WO2016098793A1 - Thiazole derivative having cyclic guanidyl group - Google Patents

Thiazole derivative having cyclic guanidyl group Download PDF

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Publication number
WO2016098793A1
WO2016098793A1 PCT/JP2015/085144 JP2015085144W WO2016098793A1 WO 2016098793 A1 WO2016098793 A1 WO 2016098793A1 JP 2015085144 W JP2015085144 W JP 2015085144W WO 2016098793 A1 WO2016098793 A1 WO 2016098793A1
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substituted
unsubstituted
group
aromatic
aromatic heterocyclic
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PCT/JP2015/085144
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French (fr)
Japanese (ja)
Inventor
一生 加藤
紀康 近藤
浩平 野津
英基 杉本
徳文 中橋
裕孝 衣田
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塩野義製薬株式会社
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Priority to JP2016564874A priority Critical patent/JPWO2016098793A1/en
Publication of WO2016098793A1 publication Critical patent/WO2016098793A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a thiazole derivative having a cyclic guanidyl group having antifungal activity or a salt thereof, and an antifungal agent containing them.
  • Non-Patent Documents 1 and 2 It is expected that the number of severely immunocompromised patients in developed countries in Europe and the United States and Japan will increase in the future, and it is important to take measures against deep mycosis. Antifungal chemotherapy has been applied to the treatment of deep mycosis. Amphotericin B has a strong fungicidal effect against Candida and Aspergillus spp., But currently, liposome preparations are mainly used to reduce nephrotoxicity. There is no problem (Non-Patent Document 3).
  • Caspofungin and Micafungin have a fungicidal activity against Candida spp. And are relatively safe. Therefore, they are frequently used for candidiasis and have a good clinical effect.
  • Non-patent Document 4 Itraconazole and voriconazole have fungicidal activity against Aspergillus spp. And are safer than amphotericin B. Therefore, itraconazole and voriconazole are frequently used for aspergillosis and contribute greatly to the improvement of mortality.
  • Non-patent Document 5 Non-patent Document 5
  • Non-patent Documents 6, 7, and 8 an increase in azole-resistant bacteria due to long-term administration
  • Patent Documents 1 to 4 disclose thiazole derivatives having a cyclic or acyclic guanidyl group, but there is no description or suggestion regarding antifungal activity.
  • Patent Documents 5 to 9 and Non-Patent Documents 9 and 10 disclose thiazole derivatives having a cyclic guanidyl group having an antifungal action. The compounds of the present invention or salts thereof, and antifungi containing them. The agent is not described.
  • An object of the present invention is to provide a novel compound that exhibits excellent antifungal activity against pathogenic fungi such as Candida and Aspergillus and various resistant bacteria and is useful as a pharmaceutical.
  • the present invention solves the above problems by synthesizing at least a thiazole derivative having a cyclic guanidyl group, and provides the following inventions.
  • n is an integer of 2 to 5.
  • the carbocyclic group of G is phenyl
  • i) The phenyl group is substituted with at least one or more substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl, or substituted or unsubstituted heterocyclic alkyl
  • the phenyl may be further substituted, and / or ii) an aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic ring in which at least one meta position of the phenyl group is substituted or unsubstituted.
  • the phenyl group may be further substituted, and The following compounds (A-1) to (A-34) are excluded. Or a pharmaceutically acceptable salt thereof.
  • G is the formula (I-G1): Wherein each symbol is as defined above, or a group represented by formula (IG2): (Where Y is a carbocyclic or heterocyclic ring, m is 0-5, X is independently halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstit
  • Each R 1 is independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or two R 1 bonded to non-adjacent carbon atoms are combined to be substituted or unsubstituted.
  • Each of R 2 is independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or R 1 and R 2 bonded to the same carbon atom together with adjacent atoms To form a substituted or unsubstituted cycloalkane, Or the compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 7, wherein R 1 and R 2 bonded to the same carbon atom are together oxo or substituted or unsubstituted methylidene.
  • X is independently halogen, cyano, acyl, acyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted
  • X is independently halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted aromatic carbocyclic group, Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or an unsubstituted aromatic carbocyclic alkyloxy, or a substituted or
  • Y is an aromatic carbocycle, m is 2, X is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic
  • the compound is an aromatic heterocyclic oxy, a substituted or unsubstituted aromatic carbocyclic alkyloxy, or a substituted or unsubstituted aromatic heterocyclic alkyloxy, or a compound thereof Pharmaceutically acceptable salt.
  • (Item 13) 13 A pharmaceutical composition comprising the compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof.
  • (Item 14) 14 The pharmaceutical composition according to item 13, which has an antifungal action.
  • (Item 15) A method for treating or preventing a disease associated with a fungal infection, which comprises administering the compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof.
  • (Item 16) 13 The compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease associated with a fungal infection.
  • a pharmaceutical composition for oral administration comprising the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • (Item 103) Sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, troche tablet, sublingual tablet, buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup, soft capsule, microcapsule or sustained-release capsule
  • the pharmaceutical composition according to (Item 102) which is an agent.
  • a pharmaceutical composition for parenteral administration comprising the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • (Item 106) Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellys
  • (Item 107) A pharmaceutical composition for children or the elderly, comprising the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has excellent antifungal activity against Candida, Aspergillus, or ringworm, and is useful as an antifungal agent.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt is also excellent in safety, pharmacokinetics, solubility, stability, etc., and is useful as a pharmaceutical product.
  • Halogen means fluorine, chlorine, bromine or iodine. Preferred is fluorine or chlorine.
  • Alkyl includes linear or branched carbon hydrogen atoms having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, Examples include isooctyl, n-nonyl, n-denyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Including linear or branched hydrocarbons.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included.
  • “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, still more preferably 3 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • non-aromatic carbocycle means a ring derived from the above “non-aromatic carbocyclic group”.
  • Cycloalkyl means a cyclic saturated hydrocarbon group, preferably having 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 3 to 8 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like can be mentioned.
  • Preferable embodiments of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • “Cycloalkane” means a ring derived from the above “cycloalkyl”.
  • Carbocyclic group includes the above “aromatic carbocyclic group” and “non-aromatic carbocyclic group”.
  • Carbocycle means a ring derived from the above “carbocyclic group”.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • the 5-membered monocyclic aromatic heterocyclic group includes pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like, and includes a 6-membered monocyclic aromatic group.
  • group heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • “Aromatic heterocycle” means a ring derived from the above “aromatic heterocyclic group”.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include, for example, indolinyl, isoindolinyl, chromanyl, isochromanyl, octahydro-7H-pyrano [2,3-c] pyridin-7-yl, hexahydro-2H-pyrano [3, 2-c] pyridin-6 (5H) -yl, 7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl, and the like.
  • non-aromatic heterocyclic ring means a ring derived from the above “non-aromatic heterocyclic group”.
  • heterocyclic group includes the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”.
  • Heterocycle means a ring derived from the above “heterocyclic group”.
  • “Acyl” means formyl and substituted carbonyl. “Substituted carbonyl” means substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl and the like can be mentioned.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
  • alkylcarbonyl examples include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, hexyloxy and the like.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy, trichloromethoxy and the like.
  • “Acyloxy” means formyloxy and carbonyloxy having a substituent.
  • “Carbonyloxy having a substituent” means a group in which the above “carbonyl having a substituent” is bonded to an oxygen atom.
  • substituted or unsubstituted alkylcarbonyloxy substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted nonaromatic carbon Ring carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy and the like.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
  • Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxyalkyl means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • Preferred embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Two alkylcarbonyl groups may be the same or different.
  • dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
  • dialkylcarbonylamino examples include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
  • Preferred embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Two alkylsulfonyl groups may be the same or different.
  • dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
  • dialkylcarbonylamino examples include dimethylsulfonylamino and diethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” replaces the hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like. . Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfanyl” include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, hexylsulfanyl and the like.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Haloalkylsulfanyl means a group in which the above “haloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfanyl” include trifluoromethylsulfanyl, trichloromethylsulfanyl and the like.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one of the hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
  • Dialkylcarbamoyl means a group in which the above “alkyl” is replaced with two of the hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. For example, dimethylcarbamoyl, ethylmethylcarbamoyl, diethylcarbamoyl and the like can be mentioned.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include methylsulfamoyl and ethylsulfamoyl.
  • Dialkylsulfamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • the two alkyl groups may be the same or different. Examples thereof include dimethylsulfamoyl and diethylsulfamoyl.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • Pentahalogenothio means a group in which the five “halogens” are bonded to a sulfur atom.
  • the five halogens may be the same or different.
  • the halogen is preferably fluorine or chlorine.
  • pentafluorothio —SF 5
  • monochlorotetrafluorothio —SCF 4
  • Carbocyclic alkyl “Aromatic carbocyclic alkyl”, “Non-aromatic carbocyclic alkyl”, “Heterocyclic alkyl”, “Aromatic heterocyclic alkyl”, “Non-aromatic heterocyclic alkyl”, “Carbocyclic alkyl” “Oxy”, “aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “heterocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, “non-aromatic heterocyclic alkyloxy", “carbon” Ring alkyloxycarbonyl ",” aromatic carbocyclic alkyloxycarbonyl ",” non-aromatic carbocyclic alkyloxycarbonyl ",” heterocyclic alkyloxycarbonyl “,” aromatic heterocyclic oxycarbonyl ",” non-aromatic heterocyclic " "Oxycarbonyl”, “carbocyclic alkyloxyalkyl”, "ar
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below: Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl, benzhydryl and the like.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below: Etc.
  • Carbocyclic alkyl includes “aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyl”.
  • Preferable embodiments of “carbocycle alkyl” include benzyl, phenethyl, benzhydryl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups shown below: Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • Non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • Heterocyclic alkyl includes “aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyl”. Preferred embodiments of “heterocyclic alkyl” include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, iso Pyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below: Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below: Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below: Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below: Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below: Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below: Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • aromatic heterocyclic alkylamino means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkylamino furanylmethylamino, imidazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benz And oxazolylmethylamino.
  • non-aromatic heterocyclic alkylamino means a group in which the “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethyl, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • “Aromatic carbocyclic oxy” means a group in which the above “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocycle for example, phenyloxy, naphthyloxy and the like can be mentioned.
