圧留去した後、得られた残留物に2N塩酸水溶液を加えpH 3に調節した。析出した固体を濾取して題記化合物を白色固体(0.79 g, 81%)として得た。
NMR (DMSO-d6) δ: 2.43 (3 H, s), 2.63-2.80 (2 H, m), 3.31-3.41 (1 H, m), 3.64-3.77 (2 H, m), 3.88 (3 H, s), 4.18 (1 H, s), 4.30-4.36 (1 H, m), 5.01-5.12 (2 H, m), 6.56 (1 H, d, J=8.4 Hz), 6.59 (1 H, s), 7.13 (1 H, s), 7.30-7.39 (5 H, m), 7.43 (1H, d, J=8.4 Hz). Reference Example 95
1-[(Benzyloxy) carbonyl] -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-2-carboxylic acid 1-benzyl 2-methyl 4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1,2-dicarboxylate (1.0 g, 2.2 mmol) in MeOH-THF-water (1: 1 : 1) Sodium hydroxide (0.43 g, 11 mmol) was added to the (11 mL) solution, and the mixture was stirred at room temperature for 0.5 hour. After the solvent was distilled off under reduced pressure, 2N hydrochloric acid aqueous solution was added to the obtained residue to adjust to pH 3. The precipitated solid was collected by filtration to give the title compound as a white solid (0.79 g, 81%).
NMR (DMSO-d 6 ) δ: 2.43 (3 H, s), 2.63-2.80 (2 H, m), 3.31-3.41 (1 H, m), 3.64-3.77 (2 H, m), 3.88 (3 H, s), 4.18 (1 H, s), 4.30-4.36 (1 H, m), 5.01-5.12 (2 H, m), 6.56 (1 H, d, J = 8.4 Hz), 6.59 (1 H , s), 7.13 (1 H, s), 7.30-7.39 (5 H, m), 7.43 (1H, d, J = 8.4 Hz).
参考例９６
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N,N-ジメチルピペラジン-2-カルボキサミド Reference Example 96
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N, N-dimethylpiperazine-2-carboxamide
96a) ベンジル 2-(ジメチルカルバモイル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　1-[(ベンジルオキシ)カルボニル]-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-2-カルボン酸(0.30 g, 0.66 mmol)、2M ジメチルアミン THF溶液(0.34 mL, 2.0 mmol)、HATU(0.30 g, 0.80 mmol)、およびトリエチルアミン(0.28 mL, 2.0 mmol)のDMF(7 mL)溶液を、室温にて1時間攪拌した。反応混合物に水(20 mL)を加え、さらに10分間攪拌した。析出した固体を濾取して、題記化合物を白色固体(0.27 g, 84%)として得た。
NMR (DMSO-d6) δ: 2.50 (3 H, s), 2.91 (3 H, brs), 2.98 (3 H, brs), 3.14 (2 H, brs), 3.29 (1 H, brs), 3.57 (1 H, brs), 3.88 - 3.92 (2 H, m), 3.92 (3 H, s), 4.02 - 4.14 (1 H, m), 5.04 - 5.26 (2 H, m), 6.40 - 6.52 (2 H, m), 7.23 (1 H, s), 7.30 - 7.42 (5 H, m), 7.57 (1 H, d, J=8.8 Hz). 96a) Benzyl 2- (dimethylcarbamoyl) -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 1-[(benzyloxy) carbonyl ] -4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-2-carboxylic acid (0.30 g, 0.66 mmol), 2M dimethylamine in THF (0.34 mL) , 2.0 mmol), HATU (0.30 g, 0.80 mmol), and triethylamine (0.28 mL, 2.0 mmol) in DMF (7 mL) were stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was further stirred for 10 minutes. The precipitated solid was collected by filtration to give the title compound as a white solid (0.27 g, 84%).
NMR (DMSO-d 6 ) δ: 2.50 (3 H, s), 2.91 (3 H, brs), 2.98 (3 H, brs), 3.14 (2 H, brs), 3.29 (1 H, brs), 3.57 (1 H, brs), 3.88-3.92 (2 H, m), 3.92 (3 H, s), 4.02-4.14 (1 H, m), 5.04-5.26 (2 H, m), 6.40-6.52 (2 H, m), 7.23 (1 H, s), 7.30-7.42 (5 H, m), 7.57 (1 H, d, J = 8.8 Hz).
96b) 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-N,N-ジメチルピペラジン-2-カルボキサミド
　ベンジル2-(ジメチルカルバモイル)-4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート(0.24 g, 0.50 mmol)のEtOH-THF(2:1)(25 mL)溶液に、Pd/C(35 mg)を加え、水素雰囲気下、室温にて終夜攪拌した。反応混合物をセライト濾過し、濾液を減圧下濃縮して題記化合物を黄色油状物(0.19 g, 100%)として得た。
NMR (DMSO-d6) δ: 2.50 (3 H, s), 2.73 (1 H, td, J=11.6, 2.8 Hz), 2.79 (1 H, dd, J=12.0, 10.8 Hz), 3.01 (3 H, s), 3.03 - 3.11 (1 H, m), 3.15 (3 H, s), 3.20 - 3.23 (1 H, m), 3.58 - 3.64 (2 H, m), 3.92 - 3.95 (1 H, m), 3.93 (3 H, s), 6.49 (1 H, d, J=2.0 Hz), 6.57 (1 H, dd, J=8.4, 2.0 Hz), 7.25 (1 H, s), 7.60 (1 H, d, J=8.4 Hz).  96b) 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N, N-dimethylpiperazine-2-carboxamide benzyl 2- (dimethylcarbamoyl) -4- [ 3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate (0.24 g, 0.50 mmol) in EtOH-THF (2: 1) (25 mL) Was added with Pd / C (35 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (0.19 g, 100%).
NMR (DMSO-d 6 ) δ: 2.50 (3 H, s), 2.73 (1 H, td, J = 11.6, 2.8 Hz), 2.79 (1 H, dd, J = 12.0, 10.8 Hz), 3.01 (3 H, s), 3.03-3.11 (1 H, m), 3.15 (3 H, s), 3.20-3.23 (1 H, m), 3.58-3.64 (2 H, m), 3.92-3.95 (1 H, m), 3.93 (3 H, s), 6.49 (1 H, d, J = 2.0 Hz), 6.57 (1 H, dd, J = 8.4, 2.0 Hz), 7.25 (1 H, s), 7.60 (1 (H, d, J = 8.4 Hz).
参考例９７
1-(3,4-ジクロロベンジル)-1,4-ジアゼパン-2-オン Reference Example 97
1- (3,4-Dichlorobenzyl) -1,4-diazepan-2-one
97a) tert-ブチル 4-(3,4-ジクロロベンジル)-3-オキソ-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル　3-オキソ-1,4-ジアゼパン-1-カルボキシラート(公知文献；US2006/25383)(1.1 g, 5 mmol)のDMF(15 mL)溶液に4-(ブロモメチル)-1,2-ジクロロベンゼン(0.73 mL, 5 mmol)、及び、水素化ナトリウム(0.20 g、5 mmol、60%油状)を加え、室温にて3時間攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、題記化合物を無色油状物(1.9 g, 100%)として得た。
LC/MS 373
NMR (DMSO-d6) δ: 1.37 (9 H, s), 1.54 - 1.75 (2 H, m), 3.35 - 3.50 (4 H, m), 4.09 (2 H, s), 4.48 (2 H, s), 7.22 (1 H, d, J=8.3 Hz), 7.47 (1 H, brs), 7.57 (1 H, d, J=8.3 Hz). 97a) tert-butyl 4- (3,4-dichlorobenzyl) -3-oxo-1,4-diazepane-1-carboxylate tert-butyl 3-oxo-1,4-diazepane-1-carboxylate (known literature) US2006 / 25383) (1.1 g, 5 mmol) in DMF (15 mL) with 4- (bromomethyl) -1,2-dichlorobenzene (0.73 mL, 5 mmol) and sodium hydride (0.20 g, 5 mmol); mmol, 60% oil) was added, and the mixture was stirred at room temperature for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless oil (1.9 g, 100%).
LC / MS 373
NMR (DMSO-d 6 ) δ: 1.37 (9 H, s), 1.54-1.75 (2 H, m), 3.35-3.50 (4 H, m), 4.09 (2 H, s), 4.48 (2 H, s), 7.22 (1 H, d, J = 8.3 Hz), 7.47 (1 H, brs), 7.57 (1 H, d, J = 8.3 Hz).
97b) 1-(3,4-ジクロロベンジル)-1,4-ジアゼパン-2-オン
　tert-ブチル 4-(3,4-ジクロロベンジル)-3-オキソ-1,4-ジアゼパン-1-カルボキシラート(1.9 g, 5 mmol)の酢酸エチル(10 mL)溶液に4N塩酸酢酸エチル溶液(10 mL, 40 mmol)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた残留物に炭酸カリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して題記化合物を淡黄色油状物(1.4 g, 100%)として得た。
LC/MS 273
NMR (DMSO-d6) δ: 1.41 - 1.58 (2 H, m), 2.78 - 2.85 (2 H, m), 3.06 - 3.52 (5 H, m), 4.47 (2 H, s), 7.27 (1 H, dd, J=8.3, 1.9 Hz), 7.52 (1 H, s), 7.59 (1 H, d, J=8.3 Hz). 97b) 1- (3,4-dichlorobenzyl) -1,4-diazepan-2-one tert-butyl 4- (3,4-dichlorobenzyl) -3-oxo-1,4-diazepan-1-carboxylate To a solution of (1.9 g, 5 mmol) in ethyl acetate (10 mL) was added 4N hydrochloric acid ethyl acetate solution (10 mL, 40 mmol), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (1.4 g, 100%).
LC / MS 273
NMR (DMSO-d 6 ) δ: 1.41-1.58 (2 H, m), 2.78-2.85 (2 H, m), 3.06-3.52 (5 H, m), 4.47 (2 H, s), 7.27 (1 H, dd, J = 8.3, 1.9 Hz), 7.52 (1 H, s), 7.59 (1 H, d, J = 8.3 Hz).
参考例９８
1-(3,4-ジクロロベンジル)-6,6-ジメチル-1,4-ジアゼパン-2-オン Reference Example 98
1- (3,4-Dichlorobenzyl) -6,6-dimethyl-1,4-diazepan-2-one
98a)tert-ブチル 6,6-ジメチル-3-オキソ-1,4-ジアゼパン-1-カルボキシラート
　6,6-ジメチル-1,4-ジアゼパン-2-オン(公知文献；Polish Journal of Chemistry, 52, 1023-1028 (1978))(7.26 g, 51 mmol)のEtOH(100 mL)溶液にジtert-ブチル　ジカルボネート(11.7 mL, 51 mmol)を加え、室温にて終夜攪拌した。溶媒を減圧留去し、残留物を酢酸エチル－ジイソプロピルエーテルより再結晶して、題記化合物を白色結晶(10.1 g, 81%)として得た。
LC/MS 243
NMR (DMSO-d6) δ: 0.76-0.88 (6H, m), 1.38 (9H, s), 2.81-2.91 (2H, m), 3.21 (2H, brs), 3.87 (2H, s), 7.45 (1H, brs). 98a) tert-butyl 6,6-dimethyl-3-oxo-1,4-diazepan-1-carboxylate 6,6-dimethyl-1,4-diazepan-2-one (public literature; Polish Journal of Chemistry, 52 , 1023-1028 (1978)) (7.26 g, 51 mmol) in EtOH (100 mL) was added ditert-butyl dicarbonate (11.7 mL, 51 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (10.1 g, 81%).
LC / MS 243
NMR (DMSO-d 6 ) δ: 0.76-0.88 (6H, m), 1.38 (9H, s), 2.81-2.91 (2H, m), 3.21 (2H, brs), 3.87 (2H, s), 7.45 ( 1H, brs).
98b)tert-ブチル 4-(3,4-ジクロロベンジル)-6,6-ジメチル-3-オキソ-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 6,6-ジメチル-3-オキソ-1,4-ジアゼパン-1-カルボキシラート(0.73 g, 3 mmol)のDMF(15 mL)溶液に4-(ブロモメチル)-1,2-ジクロロベンゼン(0.48 mL, 3.3 mmol)、及び、水素化ナトリウム(0.13 g、3.3 mmol、60%油状)を加え、室温にて終夜攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/2)で精製して、題記化合物を無色非定形固体(1.1 g, 92%)として得た。
LC/MS 401
NMR (DMSO-d6) δ: 0.70 - 0.90 (6 H, m), 1.38 (9 H, s), 3.09 - 3.28 (4 H, m), 4.08 (2 H, s), 4.45 (2 H, brs), 7.21 - 7.30 (1 H, m), 7.46 - 7.54 (1 H, m), 7.58 (1 H, d, J=8.3 Hz). 98b) tert-butyl 4- (3,4-dichlorobenzyl) -6,6-dimethyl-3-oxo-1,4-diazepan-1-carboxylate tert-butyl 6,6-dimethyl-3-oxo-1 , 4-diazepane-1-carboxylate (0.73 g, 3 mmol) in DMF (15 mL) was added 4- (bromomethyl) -1,2-dichlorobenzene (0.48 mL, 3.3 mmol) and sodium hydride ( 0.13 g, 3.3 mmol, 60% oil) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/2) to give the title compound as a colorless amorphous solid (1.1 g, 92%).
LC / MS 401
NMR (DMSO-d 6 ) δ: 0.70-0.90 (6 H, m), 1.38 (9 H, s), 3.09-3.28 (4 H, m), 4.08 (2 H, s), 4.45 (2 H, brs), 7.21-7.30 (1 H, m), 7.46-7.54 (1 H, m), 7.58 (1 H, d, J = 8.3 Hz).
98c) 1-(3,4-ジクロロベンジル)-6,6-ジメチル-1,4-ジアゼパン-2-オン
　tert-ブチル 4-(3,4-ジクロロベンジル)-6,6-ジメチル-3-オキソ-1,4-ジアゼパン-1-カルボキシラート(1.1 g, 2.8 mmol)の酢酸エチル(10 mL)溶液に4N塩酸酢酸エチル溶液(10 mL, 40 mmol)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残留物に炭酸カリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して題記化合物を淡黄色油状物(0.75 g, 90%)として得た。
LC/MS 301
NMR (DMSO-d6) δ: 0.79 (6 H, s), 2.50 (2 H, s), 2.76 (1 H, brs), 3.15 (2 H, brs), 3.40 (2 H, s), 4.45 (2 H, brs), 7.25 (1 H, dd, J=8.3, 1.9 Hz), 7.51 (1 H, d, J=2.3 Hz), 7.57 (1 H, d, J=8.3 Hz). 98c) 1- (3,4-dichlorobenzyl) -6,6-dimethyl-1,4-diazepan-2-one tert-butyl 4- (3,4-dichlorobenzyl) -6,6-dimethyl-3- To a solution of oxo-1,4-diazepane-1-carboxylate (1.1 g, 2.8 mmol) in ethyl acetate (10 mL) was added 4N hydrochloric acid ethyl acetate solution (10 mL, 40 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (0.75 g, 90%).
LC / MS 301
NMR (DMSO-d 6 ) δ: 0.79 (6 H, s), 2.50 (2 H, s), 2.76 (1 H, brs), 3.15 (2 H, brs), 3.40 (2 H, s), 4.45 (2 H, brs), 7.25 (1 H, dd, J = 8.3, 1.9 Hz), 7.51 (1 H, d, J = 2.3 Hz), 7.57 (1 H, d, J = 8.3 Hz).
参考例９９
4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-5-オン Reference Example 99
4- (3,4,5-trifluorobenzyl) -1,4-diazepan-5-one
99a)tert-ブチル 5-オキソ-4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 5-オキソ-1,4-ジアゼパン-1-カルボキシラート(2.1 g, 10 mmol)のDMF(100 mL)溶液に0℃にて水素化ナトリウム(0.46 g、60%油状)を加え、次に5-(ブロモメチル)-1,2,3-トリフルオロベンゼン(2.3 g, 10 mmol)を加え、室温にて24時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物を酢酸エチル－ヘキサンより結晶化して、題記化合物を白色固体(2.5 g, 70%)として得た。
NMR (CDCl3) δ: 1.46 (9 H, s), 2.61 - 2.91 (2 H, m), 3.22 - 3.79 (6 H, m), 4.53 (2 H, s), 6.72 - 7.03 (2 H, m). 99a) tert-butyl 5-oxo-4- (3,4,5-trifluorobenzyl) -1,4-diazepane-1-carboxylate tert-butyl 5-oxo-1,4-diazepane-1-carboxylate To a solution of (2.1 g, 10 mmol) in DMF (100 mL) was added sodium hydride (0.46 g, 60% oil) at 0 ° C, and then 5- (bromomethyl) -1,2,3-trifluorobenzene. (2.3 g, 10 mmol) was added, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound as a white solid (2.5 g, 70%).
NMR (CDCl 3 ) δ: 1.46 (9 H, s), 2.61-2.91 (2 H, m), 3.22-3.79 (6 H, m), 4.53 (2 H, s), 6.72-7.03 (2 H, m).
99b)4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-5-オン
　tert-ブチル 5-オキソ-4-(3,4,5-トリフルオロベンジル)-1,4-ジアゼパン-1-カルボキシラート(2.5 g, 7.0 mmol)と4N塩酸酢酸エチル溶液(40 mL)の混合物を室温にて3時間攪拌した。反応混合物を濃縮後、残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物を白色固体(0.98 g, 54%)として得た。
NMR (CDCl3) δ: 2.70 - 2.79 (2 H, m), 2.80 - 2.89 (2 H, m), 2.95 - 3.05 (2 H, m), 3.32 - 3.47 (2 H, m), 4.52 (2 H, s), 6.77 - 6.99 (2 H, m). 99b) 4- (3,4,5-trifluorobenzyl) -1,4-diazepan-5-one tert-butyl 5-oxo-4- (3,4,5-trifluorobenzyl) -1,4- A mixture of diazepan-1-carboxylate (2.5 g, 7.0 mmol) and 4N hydrochloric acid ethyl acetate solution (40 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a white solid (0.98 g, 54%).
NMR (CDCl 3 ) δ: 2.70-2.79 (2 H, m), 2.80-2.89 (2 H, m), 2.95-3.05 (2 H, m), 3.32-3.47 (2 H, m), 4.52 (2 H, s), 6.77-6.99 (2 H, m).
参考例１００
{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}酢酸 Reference Example 100
{4- [3-Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetic acid
100a) ベンジル 4-(2-メトキシ-2-オキソエチル)-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　ベンジル5-オキソ-1,4-ジアゼパン-1-カルボキシラート(2.6 g, 11 mmol)のDMF(100 mL)溶液に0℃にて水素化ナトリウム(0.42 g、60%油状)を加え、次にメチル ブロモアセタート(1.7 g, 11 mmol)を加え、室温にて6時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/3～酢酸エチルのみ)で精製し、題記化合物を無色油状物(2.0 g, 59%)として得た。
LC/MS 321
NMR (CDCl3) δ: 2.72 (2 H, brs), 3.49 (2 H, brs), 3.64 - 3.87 (7 H, m), 4.19 (2 H, s), 5.16 (2 H, s), 7.30 - 7.44 (5 H, m). 100a) benzyl 4- (2-methoxy-2-oxoethyl) -5-oxo-1,4-diazepane-1-carboxylate benzyl 5-oxo-1,4-diazepane-1-carboxylate (2.6 g, 11 mmol ) In DMF (100 mL) at 0 ° C. was added sodium hydride (0.42 g, 60% oil), methyl bromoacetate (1.7 g, 11 mmol) was added, and the mixture was stirred at room temperature for 6 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3 to ethyl acetate alone) to give the title compound as a colorless oil (2.0 g, 59%).
LC / MS 321
NMR (CDCl 3 ) δ: 2.72 (2 H, brs), 3.49 (2 H, brs), 3.64-3.87 (7 H, m), 4.19 (2 H, s), 5.16 (2 H, s), 7.30 -7.44 (5 H, m).
100b) メチル (7-オキソ-1,4-ジアゼパン-1-イル)アセタート
　ベンジル4-(2-メトキシ-2-オキソエチル)-5-オキソ-1,4-ジアゼパン-1-カルボキシラート(2.0 g, 6.3 mmol)、10%パラジウムカーボン(0.5 g)およびメタノール (100 mL)の混合物を水素雰囲気下室温にて1時間攪拌した。反応混合物をセライト濾過し、溶媒を減圧留去して、題記化合物を淡黄色油状物(1.2 g, 98%)として得た。
LC/MS 187
NMR (CDCl3) δ: 2.60 - 2.79 (2 H, m), 2.93 - 3.11 (4 H, m), 3.45 - 3.52 (2 H, m), 3.74 (3 H, s), 4.18 (2 H, s). 100b) Methyl (7-oxo-1,4-diazepan-1-yl) acetate benzyl 4- (2-methoxy-2-oxoethyl) -5-oxo-1,4-diazepan-1-carboxylate (2.0 g, (6.3 mmol), 10% palladium carbon (0.5 g) and methanol (100 mL) were stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (1.2 g, 98%).
LC / MS 187
NMR (CDCl 3 ) δ: 2.60-2.79 (2 H, m), 2.93-3.11 (4 H, m), 3.45-3.52 (2 H, m), 3.74 (3 H, s), 4.18 (2 H, s).
