WO2011002067A1 - Composé hétérocyclique et son utilisation - Google Patents

Composé hétérocyclique et son utilisation 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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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/fr

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    • 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
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    • 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
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    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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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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    • 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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    • 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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    • 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
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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

L'invention porte sur un dérivé hétérocyclique qui a une excellente activité inhibitrice de la production d'amyloïde β, et sur une utilisation du dérivé hétérocyclique. De façon spécifique, l'invention porte sur un composé représenté par la formule (I) ou sur un sel de celui-ci. (Dans la formule, les symboles sont tels que définis dans la description).
PCT/JP2010/061280 2009-07-02 2010-07-01 Composé hétérocyclique et son utilisation WO2011002067A1 (fr)

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JP2013508328A (ja) * 2009-10-21 2013-03-07 エフ．ホフマン−ラ ロシュ アーゲー ケモカイン受容体のモジュレーターとしてのジアゼパン誘導体
WO2013087738A1 (fr) * 2011-12-13 2013-06-20 Boehringer Ingelheim International Gmbh Nouveaux composés
WO2013187496A1 (fr) 2012-06-15 2013-12-19 田辺三菱製薬株式会社 Composé hétérocyclique aromatique
US8642774B2 (en) 2011-12-08 2014-02-04 Boehringer Ingelheim International Gmbh Compounds
US8716277B2 (en) 2011-12-14 2014-05-06 Boehringer Ingelheim International Gmbh Substituted imidazole compounds useful as positive allosteric modulators of mGlu5 receptor activity
US8741892B2 (en) 2011-12-05 2014-06-03 Boehringer Ingelheim International Gmbh Compounds
US8796467B2 (en) 2011-12-13 2014-08-05 Boehringer Ingelheim International Gmbh Compounds
WO2014130582A2 (fr) 2013-02-19 2014-08-28 Senomyx, Inc. Composés utiles comme modulateurs de trpm8
US8822464B2 (en) 2011-11-28 2014-09-02 Boehringer Ingelheim International Gmbh N-aryl-piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8822699B2 (en) 2010-09-02 2014-09-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8883789B2 (en) 2011-12-14 2014-11-11 Boehringer Ingelheim International Gmbh Piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8889677B2 (en) 2012-01-17 2014-11-18 Boehringer Ingellheim International GmbH Substituted triazoles useful as mGlu5 receptor modulators
US8937176B2 (en) 2011-12-14 2015-01-20 Boehringer Ingelheim International Gmbh Compounds
WO2015016335A1 (fr) 2013-07-31 2015-02-05 住友化学株式会社 Composé tétrazolinone et son utilisation
CN105330657A (zh) * 2015-12-08 2016-02-17 华润双鹤药业股份有限公司 5-氯-2-[5-(r)-甲基-1,4-二氮杂环庚烷-1-]苯并恶唑的制备方法
US9302996B2 (en) 2010-12-17 2016-04-05 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound
US9428478B2 (en) 2011-06-13 2016-08-30 Emory University Piperazine derivatives, compositions, and uses related thereto
CN106565611A (zh) * 2015-10-13 2017-04-19 华东师范大学 一种1-（4-环戊胺基-2-甲硫基嘧啶-5-）基乙酮的制备方法
CN108358853A (zh) * 2018-02-09 2018-08-03 中山大学 一种抗神经炎症的二苯乙烯类似物及其制备方法和应用
WO2020196327A1 (fr) * 2019-03-22 2020-10-01 株式会社ヤクルト本社 Procédé de production d'un dérivé quinolinecarboxamide ou d'un intermédiaire de production de celui-ci
WO2022057849A1 (fr) * 2020-09-17 2022-03-24 浙江海正药业股份有限公司 Dérivé de pipérazine, son procédé de préparation et son utilisation
EP3873890A4 (fr) * 2018-11-01 2022-09-07 Ahammune Biosciences Private Limited Nouveaux composés imidazoles, procédé de synthèse et d'utilisations associé
EP4011877A3 (fr) * 2020-12-11 2023-01-11 Institut de Cardiologie de Montréal Méthodes de traitement du cholestérol plasmatique élevé