  • Aromatic carbocyclic carbonyl means a group in which the above “aromatic carbocycle” is bonded to a carbonyl group. Examples include benzoyl and naphthylcarbonyl.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfinyl” means a group in which an “aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfinyl”, and “non-aromatic
  • the “non-aromatic carbocyclic” portion of the “aromatic carbocyclic sulfonyl” is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which the “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocyclic carbonyl means a group in which the above “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclopropenylcarbonyl, indanylcarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxycarbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. Examples thereof include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
  • non-aromatic carbocyclic oxycarbonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • non-aromatic carbocyclic sulfanyl means a group in which the “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic carbocyclic sulfinyl means a group in which the “non-aromatic carbocyclic ring” is bonded to a sulfinyl group.
  • examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclohexenylsulfinyl, tetrahydronaphthylsulfinyl, adamantylsulfinyl and the like.
  • non-aromatic carbocycle sulfonyl means a group in which the above “non-aromatic carbocycle” is bonded to a sulfonyl group.
  • cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • “Aromatic heterocycle oxy” means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom.
  • aromatic heterocycle oxy means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • “Aromatic heterocycle carbonyl” means a group in which the above “aromatic heterocycle” is bonded to a carbonyl group.
  • pyrrolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, oxazolylcarbonyl, indolylcarbonyl and the like can be mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • aromatic heterocyclic oxy means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which the above “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • aromatic heterocycle means a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfinyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group.
  • aromatic heterocycle a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group.
  • pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic sulfinyl”, and “Non-aromatic”
  • the “non-aromatic heterocyclic” part of the “aromatic heterocyclic sulfonyl” is the same as the above “non-aromatic heterocyclic group”.
  • Non-aromatic heterocyclic oxy means a group in which the above “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • dioxanyloxy, thiranyloxy, oxiranyloxy, oxetanyloxy, oxathiolanyloxy, azetidinyloxy, thianyloxy, thiazolidinyloxy, pyrrolidinyloxy, pyrrolinyloxy, imidazolidinyloxy, imidazo Examples include linyloxy, pyrazolidinyloxy, pyrazolinyloxy, piperidyloxy, piperazinyloxy, morpholinyloxy, indolinyloxy, chromanyloxy and the like.
  • non-aromatic heterocyclic carbonyl means a group in which the above “non-aromatic heterocyclic” is bonded to a carbonyl group. Examples include dioxanylcarbonyl, oxetanylcarbonyl, pyrazolinylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl, indolinylcarbonyl and the like.
  • non-aromatic heterocyclic oxycarbonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • non-aromatic heterocyclic oxycarbonyl for example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which the “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic heterocyclic sulfinyl means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfinyl group.
  • piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
  • non-aromatic heterocyclic sulfonyl means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • Carbocyclic oxy means a group in which the above “carbocycle” is bonded to an oxygen atom. That is, non-aromatic carbocyclic oxy and aromatic carbocyclic oxy are included.
  • Heterocyclic oxy means a group in which the above “heterocycle” is bonded to an oxygen atom. That is, non-aromatic heterocyclic oxy and aromatic heterocyclic oxy are included.
  • Substituent group A halogen, hydroxy, carboxy, imino, hydroxyamino, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, azide, Hydrazino, ureido, amidino, guanidino, alkylsilyl substituted with one or more groups selected from unsubstituted or substituted group G, alkyl substituted with one or more groups selected from unsubstituted or substituted group G Oxy, unsubstituted or alkenyloxy substituted with one or more groups selected from substituent group G, alkynyloxy substituted with one or more groups selected from unsubstituted or substituent group G, unsubstituted or substituted Alkyl substituted with one
  • Alkylcarbonylimino substituted with one or more selected groups alkenylcarbonylimino substituted with one or more groups selected from unsubstituted or substituted group G, 1 selected from unsubstituted or substituted group G Alkynylcarbonylimino substituted with the above groups, alkyloxyimino substituted with one or more groups selected from unsubstituted or substituent group G, one or more groups selected from unsubstituted or substituent group G Substituted alkenyloxyimino, unsubstituted or substituted with one or more groups selected from substituent group G, alkynyloxyimino, unsubstituted or substituted with one or more groups selected from substituent group G Carbonyloxy, unsubstituted or alkenylcarbonyloxy substituted with one or more groups selected from substituent group G, alkynylcarbonyl Ruoxy, unsubstituted or substituted with one or more groups selected from substituent group G, un
  • the substituents on the ring of “aromatic carbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” include the following substituents: B, and the like.
  • the atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B.
  • Preferred examples of the substituent include Substituent Group E. More preferably, the substituent group F is mentioned. More preferably, the substituent group F is mentioned. Another preferred embodiment includes substituent group I.
  • Substituent group B oxo, halogen, hydroxy, carboxy, imino, hydroxyimino, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, Azido, hydrazino, ureido, amidino, guanidino, unsubstituted or substituted by one or more groups selected from substituent group G, unsubstituted or substituted by one or more groups selected from substituent group A Alkyl, alkenyl substituted with one or more groups selected from unsubstituted or substituted group A, alkynyl substituted with one or more groups selected from unsubstituted or substituted group A, unsubstituted or substituted Alkyloxy substituted with one or
  • Carbocycle of “substituted or unsubstituted carbocyclic group”, “substituted or unsubstituted heterocyclic group”, “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”
  • Substituent group B is also included as a substituent on the ring of “heterocycle”. The atom at any position on the ring may be bonded to one or more groups selected from the substituent group B. When two or more substituents are present, they may be the same or different.
  • Preferred examples of the substituent include Substituent Group E. More preferably, the substituent group F is mentioned. More preferably, the substituent group F is mentioned. Another preferred embodiment includes substituent group I.
  • One or more groups selected from the substituent group A may be bonded to any position on the alkyl. When two or more substituents are present, they may be the same or different. Preferred examples of the substituent include the substituent group G. More preferably, the substituent group K is mentioned.
  • Substituent group C hydroxy, amino, unsubstituted or alkylsilyl substituted with one or more groups selected from substituent group G, unsubstituted or substituted with one or more groups selected from substituent group G Alkyl, alkenyl substituted with one or more groups selected from unsubstituted or substituted group G, alkynyl substituted with one or more groups selected from unsubstituted or substituted group G, unsubstituted or substituted groups Alkylcarbonyl substituted with one or more groups selected from G, alkenylcarbonyl substituted with one or more groups selected from unsubstituted or substituent group G, 1 selected from unsubstituted or substituent group G Alkynylcarbonyl, monoalkylamino, dialkylamino, unsubstituted or substituted with one or more groups selected from substituent group G substituted with the above groups Nyl, alkenylsulfonyl substituted with one or more groups selected from un
  • substituent group C As substituents of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino”, substituent group C can be mentioned. Substituent group H is preferable.
  • substituent group D substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, Substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or Unsubstituted aromatic carbocyclic group, substituted or unsubstituted
  • Substituent group E oxo, halogen, hydroxy, carboxy, imino, hydroxyimino, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, One or more groups selected from azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl substituted by one or more groups selected from unsubstituted or substituted group K, unsubstituted or substituted group K Substituted with one or more groups selected from unsubstituted or substituted group K, substituted with alkenyl, alkynyl, haloalkyl, substituted or substituted with one or more groups selected from substituted group K Alkenyloxy, al
  • Substituent group F oxo, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, penta Halogenothio, cyano, cyanoalkyl, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, haloalkenyloxy, Hydroxyalkyloxy, carboxyalkyloxy, alkyloxyalkyl,
  • Substituent group G halogen, hydroxy, carboxy, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, pentahalogenothio, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano , Nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, unsubstituted or substituted with one or more groups selected from substituent group K, selected from unsubstituted or substituted group K Selected from alkenyloxy, alkynyloxy, unsubstituted or substituted with one or more groups selected from unsubstituted or substituted group K, 1 Substituted with more groups Substituted al
  • Substituent group H hydroxy, amino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, Selected from alkynylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aromatic carbocyclic group substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I A non-aromatic carbocyclic group substituted with one or more groups selected from the above, an aromatic heterocyclic group substituted with one or more groups selected from unsubstituted or a substituent group I, unsubstituted or substituted
  • Substituent group I oxo, halogen, cyano, alkyl, haloalkyl, hydroxy, alkyloxy, haloalkyloxy, alkyloxyalkyl, hydroxyalkyl, unsubstituted or substituted with one or two groups selected from substituent group J Carbamoyl substituted with 1 or 2 groups selected from amino, unsubstituted or substituted group J, and sulfamoyl substituted with 1 or 2 groups selected from unsubstituted or substituted group J.
  • Substituent group J alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, carbamoyl, alkylcarbonyl, haloalkylcarbonyl, alkylsulfonyl, and haloalkylsulfonyl.
  • Substituent group K cyano, halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, haloalkenyloxy, amino, alkylamino, dialkylamino, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkylcarbonyl, Haloalkylcarbonyl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonylamino, alkylsulfonyl, and alkylsulfonylamino.
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted or unsubstituted as follows.
  • substituents of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino” include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, etc. are mentioned. When substituted with a plurality of substituents, the substituents may be the same or different.
  • Examples of the “leaving group” include halogen, C 1-6 alkylsulfonyloxy or arylsulfonyloxy.
  • R 1 , R 2 , R 3 , R 4 , X, X ′, Z, G, Y, m, and n in the compound represented by the formula (I) are shown below.
  • the following possible combinations of compounds are preferred:
  • R 1 and R 2 are preferably Each independently a hydrogen atom, halogen, hydroxy, acyl, acyloxy, sulfanyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted nonaromatic carbon Cyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or
  • R 1 and R 2 are more preferably Each independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfanyl, substituted Or an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, Two R 1 bonded to non-adjacent carbon atoms together form a substituted or unsubstituted alkylene, R 1 and R 2 bonded to the same carbon atom together with adjacent atoms form a substituted or unsubstituted cycloalkane, Or, R 1 and R 2 bonded to the same carbon atom together are oxo or substituted or unsubstituted methylidene.