100c) メチル {4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセタート
　1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(0.17 g, 1.0 mmol)、メチル (7-オキソ-1,4-ジアゼパン-1-イル)アセタート(0.27 g, 1.0 mmol)、DavePhos(0.046 g, 0.050 mmol)、Pd2(dba)3(0.039 g, 0.10 mmol)、ナトリウム tert-ブトキシド(0.14 g, 1.5 mmol)及びトルエン(5 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/4～酢酸エチルのみ)で精製し、題記化合物を無色非定形固体(0.039 g, 11%)として得た。
LC/MS 374
NMR (CDCl3) δ: 2.47 (3 H, s), 2.80 - 2.98 (2 H, m), 3.51 - 3.78 (9 H, m), 3.86 (3 H, s), 4.22 (2 H, s), 6.39 - 6.72 (2 H, m), 7.52 (1 H, d, J=8.7 Hz), 8.43 (1 H, s). 100c) Methyl {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetate 1- (4-Bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.17 g, 1.0 mmol), methyl (7-oxo-1,4-diazepan-1-yl) Acetate (0.27 g, 1.0 mmol), DavePhos (0.046 g, 0.050 mmol), Pd 2 (dba) 3 (0.039 g, 0.10 mmol), sodium tert-butoxide (0.14 g, 1.5 mmol) and toluene (5 mL) The mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4 to ethyl acetate alone) to give the title compound as a colorless amorphous solid (0.039 g, 11%).
LC / MS 374
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 2.80-2.98 (2 H, m), 3.51-3.78 (9 H, m), 3.86 (3 H, s), 4.22 (2 H, s) , 6.39-6.72 (2 H, m), 7.52 (1 H, d, J = 8.7 Hz), 8.43 (1 H, s).
100d) {4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}酢酸
　メチル{4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセタート (0.081 g, 0.22 mmol)、メタノール (2 mL)および１N水酸化ナトリウム水溶液 (2 mL)の混合物を室温で終夜攪拌した。反応混合物を1N塩酸水溶液で中和し、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を油状物(0.054 g, 69%)として得た。
LC/MS 360
NMR (CDCl3) δ: 2.47 (3 H, s), 2.82 - 3.00 (2 H, m), 3.52 - 3.75 (6 H, m), 3.86 (3 H, s), 4.25 (2 H, s), 5.41 (1 H, brs), 6.38 - 6.58 (2 H, m), 7.50 (1 H, d, J=8.7 Hz), 8.50 (1 H, s). 100d) Methyl {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetate {4- [3-Methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetate (0.081 g , 0.22 mmol), methanol (2 mL) and 1N aqueous sodium hydroxide solution (2 mL) were stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as an oil (0.054 g, 69%).
LC / MS 360
NMR (CDCl 3 ) δ: 2.47 (3 H, s), 2.82-3.00 (2 H, m), 3.52-3.75 (6 H, m), 3.86 (3 H, s), 4.25 (2 H, s) , 5.41 (1 H, brs), 6.38-6.58 (2 H, m), 7.50 (1 H, d, J = 8.7 Hz), 8.50 (1 H, s).
参考例１０１
1-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン
　1,4-ジアゼパン-5-オン (0.34 g, 3.0 mmol)、3,4-ジクロロベンズアルデヒド(0.53 g, 3.0 mmol)、ナトリウム トリアセトキシボロヒドリド(1.6 g, 7.5 mmol)及びTHF(20 mL)の混合物を室温で2時間攪拌した。反応混合物に１N水酸化ナトリウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1～ヘキサン/酢酸エチル＝1/9)で精製し、題記化合物を白色非定形固体(0.28 g, 34%)として得た。
LC/MS 273
NMR (CDCl3) δ: 2.56 - 2.68 (6 H, m), 3.25 - 3.36 (2 H, m), 3.54 (2 H, s), 6.16 (1 H, brs), 7.16 (1 H, dd, J=8.3, 1.9 Hz), 7.40 (1 H, d, J=8.3 Hz), 7.45 (1 H, d, J=1.9 Hz). Reference Example 101
1- (3,4-Dichlorobenzyl) -1,4-diazepan-5-one 1,4-diazepan-5-one (0.34 g, 3.0 mmol), 3,4-dichlorobenzaldehyde (0.53 g, 3.0 mmol) , Sodium triacetoxyborohydride (1.6 g, 7.5 mmol) and THF (20 mL) were stirred at room temperature for 2 hours. 1N Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 4/1 to hexane / ethyl acetate = 1/9) to give the title compound as a white amorphous solid (0.28 g, 34%). It was.
LC / MS 273
NMR (CDCl 3 ) δ: 2.56-2.68 (6 H, m), 3.25-3.36 (2 H, m), 3.54 (2 H, s), 6.16 (1 H, brs), 7.16 (1 H, dd, J = 8.3, 1.9 Hz), 7.40 (1 H, d, J = 8.3 Hz), 7.45 (1 H, d, J = 1.9 Hz).
参考例１０２
4-(3,4-ジクロロベンジル)-3-メチル-1,4-ジアゼパン-5-オン Reference Example 102
4- (3,4-Dichlorobenzyl) -3-methyl-1,4-diazepan-5-one
102a) tert-ブチル 3-メチル-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　1-ベンジル-3-メチルピペリジン-4-オン(4.7 g, 23 mmol)のクロロホルム(50 mL)溶液に0℃で濃硫酸(12 mL, 230 mmol)を滴下して加えた。この混合物にアジ化ナトリウム (3.0 g, 46 mmol)を少しずつ加えて、0℃で1時間攪拌した。次に５０℃で４時間攪拌した。反応混合物を０℃に冷却し、氷水を加え、炭酸カリウムを加えて反応混合物を塩基性にし、室温で終夜攪拌した。有機層を分離し、水層を酢酸エチル、クロロホルムの順で抽出した。抽出液を合わせて無水硫酸マグネシウムで乾燥し、溶媒を留去し、淡黄色固体(5.1 g)を得た。この固体(2.1 g)のメタノール(100 mL)溶液に20%水酸化パラジウムカーボン(1.0 g)を加え、室温で水素雰囲気下、終夜攪拌した。反応混合物をセライト濾過し、溶媒を留去し、白色固体を得た。この白色固体の水(20 mL)溶液に炭酸カリウム(1.4 g, 10 mmol)、酢酸エチル(50 mL)及びジtert-ブチル　ジカルボネート(2.2 g, 10 mmol)を加えて室温で4時間攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を留去し、得られた固体を酢酸エチルで洗浄して、題記化合物を白色固体(1.6 g, 72%)として得た。
LC/MS 229
NMR (CDCl3) δ: 1.22 (3 H, d, J=6.82 Hz), 1.48 (9 H, s), 2.62 (2 H, d, J=4.5 Hz), 2.88 (1 H, brs), 3.06 - 3.23 (1 H, m), 3.59 (1 H, brs), 4.06 (2 H, brs), 5.58 (1 H, brs). 102a) tert-butyl 3-methyl-5-oxo-1,4-diazepan-1-carboxylate 1-benzyl-3-methylpiperidin-4-one (4.7 g, 23 mmol) in chloroform (50 mL) Concentrated sulfuric acid (12 mL, 230 mmol) was added dropwise at 0 ° C. Sodium azide (3.0 g, 46 mmol) was added little by little to this mixture, and the mixture was stirred at 0 ° C. for 1 hr. Next, it stirred at 50 degreeC for 4 hours. The reaction mixture was cooled to 0 ° C., ice water was added, potassium carbonate was added to basify the reaction mixture and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was extracted in the order of ethyl acetate and chloroform. The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale yellow solid (5.1 g). To a solution of this solid (2.1 g) in methanol (100 mL) was added 20% palladium hydroxide carbon (1.0 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the solvent was distilled off to obtain a white solid. To this white solid solution in water (20 mL), potassium carbonate (1.4 g, 10 mmol), ethyl acetate (50 mL) and ditert-butyl dicarbonate (2.2 g, 10 mmol) were added and stirred at room temperature for 4 hours. To the reaction mixture is added saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off, and the resulting solid is washed with ethyl acetate to give the title compound as a white solid (1.6 g, 72%).
LC / MS 229
NMR (CDCl 3 ) δ: 1.22 (3 H, d, J = 6.82 Hz), 1.48 (9 H, s), 2.62 (2 H, d, J = 4.5 Hz), 2.88 (1 H, brs), 3.06 -3.23 (1 H, m), 3.59 (1 H, brs), 4.06 (2 H, brs), 5.58 (1 H, brs).
102b) tert-ブチル 4-(3,4-ジクロロベンジル)-3-メチル-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 3-メチル-5-オキソ-1,4-ジアゼパン-1-カルボキシラート (1.1 g, 4.6 mmol)のDMF (20 mL)溶液に、水素化ナトリウム(0.27 g、60%油状)を加え、次に4-(ブロモメチル)-1,2-ジクロロベンゼン(1.3 g, 5.5 mmol)を加え、室温にて終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝10/1～酢酸エチルのみ)で精製し、題記化合物を無色油状物(1.6 g, 90%)として得た。
LC/MS 387
NMR (CDCl3) δ: 1.21 (3 H, d, J=7.2 Hz), 1.44 (9 H, brs), 2.66 - 3.60 (5 H, m), 3.87 - 4.37 (3 H, m), 4.81 - 5.04 (1 H, m), 7.12 (1 H, d, J=7.9 Hz), 7.34 - 7.50 (2 H, m). 102b) tert-butyl 4- (3,4-dichlorobenzyl) -3-methyl-5-oxo-1,4-diazepane-1-carboxylate tert-butyl 3-methyl-5-oxo-1,4-diazepane To a solution of -1-carboxylate (1.1 g, 4.6 mmol) in DMF (20 mL) was added sodium hydride (0.27 g, 60% oil) followed by 4- (bromomethyl) -1,2-dichlorobenzene ( 1.3 g, 5.5 mmol) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1 to ethyl acetate alone) to give the title compound as a colorless oil (1.6 g, 90%).
LC / MS 387
NMR (CDCl 3 ) δ: 1.21 (3 H, d, J = 7.2 Hz), 1.44 (9 H, brs), 2.66-3.60 (5 H, m), 3.87-4.37 (3 H, m), 4.81- 5.04 (1 H, m), 7.12 (1 H, d, J = 7.9 Hz), 7.34-7.50 (2 H, m).
102c) 4-(3,4-ジクロロベンジル)-3-メチル-1,4-ジアゼパン-5-オン
　tert-ブチル 4-(3,4-ジクロロベンジル)-3-メチル-5-オキソ-1,4-ジアゼパン-1-カルボキシラート(1.6 g, 4.2 mmol)と4N塩酸酢酸エチル溶液(20 mL)の混合物を室温にて3時間攪拌した。反応混合物を濃縮後、残留物に1N水酸化ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物を無色油状物(1.1 g, 94%)として得た。
LC/MS 287 102c) 4- (3,4-dichlorobenzyl) -3-methyl-1,4-diazepan-5-one tert-butyl 4- (3,4-dichlorobenzyl) -3-methyl-5-oxo-1, A mixture of 4-diazepan-1-carboxylate (1.6 g, 4.2 mmol) and 4N hydrochloric acid ethyl acetate solution (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, 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 to give the title compound as a colorless oil (1.1 g , 94%).
LC / MS 287
参考例１０３
4-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン Reference Example 103
4- (3,4-Dichlorobenzyl) -1,4-diazepan-5-one
103a) tert-ブチル 4-(3,4-ジクロロベンジル)-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 5-オキソ-1,4-ジアゼパン-1-カルボキシラート(1.9 g, 8.9 mmol)のDMF(20 mL)溶液に4-(ブロモメチル)-1,2-ジクロロベンゼン(1.3 mL, 8.9 mmol)、及び、水素化ナトリウム(0.36 g、8.9 mmol、60%油状)を加え、室温にて終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製して、題記化合物を白色固体(2.1 g, 64%)として得た。
LC/MS 373
NMR (DMSO-d6) δ: 1.38 (9 H, s), 2.61 - 2.70 (2 H, m), 3.35 - 3.41 (2 H, m), 3.42 - 3.53 (4 H, m), 4.49 (2 H, s), 7.26 (1 H, dd, J=8.1, 2.1 Hz), 7.52 (1 H, d, J=2.3 Hz), 7.58 (1 H, d, J=8.3 Hz). 103a) tert-butyl 4- (3,4-dichlorobenzyl) -5-oxo-1,4-diazepane-1-carboxylate tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (1.9 g , 8.9 mmol) in DMF (20 mL) was added 4- (bromomethyl) -1,2-dichlorobenzene (1.3 mL, 8.9 mmol) and sodium hydride (0.36 g, 8.9 mmol, 60% oil). And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a white solid (2.1 g, 64%).
LC / MS 373
NMR (DMSO-d 6 ) δ: 1.38 (9 H, s), 2.61-2.70 (2 H, m), 3.35-3.41 (2 H, m), 3.42-3.53 (4 H, m), 4.49 (2 H, s), 7.26 (1 H, dd, J = 8.1, 2.1 Hz), 7.52 (1 H, d, J = 2.3 Hz), 7.58 (1 H, d, J = 8.3 Hz).
103b) 4-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン
　tert-ブチル 4-(3,4-ジクロロベンジル)-5-オキソ-1,4-ジアゼパン-1-カルボキシラート(2.1 g, 5.7 mmol)の酢酸エチル(10 mL)懸濁液に4N塩酸酢酸エチル溶液(10 mL, 40 mmol)および、メタノール(5 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、得られた残留物に炭酸カリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して題記化合物を無色油状物(1.4 g, 89%)として得た。
LC/MS 273
NMR (DMSO-d6) δ: 2.55 - 2.70 (4 H, m), 2.73 - 2.84 (2 H, m), 3.25 - 3.42 (3 H, m), 4.48 (2 H, s), 7.25 (1 H, dd, J=8.3, 2.3 Hz), 7.51 (1 H, d, J=2.3 Hz), 7.59 (1 H, d, J=8.3 Hz). 103b) 4- (3,4-Dichlorobenzyl) -1,4-diazepan-5-one tert-butyl 4- (3,4-dichlorobenzyl) -5-oxo-1,4-diazepan-1-carboxylate A 4N hydrochloric acid ethyl acetate solution (10 mL, 40 mmol) and methanol (5 mL) were added to a suspension of (2.1 g, 5.7 mmol) in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (1.4 g, 89%).
LC / MS 273
NMR (DMSO-d 6 ) δ: 2.55-2.70 (4 H, m), 2.73-2.84 (2 H, m), 3.25-3.42 (3 H, m), 4.48 (2 H, s), 7.25 (1 H, dd, J = 8.3, 2.3 Hz), 7.51 (1 H, d, J = 2.3 Hz), 7.59 (1 H, d, J = 8.3 Hz).
参考例１０４
1-(4-ブロモフェニル)-4-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン
　1-ブロモ-4-ヨードベンゼン(0.85 g, 3.0 mmol)、4-(3,4-ジクロロベンジル)-1,4-ジアゼパン-5-オン(0.82 g, 3.0 mmol)、DavePhos(0.15 g, 0.30 mmol)、Pd2(dba)3(0.14 g, 0.15 mmol)、ナトリウム tert-ブトキシド(0.58 g, 6.0 mmol)及びトルエン(10 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～ヘキサン/酢酸エチル=1/3)で精製し、題記化合物を淡黄色油状物(0.34 g, 27%)として得た。
LC/MS 429
NMR (CDCl3) δ: 2.76 - 2.95 (2 H, m), 3.25 - 3.34 (2 H, m), 3.43 - 3.54 (4 H, m), 4.57 (2 H, s), 6.69 (2 H, d, J=9.0 Hz), 7.11 (1 H, dd, J=8.1, 2.1 Hz), 7.30 - 7.43 (4 H, m). Reference Example 104
1- (4-Bromophenyl) -4- (3,4-dichlorobenzyl) -1,4-diazepan-5-one 1-bromo-4-iodobenzene (0.85 g, 3.0 mmol), 4- (3, 4-Dichlorobenzyl) -1,4-diazepan-5-one (0.82 g, 3.0 mmol), DavePhos (0.15 g, 0.30 mmol), Pd 2 (dba) 3 (0.14 g, 0.15 mmol), sodium tert-butoxide A mixture of (0.58 g, 6.0 mmol) and toluene (10 mL) was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to hexane / ethyl acetate = 1/3) to give the title compound as a pale yellow oil (0.34 g, 27%). .
LC / MS 429
NMR (CDCl 3 ) δ: 2.76-2.95 (2 H, m), 3.25-3.34 (2 H, m), 3.43-3.54 (4 H, m), 4.57 (2 H, s), 6.69 (2 H, d, J = 9.0 Hz), 7.11 (1 H, dd, J = 8.1, 2.1 Hz), 7.30-7.43 (4 H, m).
参考例１０５
4-(3,4-ジクロロベンジル)-6,6-ジメチル-1,4-ジアゼパン-5-オン Reference Example 105
4- (3,4-Dichlorobenzyl) -6,6-dimethyl-1,4-diazepan-5-one
105a) 4-(3,4-ジクロロベンジル)-6,6-ジメチル-1-[(2-ニトロフェニル)スルホニル]-1,4-ジアゼパン-5-オン
　6,6-ジメチル-1-[(2-ニトロフェニル)スルホニル]-1,4-ジアゼパン-5-オン(公知文献：EP1803710A1)(0.36 g, 1.1 mmol)のDMF (5 mL)溶液に、水素化ナトリウム(0.058 g, 1.5 mmol, 60%油状)を加え、次に4-(ブロモメチル)-1,2-ジクロロベンゼン(0.31 g, 1.3 mmol)を加え、室温にて終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～ヘキサン/酢酸エチル＝1/4)で精製し、題記化合物を淡黄色非定形固体(0.34 g, 64%)として得た。
LC/MS 486
NMR (CDCl3) δ: 1.29 (6 H, s), 3.13 (2 H, s), 3.23 - 3.34 (2 H, m), 3.44 - 3.59 (2 H, m), 4.56 (2 H, s), 7.04 (1 H, dd, J=8.3, 1.9 Hz), 7.20 (1 H, d, J=1.9 Hz), 7.33 (1 H, d, J=8.3 Hz), 7.55 - 7.80 (3 H, m), 7.98 (1 H, d, J=6.4 Hz). 105a) 4- (3,4-Dichlorobenzyl) -6,6-dimethyl-1-[(2-nitrophenyl) sulfonyl] -1,4-diazepan-5-one 6,6-dimethyl-1-[( 2-Nitrophenyl) sulfonyl] -1,4-diazepan-5-one (EP1803710A1) (0.36 g, 1.1 mmol) in DMF (5 mL) was added to sodium hydride (0.058 g, 1.5 mmol, 60 % Oil) was added, and then 4- (bromomethyl) -1,2-dichlorobenzene (0.31 g, 1.3 mmol) was added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to hexane / ethyl acetate = 1/4) to give the title compound as a pale yellow amorphous solid (0.34 g, 64%). It was.
LC / MS 486
NMR (CDCl 3 ) δ: 1.29 (6 H, s), 3.13 (2 H, s), 3.23-3.34 (2 H, m), 3.44-3.59 (2 H, m), 4.56 (2 H, s) , 7.04 (1 H, dd, J = 8.3, 1.9 Hz), 7.20 (1 H, d, J = 1.9 Hz), 7.33 (1 H, d, J = 8.3 Hz), 7.55-7.80 (3 H, m ), 7.98 (1 H, d, J = 6.4 Hz).
105b) 4-(3,4-ジクロロベンジル)-6,6-ジメチル-1,4-ジアゼパン-5-オン
　4-(3,4-ジクロロベンジル)-6,6-ジメチル-1-[(2-ニトロフェニル)スルホニル]-1,4-ジアゼパン-5-オン(0.33 g, 0.68 mmol)、4-スルファニル安息香酸(0.21 g, 1.35 mmol)、炭酸カリウム(0.38 g, 2.7 mmol)及びDMF (5 mL)の混合物を４０℃で２０時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝3/7)で精製し、題記化合物を淡黄色油状物(0.14 g, 69%)として得た。
LC/MS 301
NMR (CDCl3) δ: 1.30 (6 H, s), 1.98 (1 H, s), 2.73 - 2.85 (2 H, m), 3.07 (2 H, s), 3.31 (2 H, t, J=5.87 Hz), 3.78 (2 H, s), 7.12 - 7.22 (1 H, m), 7.34 - 7.50 (2 H, m). 105b) 4- (3,4-Dichlorobenzyl) -6,6-dimethyl-1,4-diazepan-5-one 4- (3,4-dichlorobenzyl) -6,6-dimethyl-1-[(2 -Nitrophenyl) sulfonyl] -1,4-diazepan-5-one (0.33 g, 0.68 mmol), 4-sulfanylbenzoic acid (0.21 g, 1.35 mmol), potassium carbonate (0.38 g, 2.7 mmol) and DMF (5 mL) was stirred at 40 ° C. for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 3/7) to give the title compound as a pale yellow oil (0.14 g, 69%).
LC / MS 301
NMR (CDCl 3 ) δ: 1.30 (6 H, s), 1.98 (1 H, s), 2.73-2.85 (2 H, m), 3.07 (2 H, s), 3.31 (2 H, t, J = 5.87 Hz), 3.78 (2 H, s), 7.12-7.22 (1 H, m), 7.34-7.50 (2 H, m).