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JP2013508328A (ja) * 2009-10-21 2013-03-07 エフ．ホフマン−ラ ロシュ アーゲー ケモカイン受容体のモジュレーターとしてのジアゼパン誘導体
US8901309B2 (en) 2010-09-02 2014-12-02 Takeda Pharmaceutical Company Limited Fused triazoles for the treatment or prophylaxis of mild cognitive impairment
US8822699B2 (en) 2010-09-02 2014-09-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9975871B2 (en) 2010-12-17 2018-05-22 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound
US9302996B2 (en) 2010-12-17 2016-04-05 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound
US20120236709A1 (en) * 2011-03-16 2012-09-20 Qualcomm, Incorporated System and method for preserving session context during inter-radio access technology service retry
US9428478B2 (en) 2011-06-13 2016-08-30 Emory University Piperazine derivatives, compositions, and uses related thereto
US8822464B2 (en) 2011-11-28 2014-09-02 Boehringer Ingelheim International Gmbh N-aryl-piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8741892B2 (en) 2011-12-05 2014-06-03 Boehringer Ingelheim International Gmbh Compounds
US8642774B2 (en) 2011-12-08 2014-02-04 Boehringer Ingelheim International Gmbh Compounds
US8796467B2 (en) 2011-12-13 2014-08-05 Boehringer Ingelheim International Gmbh Compounds
US8846948B2 (en) 2011-12-13 2014-09-30 Boehringer Ingelheim International Gmbh Compounds
WO2013087738A1 (fr) * 2011-12-13 2013-06-20 Boehringer Ingelheim International Gmbh Nouveaux composés
US8716277B2 (en) 2011-12-14 2014-05-06 Boehringer Ingelheim International Gmbh Substituted imidazole compounds useful as positive allosteric modulators of mGlu5 receptor activity
US8883789B2 (en) 2011-12-14 2014-11-11 Boehringer Ingelheim International Gmbh Piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8937176B2 (en) 2011-12-14 2015-01-20 Boehringer Ingelheim International Gmbh Compounds
US8889677B2 (en) 2012-01-17 2014-11-18 Boehringer Ingellheim International GmbH Substituted triazoles useful as mGlu5 receptor modulators
US10308636B2 (en) 2012-06-15 2019-06-04 Mitsubishi Tanabe Pharma Corporation Aromatic heterocyclic compound
US9546155B2 (en) 2012-06-15 2017-01-17 Mitsubishi Tanabe Pharma Corporation Aromatic heterocyclic compound
WO2013187496A1 (fr) 2012-06-15 2013-12-19 田辺三菱製薬株式会社 Composé hétérocyclique aromatique
US11028052B2 (en) 2013-02-19 2021-06-08 Firmenich Incorporated Compounds useful as modulators of TRPM8
US20150376136A1 (en) * 2013-02-19 2015-12-31 Senomyx, Inc. Compounds useful as modulators of trpm8
WO2014130582A3 (fr) * 2013-02-19 2014-10-16 Senomyx, Inc. Composés utiles comme modulateurs de trpm8
US10421727B2 (en) 2013-02-19 2019-09-24 Firmenich Incorporated Compounds useful as modulators of TRPM8
US9840471B2 (en) * 2013-02-19 2017-12-12 Senomyx, Inc. Compounds useful as modulators of TRPM8
WO2014130582A2 (fr) 2013-02-19 2014-08-28 Senomyx, Inc. Composés utiles comme modulateurs de trpm8
WO2015016335A1 (fr) 2013-07-31 2015-02-05 住友化学株式会社 Composé tétrazolinone et son utilisation
CN106565611A (zh) * 2015-10-13 2017-04-19 华东师范大学 一种1-（4-环戊胺基-2-甲硫基嘧啶-5-）基乙酮的制备方法
CN105330657A (zh) * 2015-12-08 2016-02-17 华润双鹤药业股份有限公司 5-氯-2-[5-(r)-甲基-1,4-二氮杂环庚烷-1-]苯并恶唑的制备方法
CN108358853A (zh) * 2018-02-09 2018-08-03 中山大学 一种抗神经炎症的二苯乙烯类似物及其制备方法和应用
CN108358853B (zh) * 2018-02-09 2021-06-25 中山大学 一种抗神经炎症的二苯乙烯类似物及其制备方法和应用
EP3873890A4 (fr) * 2018-11-01 2022-09-07 Ahammune Biosciences Private Limited Nouveaux composés imidazoles, procédé de synthèse et d'utilisations associé
WO2020196327A1 (fr) * 2019-03-22 2020-10-01 株式会社ヤクルト本社 Procédé de production d'un dérivé quinolinecarboxamide ou d'un intermédiaire de production de celui-ci
WO2022057849A1 (fr) * 2020-09-17 2022-03-24 浙江海正药业股份有限公司 Dérivé de pipérazine, son procédé de préparation et son utilisation
CN116348109A (zh) * 2020-09-17 2023-06-27 浙江海正药业股份有限公司 哌嗪类衍生物及其制备方法和用途
EP4011877A3 (fr) * 2020-12-11 2023-01-11 Institut de Cardiologie de Montréal Méthodes de traitement du cholestérol plasmatique élevé

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