  • R 1 and R 2 are more preferably Each R 1 is independently a hydrogen atom, halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, alkyloxy, haloalkyloxy, alkylsulfanyl, or cycloalkyl, and R 2 is a hydrogen atom, halogen, Or alkyl, Two R 1 bonded to non-adjacent carbon atoms together form an alkylene and R 2 is a hydrogen atom, R 1 and R 2 bonded to the same carbon atom, together with adjacent atoms, form an unsubstituted or halogen-substituted cycloalkane, Or, R 1 and R 2 bonded to the same carbon atom together are oxo or methylidene.
  • R 1 and R 2 are each an independent group
  • (R 1 , R 2 ) are each independently (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (Methyl, hydrogen atom), (methyl, methyl), (hydrogen atom, halogen), (halogen, hydrogen atom) or (halogen, halogen).
  • (R 1 , R 2 ) are each independently (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (methyl, hydrogen atom), (methyl, methyl), (hydrogen Atom, fluorine atom), (fluorine atom, hydrogen atom) or (fluorine atom).
  • R 1 and / or R 2 has a substituent
  • preferred substituents for R 1 or R 2 are halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfanyl, sulfino, cyano, nitro, trialkylsilyl, alkyl
  • More preferred substituents are one or more groups selected from halogen, cyano, nitro, alkyloxy, haloalkyloxy, dialkylamino and alkylsulfonyl.
  • R 1 bonded to non-adjacent carbon atoms together form a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene”.
  • Base: (In the formula, R 5 is substituted or unsubstituted alkynylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, and the other definitions are the same as above.) Etc.
  • R 5 is preferably a substituted or unsubstituted alkynylene, more preferably an unsubstituted or halogen-substituted alkynylene.
  • the alkynylene preferably has 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms.
  • R 6 and R 7 are each independently the same as the substituent of the above-mentioned “substituted or unsubstituted methylidene”.
  • Means a group represented by R 6 and R 7 are preferably each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group or substituted Or it is an unsubstituted heterocyclic group.
  • they are a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group. More preferably, they are a hydrogen atom, an unsubstituted or halogen-substituted alkyl, or an unsubstituted or halogen-substituted cycloalkyl. Particularly preferred is a hydrogen atom.
  • n is preferably 2 to 4, more preferably 2 or 3, particularly preferably 3.
  • G is preferably substituted phenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted heterocyclic group, or formula (I-G1): (In the formula, each definition is as defined above.) There is a group represented by A substituted or unsubstituted bicyclic non-aromatic carbocyclic group, a substituted or unsubstituted heterocyclic group, or a group represented by the formula (I-G1) is preferable. More preferably, it is a substituted or unsubstituted heterocyclic group, or a group represented by the formula (I-G1).
  • a substituted or unsubstituted monocyclic aromatic heterocyclic group, a substituted or unsubstituted monocyclic or bicyclic nonaromatic heterocyclic group, or a group represented by the formula (I-G1) is there.
  • G has a substituent
  • a preferred embodiment of the substituent is one or more groups selected from the substituent group B.
  • a more preferred embodiment is one or more groups selected from the substituent group E.
  • a plurality of the substituents are present, they may be the same or different.
  • substituent embodiments include oxo, halogen, hydroxy, amino, cyano, cyanoalkyl, alkyl, alkenyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, Hydroxyalkyl, hydroxyalkynyl, cyanoalkyl, alkyloxyalkyl, alkyloxyalkyloxy, alkyloxyalkyloxyalkyloxy, alkylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, monoalkylsulfonylamino, alkyloxyimino, haloalkyloxyimino , Alkyloxyalkyloxyimino, methylidene, alkylmethylidene, alkyloxycarbonylmethyl One or more groups selected from the group consisting of redene, alkyl
  • substituents When a plurality of the substituents are present, they may be the same or different.
  • the number of substituents is preferably 0 to 8, more preferably 0 to 5, and still more preferably 0 to 3.
  • the non-aromatic carbocyclic group for G include cyclopropyl and indanyl (particularly preferably, indan-4-yl).
  • the heterocyclic group of G includes thienyl (particularly preferably thiophen-2-yl or thiophen-3-yl), furyl (particularly preferably furan-3-yl), thiazole (particularly preferably thiazole-4 -Yl), pyrrolyl (particularly preferably pyrrol-2-yl), imidazolyl (particularly preferably imidazol-2-yl), pyridyl (particularly preferably pyridin-2-yl, pyridin-3-yl, pyridine- 4-yl), pyrimidinyl (particularly preferably pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), pyrazinyl (particularly preferably pyrazin-2-yl), piperidinyl (particularly preferred piperidin -3-yl, piperidin-4-yl), piperazinyl (particularly preferably piperazin-1-yl), Omorpholinyl (particularly preferably, thiomorpholin-2-yl
  • the phenyl group is at least one or more substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocycle
  • the substituent further substituted on the phenyl ”substituted with alkyl or substituted or unsubstituted heterocyclic alkyl, and the phenyl may be further substituted includes a group selected from the substituent group B.
  • the group selected from the substituent group I is mentioned.
  • halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned.
  • substituents may be the same or different.
  • the number of substituents further substituted on the phenyl is 0 to 4, preferably 0 to 2, more preferably 0 or 1.
  • the preferred substitution position of “substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl or substituted or unsubstituted heterocyclic alkyl” is ortho-position or meta. The meta position is more preferable.
  • a preferred substitution position of the substituent further substituted on the phenyl is an ortho position or a meta position, and more preferably an ortho position.
  • G is represented by the following formula: Wherein R 11 is a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic alkyl or a substituted or unsubstituted heterocyclic alkyl, and R 12 is And a group selected from a hydrogen atom or a substituent group B) It is group shown by these.
  • R 11 is preferably a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, more preferably a substituted or unsubstituted monocyclic or bicyclic aromatic carbocyclic group.
  • the substituent for R 11 include one or more groups selected from the substituent group B.
  • the group selected from the substituent group I is mentioned. More preferably, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned.
  • R 12 is preferably a hydrogen atom or a group selected from Substituent Group I, more preferably halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
  • the carbocyclic group of G is phenyl, ii) at least one meta position of the phenyl group is substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted Substituted with a substituted or unsubstituted aromatic heterocyclic alkyloxy, and the phenyl group may be further substituted.
  • the group selected from the substituent group I is mentioned. More preferably, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned.
  • the substituents may be the same or different.
  • the substitution position of the substituent is preferably the ortho position or the para position, and more preferably the ortho position.
  • the number of substituents further substituted on the phenyl is 0 to 4, preferably 0 to 2, more preferably 0 or 1.
  • G is represented by the following formula: (Wherein R 13 represents substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic Ring alkyloxy, and R 14 is a hydrogen atom or a group selected from substituent group B) It is group shown by these.
  • R 13 represents substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy. And more preferably, a substituted or unsubstituted monocyclic aromatic carbocyclic oxy, a substituted or unsubstituted monocyclic aromatic heterocyclic oxy, or a substituted or unsubstituted monocyclic aromatic carbocyclic alkyloxy It is.
  • the substituent for R 13 include one or more groups selected from the substituent group B. Preferably, the group selected from the substituent group I is mentioned.
  • halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned.
  • substituents may be the same or different.
  • the number of the substituent is 0 to 5, preferably 0 to 3, and more preferably 0 to 2.
  • the substituent is preferably substituted at at least one ortho position.
  • R 13 is preferably a hydrogen atom or a group selected from Substituent Group I, more preferably halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
  • R 3 and R 4 “a) R 3 and R 4 together with the adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle”
  • a substituted or unsubstituted monocyclic non-aromatic carbocyclic ring a substituted or unsubstituted non-aromatic carbocyclic ring having a bridged structure or a spiro structure, a substituted or unsubstituted monocyclic non-aromatic heterocyclic ring
  • it is a non-aromatic heterocyclic ring having a substituted or unsubstituted bridged structure or spiro structure.
  • the ring is preferably a 3- to 8-membered ring, more preferably a 3- to 5-membered ring.
  • R 3 and R 4 are taken together to form a substituted or unsubstituted hydroxyimino.
  • R 8 has the same meaning as the substituent of the above-mentioned “substituted or unsubstituted hydroxyimino”.
  • the wavy line between the nitrogen atom and the oxygen atom is a cis bond, a trans bond or a mixture thereof. It means that there is.) It is group shown by these.
  • R 8 is preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group. is there. More preferably, they are a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group. More preferred is unsubstituted or halogen-substituted alkyl, or unsubstituted or halogen-substituted cycloalkyl.
  • R 3 and R 4 together form a substituted or unsubstituted methylidene (Wherein R 9 and R 10 have the same meanings as the substituents of the above-mentioned “substituted or unsubstituted methylidene”.) It is group shown by these.
  • R 9 and R 10 are preferably each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted An unsubstituted heterocyclic group. More preferably, they are a hydrogen atom or substituted or unsubstituted alkyl. More preferably, both are hydrogen atoms.
  • X ′ is preferably halogen, cyano, acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted amino, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group Substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted carbocyclic alkyloxy, or substituted or unsubstituted heterocyclic alkyloxy.
  • substituted or unsubstituted alkyl substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, Substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy.
  • a substituted or unsubstituted aromatic carbocyclic group a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted aromatic heterocyclic oxy, Substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy.
  • substituent for X ′ include a group selected from the substituent group F.
  • an aromatic carbocyclic group substituted with one or more groups selected from unsubstituted or substituted group I an aromatic group substituted with one or more groups selected from unsubstituted or substituted group I
  • a non-aromatic heterocyclic group an aromatic or carbocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group I, or one or more groups selected from unsubstituted or substituted group I
  • an aromatic carbocyclic group substituted with one or more groups selected from halogen, cyano, unsubstituted or substituent group K, and one or more groups selected from unsubstituted or substituent group K And aromatic heterocyclic groups substituted with.
  • Y is preferably benzene or a heterocyclic ring. More preferably, it is benzene, a monocyclic aromatic heterocycle or a non-aromatic heterocycle, or a bicyclic or tricyclic nonaromatic heterocycle.
  • the bicyclic or tricyclic non-aromatic heterocyclic ring may have a bridge structure and / or a spiro structure. Particularly preferred is a 5- to 6-membered aromatic heterocyclic ring or a 9- to 10-membered non-aromatic heterocyclic ring.