参考例１０６
4-[4-メトキシ-2-メチル-5-(1-メチルエチル)ベンジル]-1,4-ジアゼパン-5-オン Reference Example 106
4- [4-Methoxy-2-methyl-5- (1-methylethyl) benzyl] -1,4-diazepan-5-one
106a) [4-メトキシ-2-メチル-5-(1-メチルエチル)フェニル]メタノール
　4-メトキシ-2-メチル-5-(1-メチルエチル)ベンズアルデヒド(公知文献；WO2008/137102A2)(1.9 g, 10 mmol)のメタノール溶液(50 mL)に０℃にてテトラヒドロホウ酸ナトリウム(0.57 g, 15 mmol)を加え、０℃で２時間攪拌した。反応混合物に１N塩酸を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝19/1～ヘキサン/酢酸エチル＝1/1)で精製し、題記化合物を無色油状物(1.9 g, quant.)として得た。
NMR (CDCl3) δ: 1.20 (6 H, d, J=6.8 Hz), 2.36 (3 H, s), 3.17 - 3.39 (1 H, m), 3.82 (3 H, s), 4.63 (2 H, s), 6.68 (1 H, s), 7.14 (1 H, s). 106a) [4-Methoxy-2-methyl-5- (1-methylethyl) phenyl] methanol 4-methoxy-2-methyl-5- (1-methylethyl) benzaldehyde (known document; WO2008 / 137102A2) (1.9 g , 10 mmol) in methanol (50 mL) was added sodium tetrahydroborate (0.57 g, 15 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19/1 to hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil (1.9 g, quant.).
NMR (CDCl 3 ) δ: 1.20 (6 H, d, J = 6.8 Hz), 2.36 (3 H, s), 3.17-3.39 (1 H, m), 3.82 (3 H, s), 4.63 (2 H , s), 6.68 (1 H, s), 7.14 (1 H, s).
106b) tert-ブチル 4-[4-メトキシ-2-メチル-5-(1-メチルエチル)ベンジル]-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　[4-メトキシ-2-メチル-5-(1-メチルエチル)フェニル]メタノール(1.1 g, 5.6 mmol)のTHF(25 mL)溶液に０℃でN,N-ジエチルエタンアミン(1.6 mL, 11 mmol)、メタンスルホニルクロリド(0.66 mL, 8.5 mmol)の順に加えて、０℃で１時間攪拌した。反応混合物に飽和水素化ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、残留物を得た。次に、tert-ブチル 5-オキソ-1,4-ジアゼパン-1-カルボキシラート (1.1 g, 5.1 mmol)のDMF (20 mL)溶液に、０℃にて水素化ナトリウム(0.24 g、60%油状)を加え、先に得た残留物のDMF(5 mL)溶液を加え、室温にて終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～ヘキサン/酢酸エチル＝7/3)で精製し、題記化合物を淡黄色油状物(0.4 g, 21%)として得た。
LC/MS 391
NMR (CDCl3) δ: 1.19 (6 H, d, J=7.2 Hz), 1.44 (9 H, s), 2.27 (3 H, s), 2.66 - 2.79 (2 H, m), 3.17 - 3.40 (5 H, m), 3.52 - 3.64 (2 H, m), 3.81 (3 H, s), 4.58 (2 H, s), 6.65 (1 H, s), 6.95 (1 H, s). 106b) tert-butyl 4- [4-methoxy-2-methyl-5- (1-methylethyl) benzyl] -5-oxo-1,4-diazepane-1-carboxylate [4-methoxy-2-methyl- 5- (1-Methylethyl) phenyl] methanol (1.1 g, 5.6 mmol) in THF (25 mL) at 0 ° C. with N, N-diethylethanamine (1.6 mL, 11 mmol) and methanesulfonyl chloride (0.66 mL). , 8.5 mmol) and stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydride solution was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Next, sodium hydride (0.24 g, 60% oil) was added to a solution of tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (1.1 g, 5.1 mmol) in DMF (20 mL) at 0 ° C. ) Was added, and a DMF (5 mL) solution of the previously obtained residue was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to hexane / ethyl acetate = 7/3) to give the title compound as a pale yellow oil (0.4 g, 21%). .
LC / MS 391
NMR (CDCl 3 ) δ: 1.19 (6 H, d, J = 7.2 Hz), 1.44 (9 H, s), 2.27 (3 H, s), 2.66-2.79 (2 H, m), 3.17-3.40 ( 5 H, m), 3.52-3.64 (2 H, m), 3.81 (3 H, s), 4.58 (2 H, s), 6.65 (1 H, s), 6.95 (1 H, s).
106c) 4-[4-メトキシ-2-メチル-5-(1-メチルエチル)ベンジル]-1,4-ジアゼパン-5-オン
　tert-ブチル 4-[4-メトキシ-2-メチル-5-(1-メチルエチル)ベンジル]-5-オキソ-1,4-ジアゼパン-1-カルボキシラート(0.52 g, 1.3 mmol)の酢酸エチル(5 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加えて室温にて1.5時間攪拌した。反応混合物を濃縮後、残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物を淡黄色油状物(0.34 g, 89%)として得た。
LC/MS 290
NMR (CDCl3) δ: 1.19 (6 H, d, J=7.2 Hz), 1.84 (1 H, s), 2.27 (3 H, s), 2.63 - 2.85 (4 H, m), 2.92 - 3.06 (2 H, m), 3.15 - 3.39 (3 H, m), 3.81 (3 H, s), 4.57 (2 H, s), 6.65 (1 H, s), 6.95 (1 H, s). 106c) 4- [4-Methoxy-2-methyl-5- (1-methylethyl) benzyl] -1,4-diazepan-5-one tert-butyl 4- [4-methoxy-2-methyl-5- ( 1-Methylethyl) benzyl] -5-oxo-1,4-diazepane-1-carboxylate (0.52 g, 1.3 mmol) in ethyl acetate (5 mL) was added 4N hydrochloric acid ethyl acetate solution (5 mL). Stir at room temperature for 1.5 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, 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 to give the title compound as a pale yellow oil (0.34 g, 89%).
LC / MS 290
NMR (CDCl 3 ) δ: 1.19 (6 H, d, J = 7.2 Hz), 1.84 (1 H, s), 2.27 (3 H, s), 2.63-2.85 (4 H, m), 2.92-3.06 ( 2 H, m), 3.15-3.39 (3 H, m), 3.81 (3 H, s), 4.57 (2 H, s), 6.65 (1 H, s), 6.95 (1 H, s).
参考例１０７
4-(4-ブロモフェニル)-1-メチル-1H-ピラゾール
　1,4-ジブロモベンゼン(1.2 g, 5.0 mmol)、1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(1.0 g, 5.0 mmol)、Pd(PPh3)4(0.58 g, 0.5 mmol)、2M炭酸セシウム水溶液(5.0 mL, 10 mmol)及びトルエン(20 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝19/1～ヘキサン/酢酸エチル＝13/7)で精製し、題記化合物を白色固体(0.58 g, 49%)として得た。
LC/MS 239
NMR (CDCl3) δ: 3.94 (3 H, s), 7.29 - 7.37 (2 H, m), 7.47 (2 H, d, J=8.3 Hz), 7.59 (1 H, s), 7.73 (1 H, s). Reference Example 107
4- (4-Bromophenyl) -1-methyl-1H-pyrazole 1,4-dibromobenzene (1.2 g, 5.0 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole (1.0 g, 5.0 mmol), Pd (PPh 3 ) 4 (0.58 g, 0.5 mmol), 2M aqueous cesium carbonate (5.0 mL, 10 mmol) and toluene ( 20 mL) was stirred at 100 ° C. overnight under a nitrogen atmosphere. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19/1 to hexane / ethyl acetate = 13/7) to give the title compound as a white solid (0.58 g, 49%).
LC / MS 239
NMR (CDCl 3 ) δ: 3.94 (3 H, s), 7.29-7.37 (2 H, m), 7.47 (2 H, d, J = 8.3 Hz), 7.59 (1 H, s), 7.73 (1 H , s).
参考例１０８
{4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}酢酸 Reference Example 108
{4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetic acid
108a) tert-ブチル (4-ベンジル-7-オキソ-1,4-ジアゼパン-1-イル)アセタート
　1-ベンジル-1,4-ジアゼパン-5-オン(2.0 g, 10 mmol)のDMF(50 mL)溶液に0℃にて水素化ナトリウム(0.46 g、60%油状)を加え、次にtert-ブチル ブロモアセタート(2.3 g, 12 mmol)を加え、室温にて2時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝1/4)で精製し、題記化合物を無色油状物(2.0 g, 63%)として得た。
LC/MS 319
NMR (CDCl3) δ: 1.45 (9 H, s), 2.66 - 2.85 (6 H, m), 3.33 - 3.55 (2 H, m), 3.59 (2 H, s), 4.05 (2 H, s), 7.29 - 7.41 (5 H, m). 108a) DMF (50 mL) of tert-butyl (4-benzyl-7-oxo-1,4-diazepan-1-yl) acetate 1-benzyl-1,4-diazepan-5-one (2.0 g, 10 mmol) ) Sodium hydride (0.46 g, 60% oily) was added to the solution at 0 ° C., then tert-butyl bromoacetate (2.3 g, 12 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 1/4) to give the title compound as a colorless oil (2.0 g, 63%).
LC / MS 319
NMR (CDCl 3 ) δ: 1.45 (9 H, s), 2.66-2.85 (6 H, m), 3.33-3.55 (2 H, m), 3.59 (2 H, s), 4.05 (2 H, s) , 7.29-7.41 (5 H, m).
108b) tert-ブチル (7-オキソ-1,4-ジアゼパン-1-イル)アセタート
　tert-ブチル (4-ベンジル-7-オキソ-1,4-ジアゼパン-1-イル)アセタート(2.0 g, 6.3 mmol)、20%水酸化パラジウムカーボン(0.5 g)およびTHF (100 mL)の混合物を水素雰囲気下室温にて終夜攪拌した。反応混合物をセライト濾過し、溶媒を減圧留去して、題記化合物を灰色固体(1.4 g, 97%)として得た。
LC/MS 229
NMR (CDCl3) δ: 1.47 (9 H, s), 2.64 - 2.79 (2 H, m), 2.95 - 3.17 (4 H, m), 3.41 - 3.54 (2 H, m), 4.06 (2 H, s). 108b) tert-butyl (7-oxo-1,4-diazepan-1-yl) acetate tert-butyl (4-benzyl-7-oxo-1,4-diazepan-1-yl) acetate (2.0 g, 6.3 mmol ), 20% palladium hydroxide carbon (0.5 g) and THF (100 mL) were stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound as a gray solid (1.4 g, 97%).
LC / MS 229
NMR (CDCl 3 ) δ: 1.47 (9 H, s), 2.64-2.79 (2 H, m), 2.95-3.17 (4 H, m), 3.41-3.54 (2 H, m), 4.06 (2 H, s).
108c) tert-ブチル {4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセタート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(1.3 g, 4.9 mmol)、tert-ブチル (7-オキソ-1,4-ジアゼパン-1-イル)アセタート(1.1 g, 4.9 mmol)、DavePhos(0.19 g, 0.49 mmol)、Pd2(dba)3(0.23 g, 0.25 mmol)、ナトリウム tert-ブトキシド(0.71 g, 7.4 mmol)及びトルエン(25 mL)の混合物を窒素雰囲気下、100℃で終夜攪拌した。反応混合物をセライト濾過後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝13/7～酢酸エチルのみ)で精製し、題記化合物を淡黄色非定形固体(1.1 g, 55%)として得た。
LC/MS 416
NMR (CDCl3) δ: 1.48 (9 H, s), 2.50 (3 H, s), 2.82 - 2.89 (2 H, m), 3.56 - 3.66 (4 H, m), 3.69 - 3.74 (2 H, m), 3.92 (3 H, s), 4.11 (2 H, s), 6.42 (1 H, d, J=2.3 Hz), 6.50 (1 H, dd, J=8.7, 2.3 Hz), 7.24 (1 H, s), 7.59 (1 H, d, J=8.7 Hz). 108c) tert-butyl {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetate 5- (4-Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole (1.3 g, 4.9 mmol), tert-butyl (7-oxo-1,4-diazepan-1-yl) acetate (1.1 g , 4.9 mmol), DavePhos (0.19 g, 0.49 mmol), Pd 2 (dba) 3 (0.23 g, 0.25 mmol), sodium tert-butoxide (0.71 g, 7.4 mmol) and toluene (25 mL) in a nitrogen atmosphere The mixture was stirred overnight at 100 ° C. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 13 / 7-ethyl acetate alone) to give the title compound as a pale yellow amorphous solid (1.1 g, 55%).
LC / MS 416
NMR (CDCl 3 ) δ: 1.48 (9 H, s), 2.50 (3 H, s), 2.82-2.89 (2 H, m), 3.56-3.66 (4 H, m), 3.69-3.74 (2 H, m), 3.92 (3 H, s), 4.11 (2 H, s), 6.42 (1 H, d, J = 2.3 Hz), 6.50 (1 H, dd, J = 8.7, 2.3 Hz), 7.24 (1 H, s), 7.59 (1 H, d, J = 8.7 Hz).
108d) {4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}酢酸
　tert-ブチル {4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-7-オキソ-1,4-ジアゼパン-1-イル}アセタート(1.1 g, 2.7 mmol)、ジクロロメタン(10 mL)及びTFA (5 mL)の混合物を室温で 3時間攪拌した。反応混合物を濃縮後、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ～メタノール/酢酸エチル＝7/13)で精製し、題記化合物を淡黄色非定形固体(0.75 g, 79%)として得た。
LC/MS 360
NMR (CDCl3) δ: 2.52 (3 H, s), 2.82 - 2.98 (2 H, m), 3.58 - 3.80 (6 H, m), 3.91 (3 H, s), 4.24 (2 H, s), 4.62 (1 H, brs), 6.35 - 6.57 (2 H, m), 7.24 - 7.27 (1 H, m), 7.58 (1 H, d, J=8.7 Hz). 108d) {4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetic acid tert-butyl {4 -[3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -7-oxo-1,4-diazepan-1-yl} acetate (1.1 g, 2.7 mmol), dichloromethane A mixture of (10 mL) and TFA (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate alone to methanol / ethyl acetate = 7/13) to give the title compound as a pale yellow amorphous solid (0.75 g, 79%).
LC / MS 360
NMR (CDCl 3 ) δ: 2.52 (3 H, s), 2.82-2.98 (2 H, m), 3.58-3.80 (6 H, m), 3.91 (3 H, s), 4.24 (2 H, s) , 4.62 (1 H, brs), 6.35-6.57 (2 H, m), 7.24-7.27 (1 H, m), 7.58 (1 H, d, J = 8.7 Hz).
参考例１０９
N-(3-クロロ-4-フルオロフェニル)-2-(7-オキソ-1,4-ジアゼパン-1-イル)アセトアミド Reference Example 109
N- (3-Chloro-4-fluorophenyl) -2- (7-oxo-1,4-diazepan-1-yl) acetamide
109a) tert-ブチル 4-(2-エトキシ-2-オキソエチル)-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　tert-ブチル 5-オキソ-1,4-ジアゼパン-1-カルボキシラート(2.1 g, 10 mmol)のDMF(100 mL)溶液に0℃にて水素化ナトリウム(0.46 g、60%油状)を加え、次にエチル ブロモアセタート(1.84 g, 11 mmol)を加え、室温にて終夜攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝17/3～ヘキサン/酢酸エチル＝3/17)で精製し、題記化合物を無色油状物(1.8 g, 61%)として得た。
NMR (CDCl3) δ: 1.25 - 1.32 (3 H, m), 1.47 (9 H, s), 2.63 - 2.74 (2 H, m), 3.41 - 3.50 (2 H, m), 3.57 - 3.67 (2 H, m), 3.69 - 3.77 (2 H, m), 4.14 - 4.26 (4 H, m). 109a) tert-butyl 4- (2-ethoxy-2-oxoethyl) -5-oxo-1,4-diazepane-1-carboxylate tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (2.1 g, 10 mmol) in DMF (100 mL) at 0 ° C, sodium hydride (0.46 g, 60% oil) was added, then ethyl bromoacetate (1.84 g, 11 mmol) was added, and the mixture was stirred at room temperature overnight. did. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 17 / 3-hexane / ethyl acetate = 3/17) to give the title compound as a colorless oil (1.8 g, 61%).
NMR (CDCl 3 ) δ: 1.25-1.32 (3 H, m), 1.47 (9 H, s), 2.63-2.74 (2 H, m), 3.41-3.50 (2 H, m), 3.57-3.67 (2 H, m), 3.69-3.77 (2 H, m), 4.14-4.26 (4 H, m).
109b) [4-(tert-ブトキシカルボニル)-7-オキソ-1,4-ジアゼパン-1-イル]酢酸
　tert-ブチル 4-(2-エトキシ-2-オキソエチル)-5-オキソ-1,4-ジアゼパン-1-カルボキシラート (1.8 g, 6.1 mmol)、エタノール (10 mL)および１N水酸化ナトリウム水溶液 (20 mL)の混合物を終夜攪拌した。反応混合物を1N塩酸水溶液で中和し、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を白色非定形固体(1.2 g, 70%)として得た。
NMR (CDCl3) δ: 1.47 (9 H, s), 2.59 - 2.81 (2 H, m), 3.41 - 3.53 (2 H, m), 3.58 - 3.66 (2 H, m), 3.69 - 3.78 (2 H, m), 4.21 (2 H, s), 9.04 (1 H, s). 109b) [4- (tert-Butoxycarbonyl) -7-oxo-1,4-diazepan-1-yl] acetic acid tert-butyl 4- (2-ethoxy-2-oxoethyl) -5-oxo-1,4- A mixture of diazepan-1-carboxylate (1.8 g, 6.1 mmol), ethanol (10 mL) and 1N aqueous sodium hydroxide solution (20 mL) was stirred overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a white amorphous solid (1.2 g, 70%).
NMR (CDCl 3 ) δ:   1.47 (9 H, s), 2.59-2.81 (2 H, m), 3.41-3.53 (2 H, m), 3.58-3.66 (2 H, m), 3.69-3.78 (2 H, m), 4.21 ( 2 H, s), 9.04 (1 H, s).
109c) tert-ブチル 4-{2-[(3-クロロ-4-フルオロフェニル)アミノ]-2-オキソエチル}-5-オキソ-1,4-ジアゼパン-1-カルボキシラート
　[4-(tert-ブトキシカルボニル)-7-オキソ-1,4-ジアゼパン-1-イル]酢酸 (1.1 g, 3.9 mmol)、3-クロロ-4-フルオロアニリン(0.57 g, 0.39 mmol)、HOBt (0.61 g, 4.0 mmol)、WSC (0.77 g, 4.0 mmol)、N,N-ジエチルエタンアミン (56 μL, 4.0 mmol)、およびDMF (50 mL)の混合物を室温で終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝4/1～酢酸エチルのみ)で精製し、題記化合物を白色非定形固体(1.3 g, 81%)として得た。
NMR (CDCl3) δ: 1.47 (9 H, s), 2.68 - 2.82 (2 H, m), 3.56 - 3.78 (6 H, m), 4.15 (2 H, s), 7.02 (1 H, t, J=8.7 Hz), 7.19 - 7.26 (1 H, m), 7.65 (1 H, dd, J=6.4, 2.6 Hz), 8.72 (1 H, brs). 109c) tert-butyl 4- {2-[(3-chloro-4-fluorophenyl) amino] -2-oxoethyl} -5-oxo-1,4-diazepane-1-carboxylate [4- (tert-butoxy Carbonyl) -7-oxo-1,4-diazepan-1-yl] acetic acid (1.1 g, 3.9 mmol), 3-chloro-4-fluoroaniline (0.57 g, 0.39 mmol), HOBt (0.61 g, 4.0 mmol) , WSC (0.77 g, 4.0 mmol), N, N-diethylethanamine (56 μL, 4.0 mmol), and DMF (50 mL) were stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to ethyl acetate alone) to give the title compound as a white amorphous solid (1.3 g, 81%).
NMR (CDCl 3 ) δ: 1.47 (9 H, s), 2.68-2.82 (2 H, m), 3.56-3.78 (6 H, m), 4.15 (2 H, s), 7.02 (1 H, t, J = 8.7 Hz), 7.19-7.26 (1 H, m), 7.65 (1 H, dd, J = 6.4, 2.6 Hz), 8.72 (1 H, brs).
109d) N-(3-クロロ-4-フルオロフェニル)-2-(7-オキソ-1,4-ジアゼパン-1-イル)アセトアミド
　tert-ブチル 4-{2-[(3-クロロ-4-フルオロフェニル)アミノ]-2-オキソエチル}-5-オキソ-1,4-ジアゼパン-1-カルボキシラート(1.3 g, 3.2 mmol)の酢酸エチル(3 mL)溶液に4N塩酸酢酸エチル溶液(5 mL)を加えて、室温にて2時間攪拌した。反応混合物を濃縮後、残留物に1N水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物を白色非定形固体(0.76 g, 80%)として得た。
LC/MS 300
NMR (CDCl3) δ: 2.69 - 2.83 (2 H, m), 2.96 - 3.10 (4 H, m), 3.54 - 3.72 (2 H, m), 4.14 (2 H, s), 6.98 - 7.13 (1 H, m), 7.28 - 7.35 (1 H, m), 7.68 (1 H, dd, J=6.4, 2.7 Hz), 9.00 (1 H, brs). 109d) N- (3-Chloro-4-fluorophenyl) -2- (7-oxo-1,4-diazepan-1-yl) acetamide tert-butyl 4- {2-[(3-chloro-4-fluoro Phenyl) amino] -2-oxoethyl} -5-oxo-1,4-diazepane-1-carboxylate (1.3 g, 3.2 mmol) in ethyl acetate (3 mL) was added 4N hydrochloric acid ethyl acetate solution (5 mL). In addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a white amorphous solid (0.76 g, 80%).
LC / MS 300
NMR (CDCl 3 ) δ: 2.69-2.83 (2 H, m), 2.96-3.10 (4 H, m), 3.54-3.72 (2 H, m), 4.14 (2 H, s), 6.98-7.13 (1 H, m), 7.28-7.35 (1 H, m), 7.68 (1 H, dd, J = 6.4, 2.7 Hz), 9.00 (1 H, brs).
参考例１１０
3-(3,4,5-トリフルオロベンジル)-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン Reference Example 110
3- (3,4,5-trifluorobenzyl) -3,9-diazabicyclo [4.2.1] nonan-4-one
110a) 9-ベンジル-3-(3,4,5-トリフルオロベンジル)-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン
　9-ベンジル-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン(公知文献；WO20088517A2)(0.69 g, 3.0 mmol)のDMF(5 mL)溶液に0℃にて水素化ナトリウム(0.13 g、60%油状)を加え、次に5-(ブロモメチル)-1,2,3-トリフルオロベンゼン(0.68 g, 10 mmol)を加え、室温にて終夜攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝9/1～ヘキサン/酢酸エチル＝3/17)で精製し、題記化合物を白色固体(1.12 g, quant.)として得た。
NMR (CDCl3) δ: 1.33 - 1.47 (1 H, m), 1.59 - 1.78 (1 H, m), 1.90 - 2.04 (1 H, m), 2.06 - 2.18 (1 H, m), 2.63 - 2.78 (1 H, m), 2.82 - 3.03 (2 H, m), 3.26 (2 H, t, J=6.6 Hz), 3.54 - 3.78 (3 H, m), 4.22 (1 H, d, J=14.8 Hz), 4.73 (1 H, d, J=14.8 Hz), 6.83 - 6.98 (2 H, m), 7.23 - 7.40 (5 H, m). 110a) 9-Benzyl-3- (3,4,5-trifluorobenzyl) -3,9-diazabicyclo [4.2.1] nonan-4-one 9-benzyl-3,9-diazabicyclo [4.2.1] nonane Sodium hydride (0.13 g, 60% oil) was added to a DMF (5 mL) solution of 4-one (known literature: WO20088517A2) (0.69 g, 3.0 mmol) at 0 ° C., and then 5- (bromomethyl) -1,2,3-trifluorobenzene (0.68 g, 10 mmol) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to hexane / ethyl acetate = 3/17) to give the title compound as a white solid (1.12 g, quant.).
NMR (CDCl 3 ) δ: 1.33-1.47 (1 H, m), 1.59-1.78 (1 H, m), 1.90-2.04 (1 H, m), 2.06-2.18 (1 H, m), 2.63-2.78 (1 H, m), 2.82-3.03 (2 H, m), 3.26 (2 H, t, J = 6.6 Hz), 3.54-3.78 (3 H, m), 4.22 (1 H, d, J = 14.8 Hz), 4.73 (1 H, d, J = 14.8 Hz), 6.83-6.98 (2 H, m), 7.23-7.40 (5 H, m).
110b) 3-(3,4,5-トリフルオロベンジル)-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン
　9-ベンジル-3-(3,4,5-トリフルオロベンジル)-3,9-ジアザビシクロ[4.2.1]ノナン-4-オン(1.1g, 3.0 mmol)、20%水酸化パラジウムカーボン(0.5 g)およびメタノール (50 mL)の混合物を水素雰囲気下室温にて終夜攪拌した。反応混合物をセライト濾過し、溶媒を減圧留去して、題記化合物を油状物(0.77 g, 90%)として得た。
LC/MS 285
NMR (CDCl3) δ: 1.39 - 1.55 (1 H, m), 1.65 - 2.02 (3 H, m), 2.43 (1 H, brs), 2.65 - 2.82 (1 H, m), 2.83 - 2.97 (1 H, m), 3.14 (1 H, dd, J=15.2, 6.1 Hz), 3.57 - 3.79 (3 H, m), 4.22 - 4.75 (2 H, m), 6.78 - 7.06 (2 H, m). 110b) 3- (3,4,5-trifluorobenzyl) -3,9-diazabicyclo [4.2.1] nonan-4-one 9-benzyl-3- (3,4,5-trifluorobenzyl) -3 , 9-diazabicyclo [4.2.1] nonan-4-one (1.1 g, 3.0 mmol), 20% palladium hydroxide on carbon (0.5 g) and methanol (50 mL) were stirred overnight at room temperature under a hydrogen atmosphere. . The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound as an oil (0.77 g, 90%).
LC / MS 285
NMR (CDCl 3 ) δ: 1.39-1.55 (1 H, m), 1.65-2.02 (3 H, m), 2.43 (1 H, brs), 2.65-2.82 (1 H, m), 2.83-2.97 (1 H, m), 3.14 (1 H, dd, J = 15.2, 6.1 Hz), 3.57-3.79 (3 H, m), 4.22-4.75 (2 H, m), 6.78-7.06 (2 H, m).
参考例１１１
4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-2-オン Reference Example 111
4- [3-Methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1-{[2- (trimethylsilyl) ethoxy] methyl} piperazin-2-one
111a)ベンジル 3-オキソピペラジン-1-カルボキシラート
　2-ピペラジノン(10 g, 0.10 mol)、および炭酸水素ナトリウム(9.2 g, 0.11 mol)のTHF(50 mL)－水(50 mL)溶液にクロロギ酸ベンジル(14 mL, 0.10 mol)を加え、室温で2時間攪拌した。反応混合物に酢酸エチル－水を加え、水層を酢酸エチルで抽出し、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をろ取し、ヘキサン－酢酸エチル(1：1)で洗浄し、題記化合物を白色固体(19 g, 80%)として得た。
LC/MS 235
NMR (CDCl3) δ: 3.41 (2 H, br), 3.71 (2 H, t, J=5.4 Hz), 4.17 (2 H, s), 5.17 (2 H, s), 6.71 (1 H, br), 7.37 (5 H, m). 111a) Benzyl 3-oxopiperazine-1-carboxylate 2-piperazinone (10 g, 0.10 mol) and sodium bicarbonate (9.2 g, 0.11 mol) in chloroform (50 mL) -water (50 mL) in chloroformate Benzyl (14 mL, 0.10 mol) was added and stirred at room temperature for 2 hours. Ethyl acetate-water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was collected by filtration and washed with hexane-ethyl acetate (1: 1) to give the title compound as a white solid (19 g, 80%).
LC / MS 235
NMR (CDCl 3 ) δ: 3.41 (2 H, br), 3.71 (2 H, t, J = 5.4 Hz), 4.17 (2 H, s), 5.17 (2 H, s), 6.71 (1 H, br ), 7.37 (5 H, m).
111b) ベンジル 3-オキソ-4-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-1-カルボキシラート
　ベンジル3-オキソピペラジン-1-カルボキシラート(5.5 g, 24 mmol)のDMF(50 mL)溶液にナトリウム tert-ブトキシド(2.5 g, 26 mmol)を加え、室温で10分攪拌した。さらに、[2-(クロロメトキシ)エチル](トリメチル)シラン(4.2 mL, 24 mmol)を氷冷下で加え、室温で16時間攪拌した。反応混合物に酢酸エチル－飽和食塩水－水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物シリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～1/1)で精製し、題記化合物を黄色油状物(5.5 g, 64%)として得た。
LC/MS 365
NMR (CDCl3) δ: -0.01 - 0.02 (9 H, m), 0.92 (2 H, t, J=8.1 Hz), 3.44 (2 H, br), 3.52 (2 H, t, J=8.4 Hz), 3.72 (2 H, t, J=5.1 Hz), 4.18 (2 H, s), 4.84 (2 H, s), 5.15 (2 H, s), 7.35 (5 H, brs). 111b) benzyl 3-oxo-4-{[2- (trimethylsilyl) ethoxy] methyl} piperazine-1-carboxylate benzyl 3-oxopiperazine-1-carboxylate (5.5 g, 24 mmol) in DMF (50 mL) To the mixture was added sodium tert-butoxide (2.5 g, 26 mmol), and the mixture was stirred at room temperature for 10 minutes. Furthermore, [2- (chloromethoxy) ethyl] (trimethyl) silane (4.2 mL, 24 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate-saturated brine-water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/2 to 1/1) to give the title compound as a yellow oil (5.5 g, 64%).
LC / MS 365
NMR (CDCl 3 ) δ: -0.01-0.02 (9 H, m), 0.92 (2 H, t, J = 8.1 Hz), 3.44 (2 H, br), 3.52 (2 H, t, J = 8.4 Hz ), 3.72 (2 H, t, J = 5.1 Hz), 4.18 (2 H, s), 4.84 (2 H, s), 5.15 (2 H, s), 7.35 (5 H, brs).
111c) 1-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-2-オン
　ベンジル3-オキソ-4-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-1-カルボキシラート(5.5 g, 15 mmol)のTHF(50 mL)溶液に窒素雰囲気下Ｐｄ／Ｃ(0.55 g)を加え、水素雰囲気下、室温で62時間攪拌した。触媒をろ去し、ろ液を減圧下に濃縮し、題記化合物を無色油状物(3.5 g, 100%)として得た。
NMR (CDCl3) δ: -0.01 - 0.02 (9 H, m), 0.92 (2 H, t, J=8.4 Hz), 3.08 (2 H, t, J=5.1 Hz), 3.38 (2 H, t, J=5.4 Hz), 3.51 - 3.56 (4 H, m), 4.84 (2 H, s). 111c) 1-{[2- (Trimethylsilyl) ethoxy] methyl} piperazin-2-one benzyl 3-oxo-4-{[2- (trimethylsilyl) ethoxy] methyl} piperazine-1-carboxylate (5.5 g, 15 mmol ) In THF (50 mL) was added Pd / C (0.55 g) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 62 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (3.5 g, 100%).
NMR (CDCl 3) δ: -0.01 - 0.02 (9 H, m), 0.92 (2 H, t, J = 8.4 Hz), 3.08 (2 H, t, J = 5.1 Hz), 3.38 (2 H, t , J = 5.4 Hz), 3.51-3.56 (4 H, m), 4.84 (2 H, s).
111d) 4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-1-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-2-オン
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(1.4 g, 5.0 mmol)、1-{[2-(トリメチルシリル)エトキシ]メチル}ピペラジン-2-オン(1.2 g, 5.0 mmol)、DavePhos(0.20 g, 0.50 mmol)及びナトリウム tert-ブトキシド(0.73 g, 7.6 mmol)のトルエン(10 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.23 mg, 0.25 mmol)を加え、90℃で2.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～0/1)で精製し、題記化合物を橙色固体(0.65 g, 31%)として得た。
LC/MS 418
NMR (CDCl3) δ: -0.02 - 0.00 (9 H, m), 0.93 (2 H, t, J=8.1 Hz), 2.48 (3 H, s), 3.53 - 3.58 (6 H, m), 3.92 (3 H, s), 3.97 (2 H, s), 4.91 (2 H, s), 6.40 (1 H, d, J=2.4 Hz), 6.49 (1 H, dd, J=2.1 Hz, 9.0 Hz), 7.25 (1 H, s), 7.60 (1 H, d, J=8.4 Hz). 111d) 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -1-{[2- (trimethylsilyl) ethoxy] methyl} piperazin-2-one 5- ( 4-Bromo-2-methoxyphenyl) -2-methyl-1,3-oxazole (1.4 g, 5.0 mmol), 1-{[2- (trimethylsilyl) ethoxy] methyl} piperazin-2-one (1.2 g, 5.0 mmol), DavePhos (0.20 g, 0.50 mmol) and sodium tert-butoxide (0.73 g, 7.6 mmol) in toluene (10 mL) under a nitrogen atmosphere, Pd 2 (dba) 3 (0.23 mg, 0.25 mmol) was added. And stirred at 90 ° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 2-0 / 1) to give the title compound as an orange solid (0.65 g, 31%).
LC / MS 418
NMR (CDCl 3 ) δ: -0.02-0.00 (9 H, m), 0.93 (2 H, t, J = 8.1 Hz), 2.48 (3 H, s), 3.53-3.58 (6 H, m), 3.92 (3 H, s), 3.97 (2 H, s), 4.91 (2 H, s), 6.40 (1 H, d, J = 2.4 Hz), 6.49 (1 H, dd, J = 2.1 Hz, 9.0 Hz ), 7.25 (1 H, s), 7.60 (1 H, d, J = 8.4 Hz).
参考例１１２
tert-ブチル {4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート Reference Example 112
tert-butyl {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-oxopiperazin-1-yl} acetate
112a)ベンジル 4-(2-tert-ブトキシ-2-オキソエチル)-3-オキソピペラジン-1-カルボキシラート
　ベンジル3-オキソピペラジン-1-カルボキシラート(19 g, 80 mmol)のDMF(180 mL)溶液にナトリウム tert-ブトキシド(7.7 g, 80 mmol)を加え、室温で10分攪拌した。さらに、ブロモ酢酸 tert-ブチル(12 mL, 80 mmol)を氷冷下で加え、室温で6時間攪拌した。反応混合物に酢酸エチル－飽和食塩水－水を加え、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をろ取し、ヘキサン－酢酸エチル(1：1)で洗浄し、題記化合物を白色固体(23 g, 81%)として得た。
LC/MS 293 ([M+H]+-tBu)
NMR (CDCl3) δ: 1.48 (9 H, s), 3.45 (2 H, m), 3.79 (2 H, t, J=5.7 Hz), 4.07 (2 H, s), 4.22 (2 H, s), 5.17 (2 H, s), 7.37 (5 H, m). 112a) Benzyl 4- (2-tert-butoxy-2-oxoethyl) -3-oxopiperazine-1-carboxylate Benzyl 3-oxopiperazine-1-carboxylate (19 g, 80 mmol) in DMF (180 mL) To the mixture was added sodium tert-butoxide (7.7 g, 80 mmol), and the mixture was stirred at room temperature for 10 minutes. Furthermore, tert-butyl bromoacetate (12 mL, 80 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate-saturated brine-water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was collected by filtration and washed with hexane-ethyl acetate (1: 1) to give the title compound as a white solid (23 g, 81%).
LC / MS 293 ([M + H] + -tBu)
NMR (CDCl 3 ) δ: 1.48 (9 H, s), 3.45 (2 H, m), 3.79 (2 H, t, J = 5.7 Hz), 4.07 (2 H, s), 4.22 (2 H, s ), 5.17 (2 H, s), 7.37 (5 H, m).
112b)tert-ブチル (2-オキソピペラジン-1-イル)アセタート
　ベンジル4-(2-tert-ブトキシ-2-オキソエチル)-3-オキソピペラジン-1-カルボキシラート(26 g, 74 mmol)のTHF(250 mL)溶液に窒素雰囲気下Ｐｄ／Ｃ(1.3 g)を加え、水素雰囲気下、室温で20時間攪拌した。触媒をろ去し、ろ液を減圧下に濃縮した。残留物のTHF(250 mL)溶液に窒素雰囲気下Ｐｄ／Ｃ(1.3 g)を加え、水素雰囲気下、室温で62時間攪拌した。触媒をろ去、ろ液を減圧下に濃縮し、題記化合物を白色固体(16 g, 100%)として得た。
NMR (CDCl3) δ: 1.49 (9 H, s), 1.68 (1 H, br), 3.14 (2 H, t, J=5.4 Hz), 3.40 (2 H, t, J=5.7 Hz), 3.57 (2 H, s), 4.04 (2 H, s). 112b) tert-butyl (2-oxopiperazin-1-yl) acetate benzyl 4- (2-tert-butoxy-2-oxoethyl) -3-oxopiperazine-1-carboxylate (26 g, 74 mmol) in THF ( (250 mL) Pd / C (1.3 g) was added to the solution under a nitrogen atmosphere, and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the residue in THF (250 mL) was added Pd / C (1.3 g) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 62 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (16 g, 100%).
NMR (CDCl 3 ) δ: 1.49 (9 H, s), 1.68 (1 H, br), 3.14 (2 H, t, J = 5.4 Hz), 3.40 (2 H, t, J = 5.7 Hz), 3.57 (2 H, s), 4.04 (2 H, s).
112c)tert-ブチル {4-[3-メトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート
　5-(4-ブロモ-2-メトキシフェニル)-2-メチル-1,3-オキサゾール(1.3 g, 5.0 mmol)、tert-ブチル (2-オキソピペラジン-1-イル)アセタート(1.1 g, 5.0 mmol)、DavePhos(0.20 g, 0.50 mmol)及びナトリウム tert-ブトキシド(0.72 g, 7.5 mmol)のトルエン(10 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.23 mg, 0.25 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝8/2～0/1)で精製し、題記化合物を橙色無定形固体(0.77 g, 38%)として得た。
LC/MS 402
NMR (CDCl3) δ: 1.50 (9 H, s), 2.52 (3 H, s), 3.60 (4 H, m), 3.95 (3 H, s), 4.02 (2 H, s), 4.13 (2 H, s), 6.42 (1 H, d, J=2.4 Hz), 6.52 (1 H, dd, J=2.1 Hz, 8.4 Hz), 7.25 (1 H, s), 7.62 (1 H, d, J=8.4 Hz). 112c) tert-butyl {4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -2-oxopiperazin-1-yl} acetate 5- (4-bromo- 2-Methoxyphenyl) -2-methyl-1,3-oxazole (1.3 g, 5.0 mmol), tert-butyl (2-oxopiperazin-1-yl) acetate (1.1 g, 5.0 mmol), DavePhos (0.20 g, 0.50 mmol) and sodium tert-butoxide (0.72 g, 7.5 mmol) in toluene (10 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (0.23 mg, 0.25 mmol) was added and stirred at 90 ° C. for 1.5 hours. . The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 2-0 / 1) to give the title compound as an orange amorphous solid (0.77 g, 38%).
LC / MS 402
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 2.52 (3 H, s), 3.60 (4 H, m), 3.95 (3 H, s), 4.02 (2 H, s), 4.13 (2 H, s), 6.42 (1 H, d, J = 2.4 Hz), 6.52 (1 H, dd, J = 2.1 Hz, 8.4 Hz), 7.25 (1 H, s), 7.62 (1 H, d, J = 8.4 Hz).
参考例１１３
1-(4-メトキシベンジル)ピペラジン-2-オン　塩酸塩
　tert-ブチル 4-(4-メトキシベンジル)-3-オキソピペラジン-1-カルボキシラート(390 mg, 1.22 mmol)および4N塩酸酢酸エチル溶液(4 mL)の混合物を室温で2時間攪拌し、溶媒を減圧留去した。得られた残留物を酢酸エチルで洗浄し、題記化合物を無色固体 (285 mg, 91%)として得た。
NMR (DMSO-d6) δ: 3.29 - 3.47 (6 H, m), 3.74 (3 H, s), 4.50 (2 H, s), 6.86 - 6.94 (2 H, m), 7.18 - 7.28 (2 H, m), 9.81 (2 H, brs). Reference Example 113
1- (4-Methoxybenzyl) piperazin-2-one hydrochloride tert-butyl 4- (4-methoxybenzyl) -3-oxopiperazine-1-carboxylate (390 mg, 1.22 mmol) and 4N hydrochloric acid ethyl acetate solution ( 4 mL) was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound as a colorless solid (285 mg, 91%).
NMR (DMSO-d 6 ) δ: 3.29-3.47 (6 H, m), 3.74 (3 H, s), 4.50 (2 H, s), 6.86-6.94 (2 H, m), 7.18-7.28 (2 H, m), 9.81 (2 H, brs).
参考例１１４
tert-ブチル 4-(4-メトキシベンジル)-3-オキソピペラジン-1-カルボキシラート
　水素化ナトリウム(960 mg、60%油状)のDMF(60 mL)懸濁液にtert-ブチル 3-オキソピペラジン-1-カルボキシラート(4.00 g, 20.0 mmol)のDMF(20 mL)懸濁液を0℃で加え、室温で1時間攪拌した。この反応液に、4-メトキシベンジルクロリド(3.25 mL, 24.0 mmol)を0℃で加え、室温で2時間攪拌後、氷冷下、水に注いだ。生じた沈殿物を濾取し、水およびヘキサンで洗浄し、題記化合物を無色固体 (4.54 g, 71%)として得た。
NMR (CDCl3) δ: 1.46 (9 H, s), 3.20 - 3.27 (2 H, m), 3.53 - 3.59 (2 H, m), 3.80 (3 H, s), 4.13 (2 H, s), 4.55 (2 H, s), 6.82 - 6.90 (2 H, m), 7.15 - 7.22 (2 H, m). Reference Example 114
tert-Butyl 4- (4-methoxybenzyl) -3-oxopiperazine-1-carboxylate To a suspension of sodium hydride (960 mg, 60% oil) in DMF (60 mL) was added tert-butyl 3-oxopiperazine- A suspension of 1-carboxylate (4.00 g, 20.0 mmol) in DMF (20 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. To this reaction solution, 4-methoxybenzyl chloride (3.25 mL, 24.0 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours, and then poured into water under ice cooling. The resulting precipitate was collected by filtration, and washed with water and hexane to give the title compound as a colorless solid (4.54 g, 71%).