  • X is preferably each independently halogen, cyano, acyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted Or unsubstituted aromatic
  • X is independently halogen, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted non-aromatic carbocyclic alkyl, substituted or unsubstituted aromatic Heterocyclic alkyl, substituted or unsubstituted non
  • X has a cyclic group
  • preferred embodiments of the ring include monocyclic substituted or unsubstituted aromatic carbocyclic ring, monocyclic or bicyclic substituted or unsubstituted aromatic heterocyclic ring, or monocyclic or It is a bicyclic substituted or unsubstituted non-aromatic heterocycle.
  • a 6-membered substituted or unsubstituted aromatic carbocyclic ring, a 5 to 6-membered monocyclic ring or a 9 to 10-membered bicyclic substituted or unsubstituted aromatic heterocyclic ring, or a 5 to 6-membered ring is used.
  • a 9 to 10-membered bicyclic substituted or unsubstituted non-aromatic heterocyclic ring examples include benzyl and naphthyl (particularly preferably naphthalen-2-yl).
  • the non-aromatic carbocyclic group of X the following formula: Group etc. which are shown by these, etc. are mentioned. Particularly preferably, the following formula: Group etc. which are shown by these, etc. are mentioned.
  • Examples of the aromatic heterocyclic group of X include pyrazolyl, oxazolyl, isoxazolyl, furyl, imidazolyl, thienyl, thiazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, quinazolyl and the like. Particularly preferably, the following formula: The group shown by these is mentioned.
  • non-aromatic heterocyclic group of X the following formula: Group etc. which are shown by these, etc. are mentioned. Particularly preferably, the following formula: Group etc. which are shown by these, etc. are mentioned.
  • substituent group A When X has a substituent, examples of the substituent include Substituent Group A, Substituent Group B, Substituent Group C, and Substituent Group D.
  • substituent group G, the substituent group E, the substituent group H, etc. are mentioned, More preferably, the substituent group K, the substituent group F, or the substituent group J etc. are mentioned.
  • substituents include one or more selected from oxo, halogen, hydroxy, unsubstituted or substituted with one or more groups selected from substituent group C, unsubstituted or substituent group C Carbamoyl substituted with a group, cyano, alkyl substituted with one or more groups selected from unsubstituted or substituent group G, alkenyl substituted with one or more groups selected from unsubstituted or substituent group G Alkyloxy substituted with one or more groups selected from unsubstituted or substituted group G, alkenyloxy substituted with one or more groups selected from unsubstituted or substituted group G, alkynyloxy, hydroxyalkynyl Alkyloxyalkyloxyalkyloxy substituted with one or more groups selected from cyanoalkyl, unsubstituted or substituted group G Alkylcarbonyl substituted with one or more groups selected from unsubstituted or substituted group G, alkylcarbony
  • substituents When a plurality of the substituents are present, they may be the same or different. More preferably, oxo, halogen, hydroxy, cyano, unsubstituted or substituted with one or more groups selected from substituent group G, unsubstituted or substituted with one or more groups selected from substituent group G Alkenyl substituted with one or more groups selected from unsubstituted or substituted group G, alkenyloxy substituted with one or more groups selected from unsubstituted or substituted group G, alkynyloxy , Hydroxyalkyl, cyanoalkyl, alkyloxyalkyl, alkyloxyalkyloxy, unsubstituted or substituted with one or more groups selected from substituent group G, from unsubstituted or substituted group G Alkylcarbonyl, unsubstituted or substituted group H substituted with one or more selected groups One or more groups selected from one or more groups selected from amino, unsubstituted or
  • M is preferably 0 to 3, more preferably 0 to 2.
  • R 15 is a hydrogen atom or substituted or unsubstituted alkyl
  • W is a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • X 1A is Each independently halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy, Substituted or unsubstituted amino, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted
  • U is preferably a single bond, —O—, —NR 15 —, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, —O— (CR 16 R 17 ) e —, —O— (CR 16 R 17 ) e —O—, — (CR 16 R 17 ) e —O—, — (CR 16 R 17 ) e —O— (CR 16 R 17 ) e —, —NR 15 — (CR 16 R 17 ) e -, - (CR 16 R 17) e -NR 15 -, - NR 15 - (CR 16 R 17) e -O -, - O- (CR 16 R 17) e -NR 15 -, or - (CR 16 R 17) e -NR 15 - (CR 16 R 17) e -, it is.
  • R 16 and R 17 are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted cycloalkyl, or R 16 and R 17 together may form an oxo.
  • e is 1 to 4.
  • W is preferably an aromatic carbocycle, a non-aromatic carbocycle, an aromatic heterocycle, or a non-aromatic heterocycle. More preferred are benzene, naphthalene, monocyclic or polycyclic non-aromatic carbocycle, monocyclic aromatic heterocycle or nonaromatic heterocycle, or bicyclic or tricyclic nonaromatic heterocycle.
  • the polycyclic non-aromatic carbocyclic ring and the bicyclic or tricyclic non-aromatic heterocyclic ring may have a bridge structure and / or a spiro structure.
  • X 1A is preferably each independently halogen, cyano, acyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic A group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstitute
  • An antifungal agent means a substance that acts on a pathogenic fungus and has the ability to suppress or sterilize its growth. It may be something that suppresses fungal growth or kills some fungi to reduce their number.
  • pathogenic fungi examples include yeast-like fungi, filamentous fungi, zygomycetes, and the like.
  • yeast-like fungi examples include Candida genus (Candida albicans, Candida glabrata, Candida giermondii, Candida crusei, Candida parapsilosis, Candida tropicalis, etc.), Cryptococcus genus (such as Cryptococcus neoformans), Examples include the genus Malassezia (such as Malassezia fullfur) and the genus Trichosporon (such as Trichosporon and Asahi).
  • Aspergillus genus (Aspergillus fumigatus, Aspergillus tereus, Aspergillus niguel, Aspergillus flavus, etc.), Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonlances, etc.
  • Genus Fusarium such as Fusarium solani
  • genus Sedsporium such as Sedosporum / Apiospermum
  • microspores such as Microsporum canis.
  • the zygomycete examples include a genus Mucor (mucor, plumbeus, etc.), a genus Rhizopus (eg, Rhizopus oryzae), and a genus Absidia (eg, Absidia cholinebifera).
  • the antifungal agent of the present invention exhibits an excellent antifungal action against bacterial species such as Candida, Aspergillus, and Cryptococcus, and more excellent antifungal action against Aspergillus.
  • the antifungal agent of the present invention exhibits excellent antifungal activity against bacterial species such as Candida albicans, Aspergillus fumigatus, Aspergillus flavus and Cryptococcus neoformans.
  • the antifungal agent of the present invention exhibits excellent antifungal activity against various resistant bacteria.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof exhibits excellent safety.
  • Safety is evaluated by various tests, for example, cytotoxicity test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse micronucleus It can be evaluated by various safety tests selected from a test and an in vivo rat liver UDS test.
  • Examples of the pharmaceutically acceptable salt of the compound of the formula (I) include salts that are generally known in basic groups such as amino groups or acidic groups such as hydroxy or carboxy groups.
  • salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • Salts with organic carboxylic acids
  • Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
  • Preferred salts include pharmacologically acceptable salts.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid, Stone acid, oxalic acid, maleic acid, fuma
  • organic bases eg, trimethylamine, triethylamine, dicyclohexylamine,
  • the compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof.
  • the compound represented by the formula (I) includes the following tautomers.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal, and / or a crystal polymorph.
  • the invention also encompasses such various solvates, co-crystals and polymorphs.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included.
  • a method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • formulation adjuvants such as excipients, simple substances and diluents usually used in the formulation may be appropriately mixed.
  • formulation adjuvants such as excipients, simple substances and diluents usually used in the formulation may be appropriately mixed.
  • formulation adjuvants such as excipients, simple substances and diluents usually used in the formulation may be appropriately mixed.
  • These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection.
  • the administration method, the dose, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, 0.01 to 1000 mg / kg is administered in 1 to several divided doses a day by oral or parenteral administration (eg, injection
  • the compound of the present invention has a high antifungal activity against various fungi, it is useful as an antifungal agent, particularly a therapeutic and / or prophylactic agent for deep mycosis. Furthermore, since the compound of the present invention has excellent antifungal activity against various fungi under serum-added conditions, it has utility as a pharmaceutical product.
  • the compound of the present invention has utility as a pharmaceutical in that it has not only an antifungal action but also one or more of the following characteristics.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
  • High metabolic stability eg stability to rat and / or human metabolic enzymes).
  • composition of the present invention can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, syrups
  • the tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • injections, drops, external preparations eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas
  • Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered.
  • the injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
  • Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. Also, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day.
  • parenteral administration although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the compound of the present invention is combined with a polyene drug, a fungine drug, an azole drug or the like (hereinafter referred to as a concomitant drug) for the purpose of enhancing the action of the compound or reducing the dose of the compound.
  • a concomitant drug for the purpose of enhancing the action of the compound or reducing the dose of the compound.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
  • Step 1 In this step, the compound represented by the formula [2a] is reacted with guanidine hydrochloride to produce the compound represented by the formula [3a].
  • Examples of the compound represented by the formula [2a] include 1,3-propanediamine, 1,2-ethanediamine and the like.
  • the reaction temperature may be 0 to 150 ° C., and the reaction time may be 0.5 to 48 hours.
  • Step 2 In this method, the compound represented by the formula [3a] is reacted with the compound represented by the formula [4a] to produce the compound represented by the formula [5a].
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • alcohol solvents eg, methanol, ethanol, isopropanol, etc.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolide Non-acetate
  • acetate solvents eg, ethyl acetate, propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran
  • the solvent can be used as a two-layer solvent with water or a water-containing solvent as necessary. Preferred are ether solvents and ketone solvents.
  • the reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
  • Step 3 In this step, the compound represented by the formula [5a] is deprotected to produce the compound represented by the formula [6a].
  • the deprotection reaction of the protecting group is known and can be carried out by the method described in, for example, Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like.
  • the reaction solvent the solvents described in Step 2 can be used alone or in combination. Alcohol solvents and water are preferred.
  • the reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
  • Step 4 In this method, the compound represented by the formula [6a] and the compound represented by the formula [7a] are reacted to produce the compound represented by the formula [1].
  • the reaction solvent the solvents described in Step 2 of Production A can be used alone or in combination. Alcohol solvents are preferred.