NMR (CDCl 3 ) δ: 1.46 (9 H, s), 3.20-3.27 (2 H, m), 3.53-3.59 (2 H, m), 3.80 (3 H, s), 4.13 (2 H, s) , 4.55 (2 H, s), 6.82-6.90 (2 H, m), 7.15-7.22 (2 H, m).
参考例１１５
1-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1,4-ジアゼパン-5-オン
　1-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペリジン-4-オン(55.4 mg, 0.194 mmol)および硫酸(1 mL)の混合物に、アジ化ナトリウム(15.1 mg, 0.232 mmol)を0℃で加え、室温で2時間攪拌した。反応液を酢酸エチルと飽和炭酸水素ナトリウム水溶液の混合液に0℃で注ぎ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、題記化合物を褐色固体(52.6 mg, 90%)として得た。
LC/MS 301
NMR (CDCl3) δ: 2.74 - 2.81 (2 H, m), 3.37 - 3.44 (2 H, m), 3.53 - 3.62 (4 H, m), 3.88 (3 H, s), 3.92 (3 H, s), 6.40 - 6.51 (3 H, m), 7.38 (1 H, d, J=8.2 Hz), 7.73 (1 H, s), 7.78 (1 H, s). Reference Example 115
1- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-diazepan-5-one 1- [3-methoxy-4- (1-methyl-1H- To a mixture of (pyrazol-4-yl) phenyl] piperidin-4-one (55.4 mg, 0.194 mmol) and sulfuric acid (1 mL) was added sodium azide (15.1 mg, 0.232 mmol) at 0 ° C. and 2 hours at room temperature. Stir. The reaction mixture was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution at 0 ° C., and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (52.6 mg, 90%).
LC / MS 301
NMR (CDCl 3 ) δ: 2.74-2.81 (2 H, m), 3.37-3.44 (2 H, m), 3.53-3.62 (4 H, m), 3.88 (3 H, s), 3.92 (3 H, s), 6.40-6.51 (3 H, m), 7.38 (1 H, d, J = 8.2 Hz), 7.73 (1 H, s), 7.78 (1 H, s).
参考例１１６
1-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]ピペリジン-4-オン
　8-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1,4-ジオキサ-8-アザスピロ[4.5]デカン(205 mg, 0.622 mmol)および6N塩酸(6 mL)の混合物を100℃で2時間攪拌後、8N水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～8/2)で精製し、題記化合物を褐色液体(55.4 mg, 31%)として得た。
NMR (CDCl3) δ: 2.54 - 2.62 (4 H, m), 3.59 - 3.65 (4 H, m), 3.90 (3 H, s), 3.93 (3 H, s), 6.55 - 6.62 (2 H, m), 7.41 (1 H, d, J=8.2 Hz), 7.74 (1 H, d, J=0.6 Hz), 7.79 (1 H, d, J=0.6 Hz). Reference Example 116
1- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] piperidin-4-one 8- [3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) ) Phenyl] -1,4-dioxa-8-azaspiro [4.5] decane (205 mg, 0.622 mmol) and 6N hydrochloric acid (6 mL) were stirred at 100 ° C for 2 hours, then neutralized with 8N aqueous sodium hydroxide solution And extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-8 / 2) to give the title compound as a brown liquid (55.4 mg, 31%).
NMR (CDCl 3 ) δ: 2.54-2.62 (4 H, m), 3.59-3.65 (4 H, m), 3.90 (3 H, s), 3.93 (3 H, s), 6.55-6.62 (2 H, m), 7.41 (1 H, d, J = 8.2 Hz), 7.74 (1 H, d, J = 0.6 Hz), 7.79 (1 H, d, J = 0.6 Hz).
参考例１１７
8-[3-メトキシ-4-(1-メチル-1H-ピラゾール-4-イル)フェニル]-1,4-ジオキサ-8-アザスピロ[4.5]デカン
　窒素雰囲気下、4-(4-ブロモ-2-メトキシフェニル)-1-メチル-1H-ピラゾール(223 mg, 1.00 mmol)、1,4-ジオキサ-8-アザスピロ[4.5]デカン(154 μL, 1.20 mmol)、DavePhos(39.4 mg, 0.100 mmol)、Pd2(dba)3(45.8 mg, 0.0500 mmol)およびナトリウム tert-ブトキシド(144 mg, 1.50 mmol)のトルエン(10 mL)混合液を100℃で14時間攪拌後、濾過して、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝3/7～7/3)で精製し、題記化合物を白色固体(211 mg, 64%)として得た。
LC/MS 330
NMR (CDCl3) δ: 1.83 - 1.90 (4 H, m), 3.29 - 3.38 (4 H, m), 3.88 (3 H, s), 3.92 (3 H, s), 4.00 (4 H, s), 6.53 - 6.59 (2 H, m), 7.34 - 7.38 (1 H, m), 7.73 (1 H, s), 7.78 (1 H, d, J=0.8 Hz). Reference Example 117
8- [3-Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -1,4-dioxa-8-azaspiro [4.5] decane Under nitrogen atmosphere, 4- (4-Bromo-2 -Methoxyphenyl) -1-methyl-1H-pyrazole (223 mg, 1.00 mmol), 1,4-dioxa-8-azaspiro [4.5] decane (154 μL, 1.20 mmol), DavePhos (39.4 mg, 0.100 mmol), A mixture of Pd 2 (dba) 3 (45.8 mg, 0.0500 mmol) and sodium tert-butoxide (144 mg, 1.50 mmol) in toluene (10 mL) was stirred at 100 ° C. for 14 hours, filtered, and the solvent was distilled under reduced pressure. Left. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-7 / 3) to give the title compound as a white solid (211 mg, 64%).
LC / MS 330
NMR (CDCl 3 ) δ: 1.83-1.90 (4 H, m), 3.29-3.38 (4 H, m), 3.88 (3 H, s), 3.92 (3 H, s), 4.00 (4 H, s) , 6.53-6.59 (2 H, m), 7.34-7.38 (1 H, m), 7.73 (1 H, s), 7.78 (1 H, d, J = 0.8 Hz).
参考例１１８
tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 118
tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
118a) 1-(4-ブロモフェニル)-3-メチル-1H-1,2,4-トリアゾール
　4-ブロモアニリン(70 g, 410 mmol)の濃塩酸(340 mL)溶液に亜硝酸ナトリウム(30 g, 430 mmol)の水(81 mL)溶液を-20℃で加え、-20℃で30分間、0℃で30分間攪拌した。反応溶液に塩化すず(230 g, 1.2 mol)の濃塩酸(340 mL)溶液を-20℃でゆっくり滴下し、室温で40分間攪拌した。反応混合物を0℃に冷却し、生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物を10%炭酸カリウム水溶液で中和し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物のMeOH(400 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(43 g, 200 mmol)を加え、室温で1時間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(400 mL)溶液にオルトギ酸メチル(200 mL)、ピリジン(400 mL)を加え、100℃で6時間攪拌した。反応混合物を室温まで冷却し、酢酸エチルで希釈した。水、飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をヘキサンより再結晶して、題記化合物を黄色固体(32 g, 34%(2 steps))として得た。
LC/MS 240.1 
NMR (CDCl3) δ: 2.49 (3 H, s) 7.52 - 7.55 (2 H, m) 7.59 - 7.63 (2 H, m) 8.43 (1 H, s). 118a) 1- (4-Bromophenyl) -3-methyl-1H-1,2,4-triazole 4-bromoaniline (70 g, 410 mmol) in concentrated hydrochloric acid (340 mL) solution with sodium nitrite (30 g , 430 mmol) in water (81 mL) was added at −20 ° C., and the mixture was stirred at −20 ° C. for 30 minutes and at 0 ° C. for 30 minutes. To the reaction solution, a solution of tin chloride (230 g, 1.2 mol) in concentrated hydrochloric acid (340 mL) was slowly added dropwise at −20 ° C. and stirred at room temperature for 40 minutes. The reaction mixture was cooled to 0 ° C., and the resulting precipitate was collected by filtration and washed with diethyl ether. The resulting solid was neutralized with 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Methylethaneimidethioate hydroiodide (43 g, 200 mmol) was added to a solution of the residue in MeOH (400 mL), and the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. Methyl orthoformate (200 mL) and pyridine (400 mL) were added to a toluene (400 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. After washing with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane to give the title compound as a yellow solid (32 g, 34% (2 steps)).
LC / MS 240.1
NMR (CDCl 3 ) δ: 2.49 (3 H, s) 7.52-7.55 (2 H, m) 7.59-7.63 (2 H, m) 8.43 (1 H, s).
118b)tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモフェニル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.3 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(230 mg, 1.3 mmol)、DavePhos(50 mg, 0.13 mmmol)及びナトリウム tert-ブトキシド(180 mg, 1.9 mmol)のトルエン(3.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(58 mg, 0.063 mmol)を加え、90℃で1.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/4～7/3)で精製し、題記化合物を淡黄色固体(110 mg, 26%)として得た。
LC/MS 344 
NMR (CDCl3) δ: 1.49 (9 H, s) 2.48 (3 H, s) 3.11 - 3.26 (4 H, m) 3.54 - 3.67 (4 H, m) 6.87 - 7.09 (2 H, m) 7.44 - 7.56 (2 H, m) 8.31 (1 H, s). 118b) tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromophenyl) -3-methyl- 1H-1,2,4-triazole (300 mg, 1.3 mmol), tert-butyl piperazine-1-carboxylate (230 mg, 1.3 mmol), DavePhos (50 mg, 0.13 mmmol) and sodium tert-butoxide (180 mg , 1.9 mmol) in toluene (3.0 mL) was added Pd 2 (dba) 3 (58 mg, 0.063 mmol) in a nitrogen atmosphere and stirred at 90 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 4-7 / 3) to give the title compound as a pale yellow solid (110 mg, 26%).
LC / MS 344
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.48 (3 H, s) 3.11-3.26 (4 H, m) 3.54-3.67 (4 H, m) 6.87-7.09 (2 H, m) 7.44- 7.56 (2 H, m) 8.31 (1 H, s).
参考例１１９
tert-ブチル 4-[2-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 119
tert-butyl 4- [2-fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
119a) (4-ブロモ-3-フルオロフェニル)ヒドラジン
　4-ブロモ-3-フルオロアニリン(4.3 g, 22 mmol)の濃塩酸(25 mL)溶液に亜硝酸ナトリウム(1.6 g, 24 mmol)の水(2.0 mL)溶液を-20℃で加え、0℃で30分間攪拌した。反応混合物を塩化すず(16 g, 84 mmol)の濃塩酸(30 mL)溶液中に-20℃で滴下し、室温で1時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物を10%炭酸カリウム水溶液で中和し、酢酸エチルを加えた。不溶物を除去後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色固体(2.3 g, 49%)として得た。
NMR (CDCl3) δ: 3.59 (2 H, brs.) 5.29 (1 H, brs.) 6.48 (1 H, dd, J=8.1, 2.5 Hz) 6.68 (1 H, dd, J=10.8, 2.5 Hz) 7.27 - 7.35 (1 H, m). 119a) (4-Bromo-3-fluorophenyl) hydrazine 4-Bromo-3-fluoroaniline (4.3 g, 22 mmol) in concentrated hydrochloric acid (25 mL) was added to a solution of sodium nitrite (1.6 g, 24 mmol) in water ( 2.0 mL) solution was added at −20 ° C. and stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (16 g, 84 mmol) in concentrated hydrochloric acid (30 mL) at −20 ° C. and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.3 g, 49%).
NMR (CDCl 3 ) δ: 3.59 (2 H, brs.) 5.29 (1 H, brs.) 6.48 (1 H, dd, J = 8.1, 2.5 Hz) 6.68 (1 H, dd, J = 10.8, 2.5 Hz ) 7.27-7.35 (1 H, m).
119b) 1-(4-ブロモ-3-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール
　(4-ブロモ-3-フルオロフェニル)ヒドラジン(3.3 g, 16 mmol)のMeOH(28 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(3.4 g, 17 mmol)を加え、室温で30分間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(28 mL)溶液にオルトギ酸メチル(15 mL)、ピリジン(28 mL)を加え、100℃で7時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=2/3)で精製し、題記化合物を無色固体(3.6 g, 89%)として得た。
LC/MS 256 
NMR (CDCl3) δ: 2.49 (3 H, s) 7.35 (1 H, ddd, J=8.7, 2.3, 1.1 Hz) 7.52 (1 H, dd, J=9.0, 2.3 Hz) 7.60 - 7.73 (1 H, m) 8.44 (1 H, s). 119b) 1- (4-Bromo-3-fluorophenyl) -3-methyl-1H-1,2,4-triazole (4-bromo-3-fluorophenyl) hydrazine (3.3 g, 16 mmol) in MeOH (28 To the solution was added methyl ethaneimidothioate hydroiodide (3.4 g, 17 mmol), and the mixture was stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. Methyl orthoformate (15 mL) and pyridine (28 mL) were added to a toluene (28 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 7 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (3.6 g, 89%).
LC / MS 256
NMR (CDCl 3 ) δ: 2.49 (3 H, s) 7.35 (1 H, ddd, J = 8.7, 2.3, 1.1 Hz) 7.52 (1 H, dd, J = 9.0, 2.3 Hz) 7.60-7.73 (1 H , m) 8.44 (1 H, s).
119c) tert-ブチル 4-[2-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-3-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(500 mg, 2.0 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(360 mg, 2.0 mmol)、DavePhos(77 mg, 0.20 mmmol)及びナトリウム tert-ブトキシド(280 mg, 2.9 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(89 mg, 0.098 mmol)を加え、90℃で12.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～4/1)で精製し、題記化合物を淡橙色固体(160 mg, 23%)として得た。
LC/MS 362 
NMR (CDCl3) δ: 1.49 (9 H, s) 2.48 (3 H, s) 2.98 - 3.13 (4 H, m) 3.56 - 3.67 (4 H, m) 7.00 (1 H, t, J=8.9 Hz) 7.29 - 7.36 (1 H, m) 7.39 (1 H, dd, J=12.6, 2.4 Hz) 8.34 (1 H, s). 119c) tert-butyl 4- [2-fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-3- Fluorophenyl) -3-methyl-1H-1,2,4-triazole (500 mg, 2.0 mmol), tert-butyl piperazine-1-carboxylate (360 mg, 2.0 mmol), DavePhos (77 mg, 0.20 mmmol) Pd 2 (dba) 3 (89 mg, 0.098 mmol) was added to a toluene (2.0 mL) solution of sodium tert-butoxide (280 mg, 2.9 mmol) in a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 12.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to 4/1) to give the title compound as a pale orange solid (160 mg, 23%).
LC / MS 362
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.48 (3 H, s) 2.98-3.13 (4 H, m) 3.56-3.67 (4 H, m) 7.00 (1 H, t, J = 8.9 Hz ) 7.29-7.36 (1 H, m) 7.39 (1 H, dd, J = 12.6, 2.4 Hz) 8.34 (1 H, s).
参考例１２０
tert-ブチル 4-[2-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 120
tert-butyl 4- [2-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
120a)1-(4-ブロモ-3-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　1-(4-ブロモ-3-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(500 mg, 2.0 mmol)のDMF(10 mL)溶液にナトリウムメトキシド 28%MeOH溶液(1.1 mL, 5.9 mmol)を加え、80℃で3.5時間攪拌した。反応混合物を室温まで冷却後、水で希釈した。生じた沈殿物をろ取し、得られた固形物を水で洗浄し、題記化合物を無色固体(390 mg, 75%)として得た。
LC/MS 268
NMR (CDCl3) δ: 2.50 (3 H, s) 3.99 (3 H, s) 7.06 (1 H, dd, J=8.3, 2.3 Hz) 7.28 (1 H, d, J=2.3 Hz) 7.62 (1 H, d, J=8.3 Hz) 8.43 (1 H, s). 120a) 1- (4-Bromo-3-methoxyphenyl) -3-methyl-1H-1,2,4-triazole 1- (4-bromo-3-fluorophenyl) -3-methyl-1H-1,2 , 4-triazole (500 mg, 2.0 mmol) in DMF (10 mL) was added sodium methoxide 28% MeOH solution (1.1 mL, 5.9 mmol), and the mixture was stirred at 80 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, and the obtained solid was washed with water to give the title compound as a colorless solid (390 mg, 75%).
LC / MS 268
NMR (CDCl 3 ) δ: 2.50 (3 H, s) 3.99 (3 H, s) 7.06 (1 H, dd, J = 8.3, 2.3 Hz) 7.28 (1 H, d, J = 2.3 Hz) 7.62 (1 (H, d, J = 8.3 Hz) 8.43 (1 H, s).
120b)tert-ブチル 4-[2-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-3-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(400 mg, 1.5 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(280 mg, 1.5 mmol)、DavePhos(59 mg, 0.15 mmmol)及びナトリウム tert-ブトキシド(220 mg, 2.2 mmol)のトルエン(5.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(68 mg, 0.075 mmol)を加え、90℃で13時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/1～酢酸エチルのみ)で精製し、題記化合物を淡黄色固体(320 mg, 57%)として得た。
LC/MS 374 
NMR (CDCl3) δ: 1.49 (9 H, s) 2.49 (3 H, s) 2.92 - 3.11 (4 H, m) 3.49 - 3.68 (4 H, m) 3.95 (3 H, s) 6.95 (1 H, d, J=8.3 Hz) 7.10 (1 H, dd, J=8.3, 2.7 Hz) 7.20 (1 H, d, J=2.7 Hz) 8.35 (1 H, s). 120b) tert-butyl 4- [2-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-3- Methoxyphenyl) -3-methyl-1H-1,2,4-triazole (400 mg, 1.5 mmol), tert-butyl piperazine-1-carboxylate (280 mg, 1.5 mmol), DavePhos (59 mg, 0.15 mmmol) Pd 2 (dba) 3 (68 mg, 0.075 mmol) was added to a toluene (5.0 mL) solution of sodium tert-butoxide (220 mg, 2.2 mmol) in a nitrogen atmosphere, and the mixture was stirred at 90 ° C. for 13 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate alone) to give the title compound as a pale yellow solid (320 mg, 57%).
LC / MS 374
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.49 (3 H, s) 2.92-3.11 (4 H, m) 3.49-3.68 (4 H, m) 3.95 (3 H, s) 6.95 (1 H , d, J = 8.3 Hz) 7.10 (1 H, dd, J = 8.3, 2.7 Hz) 7.20 (1 H, d, J = 2.7 Hz) 8.35 (1 H, s).
参考例１２１
tert-ブチル 4-[3-フルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(400 mg, 1.6 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(290 mg, 1.6 mmol)、DavePhos(62 mg, 0.16 mmmol)及びナトリウム tert-ブトキシド(230 mg, 2.3 mmol)のトルエン(4.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(72 mg, 0.078 mmol)を加え、80℃で14時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=1/1)で精製し、題記化合物を無色固体(240 mg, 43%)として得た。
LC/MS 362 
NMR (CDCl3) δ: 1.49 (9 H, s) 2.49 (3 H, s) 3.15 - 3.29 (4 H, m) 3.50 - 3.68 (4 H, m) 6.65 - 6.80 (2 H, m) 7.58 - 7.69 (1 H, m) 8.38 (1 H, d, J=2.6 Hz). Reference Example 121
tert-butyl 4- [3-fluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo-2-fluorophenyl ) -3-Methyl-1H-1,2,4-triazole (400 mg, 1.6 mmol), tert-butyl piperazine-1-carboxylate (290 mg, 1.6 mmol), DavePhos (62 mg, 0.16 mmmol) and sodium Under a nitrogen atmosphere, Pd 2 (dba) 3 (72 mg, 0.078 mmol) was added to a toluene (4.0 mL) solution of tert-butoxide (230 mg, 2.3 mmol), and the mixture was stirred at 80 ° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless solid (240 mg, 43%).
LC / MS 362
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.49 (3 H, s) 3.15-3.29 (4 H, m) 3.50-3.68 (4 H, m) 6.65-6.80 (2 H, m) 7.58- 7.69 (1 H, m) 8.38 (1 H, d, J = 2.6 Hz).
参考例１２２
tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-プロポキシフェニル]ピペラジン-1-カルボキシラート Reference Example 122
tert-butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3-propoxyphenyl] piperazine-1-carboxylate
122a)1-(4-ブロモ-2-プロポキシフェニル)-3-メチル-1H-1,2,4-トリアゾール
　1-プロパノール(180 μL, 2.3 mmol)のDMF(3.0 mL)溶液に水素化ナトリウム(94 mg, 2.3 mmol)を0℃で加え、30分間攪拌した。反応溶液に1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(200 mg, 0.78 mmol)を0℃で加え、80℃で3時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=2/3)で精製し、題記化合物を無色固体(190 mg, 84%)として得た。
LC/MS 296 
NMR (CDCl3) δ: 1.03 (3 H, t, J=7.5 Hz) 1.74 - 1.96 (2 H, m) 2.48 (3 H, s) 4.04 (2 H, t, J=6.4 Hz) 7.16 - 7.23 (2 H, m) 7.68 (1 H, d, J=9.0 Hz) 8.67 (1 H, s). 122a) 1- (4-Bromo-2-propoxyphenyl) -3-methyl-1H-1,2,4-triazole 1-propanol (180 μL, 2.3 mmol) in DMF (3.0 mL) in sodium hydride (3.0 mL) 94 mg, 2.3 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. 1- (4-Bromo-2-fluorophenyl) -3-methyl-1H-1,2,4-triazole (200 mg, 0.78 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (190 mg, 84%).
LC / MS 296
NMR (CDCl 3 ) δ: 1.03 (3 H, t, J = 7.5 Hz) 1.74-1.96 (2 H, m) 2.48 (3 H, s) 4.04 (2 H, t, J = 6.4 Hz) 7.16-7.23 (2 H, m) 7.68 (1 H, d, J = 9.0 Hz) 8.67 (1 H, s).
122b)tert-ブチル 4-[4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)-3-プロポキシフェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2-プロポキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(190 mg, 0.65 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(120 mg, 0.65 mmol)、DavePhos(26 mg, 0.065 mmmol)及びナトリウム tert-ブトキシド(94 mg, 0.97 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(30 mg, 0.033 mmol)を加え、80℃で13時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=1/1)で精製し、題記化合物を無色固体(200 mg, 78%)として得た。
LC/MS 402 
NMR (CDCl3) δ: 1.00 (3 H, t, J=7.5 Hz) 1.49 (9 H, s) 1.71 - 1.91 (2 H, m) 2.47 (3 H, s) 3.14 - 3.23 (4 H, m) 3.52 - 3.66 (4 H, m) 3.99 (2 H, t, J=6.4 Hz) 6.49 - 6.65 (2 H, m) 7.58 (1 H, d, J=8.7 Hz) 8.51 (1 H, s). 122b) tert-Butyl 4- [4- (3-methyl-1H-1,2,4-triazol-1-yl) -3-propoxyphenyl] piperazine-1-carboxylate 1- (4-Bromo-2- (Propoxyphenyl) -3-methyl-1H-1,2,4-triazole (190 mg, 0.65 mmol), tert-butyl piperazine-1-carboxylate (120 mg, 0.65 mmol), DavePhos (26 mg, 0.065 mmmol) Pd 2 (dba) 3 (30 mg, 0.033 mmol) was added to a toluene (2.0 mL) solution of sodium tert-butoxide (94 mg, 0.97 mmol) in a nitrogen atmosphere, and the mixture was stirred at 80 ° C. for 13 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless solid (200 mg, 78%).
LC / MS 402
NMR (CDCl 3 ) δ: 1.00 (3 H, t, J = 7.5 Hz) 1.49 (9 H, s) 1.71-1.91 (2 H, m) 2.47 (3 H, s) 3.14-3.23 (4 H, m ) 3.52-3.66 (4 H, m) 3.99 (2 H, t, J = 6.4 Hz) 6.49-6.65 (2 H, m) 7.58 (1 H, d, J = 8.7 Hz) 8.51 (1 H, s) .
参考例１２３
tert-ブチル 4-[3-エトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 123
tert-butyl 4- [3-ethoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate
123a)5-(4-ブロモ-2-エトキシフェニル)-2-メチル-1,3-オキサゾール
　5-(4-ブロモ-2-フルオロフェニル)-2-メチル-1,3-オキサゾール(200 mg, 0.78 mmol)のDMF(4.0 mL)溶液にナトリウムエトキシド 20%EtOH溶液(800 μL, 2.3 mmol)を加え、80℃で3時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=2/3)で精製し、題記化合物を無色固体(190 mg, 88%)として得た。
LC/MS 282 
NMR (CDCl3) δ: 1.54 (3 H, t, J=7.0 Hz) 2.52 (3 H, s) 4.15 (2 H, q, J=7.0 Hz) 7.08 (1 H, d, J=1.9 Hz) 7.15 (1 H, dd, J=8.3, 1.9 Hz) 7.43 (1 H, s) 7.59 (1 H, d, J=8.3 Hz). 123a) 5- (4-Bromo-2-ethoxyphenyl) -2-methyl-1,3-oxazole 5- (4-Bromo-2-fluorophenyl) -2-methyl-1,3-oxazole (200 mg, Sodium ethoxide 20% EtOH solution (800 μL, 2.3 mmol) was added to a DMF (4.0 mL) solution of 0.78 mmol), and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (190 mg, 88%).
LC / MS 282
NMR (CDCl 3 ) δ: 1.54 (3 H, t, J = 7.0 Hz) 2.52 (3 H, s) 4.15 (2 H, q, J = 7.0 Hz) 7.08 (1 H, d, J = 1.9 Hz) 7.15 (1 H, dd, J = 8.3, 1.9 Hz) 7.43 (1 H, s) 7.59 (1 H, d, J = 8.3 Hz).
123b)tert-ブチル 4-[3-エトキシ-4-(2-メチル-1,3-オキサゾール-5-イル)フェニル]ピペラジン-1-カルボキシラート
　5-(4-ブロモ-2-エトキシフェニル)-2-メチル-1,3-オキサゾール(190 mg, 0.68 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(130 mg, 0.68 mmol)、DavePhos(27 mg, 0.068 mmmol)及びナトリウム tert-ブトキシド(99 mg, 1.0 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(31 mg, 0.034 mmol)を加え、90℃で6.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/9～7/3)で精製し、題記化合物を淡黄色固体(220 mg, 84%)として得た。
LC/MS 388 
NMR (CDCl3) δ: 1.49 (9 H, s) 1.53 (3 H, t, J=7.2 Hz) 2.50 (3 H, s) 3.12 - 3.25 (4 H, m) 3.53 - 3.66 (4 H, m) 4.13 (2 H, q, J=7.2 Hz) 6.48 (1 H, d, J=2.3 Hz) 6.56 (1 H, dd, J=8.7, 2.3 Hz) 7.29 (1 H, s) 7.60 (1 H, d, J=8.7 Hz). 123b) tert-butyl 4- [3-ethoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] piperazine-1-carboxylate 5- (4-bromo-2-ethoxyphenyl)- 2-Methyl-1,3-oxazole (190 mg, 0.68 mmol), tert-butyl piperazine-1-carboxylate (130 mg, 0.68 mmol), DavePhos (27 mg, 0.068 mmmol) and sodium tert-butoxide (99 mg , 1.0 mmol) in toluene (2.0 mL) was added with Pd 2 (dba) 3 (31 mg, 0.034 mmol) in a nitrogen atmosphere and stirred at 90 ° C. for 6.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 9-7 / 3) to give the title compound as a pale yellow solid (220 mg, 84%).
LC / MS 388
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 1.53 (3 H, t, J = 7.2 Hz) 2.50 (3 H, s) 3.12-3.25 (4 H, m) 3.53-3.66 (4 H, m ) 4.13 (2 H, q, J = 7.2 Hz) 6.48 (1 H, d, J = 2.3 Hz) 6.56 (1 H, dd, J = 8.7, 2.3 Hz) 7.29 (1 H, s) 7.60 (1 H , d, J = 8.7 Hz).
参考例１２４
tert-ブチル 4-[3-(1-メチルエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 124
tert-butyl 4- [3- (1-methylethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
124a) 1-[4-ブロモ-2-(1-メチルエトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール
　2-プロパノール(180 μL, 2.3 mmol)のDMF(3.0 mL)溶液に水素化ナトリウム(94 mg, 2.3 mmol)を0℃で加え、30分間攪拌した。反応溶液に1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(200 mg, 0.78 mmol)を0℃で加え、80℃で4.5時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=2/3)で精製し、題記化合物を無色固体(130 mg, 57%)として得た。
LC/MS 296 
NMR (CDCl3) δ: 1.38 (6 H, d, J=6.0 Hz) 2.48 (3 H, s) 4.64 (1 H, spt, J=6.0 Hz) 7.13 - 7.22 (2 H, m) 7.68 (1 H, d, J=9.1 Hz) 8.68 (1 H, s). 124a) 1- [4-Bromo-2- (1-methylethoxy) phenyl] -3-methyl-1H-1,2,4-triazole 2-propanol (180 μL, 2.3 mmol) in DMF (3.0 mL) To the solution, sodium hydride (94 mg, 2.3 mmol) was added at 0 ° C. and stirred for 30 minutes. 1- (4-Bromo-2-fluorophenyl) -3-methyl-1H-1,2,4-triazole (200 mg, 0.78 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at 80 ° C. for 4.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (130 mg, 57%).
LC / MS 296
NMR (CDCl 3 ) δ: 1.38 (6 H, d, J = 6.0 Hz) 2.48 (3 H, s) 4.64 (1 H, spt, J = 6.0 Hz) 7.13-7.22 (2 H, m) 7.68 (1 (H, d, J = 9.1 Hz) 8.68 (1 H, s).
124b)tert-ブチル 4-[3-(1-メチルエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-[4-ブロモ-2-(1-メチルエトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール(130 mg, 0.44 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(81 mg, 0.44 mmol)、DavePhos(17 mg, 0.044 mmmol)及びナトリウム tert-ブトキシド(63 mg, 0.97 mmol)のトルエン(1.5 mL)溶液に窒素雰囲気下、Pd2(dba)3(20 mg, 0.022 mmol)を加え、90℃で15時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/9～7/3)で精製し、題記化合物を無色固体(120 mg, 70%)として得た。
LC/MS 402 
NMR (CDCl3) δ: 1.32 (6 H, d, J=6.4 Hz) 1.49 (9 H, s) 2.47 (3 H, s) 3.09 - 3.24 (4 H, m) 3.50 - 3.66 (4 H, m) 4.48 - 4.64 (1 H, m) 6.47 - 6.69 (2 H, m) 7.59 (1 H, d, J=8.7 Hz) 8.53 (1 H, s). 124b) tert-butyl 4- [3- (1-methylethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- [4 -Bromo-2- (1-methylethoxy) phenyl] -3-methyl-1H-1,2,4-triazole (130 mg, 0.44 mmol), tert-butyl piperazine-1-carboxylate (81 mg, 0.44 mmol) ), DavePhos (17 mg, 0.044 mmmol) and sodium tert-butoxide (63 mg, 0.97 mmol) in toluene (1.5 mL) under a nitrogen atmosphere, Pd 2 (dba) 3 (20 mg, 0.022 mmol) was added, Stir at 90 ° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 9-7 / 3) to give the title compound as a colorless solid (120 mg, 70%).
LC / MS 402
NMR (CDCl 3 ) δ: 1.32 (6 H, d, J = 6.4 Hz) 1.49 (9 H, s) 2.47 (3 H, s) 3.09-3.24 (4 H, m) 3.50-3.66 (4 H, m ) 4.48-4.64 (1 H, m) 6.47-6.69 (2 H, m) 7.59 (1 H, d, J = 8.7 Hz) 8.53 (1 H, s).
参考例１２５
tert-ブチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート Reference Example 125
tert-butyl 4- [4- (2-methyl-1,3-oxazol-5-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxylate
125a) 5-[4-ブロモ-2-(2,2,2-トリフルオロエトキシ)フェニル]-2-メチル-1,3-オキサゾール
　5-(4-ブロモ-2-フルオロフェニル)-2-メチル-1,3-オキサゾール(300 mg, 1.2 mmol)のDMF(4.0 mL)溶液に炭酸カリウム(320 mg, 2.3 mmol)及び2,2,2-トリフルオロエタノール(140 μL, 2.0 mmol)を加え、80℃で3日間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=3/7)で精製した。残留物を分取HPLCにて精製し、分取したフラクションを濃縮した。残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、題記化合物を無色非定形固体(150 mg, 38%)として得た。
LC/MS 336 
NMR (CDCl3) δ: 2.53 (3 H, s) 4.47 (2 H, q, J=7.7 Hz) 7.05 (1 H, d, J=1.9 Hz) 7.27 - 7.30 (1 H, m) 7.40 (1 H, s) 7.64 (1 H, d, J=8.3 Hz). 125a) 5- [4-Bromo-2- (2,2,2-trifluoroethoxy) phenyl] -2-methyl-1,3-oxazole 5- (4-Bromo-2-fluorophenyl) -2-methyl Potassium carbonate (320 mg, 2.3 mmol) and 2,2,2-trifluoroethanol (140 μL, 2.0 mmol) were added to a DMF (4.0 mL) solution of -1,3-oxazole (300 mg, 1.2 mmol), Stir at 80 ° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 3/7). The residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless amorphous solid (150 mg, 38%).
LC / MS 336
NMR (CDCl 3 ) δ: 2.53 (3 H, s) 4.47 (2 H, q, J = 7.7 Hz) 7.05 (1 H, d, J = 1.9 Hz) 7.27-7.30 (1 H, m) 7.40 (1 H, s) 7.64 (1 H, d, J = 8.3 Hz).
125b)tert-ブチル 4-[4-(2-メチル-1,3-オキサゾール-5-イル)-3-(2,2,2-トリフルオロエトキシ)フェニル]ピペラジン-1-カルボキシラート
　5-[4-ブロモ-2-(2,2,2-トリフルオロエトキシ)フェニル]-2-メチル-1,3-オキサゾール(150 mg, 0.44 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(83 mg, 0.44 mmol)、DavePhos(17 mg, 0.044 mmmol)及びナトリウム tert-ブトキシド(64 mg, 0.67 mmol)のトルエン(1.5 mL)溶液に窒素雰囲気下、Pd2(dba)3(20 mg, 0.022 mmol)を加え、90℃で15時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=2/3)で精製し、題記化合物を無色非定形固体(150 mg, 79%)として得た。
LC/MS 442 
NMR (CDCl3) δ: 1.49 (9 H, s) 2.43 - 2.61 (3 H, m) 3.10 - 3.32 (4 H, m) 3.51 - 3.72 (4 H, m) 4.44 (2 H, q, J=7.9 Hz) 6.40 (1 H, d, J=2.3 Hz) 6.65 (1 H, dd, J=8.7, 2.3 Hz) 7.25 (1 H, s) 7.64 (1 H, d, J=8.7 Hz). 125b) tert-butyl 4- [4- (2-methyl-1,3-oxazol-5-yl) -3- (2,2,2-trifluoroethoxy) phenyl] piperazine-1-carboxylate 5- [ 4-Bromo-2- (2,2,2-trifluoroethoxy) phenyl] -2-methyl-1,3-oxazole (150 mg, 0.44 mmol), tert-butyl piperazine-1-carboxylate (83 mg, 0.44 mmol), DavePhos (17 mg, 0.044 mmmol) and sodium tert-butoxide (64 mg, 0.67 mmol) in toluene (1.5 mL) under a nitrogen atmosphere, Pd 2 (dba) 3 (20 mg, 0.022 mmol) In addition, the mixture was stirred at 90 ° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate / hexane = 2/3) to give the title compound as a colorless amorphous solid (150 mg, 79%).
LC / MS 442
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.43-2.61 (3 H, m) 3.10-3.32 (4 H, m) 3.51-3.72 (4 H, m) 4.44 (2 H, q, J = 7.9 Hz) 6.40 (1 H, d, J = 2.3 Hz) 6.65 (1 H, dd, J = 8.7, 2.3 Hz) 7.25 (1 H, s) 7.64 (1 H, d, J = 8.7 Hz).
参考例１２６
tert-ブチル 4-[2,3-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 126
tert-butyl 4- [2,3-difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
126a)1-(4-ブロモ-2,3-ジフルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール
　4-ブロモ-2,3-ジフルオロアニリン(4.9 g, 24 mmol)の濃塩酸(20 mL)溶液に亜硝酸ナトリウム(1.7 g, 25 mmol)の水(2.5 mL)溶液を-20℃で加え、0℃で30分間攪拌した。反応混合物を塩化すず(17 g, 89 mmol)の濃塩酸(20 mL)溶液中に-20℃で滴下し、室温で1.5時間攪拌した。生じた析出物をろ取しジエチルエーテルで洗浄した。得られた固形物のMeOH(25 mL)溶液にメチル エタンイミドチオアート　ヨウ化水素酸塩(5.1 g, 24 mmol)を加え、トリエチルアミン(3.3 mL, 24 mmol)を0℃で滴下した。室温で1時間攪拌し、溶媒を減圧留去した。得られた残留物のトルエン(20 mL)溶液にオルトギ酸メチル(15 mL)、ピリジン(15 mL)を加え、100℃で3時間攪拌した。反応混合物を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=2/3)で精製し、題記化合物を無色固体(2.6 g, 40%(2 steps))として得た。
LC/MS 274 
NMR (CDCl3) δ: 2.50 (3 H, s) 7.39 - 7.54 (1 H, m) 7.56 - 7.70 (1 H, m) 8.55 (1 H, d, J=2.7 Hz). 126a) 1- (4-Bromo-2,3-difluorophenyl) -3-methyl-1H-1,2,4-triazole 4-bromo-2,3-difluoroaniline (4.9 g, 24 mmol) in concentrated hydrochloric acid A solution of sodium nitrite (1.7 g, 25 mmol) in water (2.5 mL) was added to the (20 mL) solution at −20 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was added dropwise to a solution of tin chloride (17 g, 89 mmol) in concentrated hydrochloric acid (20 mL) at −20 ° C. and stirred at room temperature for 1.5 hours. The resulting precipitate was collected by filtration and washed with diethyl ether. Methylethaneimidothioate hydroiodide (5.1 g, 24 mmol) was added to a solution of the obtained solid in MeOH (25 mL), and triethylamine (3.3 mL, 24 mmol) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. Methyl orthoformate (15 mL) and pyridine (15 mL) were added to a toluene (20 mL) solution of the obtained residue, and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 2/3) to give the title compound as a colorless solid (2.6 g, 40% (2 steps)).
LC / MS 274
NMR (CDCl 3 ) δ: 2.50 (3 H, s) 7.39-7.54 (1 H, m) 7.56-7.70 (1 H, m) 8.55 (1 H, d, J = 2.7 Hz).
126b)tert-ブチル 4-[2,3-ジフルオロ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-(4-ブロモ-2,3-ジフルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(300 mg, 1.1 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(200 mg, 1.31 mmol)、DavePhos(43 mg, 0.11 mmmol)及びナトリウム tert-ブトキシド(160 mg, 1.6 mmol)のトルエン(3.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(50 mg, 0.055 mmol)を加え、90℃で14時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=1/1)で精製し、題記化合物を無色固体(240 mg, 58%)として得た。
LC/MS 380 
NMR (CDCl3) δ: 1.49 (9 H, s) 2.49 (3 H, s) 3.03 - 3.16 (4 H, m) 3.57 - 3.69 (4 H, m) 6.78 (1 H, ddd, J=9.1, 7.9, 2.3 Hz) 7.48 (1 H, ddd, J=9.1, 7.9, 2.3 Hz) 8.43 (1 H, d, J=2.7 Hz). 126b) tert-butyl 4- [2,3-difluoro-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- (4-bromo- 2,3-difluorophenyl) -3-methyl-1H-1,2,4-triazole (300 mg, 1.1 mmol), tert-butyl piperazine-1-carboxylate (200 mg, 1.31 mmol), DavePhos (43 mg , 0.11 mmmol) and sodium tert-butoxide (160 mg, 1.6 mmol) in toluene (3.0 mL) under nitrogen atmosphere, Pd 2 (dba) 3 (50 mg, 0.055 mmol) was added and stirred at 90 ° C. for 14 hours did. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to give the title compound as a colorless solid (240 mg, 58%).
LC / MS 380
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.49 (3 H, s) 3.03-3.16 (4 H, m) 3.57-3.69 (4 H, m) 6.78 (1 H, ddd, J = 9.1, (7.9, 2.3 Hz) 7.48 (1 H, ddd, J = 9.1, 7.9, 2.3 Hz) 8.43 (1 H, d, J = 2.7 Hz).
参考例127
tert-ブチル 4-[3-(2,2-ジフルオロエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート Reference Example 127
tert-butyl 4- [3- (2,2-difluoroethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate
127a)1-[4-ブロモ-2-(2,2-ジフルオロエトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール
　2,2ジフルオロエタノール(99 μL, 1.6 mmol)のDMF(4.0 mL)溶液に水素化ナトリウム(62 mg, 1.6 mmol)を0℃で加え、10分間攪拌した。反応溶液に1-(4-ブロモ-2-フルオロフェニル)-3-メチル-1H-1,2,4-トリアゾール(200 mg, 0.78 mmol)を0℃で加え、80℃で1時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン=3/7)で精製し、題記化合物を無色固体(230 mg, 94%)として得た。
LC/MS 318 
NMR (CDCl3) δ: 2.48 (3 H, s) 4.29 (2 H, td, J=12.8, 4.0 Hz) 6.10 (1 H, tt, J=54.5, 3.8 Hz) 7.19 (1 H, d, J=1.9 Hz) 7.31 (1 H, dd, J=8.7, 1.9 Hz) 7.70 (1 H, d, J=8.7 Hz) 8.58 (1 H, s). 127a) 1- [4-Bromo-2- (2,2-difluoroethoxy) phenyl] -3-methyl-1H-1,2,4-triazole 2,2 difluoroethanol (99 μL, 1.6 mmol) in DMF ( 4.0 mL) solution was added sodium hydride (62 mg, 1.6 mmol) at 0 ° C. and stirred for 10 minutes. To the reaction solution, 1- (4-bromo-2-fluorophenyl) -3-methyl-1H-1,2,4-triazole (200 mg, 0.78 mmol) was added at 0 ° C., and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate / hexane = 3/7) to give the title compound as a colorless solid (230 mg, 94%).