  • the reaction temperature is 0 to 120 ° C., and the reaction time is 0.5 to 24 hours.
  • Step 1 In this step, the compound represented by the formula [1b] is reacted with carbon disulfide and an alkyl halide in the presence of a base to produce a compound represented by the formula [2b].
  • the alkyl halide include methyl iodide, methyl bromide, and ethyl iodide.
  • Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium hydrogen carbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides eg, sodium hydride
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide
  • metal carbonates eg, sodium carbonate
  • Calcium carbonate calcium carbonate
  • reaction solvent the solvents described in Step 2 of Production Method A can be used alone or in combination.
  • the reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
  • Step 2 In this step, the compound represented by the formula [2b] is reacted with the compound represented by the formula [2a] to produce a compound represented by the formula [3b].
  • the reaction solvent the solvents described in Step 2 of Production Method A can be used alone or in combination. Preferred are ether solvents (tetrahydrofuran) and amide solvents.
  • the reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
  • Step 3 In this step, the compound represented by the formula [3b] is reacted with the compound represented by the formula [4b] in the presence of a palladium catalyst to produce a compound represented by the formula [1].
  • a palladium catalyst In addition, about the compound shown by Formula: [4b], you may use boronic acid ester.
  • the solvent described in the step 2 of production method A can be used.
  • N-dimethylformamide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) or ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
  • the base described in the first step of production method B can be used.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction is used in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.)
  • a palladium catalyst eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.
  • a phosphine ligand eg PPh 3 , BINAP etc.
  • the reaction When performing the reaction using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • Examples of the compound represented by the formula: R 3 —B (OH) 2 include phenylboronic acid.
  • Step 1 In this step, the compound represented by the formula [7a] is reacted with thiourea to produce the compound represented by the formula [1c].
  • the reaction solvent the solvents described in Step 2 of Production A can be used alone or in combination. Alcohol solvents are preferred.
  • the reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
  • Step 2 In this step, the compound represented by the formula [2c] is produced from the compound represented by the formula [1c].
  • Step 3 In this step, the compound represented by the formula [2c] is reacted with the compound represented by the formula [2a] to produce a compound represented by the formula [1].
  • the NMR analysis obtained in the examples was performed at 300 MHz or 400 MHz and measured using DMSO-D6, CDCl 3 or the like.
  • Step 2 Synthesis of Compound 2c
  • Compound 2b (15.9 g, 56.1 mmol) was dissolved in tetrahydrofuran (200 mL), 1,3-diaminopropane (4.01 mL, 47.7 mmol) was added, and the mixture was heated at 70 ° C. for 2 hours. Stir. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 2c (5.48 g, 37%).
  • Step 3 Synthesis of Compound I-2
  • Compound 2c (30 mg, 0.115 mmol) was dissolved in tetrahydrofuran (0.3 mL), and 5-chlorothiophene-2-boronic acid (9.4 mg, 0.172 mmol), Pd (Dppf) (9.4 mg, 0.011 mmol), 2 mol / L sodium carbonate aqueous solution (0.23 mL) was added, and microwave irradiation was performed at 150 ° C. for 15 minutes.
  • Step 2 Synthesis of Compound I-3 4-Chlorophenol (27 mg, 0.21 mol) was dissolved in dimethylacetamide (1 mL), and Compound 3b (50 mg, 0.14 mol) obtained in Step 1 and potassium carbonate (97 mg) were dissolved. , 0.70 mol) was added, and the mixture was stirred at 65 ° C. for 3 hours. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-3 (11 mg, 27%).
  • Step 3 Synthesis of I-4 Compound 4d (70 mg, 0.207 mmol) was dissolved in DMA (1.5 mL), and compound 4e (34 mg, 0.207 mmol) and cesium carbonate (270 mg, 0.828 mmol) were added. Stir at 130 ° C. for 4 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-4 (21 mg, yield 25%). .
  • Step 2 Synthesis of I-5 Under a nitrogen stream, chloroiodomethane (0.31 mL, 4.23 mmol) was added to a solution of compound 5c (300 mg, 1.06 mmol) in tetrahydrofuran (3 mL), and the mixture was cooled to ⁇ 78 ° C. A tetrahydrofuran solution (7.1 mL, 5.3 mmol) of 0.75 mol / LLDA was added dropwise and stirred for 1 hour. Acetic acid (0.3 mL, 5.25 mmol) was added and the temperature was raised to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound I-6
  • Crude compound 6b 34 mg, 0.062 mmol was dissolved in DMF (0.7 mL) and piperidine (0.14 mL, 1.41 mmol) was added. After stirring at room temperature for 1 hour, compound 6c (17.7 mg, 0.089 mmol) was added and stirred at room temperature for 2 hours.
  • Sodium bicarbonate water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-6 (19.9 mg, yield 76%).
  • Step 2 Synthesis of Compound I-7 A mixture of compound 7b and compound 7c (50 mg, 0.132 mmol) was dissolved in ethanol (1 mL), phenylboronic acid (22.6 mg, 0.185 mmol), dichlorobistriphenylphosphine palladium ( 9.3 mg, 0.013 mmol) and 2.3 mol / L aqueous potassium carbonate (0.2 mL, 0.46 mmol) were added. After stirring at 120 ° C. for 3 hours, sodium bicarbonate water was added. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Synthesis of Compound I-8 Step 1 Synthesis of Compound 8b To a solution of Compound 8a (5 g, 23.8 mmol) in ethanol was added methylamine (40% methanol solution, 28 mL) and sodium cyanoborohydride (2.23 g, 35.8 mmol). Next, acetic acid (5.5 mL) was added dropwise, and the mixture was heated to reflux for 4 hours. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Step 2 Compound 8c synthesis
  • Compound 8b (1.5 g, 6.63 mmol) was dissolved in tetrahydrofuran (15 mL), and Boc 2 O (1.7 mL, 7.3 mmol) and DMAP (81 mg, 0.663 mmol) were added. . After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 8c (1.26 g, yield 58%).
  • Step 3 Synthesis of Compound 8e
  • Compound 8c (1.25 g, 3.83 mmol) was dissolved in toluene (13 mL) and 1-ethoxytri-n-butyltin (1.42 mL, 4.21 mmol), dichlorobistriphenylphosphine palladium ( 0.27 g, 0.383 mmol) was added to replace the system with nitrogen.
  • water was added and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 4 Synthesis of Compound I-8
  • Compound 8e 60 mg, 0.18 mmol was dissolved in dichloromethane (1.5 mL), and triethylamine (0.076 mL, 0.55 mmol) and benzenesulfonyl chloride (0.023 mL, 0. 183 mmol) was added. After stirring at room temperature for 1 hour, sodium bicarbonate water was added for neutralization. The mixture was neutralized with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound 9c
  • methanol 5 mL
  • hydrochloric acid-dioxane solution 3.4 mL, 13.6 mmol
  • the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was used in the next reaction as it was.
  • Step 3 Synthesis of Compound I-9
  • a solution of compound 9c 50 mg, 0.160 mmol
  • dimethylacetamide 1 mL
  • sodium hydride 38.6 mg, 0.319 mmol
  • 4-fluorobenzonitrile 38.6 mg, 0.319 mmol
  • the obtained residue was purified by preparative HPLC (10 mmol / L aqueous ammonium carbonate-acetonitrile solvent) to obtain Compound I-9 (9 mg, 14%).
  • Step 2 Synthesis of Compound 10c
  • 1 H-NMR (DMSO-d 6 ) ⁇ : 1.29 (s, 9H), 1.78 (m, 2H), 3.25 (m, 4H), 6.28 (s, 1H), 8.99 (s, 2H).
  • Step 3 Synthesis of Compound 10d
  • 1 H-NMR (DMSO-d 6 ) ⁇ : 1.79-1.76 (m, 2H), 3.26-3.22 (m, 4H), 6.79 (br, 2H), 8.90 (br, 2H).
  • Step 4 Synthesis of Compound 10e Ethanol (400 mL) was added to Compound 10d (37.5 g, 0.23 mol), and 1-bromobutane-2,3-dione (36 g, 0.23 mol) was added under ice cooling. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (400 mL) was added, and the mixture was extracted with methylene chloride (300 mL ⁇ 3). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.
  • Step 5 Synthesis of Compound 10f
  • Compound 10e (13.8 g, 61.5 mmol) was suspended in acetic acid (100 mL), 38% hydrogen bromide in acetic acid (100 mL) was added at room temperature, and the mixture was stirred for 10 min.
  • Bromine (3.5 mL) was added dropwise to the obtained reaction solution at room temperature, and the mixture was stirred overnight at room temperature.
  • Acetone (100 mL) was added to the reaction solution and stirred for 10 minutes. The resulting solid was filtered and washed with acetone to give compound 10f (16.5 g, 58%).
  • 1 H-NMR (DMSO-d 6 ) ⁇ : 3.47 (t, 4H), 5.02 (s, 2H), 8.29 (s, 1H), 8.92 (b, 2H).
  • Step 6 Synthesis of I-10 Compound 10f (45 mg, 0.12 mmol) was suspended in ethanol (2 mL), pyridazine-3-carbothioamide (18 mg, 0.13 mmol) was added, and the mixture was heated to reflux for 3 hours. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform-methanol) to obtain compound I-9 (11 mg, 27%).
  • Synthesis of Compound I-16 Step 1 Synthesis of Compound I-16 Compound 16a synthesized in the same manner as in Example 15 by dissolving N- (2-methoxyethyl) methylamine (24 mg, 0.27 mmol) in dimethylacetamide (0.5 mL) (20 mg, 0.053 mmol) and cesium carbonate (52 mg, 0.16 mmol) were added and stirred at 120 ° C. overnight. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound 18d
  • a solution of compound 18c (420 mg, 0.93 mmol) in methanol (4 mL) was added 4 mol / L hydrochloric acid-dioxane solution (1.17 mL, 4.67 mmol), and the mixture was stirred at room temperature for 1 hour. Further, a 4 mol / L hydrochloric acid (1.17 mL, 4.67 mmol) dioxane solution was added, and the mixture was allowed to stand for 12 hours. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diisopropyl ether to obtain Compound 18d as a crude product.