LC / MS 318
NMR (CDCl 3 ) δ: 2.48 (3 H, s) 4.29 (2 H, td, J = 12.8, 4.0 Hz) 6.10 (1 H, tt, J = 54.5, 3.8 Hz) 7.19 (1 H, d, J = 1.9 Hz) 7.31 (1 H, dd, J = 8.7, 1.9 Hz) 7.70 (1 H, d, J = 8.7 Hz) 8.58 (1 H, s).
127b)tert-ブチル 4-[3-(2,2-ジフルオロエトキシ)-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]ピペラジン-1-カルボキシラート
　1-[4-ブロモ-2-(2,2-ジフルオロエトキシ)フェニル]-3-メチル-1H-1,2,4-トリアゾール(230 mg, 0.73 mmol)、tert-ブチル ピペラジン-1-カルボキシラート(140 mg, 0.73 mmol)、DavePhos(29 mg, 0.073 mmmol)及びナトリウム tert-ブトキシド(110 mg, 1.1 mmol)のトルエン(2.0 mL)溶液に窒素雰囲気下、Pd2(dba)3(33 mg, 0.037 mmol)を加え、90℃で14時間攪拌した。反応混合物を室温まで冷却し、水で希釈し、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=3/7～7/3)で精製し、題記化合物を黄色固体(250 mg, 80%)として得た。
LC/MS 424 
NMR (CDCl3) δ:1.49 (9 H, s) 2.48 (3 H, s) 3.12 - 3.29 (4 H, m) 3.53 - 3.66 (4 H, m) 4.22 (2 H, td, J=13.0, 3.8 Hz) 6.04 (1 H, tt, J=54.9, 3.8 Hz) 6.51 (1 H, d, J=2.3 Hz) 6.65 (1 H, dd, J=8.7, 2.3 Hz) 7.57 (1 H, d, J=8.7 Hz) 8.41 (1 H, s). 127b) tert-butyl 4- [3- (2,2-difluoroethoxy) -4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine-1-carboxylate 1- [4-Bromo-2- (2,2-difluoroethoxy) phenyl] -3-methyl-1H-1,2,4-triazole (230 mg, 0.73 mmol), tert-butyl piperazine-1-carboxylate (140 mg, 0.73 mmol), DavePhos (29 mg, 0.073 mmmol) and sodium tert-butoxide (110 mg, 1.1 mmol) in toluene (2.0 mL) under a nitrogen atmosphere, Pd 2 (dba) 3 (33 mg, 0.037 mmol) ) Was added and stirred at 90 ° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 3 / 7-7 / 3) to give the title compound as a yellow solid (250 mg, 80%).
LC / MS 424
NMR (CDCl 3 ) δ: 1.49 (9 H, s) 2.48 (3 H, s) 3.12-3.29 (4 H, m) 3.53-3.66 (4 H, m) 4.22 (2 H, td, J = 13.0, 3.8 Hz) 6.04 (1 H, tt, J = 54.9, 3.8 Hz) 6.51 (1 H, d, J = 2.3 Hz) 6.65 (1 H, dd, J = 8.7, 2.3 Hz) 7.57 (1 H, d, J = 8.7 Hz) 8.41 (1 H, s).
参考例128
1-(3,4,5-トリフルオロベンジル)ピペラジン-2-オン Reference Example 128
1- (3,4,5-trifluorobenzyl) piperazin-2-one
128a)ベンジル 3-オキソ-4-(3,4,5-トリフルオロベンジル)ピペラジン-1-カルボキシラート
　ベンジル3-オキソピペラジン-1-カルボキシラート(1.8 g, 7.5 mmol)のDMF(17 mL)溶液にナトリウム tert-ブトキシド(0.72 g, 7.5 mmol)を加え、室温で10分攪拌した。さらに、同温で[2-(クロロメトキシ)エチル](トリメチル)シラン(4.2 mL, 24 mmol)を加え、室温で16時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラム(ヘキサン/酢酸エチル=8/2～1/1)で精製し、題記化合物を無色油状物(1.3 g, 46%)として得た。
LC/MS 379.0
NMR (CDCl3) δ: 3.31 (2 H, br), 3.72 (2 H, t, J=5.7 Hz), 4.26 (2 H, s), 4.54 (2 H, s), 5.17 (2 H, s), 6.89 - 6.94 (2 H, m), 7.37 (5 H, m).
128b) 1-(3,4,5-トリフルオロベンジル)ピペラジン-2-オン
　窒素雰囲気下、ベンジル 3-オキソ-4-(3,4,5-トリフルオロベンジル)ピペラジン-1-カルボキシラート(1.3 g, 3.5 mmol)のTHF(15 mL)溶液に10%Pd－C(0.13 g)を加え、水素雰囲気下、室温で15時間攪拌した。触媒をろ去し、ろ液を減圧下に濃縮し、題記化合物を黒色固体(0.79 g, 93%)として得た。
NMR (CDCl3) δ: 1.73 (1 H, br), 3.09 (2 H, t, J=5.1 Hz), 3.26 (2 H, t, J=5.7 Hz), 3.62 (2 H, s), 4.53 (2 H, s), 6.90 - 6.94 (2 H, m),. 128a) Benzyl 3-oxo-4- (3,4,5-trifluorobenzyl) piperazine-1-carboxylate Benzyl 3-oxopiperazine-1-carboxylate (1.8 g, 7.5 mmol) in DMF (17 mL) To the mixture was added sodium tert-butoxide (0.72 g, 7.5 mmol), and the mixture was stirred at room temperature for 10 minutes. Furthermore, [2- (chloromethoxy) ethyl] (trimethyl) silane (4.2 mL, 24 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 8/2 to 1/1) to give the title compound as a colorless oil (1.3 g, 46%).
LC / MS 379.0
NMR (CDCl 3 ) δ: 3.31 (2 H, br), 3.72 (2 H, t, J = 5.7 Hz), 4.26 (2 H, s), 4.54 (2 H, s), 5.17 (2 H, s ), 6.89-6.94 (2 H, m), 7.37 (5 H, m).
128b) 1- (3,4,5-trifluorobenzyl) piperazin-2-one Under nitrogen atmosphere, benzyl 3-oxo-4- (3,4,5-trifluorobenzyl) piperazine-1-carboxylate (1.3 g, 3.5 mmol) in THF (15 mL) was added 10% Pd-C (0.13 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a black solid (0.79 g, 93%).
NMR (CDCl 3 ) δ: 1.73 (1 H, br), 3.09 (2 H, t, J = 5.1 Hz), 3.26 (2 H, t, J = 5.7 Hz), 3.62 (2 H, s), 4.53 (2 H, s), 6.90-6.94 (2 H, m) ,.
参考例129
tert-ブチル {4-[3-メトキシ-4-(3-メチル-1H-1,2,4-トリアゾール-1-イル)フェニル]-2-オキソピペラジン-1-イル}アセタート
　1-(4-ブロモ-2-メトキシフェニル)-3-メチル-1H-1,2,4-トリアゾール(0.86 g, 4.0 mmol)、tert-ブチル (2-オキソピペラジン-1-イル)アセタート(1.1 g, 4.0 mmol)、DavePhos(0.18 g, 0.40 mmol)及び炭酸セシウム(0.16 g, 6.0 mmol)のDME(4 mL)－水(4 mL)溶液に窒素雰囲気下、Pd2(dba)3(0.18 mg, 0.20 mmol)を加え、80℃で30時間攪拌した。反応混合物を酢酸エチル－飽和食塩水で希釈し、水層を酢酸エチルで抽出、有機層を合わせ飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラム(ヘキサン/酢酸エチル=8/2～0/1)で精製し、題記化合物を橙色無定形固体(0.77 g, 38%)として得た。
LC/MS 402.1
NMR (CDCl3) δ: 1.50 (9 H, s), 2.52 (3 H, s), 3.60 (4 H, m), 3.95 (3 H, s), 4.02 (2 H, s), 4.13 (2 H, s), 6.42 (1 H, d, J=2.4 Hz), 6.52 (1 H, dd, J=2.1 Hz, 8.4 Hz), 7.25 (1 H, s), 7.62 (1 H, d, J=8.4 Hz). Reference Example 129
tert-butyl {4- [3-methoxy-4- (3-methyl-1H-1,2,4-triazol-1-yl) phenyl] -2-oxopiperazin-1-yl} acetate 1- (4- Bromo-2-methoxyphenyl) -3-methyl-1H-1,2,4-triazole (0.86 g, 4.0 mmol), tert-butyl (2-oxopiperazin-1-yl) acetate (1.1 g, 4.0 mmol) , DavePhos (0.18 g, 0.40 mmol) and cesium carbonate (0.16 g, 6.0 mmol) in DME (4 mL) -water (4 mL) solution under nitrogen atmosphere, Pd 2 (dba) 3 (0.18 mg, 0.20 mmol) And stirred at 80 ° C. for 30 hours. The reaction mixture was diluted with ethyl acetate-saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column (hexane / ethyl acetate = 8 / 2-0 / 1) to give the title compound as an orange amorphous solid (0.77 g, 38%).
LC / MS 402.1
NMR (CDCl 3 ) δ: 1.50 (9 H, s), 2.52 (3 H, s), 3.60 (4 H, m), 3.95 (3 H, s), 4.02 (2 H, s), 4.13 (2 H, s), 6.42 (1 H, d, J = 2.4 Hz), 6.52 (1 H, dd, J = 2.1 Hz, 8.4 Hz), 7.25 (1 H, s), 7.62 (1 H, d, J = 8.4 Hz).
参考例130
メチル アミノ[4-(トリフルオロメチル)フェニル]アセタート
　4-(トリフルオロメチル)ベンズアルデヒド (10 g, 57 mmol)と4-ジメチルアミノピリジン (70 mg, 0.57 mmol)のアセトニトリル (100 mL)溶液に、トリメチルシリルシアニド (7.5 mL, 60 mmol)を氷冷下で滴下し、室温で1時間撹拌した。溶媒を減圧留去した後、得られた残留物を8Mアンモニア MeOH溶液 (100 mL)に溶解し、封管中で40℃で4時間撹拌した。溶媒を減圧留去した後、得られた残留物をメタノール (20 mL)に溶解させ、メタノール(100 mL)に塩化アセチル (70 mL)を-10℃で滴下し同温度で30分間撹拌して調製した反応混合物に加え、室温で終夜撹拌した。溶媒を減圧留去して得られた残留物に水を加え、飽和炭酸水素ナトリウム水溶液で塩基性にした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をNHシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=7/3～3/7)で精製し、題記化合物を褐色油状物(6.5 g, 48%)として得た。
LC/MS 234.1
NMR (CDCl3) δ: 1.91 (2 H, brs), 3.72 (3 H, s), 4.69 (1 H, s), 7.47 - 7.57 (2 H, m), 7.57 - 7.66 (2 H, m). Reference Example 130
To a solution of methylamino [4- (trifluoromethyl) phenyl] acetate 4- (trifluoromethyl) benzaldehyde (10 g, 57 mmol) and 4-dimethylaminopyridine (70 mg, 0.57 mmol) in acetonitrile (100 mL), Trimethylsilylcyanide (7.5 mL, 60 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 8M ammonia MeOH solution (100 mL) and stirred in a sealed tube at 40 ° C. for 4 hours. After the solvent was distilled off under reduced pressure, the resulting residue was dissolved in methanol (20 mL), acetyl chloride (70 mL) was added dropwise to methanol (100 mL) at -10 ° C, and the mixture was stirred at the same temperature for 30 min. It was added to the prepared reaction mixture and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 7 / 3-3 / 7) to give the title compound as a brown oil (6.5 g, 48%).
LC / MS 234.1
NMR (CDCl 3 ) δ: 1.91 (2 H, brs), 3.72 (3 H, s), 4.69 (1 H, s), 7.47-7.57 (2 H, m), 7.57-7.66 (2 H, m) .
試験例
(１)初代神経細胞を用いたアミロイドβ産生抑制率の測定
　化合物のアミロイドβ産生抑制活性は下記に従い、1、3、10、30 μM の 4点で測定した。初代神経細胞は、ラット胎児 (日本クレア:SDラット、胎生17日齢) の大脳皮質より回収し、neurobasal培地(Invitrogen社製)で50万個/mlに懸濁した。続いてポリLリジンコート96ウエルプレートに100 μlずつ播種し、37℃、5% CO2 で 7日間培養した。培地を全量除去し、新しい neurobasal 培地 を 75 μL / wellで 添加した。そこに評価対象化合物を各測定濃度の 2倍になるように添加した neurobasal 培地を 75 μL / well ずつ加え、3日間培養した。各ウェルから培養上清を回収し、適宜希釈して、BNT77抗体-BA27抗体（Aβ40用）、BNT77抗体-BC05抗体（Aβ42 用）sandwich ELISA にかけ、Aβ40 および Aβ42 量を測定した。化合物のアミロイドβ産生抑制率（％）は、以下の式により計算した。
（１－（化合物添加時のアミロイドβ産生量）/（化合物未添加時のアミロイドβ産生量））× 100
　また、ATP量を指標とした方法（方法１）と呼吸活性を指標とした方法（方法２）により評価対象化合物の細胞障害性を測定し、アミロイドβ産生抑制作用が細胞障害性に依存しないことを確認した。
（方法１）培養上清回収後の細胞に新しい neurobasal 培地を 75μL / well 添加し、約30分間静置して室温に戻した。Cell-Titer Glo (Promega社製) を 75μL / well 加え 2分間振とうした後、約 10分間反応させ、蛍光強度を測定して ATP 量を指標とした細胞障害性を定量した。
（方法２）培養上清回収後の細胞にCell Counting Kit-8 (Dojindo社製) を10%含む新しい neurobasal 培地を、100μL / well 添加し、約 2時間反応させ、450nmの吸光度を測定して 呼吸活性を指標とした細胞障害性を定量した。
試験結果を表１４８および１４９に示す。 Test example
(1) Measurement of inhibition rate of amyloid β production using primary neurons The amyloid β production inhibitory activity of the compounds was measured at 4 points of 1, 3, 10, and 30 μM according to the following. Primary neurons were collected from the cerebral cortex of a rat fetus (CLEA Japan, SD rat, embryonic day 17) and suspended at 500,000 cells / ml in neurobasal medium (Invitrogen). Subsequently, 100 μl each was seeded on a poly L lysine-coated 96-well plate and cultured at 37 ° C. and 5% CO 2 for 7 days. All the medium was removed and fresh neurobasal medium was added at 75 μL / well. Thereto was added 75 μL / well of neurobasal medium supplemented with the compound to be evaluated so as to be twice the measured concentration, followed by culturing for 3 days. The culture supernatant was collected from each well, diluted appropriately, and subjected to sandwich ELISA by BNT77 antibody-BA27 antibody (for Aβ40) and BNT77 antibody-BC05 antibody (for Aβ42), and the amounts of Aβ40 and Aβ42 were measured. The amyloid β production inhibition rate (%) of the compound was calculated by the following formula.
(1- (Amyloid β production when compound is added) / (Amyloid β production when compound is not added)) × 100
In addition, the cytotoxicity of the evaluation target compound is measured by the method using ATP content as an index (method 1) and the method using respiratory activity as an index (method 2), and the amyloid β production inhibitory action does not depend on the cytotoxicity. It was confirmed.
(Method 1) 75 μL / well of new neurobasal medium was added to the cells after collection of the culture supernatant, and the cells were allowed to stand for about 30 minutes and returned to room temperature. Cell-Titer Glo (Promega) was added at 75 μL / well, shaken for 2 minutes, allowed to react for about 10 minutes, and the fluorescence intensity was measured to determine the cytotoxicity using the ATP content as an index.
(Method 2) Add 100 μL / well of new neurobasal medium containing 10% Cell Counting Kit-8 (Dojindo) to the cells after collecting the culture supernatant, react for about 2 hours, and measure the absorbance at 450 nm. Cytotoxicity was quantified using respiratory activity as an index.
The test results are shown in Tables 148 and 149.
Figure JPOXMLDOC01-appb-T000323
Figure JPOXMLDOC01-appb-T000323
Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000324
　本発明化合物またはそのプロドラッグは、優れたアミロイドβ産生抑制作用を示すので、軽度認知障害、アルツハイマー病等の疾患の臨床上有用な予防または治療薬を提供することができる。また、本発明化合物またはそのプロドラッグは、薬効、低毒性、安定性、体内動態等の点で優れているので、医薬として有用である。 Since the compound of the present invention or a prodrug thereof exhibits an excellent amyloid β production inhibitory action, it can provide a clinically useful preventive or therapeutic drug for diseases such as mild cognitive impairment and Alzheimer's disease. In addition, the compound of the present invention or a prodrug thereof is useful as a medicine because it is excellent in drug efficacy, low toxicity, stability, pharmacokinetics and the like.
　本出願は日本で出願された特願２００９－１５８２７０を基礎としており、その内容は本明細書にすべて包含される。また、本明細書で引用した特許文献および非特許文献は、引用したことによってその内容の全てが開示されたと同程度に本明細書中に組み込まれるものである。 This application is based on Japanese Patent Application No. 2009-158270 filed in Japan, the contents of which are incorporated in full herein. In addition, patent documents and non-patent documents cited in the present specification are incorporated in the present specification to the same extent as the entire contents of the cited documents are disclosed by being cited.