  • Step 3 Synthesis of I-18 Dimethylformamide (1 mL), benzyl bromide (0.022 mL, 0.183 mmol) and potassium carbonate (58,4 mg, 0.423 mmol) were added to compound 18d (62 mg, 0.14 mmol), and the mixture was stirred at room temperature for 90 minutes. Further, potassium carbonate (40 mg, 0.282 mmol) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound 19c
  • hydrobromic acid (25% acetic acid solution, 77 mL, 354 mmol)
  • bromine 0.84 mL, 17.2 mol
  • 23 23 at room temperature.
  • stir for hours After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 19c (2.15 g, yield 42%).
  • 1 H-NMR (CDCl 3 ) ⁇ : 1.97-2.04 (m, 2H), 3.45-3.47 (m, 4H), 4.40 (s, 2H), 7.55 (s, 1H).
  • Step 3 Synthesis of Compound 19d
  • Compound 19c 400 mg, 1.32 mmol
  • tert-butyl 4- (aminocarbothioyl) tetrahydropyridine-1 (2H) -carboxylate 322 mg, 1.32 mmol
  • microwave irradiation was performed at 120 ° C. for 7 minutes.
  • the reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain Compound 19d (636 mg) as a crude product.
  • Step 4 Synthesis of Compound 19e
  • Compound 19d (418 mg, 0.93 mmol) was dissolved in methanol (4 mL), 4 mol / L hydrochloric acid (dioxane solution, 4 mL, 16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in water, and it was added to a 1 mol / L aqueous sodium hydroxide solution and extracted with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Step 5 Synthesis of Compound I-19
  • Compound 19e 50 mg, 0.143 mmol
  • methylene chloride 1 mL
  • triethylamine 40 ⁇ L, 0.287 mmol
  • isopropyl chloroformate 18 ⁇ L, 0.158 mmol
  • Triethylamine (40 ⁇ L, 0.287 mmol) and isopropyl chloroformate (33 ⁇ L, 0.286 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with chloroform.
  • Step 2 Synthesis of Compound 20c
  • Compound 20b 140 mg, 0.67 mmol
  • ethanol 2 mL
  • 2 mol / L aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 2 hr.
  • Ethanol was distilled off under reduced pressure, and the pH was adjusted to 2 with 2 moL / L hydrochloric acid.
  • the obtained solid was collected by filtration, washed with water, and dried under reduced pressure to obtain compound 20c.
  • 1H-NMR (CDCl3) ⁇ : 1.37 (J 7.0 Hz, d, 6H), 2.85 (s, 5H), 3.22-3.29 (m, 1H), 9.21 (s, 1H).
  • Step 3 Synthesis of Compound 20d
  • Compound 20c (80 mg, 0.44 mmol) was dissolved in dimethylformamide (1 mL), CDI (216 mg, 1.33 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 28% Aqueous ammonia solution (1 mL) was added, and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 20d (65 mg, 82%).
  • Step 4 Synthesis of Compound 20e
  • Compound 20d (61 mg, 0.34 mmol) was dissolved in tetrahydrofuran (1 mL), Lawesson's reagent (138 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 20e (41 mg, 62%).
  • Step 5 Synthesis of Compound I-20 I-20 was obtained in the same manner as in Example 10 using Compound 20e.
  • Step 2 Synthesis of Compound I-21
  • Compound 21b (380 mg) and compound 21c (205 mg, 0.6 mmol) were dissolved in ethanol (20 mL) and stirred at room temperature for 23 hours. The precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure to obtain Compound I-21 (393 mg, yield 61%).
  • Tetrahydrofuran 50 mL was added for dilution, and 2 mol / L trimethylsilyldiazomethane in hexane (55.9 mL, 112 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and acetic acid (60 mL) was added to the resulting solid under ice cooling. Subsequently, a 47% aqueous solution of hydrogen bromide (14.7 mL, 127 mmol) was added to the solution all at once, and the mixture was stirred at 0 ° C. for 30 minutes.
  • the reaction solution was diluted with water, and 2 moL / L aqueous sodium hydroxide solution was added to adjust the pH to 5. Then, saturated sodium bicarbonate water was added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 23b (7.21 g) as a crude product. The composition of compound 23b (7.21 g) was dissolved in ethanol (60 mL), and compound 23c (4.87 g, 30.7 mmol) was added. After stirring at room temperature for 1 hour, the mixture was allowed to stand overnight.
  • Step 2 Synthesis of Compound I-23 2-Phenylmorpholine (209 mg, 1.28 mmol) was dissolved in N, N-dimethylacetamide (2 mL), Compound 23d (80 mg, 0.21 mmol), cesium carbonate (278 mg, 0.85 mmol). After sealing, the temperature was raised to 180 ° C. and stirred for 3 days. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound 25c
  • Compound 25c was synthesized in the same manner as in Example 26 using Compound 25b.
  • Step 4 Synthesis of Compound I-25
  • Compound 25c (20 mg, 0.044 mmol) was dissolved in dimethylacetamide (1 mL), and 3-cyanophenol (8 mg, 0.067 mmol) and potassium carbonate (18 mg, 0.13 mmol) were added. Furthermore, it stirred at 100 degreeC for 5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-25 (5 mg, 24%).
  • Step 2 Synthesis of Compound 26d
  • compound 26b (2.06 g, 8.40 mmol) in toluene (20 mL)
  • compound 26c (3.34 g, 9.24 mmol)
  • tetrakis (triphenylphosphine) palladium (0.971 g, 0.84 mmol)
  • a saturated aqueous potassium fluoride solution was added, and the mixture was stirred for 1 hour at room temperature and filtered. Water was added and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 26d as a crude product.
  • Step 3 Synthesis of Compound 26g Tetrahydrofuran (40 mL) and water (5 mL) were added to compound 26d (1.99 g, 8.40 mmol) and cooled to 0 ° C. N-bromosuccinimide (1.65 g, 9.24 mmol) was added and stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. After standing for 12 hours, N-bromosuccinimide (150 mg, 0.84 mmol) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 4 Synthesis of Compound I-26
  • Compound 26g 35 mg, 0.101 mmol
  • triphenylphosphine 39.7 mg, 0.152 mmol
  • 4-hydroxybenzonitrile (14.4 mg, 0.121 mmol) was added and cooled to 0 ° C.
  • Diisopropyl azodicarboxylate 0.029 mL, 0.152 mmol
  • the reaction solution was concentrated and purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-26 (4 mg, 9%).
  • Step 2 Synthesis of Compound 27b
  • Compound 27a 1000 mg, 2.5 mmol
  • tetrahydrofuran 25 mL
  • aqueous hydrochloric acid a mixed solution of tetrahydrofuran (25 mL) -2 mol aqueous hydrochloric acid and stirred at 65 ° C. for 6 hours.
  • the mixture was concentrated under reduced pressure, made basic by adding saturated aqueous sodium hydrogen carbonate, and extracted three times with 5% methanol / chloroform.
  • the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 27b (810 mg, 91%).
  • Step 3 Synthesis of Compound I-27
  • Compound 27b (30 mg, 0.084 mmol) was dissolved in ethanol (1 mL), and triethylamine (13 mg, 0.13 mmol) and O-methylhydroxylamine (11 mg, 0.13 mmol) were added. And stirred at room temperature for 3 hours. Water was added, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain Compound I-27 (15 mg, 46%).
  • Step 2 Synthesis of Compound 30d
  • Compound 30c 200 mg, 0.630 mmol
  • methanol 4 mL
  • 1 mol / L aqueous sodium hydroxide solution 1.9 mL, 1.9 mmol
  • a 10% aqueous citric acid solution was added.
  • the precipitated solid was collected by filtration to obtain compound 30d (183 mg, yield 96%).
  • Step 3 Synthesis of Compound I-30 To a solution of compound 30d (40 mg, 0.132 mmol) in DMF (1 mL) was added N-methylbenzylamine (24 mg, 0.198 mmol), HATU (75 mg, 0.198 mmol), triethylamine (0 0.055 mL, 0.396 mmol) was added. After stirring for 2 hours at room temperature, water was added. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to obtain Compound I-30 (20.2 mg, 38% yield).
  • Synthesis of Compound I-32 Step 1 Synthesis of Compound I-32 Compound 32a (50 mg, 0.17 mmol) was dissolved in DMA (1 mL), piperidine (17 ⁇ L, 0.17 mmol) was added, and the mixture was stirred at 100 ° C. for 30 minutes under microwave irradiation. Piperidine (85 ⁇ L, 0.85 mmol) was added, and the mixture was stirred at 150 ° C. for 3 hours under microwave irradiation. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
  • Synthesis of Compound I-33 Step 1 Synthesis of Compound 33b To a solution of Compound 31a (150 mg, 0.964 mmol) in dioxane (2.5 mL), 4-chloroaniline (160 mg, 1.25 mmol) and Pd (OAc) 2 (43 mg, 0.193 mmol), Xantphos (223 mg, 0.386 mmol) and potassium carbonate (200 mg, 1.446 mmol) were added. The system was purged with nitrogen and reacted at 120 ° C. for 15 minutes under microwave irradiation. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
  • Synthesis of Compound I-34 Step 1 Synthesis of Compound 34b A hexane solution (12.5 mL, 25 mmol) of 2 mol / L trimethylsilyldiazomethane was dissolved in tetrahydrofuran (40 mL), and Compound 34a (2 g, 11.36 mmol) was added under ice cooling. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (16 mL), and 47% hydrobromic acid (3.28 mL, 28.4 mmol) was added under ice cooling. After stirring for 1 hour, sodium hydroxide was added to adjust the pH to 5, and then sodium bicarbonate water was added to neutralize.
  • Step 2 Synthesis of Compound 34d
  • Compound 34b (1.96 g, 8.34 mmol) and compound 34c (1.1 g, 6.95 mmol) were suspended in ethanol (25 mL). After stirring at 100 ° C. for 1 hour, the mixture was allowed to cool to room temperature and neutralized by adding sodium bicarbonate water. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 34d (609 mg, yield 30%).
  • Step 3 Synthesis of Compound I-34
  • Compound 34d (30 mg, 0.102 mmol) and phenol (19 mg, 0.204 mmol) were dissolved in DMSO (0.6 mL).
  • Cesium carbonate (66.5 mg, 0.204 mmol) was added and stirred at 120 ° C. for 10 hours.
  • Water was added and extracted with chloroform, and the organic layer was concentrated under reduced pressure.
  • the obtained residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to obtain Compound I-34 (9 mg, yield 25%).
  • Synthesis of Compound I-35 Step 1 Synthesis of Compound I-35 Compound 35b (38 mg, 0.953 mmol) was dissolved in DMF (1.5 mL), and 60% sodium hydride (38.1 mg, 0.953 mmol) was added under ice cooling. Stir. After 10 minutes, compound 35a (70 mg, 0.238 mmol) was added and stirred at 120 ° C. for 3 hours. The mixture was ice-cooled, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Synthesis of Compound I-36 Step 1 Synthesis of Compound 36b To a solution of Compound 36a (1 g, 5.7 mmol) in tetrahydrofuran (10 mL) under cooling with ice, oxalyl chloride (0.55 mL, 6.27 mmol), DMF (0.02 mL, 0.285 mmol) was added. After 10 minutes, the mixture was warmed to room temperature and stirred for 1 hour. Tetrahydrofuran (10 mL) was added for dilution, and a 2 mol / L trimethylsilyldiazomethane hexane solution (6.27 mL, 12.5 mmol) was added dropwise under ice cooling.
  • Step 2 Synthesis of Compound 36d
  • Compound 36b (990 mg, 3.92 mmol) was dissolved in ethanol (10 mL), and Compound 36c (541 mg, 3.42 mmol) was added. After stirring at room temperature for 2 hours, the mixture was neutralized with an aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 36d (368 mg, yield 30%).
  • Step 3 Synthesis of Compound I-36 To a solution of Compound 36d (70 mg, 0.23 mmol) in DMA (1.5 mL), 4-chlorophenol (57.7 mg, 0.449 mmol), copper iodide (8.6 mg, 0.045 mmol), N, N-dimethylglycine (9.3 mg, 0.09 mmol) and potassium carbonate (93 mg, 0.674 mmol) were added. After stirring at 200 ° C. for 2 hours, ethyl acetate and water were added. The insoluble material was filtered off through celite. The organic layer and the aqueous layer were separated, and the organic layer was washed with water and saturated brine.
  • Synthesis of Compound I-38 Step 1 Synthesis of Compound 38b To a solution of Compound 38a (1 g, 2.68 mmol) synthesized in the same manner as in Example 34 in DMA (15 mL), 4-chlorophenol (0.318 mL, 3.22 mmol) and cesium carbonate were added. (2.19 g, 6.71 mmol) was added. After stirring at 120 ° C. for 4 hours, an aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound I-38 A 1 mol / L diethyl zinc hexane solution (0.645 mL, 0.645 mmol) was dissolved in tetrahydrofuran (0.75 mL) and NMP (0.5 mL). Compound 38b (75 mg, 0.16 mmol) and Pd (PPh 3 ) 4 (37 mg, 0.03 mmol) were added simultaneously with ice cooling. After stirring for 10 minutes, the temperature was raised to 80 ° C. After 3 hours, sodium bicarbonate water was added and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Synthesis of Compound I-39 Step 1 Synthesis of Compound I-39 4-fluorobenzeneboronic acid (50 mg, 0.36 mmol) was added to a solution of Compound 39a (70 mg, 0.24 mmol) synthesized in the same manner as in Example 1 in ethanol (1.5 mL). And dichlorobistriphenylphosphine palladium (17 mg, 0.024 mmol), 2 mol / L aqueous potassium carbonate solution (0.36 mL, 0.72 mmol) were added. The system was purged with nitrogen, stirred at 100 ° C. for 4 hours, water was added, and the mixture was extracted with chloroform.
  • Step 2 Synthesis of Compound 44d
  • Compound 44b (950 mg, 2.98 mmol) was dissolved in toluene (15 mL), and 1-ethoxyvinyltri-n-butyltin (1.1 mL, 3.28 mmol), Pd (PPh 3 ) 4 (209 mg, 0.298 mmol) was added. After stirring at 90 ° C. for 2 hours, water was added. Extraction with ethyl acetate was performed, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 3 Synthesis of Compound I-44
  • a solution of compound 44d 63 mg, 0.14 mmol
  • DMF 1.2 mL
  • sodium methoxide 80 mg, 0.41 mmol
  • an aqueous ammonium chloride solution was added.
  • the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • the resulting residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to give compound I-44 (7.7 mg, yield 13%).
  • Step 2 Synthesis of Compound I-45
  • Compound 45b 100 mg, 0.36 mmol
  • tetrahydrofuran 5 mL
  • tetrahydrofuran 5 mL
  • tetrahydrofuran 5 mL
  • Acetic acid 0.5 mL was added, water was added, and the temperature was raised to room temperature.
  • Step 2 Synthesis of Compound I-46
  • Compound I-46 was synthesized in the same manner as in Example 45 using Compound 46b.
  • Step 2 Synthesis of Compound I-47 Compound 47c (50 mg, 0.133 mmol), phenylboronic acid (24.3 mg, 0.2 mmol), PdCl2 (dtbpf) (8.67 mg, 0.013 mmol) in tetrahydrofuran (1 ml) 2 mol / L aqueous sodium carbonate solution (0.266 ml, 0.532 mmol) was added, and the mixture was stirred at 130 ° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with chloroform-methanol (9: 1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Synthesis of Compound I-50 Step 1 Synthesis of Compound I-50 2,4-Dimethylphenol (66 mg, 0.54 mmol) and Compound 50a (80 mg, 0.27 mmol) were dissolved in N, N-dimethylacetamide (2.6 mL) to obtain cesium carbonate. (354 mg, 1.09 mmol) was added. After sealing, the temperature was raised to 200 ° C. with a microwave and stirred for 15 minutes. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound I-51
  • Compound 51b 360.3 mg, 1.466 mmol
  • 1-ethoxyvinyltri-n-butyltin 545 ⁇ l, 1.613 mmol
  • Pd (PPh 3 ) 4 169 mg, 0.147 mmol
  • Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound I-53
  • Compound 53d (30 mg, 0.087 mmol), phenylboronic acid (16 mg, 0.13 mmol), PdCl 2 (dtbpf) (5.7 mg, 8.74 ⁇ mol) was added to tetrahydrofuran (0.6 ml).
  • 2 mol / L aqueous sodium carbonate solution (0.131 ml, 0.262 mmol) was added, and the mixture was stirred at 130 ° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 3 Synthesis of Compound I-54
  • phenylboronic acid 38 mg, 0.31 mmol
  • bis (triphenylphosphine) palladium (II) dichloride (18 mg, 0.026 mmol) were ethanol. (1.5 mL) was dissolved, and 2 moL / L potassium carbonate aqueous solution (0.26 mL, 0.52 mmol) was added. After sealing, the temperature was raised to 100 ° C. and stirred for 2 hours. After allowing to cool to room temperature, water was added and the mixture was extracted with chloroform.
  • Step 2 Synthesis of Compound I-55
  • Synthesis of Compound I-56 Step 1 Synthesis of Compound 56b A solution of compound 56a (1 g, 8.29 mmol) in dichloromethane (7 mL) was ice-cooled, and bromine (0.43 mL, 8.29 mmol) was added dropwise. After raising the temperature at room temperature and stirring for 1 hour, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound 56c
  • 1 H-NMR (CDCl3) ⁇ : 1.38-1.43 (m, 2H), 1.71-1.77 (m, 2H), 4.18 (s, 2H), 6.85 (m, 2H), 7.27 (m, 2H).
  • Step 3 Synthesis of Compound I-56
  • Compound 56d 70 mg, 0.44 mmol
  • ethanol 1.5 mL
  • sodium bicarbonate water was added for neutralization.
  • Extraction was performed with chloroform, and the organic layer was washed with saturated brine.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-56 (110 mg, yield 61%).
  • Synthesis of Compound I-57 Step 1 Synthesis of Compound 57b To a solution of Compound 57a (4.5 g, 8.22.8 mmol) in DMF (40 mL) was added 4-chlorophenol (2.94 g, 22.8 mmol), potassium carbonate (9.47 g, 68). .5 mmol) was added sequentially. After stirring at 80 ° C. for 3 hours, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • Step 2 Synthesis of Compound I-57
  • chloroiodomethane 1.7 mL, 23.5 mmol
  • 0.5 mol / LLDA 56.4 mL, 28.2 mmol
  • Acetic acid 1.7 mL, 29.7 mmol
  • water was added.
  • the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound I-58 Cyclohexane-1,3-diamine (157 mg, 1.38 mmol) was added to a solution of the crude product 58b (100 mg, 0.28 mmol) in DMF (30 mL) and stirred at 85 ° C. for 12 hours. . After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. It dried with the anhydrous sodium sulfate and the solvent was depressurizingly distilled. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-58 (48 mg, yield 46%).
  • LCMS measurement condition A: retention time: 1.61 minutes, [M + H] + : 382
  • Step 2 Synthesis of Compound 829c
  • Compound 829c (7.13 g, 75%) was obtained in the same manner as in Steps 2 and 3 of Example 23 using Compound 829b.
  • Step 3 Synthesis of Compound I-829
  • Compound 1-829 (7.27 g, 87%) was obtained in the same manner as in Step 4 of Example 23 using Compound 829c.
  • Step 2 Synthesis of Compound 832c 3-Bromo-2-methylpyridine (491 mg, 2.86 mmol) was dissolved in toluene (5 mL), cooled to ⁇ 70 ° C., and 1.6 mol / L n-butyllithium-hexane solution. (1.53 mL, 2.45 mmol) was added and stirred for 20 minutes. Subsequently, Compound 2 (500 mg, 2.04 mmol) was dissolved in toluene (5 mL) and added dropwise, followed by stirring for 1 hour. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Synthesis of Compound I-832
  • Compound 1-832 (126 mg, 44%) was obtained in the same manner as in Step 3 of Example 8 using Compound 832c and Compound 8d.
  • Step 2 Synthesis of Compound 835e
  • Compound 835c 100 mg, 0.41 mmol was dissolved in 1,2-dichloroethane (1 mL), and DMAP (5.0 mg, 0.041 mmol) and Compound 835d (145 mg, 0.82 mmol) were added. It was. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 835e (108.0 mg, 75% yield). .