Claims (19)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    Ｒ１は、水素原子または置換されていてもよいＣ１－６アルキル基；
    Ｒ２およびＲ３は、同一または異なって、
    水素原子、
    ハロゲン原子、
    ヒドロキシ、
    置換されていてもよいＣ１－６アルキル基、
    置換されていてもよいＣ１－６アルコキシ基、
    置換されていてもよいＣ１－６アルキルチオ基、
    置換されていてもよいＣ１－６アルキルスルホニル基、または
    置換されていてもよいＣ１－６アルキルスルフィニル基；
    ｎは、１または２；
    Ｙは、
    結合手、
    －Ｒａ１－、
    －Ｒａ１ＣＯ－、
    －Ｒａ１ＣＯＮ（Ｒｂ１）－、
    －Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２－、
    －Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｎ（Ｒｂ２）－、
    －Ｒａ１ＣＯＮ（Ｒｂ１）Ｒａ２Ｏ－、
    －Ｒａ１Ｏ－、
    －ＣＯ－、
    －ＣＯ－ＣＯ－、
    －ＣＯ－ＣＨ＝ＣＨ－、
    －ＣＯＲａ１－、
    －ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
    －ＣＯＲａ１Ｎ（Ｒｂ１）－、
    －ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
    －ＣＯＲａ１Ｏ－、
    －ＣＯＲａ１ＳＲａ２－、
    －ＣＯＮ（Ｒｂ１）－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
    －ＣＯＮ（Ｒｂ１）ＳＯ２－
    　　　（式中、Ｒａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレン基；
    　　　Ｒｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）；
    環Ａは、酸素原子、硫黄原子および窒素原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよいＣ１－６アルキル基をさらに有していてもよい、５員芳香族複素環；
    環Ｂは、環構成原子として炭素原子以外に１個または２個の窒素原子を有していてもよい、さらに置換されていてもよい６員芳香環；
    環Ｄは、置換されていてもよい複素環；
    環Ｅは、
    ｉ）置換されていてもよいベンゼン環、
    ｉｉ）置換されていてもよいナフタレン環、
    ｉｉｉ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい単環式４～７員複素環、
    ｉｖ）窒素原子、酸素原子および硫黄原子から選ばれる１～３個のヘテロ原子を有する、置換されていてもよい９員または１０員の縮合複素環、
    ｖ）置換されていてもよい３～７員飽和炭素環、
    ｖｉ）置換されていてもよい９～１３員の縮合炭素環、または
    ｖｉｉ）置換されていてもよい１３～１５員のスピロ複素環；
    を示す］で表される化合物
    ［但し、以下の化合物を除く。
    （１）式（Ｉ）の部分構造式
    Figure JPOXMLDOC01-appb-C000002
    が、
    Figure JPOXMLDOC01-appb-C000003
    である、式（Ｉ）で表される化合物、
    （２）Ｒ１が置換されていてもよいアミノ基を有するメチル基であり、かつ式（Ｉ）の部分構造式：
    Figure JPOXMLDOC01-appb-C000004
    が、
    Figure JPOXMLDOC01-appb-C000005
    である、式（Ｉ）で表される化合物、
    （３）以下の式：
    Figure JPOXMLDOC01-appb-C000006
    （式中、環ＥＸは、置換されていてもよい２，３－ジヒドロ－１－ベンゾフラン環または置換されていてもよいクロマン環を示す）で表される化合物、
    （４）以下の式：
    Figure JPOXMLDOC01-appb-C000007
    （式中、Ｒｙ１は、水素原子またはＣ１－６アルキル基；Ｒｙ２は、水素原子または置換されていてもよいメチル基を示す）で表される化合物、
    （５）（３Ｒ）－Ｎ－（３－クロロ－４－ヒドロキシフェニル）－１－（２－｛４－［４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－イル｝－２－オキソエチル）ピロリジン－３－カルボキサミド、
    （６）１－｛［４－クロロ－５－メチル－３－（トリフルオロメチル）－１Ｈ－ピラゾール－１－イル］アセチル｝－４－［４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン、
    （７）１－シクロブチル－４－（｛４－［４－（３－メチル－１，２，４－オキサジアゾール－５－イル）フェニル］ピペラジン－１－イル｝アセチル）ピペラジン、
    （８）（２Ｒ，５Ｓ）－４－［３－メトキシ－４－（１，３－オキサゾール－５－イル）フェニル］－２，５－ジメチル－Ｎ－［４－（トリフルオロメチル）ピリジン－３－イル］ピペラジン－１－カルボキサミド、
    （９）（２Ｒ，５Ｓ）－４－［３－メトキシ－４－（１Ｈ－１，２，４－トリアゾール－１－イル）フェニル］－２，５－ジメチル－Ｎ－［４－（トリフルオロメチル）ピリジン－３－イル］ピペラジン－１－カルボキサミド、
    （１０）（３Ｒ）－Ｎ－（３－クロロ－４－ヒドロキシフェニル）－１－（２－オキソ－２－｛４－［４－（１Ｈ－１，２，３－トリアゾール－１－イル）フェニル］ピペラジン－１－イル｝エチル）ピロリジン－３－カルボキサミド、
    （１１）３－［３－（３－メチルブチル）－１，２，４－オキサジアゾール－５－イル］－６－（４－｛［２－（トリフルオロメチル）フェニル］カルボニル｝ピペラジン－１－イル）ピリダジン、
    （１２）３－（３－プロピル－１，２，４－オキサジアゾール－５－イル）－６－（４－｛［２－（トリフルオロメチル）フェニル］カルボニル｝ピペラジン－１－イル）ピリダジン、
    （１３）１－シクロペンチル－４－｛５－［３－（１－メチルエチル）－１，２，４－オキサジアゾール－５－イル］ピリジン－２－イル｝ピペラジン－２－オン、
    （１４）（２Ｓ）－１－［１－（４－クロロベンジル）ピペリジン－４－イル］－４－［３－クロロ－５－（１，３－オキサゾール－５－イル）ピリジン－２－イル］－２－エチルピペラジン、
    （１５）Ｎ－｛［（５Ｓ）－３－（３－フルオロ－４－｛４－［３－フルオロ－４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－イル｝フェニル）－２－オキソ－１，３－オキサゾリジン－５－イル］メチル｝アセトアミド、および
    （１６）Ｎ－｛［（５Ｓ）－３－（３－フルオロ－４－｛４－［２－フルオロ－４－（１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－イル｝フェニル）－２－オキソ－１，３－オキサゾリジン－５－イル］メチル｝アセトアミド］またはその塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
    R 2 and R 3 are the same or different and
    Hydrogen atom,
    Halogen atoms,
    Hydroxy,
    An optionally substituted C 1-6 alkyl group,
    An optionally substituted C 1-6 alkoxy group,
    An optionally substituted C 1-6 alkylthio group,
    An optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkylsulfinyl group;
    n is 1 or 2;
    Y is
    Join hands,
    -Ra 1- ,
    -Ra 1 CO-,
    -Ra 1 CON (Rb 1 )-,
    -Ra 1 CON (Rb 1 ) Ra 2- ,
    -Ra 1 CON (Rb 1 ) Ra 2 N (Rb 2 )-,
    -Ra 1 CON (Rb 1 ) Ra 2 O-,
    -Ra 1 O-,
    -CO-,
    -CO-CO-,
    -CO-CH = CH-,
    -CORa 1- ,
    -CORa 1 CON (Rb 1 )-,
    -CORa 1 N (Rb 1 )-,
    -CORa 1 N (Rb 1 ) CO-,
    -CORa 1 O-,
    -CORa 1 SRa 2- ,
    -CON (Rb 1 )-,
    -CON (Rb 1 ) Ra 1- ,
    -CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
    -CON (Rb 1 ) Ra 1 O-,
    —CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
    Wherein Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene groups;
    Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group);
    Ring A may further have an optionally substituted C 1-6 alkyl group having 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 5-membered aromatic group Heterocycle;
    Ring B may have 1 or 2 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and may be further substituted 6-membered aromatic ring;
    Ring D is an optionally substituted heterocycle;
    Ring E is
    i) an optionally substituted benzene ring,
    ii) an optionally substituted naphthalene ring,
    iii) an optionally substituted monocyclic 4 to 7-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
    iv) an optionally substituted 9-membered or 10-membered fused heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms;
    v) an optionally substituted 3- to 7-membered saturated carbocyclic ring,
    vi) an optionally substituted 9-13 membered fused carbocycle, or vii) an optionally substituted 13-15 membered spiro heterocycle;
    ] [Excluding the following compounds].
    (1) Partial structural formula of formula (I)
    Figure JPOXMLDOC01-appb-C000002
    But,
    Figure JPOXMLDOC01-appb-C000003
    A compound of formula (I),
    (2) R 1 is a methyl group having an optionally substituted amino group, and a partial structural formula of the formula (I):
    Figure JPOXMLDOC01-appb-C000004
    But,
    Figure JPOXMLDOC01-appb-C000005
    A compound of formula (I),
    (3) The following formula:
    Figure JPOXMLDOC01-appb-C000006
    (Wherein ring E X is substituted represents an chroman ring be also be 2,3-dihydro-1-benzofuran ring or a substituted optionally) a compound represented by,
    (4) The following formula:
    Figure JPOXMLDOC01-appb-C000007
    (Wherein Ry 1 represents a hydrogen atom or a C 1-6 alkyl group; Ry 2 represents a hydrogen atom or an optionally substituted methyl group),
    (5) (3R) -N- (3-Chloro-4-hydroxyphenyl) -1- (2- {4- [4- (1,3-oxazol-5-yl) phenyl] piperazin-1-yl} -2-oxoethyl) pyrrolidine-3-carboxamide,
    (6) 1-{[4-Chloro-5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] acetyl} -4- [4- (1,3-oxazol-5-yl) Phenyl] piperazine,
    (7) 1-cyclobutyl-4-({4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] piperazin-1-yl} acetyl) piperazine,
    (8) (2R, 5S) -4- [3-methoxy-4- (1,3-oxazol-5-yl) phenyl] -2,5-dimethyl-N- [4- (trifluoromethyl) pyridine- 3-yl] piperazine-1-carboxamide,
    (9) (2R, 5S) -4- [3-Methoxy-4- (1H-1,2,4-triazol-1-yl) phenyl] -2,5-dimethyl-N- [4- (trifluoro Methyl) pyridin-3-yl] piperazine-1-carboxamide,
    (10) (3R) -N- (3-Chloro-4-hydroxyphenyl) -1- (2-oxo-2- {4- [4- (1H-1,2,3-triazol-1-yl) Phenyl] piperazin-1-yl} ethyl) pyrrolidine-3-carboxamide,
    (11) 3- [3- (3-Methylbutyl) -1,2,4-oxadiazol-5-yl] -6- (4-{[2- (trifluoromethyl) phenyl] carbonyl} piperazine-1 -Il) pyridazine,
    (12) 3- (3-Propyl-1,2,4-oxadiazol-5-yl) -6- (4-{[2- (trifluoromethyl) phenyl] carbonyl} piperazin-1-yl) pyridazine ,
    (13) 1-cyclopentyl-4- {5- [3- (1-methylethyl) -1,2,4-oxadiazol-5-yl] pyridin-2-yl} piperazin-2-one,
    (14) (2S) -1- [1- (4-Chlorobenzyl) piperidin-4-yl] -4- [3-chloro-5- (1,3-oxazol-5-yl) pyridin-2-yl ] -2-ethylpiperazine,
    (15) N-{[(5S) -3- (3-Fluoro-4- {4- [3-fluoro-4- (1,3-oxazol-5-yl) phenyl] piperazin-1-yl} phenyl ) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide, and (16) N-{[(5S) -3- (3-fluoro-4- {4- [2-fluoro-4 -(1,3-oxazol-5-yl) phenyl] piperazin-1-yl} phenyl) -2-oxo-1,3-oxazolidine-5-yl] methyl} acetamide] or a salt thereof.
  2. 　（１）Ｙが、
    結合手、
    －Ｒａ１ＣＯＮ（Ｒｂ１）－、
    －ＣＯ－、
    －ＣＯ－ＣＯ－、
    －ＣＯ－ＣＨ＝ＣＨ－、
    －ＣＯＲａ１－、
    －ＣＯＲａ１ＣＯＮ（Ｒｂ１）－、
    －ＣＯＲａ１Ｎ（Ｒｂ１）－、
    －ＣＯＲａ１Ｎ（Ｒｂ１）ＣＯ－、
    －ＣＯＲａ１Ｏ－、
    －ＣＯＲａ１ＳＲａ２－、
    －ＣＯＮ（Ｒｂ１）－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１ＣＯＮ（Ｒｂ２）－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１Ｏ－、
    －ＣＯＮ（Ｒｂ１）Ｒａ１Ｎ（Ｒｂ２）ＣＯ－、または
    －ＣＯＮ（Ｒｂ１）ＳＯ２－
    　　　（式中、Ｒａ１およびＲａ２は、同一または異なって、置換されていてもよいＣ１－６アルキレン基；
    　　　Ｒｂ１およびＲｂ２は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す）であり、
    （２）環Ａが、
    置換されていてもよいＣ１－６アルキル基をさらに有していてもよいオキサゾール環、
    置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，３－トリアゾール環、
    置換されていてもよいＣ１－６アルキル基をさらに有していてもよい１，２，４－トリアゾール環、または
    置換されていてもよいＣ１－６アルキル基をさらに有していてもよいピラゾール環
    である、請求項１記載の化合物またはその塩。     (1) Y is
    Join hands,
    -Ra 1 CON (Rb 1 )-,
    -CO-,
    -CO-CO-,
    -CO-CH = CH-,
    -CORa 1- ,
    -CORa 1 CON (Rb 1 )-,
    -CORa 1 N (Rb 1 )-,
    -CORa 1 N (Rb 1 ) CO-,
    -CORa 1 O-,
    -CORa 1 SRa 2- ,
    -CON (Rb 1 )-,
    -CON (Rb 1 ) Ra 1- ,
    -CON (Rb 1 ) Ra 1 CON (Rb 2 )-,
    -CON (Rb 1 ) Ra 1 O-,
    —CON (Rb 1 ) Ra 1 N (Rb 2 ) CO—, or —CON (Rb 1 ) SO 2 —
    Wherein Ra 1 and Ra 2 are the same or different and may be substituted C 1-6 alkylene groups;
    Rb 1 and Rb 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group),
    (2) Ring A is
    An oxazole ring which may further have an optionally substituted C 1-6 alkyl group,
    A 1,2,3-triazole ring optionally further having an optionally substituted C 1-6 alkyl group,
    It may have an optionally substituted C 1-6 alkyl group may further have a 1,2,4-triazole ring, or a C 1-6 alkyl group which may be substituted further The compound or its salt of Claim 1 which is a pyrazole ring.
  3. 　環Ｄが、１個または２個のオキソ基を有する、さらに置換されていてもよい複素環である、請求項１記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein ring D is a heterocyclic ring which has one or two oxo groups and may be further substituted.
  4. 　Ｒ１が、Ｃ１－６アルキル基；
    Ｒ２およびＲ３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基；
    ｎが、１または２；
    Ｙが、－ＣＯ－、－Ｒａ１－、－ＣＯＲａ１－、－ＣＯＮ（Ｒｂ１）－、－ＣＯＮ（Ｒｂ１）Ｒａ１－または－Ｒａ１ＣＯＮ（Ｒｂ１）－
    　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上存在する場合には、該置換基同士が結合して環を形成してもよい）；
    　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）；
    環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
    環Ｂが、ベンゼン環；
    環Ｄが、オキソ基、Ｃ１－６アルキル基およびＣ１－６アルコキシ－カルボニル基から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）；
    環Ｅが、それぞれ（１）ハロゲン原子、（２）ハロゲン原子で置換されたＣ１－６アルキル基、（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環；
    である請求項1記載の化合物またはその塩。     R 1 is a C 1-6 alkyl group;
    R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group;
    n is 1 or 2;
    Y is, -CO -, - Ra 1 - , - CORa 1 -, - CON (Rb 1) -, - CON (Rb 1) Ra 1 - or -Ra 1 CON (Rb 1) -
    (In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
    Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
    Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
    Ring B is a benzene ring;
    Ring D is a heterocycle optionally substituted with 1 to 3 substituents selected from an oxo group, a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (two or more such substituents When present, the substituents may be bonded to form a crosslinked structure);
    Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a halogen atom. A benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring;
    2. The compound according to claim 1, or a salt thereof.
  5. 　Ｒ１が、Ｃ１－６アルキル基；
    Ｒ２およびＲ３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルコキシ基；
    ｎが、１または２；
    Ｙが、－ＣＯ－、－ＣＯＲａ１－、－ＣＯＮ（Ｒｂ１）－、または－ＣＯＮ（Ｒｂ１）Ｒａ１－
    　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基およびシアノ基から選択される置換基で置換されていてもよいＣ１－６アルキレン基（該置換基が２個以上存在する場合には、該置換基同士が結合して環を形成してもよい）；
    　　　Ｒｂ１は、水素原子を示す）；
    環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
    環Ｂが、ベンゼン環；
    環Ｄが、Ｃ１－６アルキル基およびＣ１－６アルコキシ－カルボニル基から選択される１～３個の置換基で置換されていてもよい複素環（該置換基が２個以上存在する場合には、該置換基同士が結合して架橋構造を形成してもよい）；
    環Ｅが、それぞれ（１）ハロゲン原子、（２）ハロゲン原子で置換されたＣ１－６アルキル基、（３）ハロゲン原子で置換されたＣ１－６アルコキシ基、および（４）ハロゲン原子で置換されたＣ１－６アルキル基で置換されたフェニル基から選択される１～３個の置換基で置換されていてもよい、ベンゼン環、ナフタレン環、ベンゾイミダゾール環、インダゾール環、シクロヘキサン環、ピロリジン環またはピラゾール環；
    である請求項1記載の化合物またはその塩。     R 1 is a C 1-6 alkyl group;
    R 2 and R 3 are the same or different and are a hydrogen atom, a halogen atom or a C 1-6 alkoxy group;
    n is 1 or 2;
    Y is —CO—, —CORa 1 —, —CON (Rb 1 ) —, or —CON (Rb 1 ) Ra 1 —.
    (In the formula, Ra 1 represents a C 1-6 alkyl group which may be substituted with a hydroxy group and a C 1-6 alkylene group which may be substituted with a substituent selected from a cyano group (the substituent is When two or more are present, the substituents may combine to form a ring);
    Rb 1 represents a hydrogen atom);
    Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
    Ring B is a benzene ring;
    Ring D may be substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group (when two or more substituents are present) May be bonded to each other to form a crosslinked structure);
    Ring E is respectively (1) a halogen atom, (2) a C 1-6 alkyl group substituted with a halogen atom, (3) a C 1-6 alkoxy group substituted with a halogen atom, and (4) a halogen atom. A benzene ring, naphthalene ring, benzimidazole ring, indazole ring, cyclohexane ring, which may be substituted with 1 to 3 substituents selected from a phenyl group substituted with a substituted C 1-6 alkyl group, Pyrrolidine ring or pyrazole ring;
    2. The compound according to claim 1, or a salt thereof.
  6. 　Ｒ１が、Ｃ１－６アルキル基；
    Ｒ２およびＲ３の、一方が水素原子、他方が水素原子またはＣ１－６アルコキシ基；
    ｎが、１または２；
    Ｙが、Ｃ１－６アルキレン基または－Ｒａ１ＣＯＮ（Ｒｂ１）－
    　　　（式中、Ｒａ１は、Ｃ１－６アルキレン基；
    　　　Ｒｂ１は、水素原子またはハロゲン原子で置換されたＣ１－６アルキル基を示す）；
    環Ａが、ピラゾール環、オキサゾール環またはトリアゾール環；
    環Ｂが、ベンゼン環；
    環Ｄが、1個のオキソ基を有する複素環；
    環Ｅが、１～３個のハロゲン原子で置換されたベンゼン環；
    である請求項1記載の化合物またはその塩。     R 1 is a C 1-6 alkyl group;
    One of R 2 and R 3 is a hydrogen atom, the other is a hydrogen atom or a C 1-6 alkoxy group;
    n is 1 or 2;
    Y is a C 1-6 alkylene group or —Ra 1 CON (Rb 1 ) —
    Wherein Ra 1 is a C 1-6 alkylene group;
    Rb 1 represents a C 1-6 alkyl group substituted with a hydrogen atom or a halogen atom);
    Ring A is a pyrazole ring, an oxazole ring or a triazole ring;
    Ring B is a benzene ring;
    Ring D is a heterocycle having one oxo group;
    A benzene ring in which ring E is substituted with 1 to 3 halogen atoms;
    2. The compound according to claim 1, or a salt thereof.
  7. 　Ｒ１が、Ｃ１－６アルキル基；
    Ｒ２およびＲ３の一方が水素原子、他方がＣ１－６アルコキシ基；
    ｎが、１；
    Ｙが、－ＣＯＮ（Ｒｂ１）Ｒａ１－
    　　　（式中、Ｒａ１は、ヒドロキシ基で置換されていてもよいＣ１－６アルキル基で置換されていてもよい、Ｃ１－６アルキレン基；
    　　　Ｒｂ１は、水素原子）；
    環Ａが、オキサゾール環；
    環Ｂが、ベンゼン環；
    環Ｄが、複素環；
    環Ｅが、ハロゲン原子で置換された１～３個のＣ１－６アルキル基で置換された、ベンゼン環；
    である請求項1記載の化合物またはその塩。     R 1 is a C 1-6 alkyl group;
    One of R 2 and R 3 is a hydrogen atom and the other is a C 1-6 alkoxy group;
    n is 1;
    Y is —CON (Rb 1 ) Ra 1 —
    Wherein Ra 1 is a C 1-6 alkylene group which may be substituted with a C 1-6 alkyl group which may be substituted with a hydroxy group;
    Rb 1 is a hydrogen atom);
    Ring A is an oxazole ring;
    Ring B is a benzene ring;
    Ring D is a heterocycle;
    A benzene ring in which ring E is substituted with 1 to 3 C 1-6 alkyl groups substituted with a halogen atom;
    2. The compound according to claim 1, or a salt thereof.
  8. 　４－［３－メトキシ－４－（２－メチル－１，３－オキサゾール－５－イル）フェニル］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピペラジン－１－カルボキサミドまたはその塩。 4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) phenyl] -N- [4- (trifluoromethyl) benzyl] piperazine-1-carboxamide or a salt thereof.
  9. 　Ｎ－｛２－ヒドロキシ－２－メチル－１－［４－（トリフルオロメチル）フェニル］プロピル｝－４－［３－メトキシ－４－（２－メチル－１，３－オキサゾール－５－イル）フェニル］ピペラジン－１－カルボキサミドまたはその塩。 N- {2-hydroxy-2-methyl-1- [4- (trifluoromethyl) phenyl] propyl} -4- [3-methoxy-4- (2-methyl-1,3-oxazol-5-yl) Phenyl] piperazine-1-carboxamide or a salt thereof.
  10. 　請求項１記載の化合物またはその塩のプロドラッグ。 A prodrug of the compound according to claim 1 or a salt thereof.
  11. 　請求項１記載の化合物またはその塩、あるいはそのプロドラッグを含有する医薬。 A pharmaceutical comprising the compound according to claim 1 or a salt thereof, or a prodrug thereof.
  12. 　アミロイドβ産生抑制薬である請求項１１記載の医薬。 The medicament according to claim 11, which is an amyloid β production inhibitor.
  13. 　軽度認知障害またはアルツハイマー病の予防または治療薬である請求項１１記載の医薬。 The medicament according to claim 11, which is a prophylactic or therapeutic drug for mild cognitive impairment or Alzheimer's disease.
  14. 　哺乳動物に対して、請求項１記載の化合物またはその塩、あるいはそのプロドラッグを有効量投与することを特徴とする、アミロイドβ産生抑制方法。 A method for inhibiting amyloid β production, comprising administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to a mammal.
  15. 　哺乳動物に対して、請求項１記載の化合物またはその塩、あるいはそのプロドラッグを有効量投与することを特徴とする、軽度認知障害またはアルツハイマー病の予防または治療方法。 A method for preventing or treating mild cognitive impairment or Alzheimer's disease, comprising administering an effective amount of the compound of claim 1 or a salt thereof, or a prodrug thereof to a mammal.
  16. 　アミロイドβ産生抑制薬を製造するための、請求項１記載の化合物またはその塩、あるいはそのプロドラッグの使用。 Use of the compound according to claim 1 or a salt thereof, or a prodrug thereof for producing an amyloid β production inhibitor.
  17. 　軽度認知障害またはアルツハイマー病の予防または治療薬を製造するための、請求項１記載の化合物またはその塩、あるいはそのプロドラッグの使用。 Use of the compound according to claim 1 or a salt thereof, or a prodrug thereof for the manufacture of a preventive or therapeutic agent for mild cognitive impairment or Alzheimer's disease.
  18. 　アミロイドβ産生抑制のための、請求項１記載の化合物またはその塩、あるいはそのプロドラッグ。 The compound according to claim 1, or a salt thereof, or a prodrug thereof for suppressing amyloid β production.
  19. 　軽度認知障害またはアルツハイマー病の予防または治療のための、請求項１記載の化合物またはその塩、あるいはそのプロドラッグ。 The compound according to claim 1, or a salt thereof, or a prodrug thereof for the prevention or treatment of mild cognitive impairment or Alzheimer's disease.
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