  • Step 3 Synthesis of Compound 835f
  • a toluene solution (2 mL) of tri-n-butyltin (177 mg, 0.608 mmol) was heated to 80 ° C., and a toluene solution (1 mL) of Compound 835e (108 mg, 0.304 mmol) was added dropwise. Heated to reflux for hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 835f (15.8 mg, yield 23%).
  • Step 4 Synthesis of Compound 835g
  • Compound 835f (15.8 mg, 0.069 mmol) was dissolved in a 7 mol / L ammonia-methanol solution (2 mL). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure to obtain 835 g (14.0 mg) of a compound as a crude product.
  • Step 5 Synthesis of Compound 835h Lawesson's reagent (33.5 mg, 0.083 mmol) was added to a solution of compound 835 g (14.0 mg) in toluene (2 mL), and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 835h (9.9 mg, 66% yield).
  • Step 6 Synthesis of Compound I-835
  • Compound 835h (9.9 mg, 0.046 mmol) and compound 835i (19.3 mg, 0.05 mmol) were suspended in ethanol (0.2 mL). The mixture was heated to reflux for 5 hours and then allowed to cool to room temperature. Sodium bicarbonate water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-835 (6.1 mg, yield 32%).
  • Step 2 Synthesis of Compound 836c
  • Compound 3 was obtained as a crude product in the same manner as in Step 4 of Example 57 using Compound 836b.
  • Step 3 Synthesis of Compound 836d
  • a solution of Compound 836c (126.0 mg, 0.695 mmol) in tetrahydrofuran (4 mL) was added Lawesson's reagent (309 mg, 0.765 mmol).
  • aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 836d (58.2 mg, 43% yield).
  • Step 4 Synthesis of Compound I-836
  • Compound I-836 (25.1 mg, yield 62%) was obtained using Compound 4 in the same manner as in Step 6 of Example 57.
  • Step 2 Synthesis of Compound 837d
  • Lithium aluminum hydride 124 mg, 3.26 mmol
  • tetrahydrofuran 10 mL
  • a solution of compound 837c 500 mg, 1.48 mmol
  • tetrahydrofuran 15 mL
  • sodium sulfate decahydrate 5 g
  • Step 4 Synthesis of Compound I-837
  • potassium carbonate (23.3 mg, 0.168 mmol) and 2-methylpyridin-3-ol (11.0 mg, 0.101 mmol).
  • the mixture was allowed to cool to room temperature.
  • Sodium bicarbonate water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-837 (8.0 mg, yield 25%).
  • Step 2 Synthesis of Compound 839c
  • methylamine 33% ethanol solution, 10 mL
  • the residue obtained by evaporating the solvent under reduced pressure was purified by amino silica gel column chromatography (chloroform-methanol) to obtain Compound 839c (735.8 mg, yield 67%).
  • Step 4 Synthesis of Compound 839e
  • Compound 839e (19 mg, 18% yield) was obtained in the same manner as in Step 3 of Example 58, using Compound 839d and Compound 839f.
  • Step 2 Synthesis of Compound 840c
  • thionyl chloride 29.8 g, 251 mmol
  • N, N-dimethylformamide 0.5 ml
  • the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in tetrahydrofuran (200 ml), and a 2 mol / L trimethylsilyldiazomethane hexane solution (138 ml, 276 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 50 minutes.
  • Step 3 Synthesis of Compound 840d
  • Compound 840c 500 mg, 1.86 mmol was dissolved in N, N-dimethylformamide (10 ml), and under a nitrogen atmosphere, carbon disulfide (0.28 ml, 4.65 mmol) and sodium hydride ( 190 mg, 4.65 mmol) was added at 0 degrees and stirred at 0 degrees for 20 minutes.
  • Methyl iodide (0.58 ml, 9.3 mmol) was added at 0 degree, and the mixture was further stirred at 0 degree for 1 hour. Water was added and extracted with ethyl acetate.
  • Step 4 Synthesis of Compound I-840
  • Compound 840d (101 mg, 0.27 mmol) was dissolved in N, N-dimethylacetamide (1 ml) and 1- (aminomethyl) cyclobutanamine dihydrochloride (230 mg, 1.33 mmol) and Triethylamine (0.75 ml, 5.42 mmol) was added and stirred at 100 degrees for 6 hours. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Compound 841b (327 mg, 0.6 mmol) was dissolved in tetrahydrofuran (10 mL), a solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (0.69 ml, 0.9 mmol) was added at ⁇ 30 degrees, and ⁇ 30 degrees for 1 hour. Stir. 2-Methyl-3-formylpyridine (160 mg, 1.32 mmol) was added at ⁇ 30 degrees, and the mixture was warmed to room temperature and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Compound 841c (90 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 841d (48 mg, 81%). LCMS (measurement conditions A); retention time: 0.65 minutes, [M + H] +: 387
  • Step 4 Compound 841d (36 mg, 0.093 mmol) was dissolved in tetrahydrofuran (5 mL), manganese dioxide (81 mg, 0.93 mmol) was added, and the mixture was stirred at 65 degrees for 6 hours. Insoluble matter was removed by Celite filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-841 (12 mg, 34%).
  • Step 2 Synthesis of Compound 842c
  • a solution of compound 842b (116 mg, 0.54 mmol) in ethanol (3 mL) was added 2 mol / L aqueous sodium hydroxide solution (3 mL), and the mixture was heated to reflux for 6 hours.
  • Water was added, the pH was adjusted to 2 with a 2 mol / L hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was dissolved in DMF (1 mL), CDI (138 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature for 30 min.
  • Step 3 Synthesis of Compound 842d
  • tetrahydrofuran 5 mL
  • Lawesson's reagent 180 mg, 0.45 mmol
  • Water 5 ml
  • sodium bicarbonate water 5 ml
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 4 Synthesis of Compound I-842
  • Compound I-842 (35 mg, 45%) was obtained in the same manner as in Step 6 of Example 10 using Compound 842d and Compound 10f.
  • 1H-NMR (DMSO-D6) ⁇ : 1.80-1.87 (m, 2H), 3.29-3.42 (m, 7H), 3.62-3.65 (m, 2H), 4.09 (s, 3H), 4.20-4.22 (m, 2H), 6.31 (s, 1H), 7.10 (s, 1H), 8.13 (s, 1H), 8.25 (s, 2H).
  • Step 2 Synthesis of Compound I-844
  • Compound I-844 (51 mg, 53%) was obtained in the same manner as in Step 2 of Example 39, using Compound 844b and Compound 45c.
  • Step 2 Synthesis of Compound 846c
  • Compound 846b (104 mg, 0.45 mmol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (22 mg, 0.54 mmol) and methyl iodide (0.034 mL, 0.54 mmol) were added, Stir at 100 degrees for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 846c (31 mg, 28%).
  • Step 3 Synthesis of Compound I-846
  • Compound I-846 (18 mg, 39%) was obtained in the same manner as in Step 2 of Example 39 using Compound 846c and Compound 45c.
  • Step 2 Compound 847b (31 mg, 0.077 mmol) was dissolved in DMA (1 mL), 2,6-dimethylpyridine (19 mg, 0.154 mmol) and potassium carbonate (53 mg, 0.39 mmol) were added, and the mixture was stirred at 100 degrees for 2 hours. did. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-847 (8 mg, 24%).
  • Test Example 1 MIC Test Method The antifungal activity of the test substance was evaluated using a micro liquid dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI).
  • the medium for measurement is minimal synthetic medium for yeast culture (2% glucose, 0.67% yeast nitrogen base w / o amino acid, 0.2% amino acid / nucleotide mix) and morpholine propane sulfonic acid (MOPS, final concentration 50 mM). ) was added to obtain a buffer solution, and 1M sodium hydroxide was added to adjust the pH to 7.0 (YNB / MOPS).
  • test drug was serially diluted 2-fold with DMSO, and 2 ⁇ L was dispensed into each well of a 96-well microplate.
  • Candida albicans ATCC MYA-574 (fluconazole resistant strain) cultured overnight at 35 ° C on a Sabro-Agar medium was suspended in sterile physiological saline, then the turbidity was measured with a spectrophotometer, and the bacterial suspension was treated with YNB.
  • An inoculum (about 2.5 ⁇ 10 3 CFU / mL) was prepared by dilution with / MOPS.
  • Aspergillus fumigatus ATCC204305, Aspergillus flavus IFM50915 and Aspergillus terreus IFM46871 stored at ⁇ 80 ° C. were diluted with YNB / MOPS to prepare an inoculum solution (1 ⁇ 10 4 CFU / mL). 198 ⁇ L of the inoculum solution was dispensed into each well to prepare a microplate containing a test substance, a medium, and bacterial cells of a predetermined concentration.
  • Candida albicans was cultured at 35 ° C. for 1 day, and Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus were cultured at 35 ° C.
  • the MIC of Candida albicans was set to the minimum concentration that inhibits growth by 50% or more in turbidity compared to the control without addition of the test substance.
  • the MIC of Aspergillus fumigatus and Aspergillus terreus was 100% visually, and the MIC of Aspergillus flavus was the minimum concentration that visually inhibited 50%.
  • Aspergillus fumigatus was also subjected to MIC measurement under the condition that 50% bovine serum (BS) was added to the YNB / MOPS medium.
  • the strains and conditions used are shown in Table 174.
  • Tables 175 to 182 show the results of MIC measurement of the bacteria / strain number 1.
  • Tables 183 to 189 show the results of MIC measurement of the bacteria / strain number 2.
  • Tables 190 to 194 show the results of MIC measurement of the bacteria / strain number 3.
  • Table 195 and Table 196 show the MIC measurement results of the bacteria / strain number 4.
  • Table 197 and Table 198 show the MIC measurement results of the bacteria / strain number 5.
  • Test Example 2 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • the bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group.
  • Test Example 4 Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
  • the compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.
  • Test Example 5 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in the K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ mol / L or more was designated as (+), and the case where it was 3 ⁇ mol / L or less was designated as ( ⁇ ).
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated.
  • MicroF containing 110 mL Exposure medium (Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Test Example 7 hERG Test
  • HEK293 cells expressing human ether-a-go-related gene (hERG) channel it is important for ventricular repolarization process
  • I Kr delayed rectifier K + current
  • the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 10 Visual Solubility Test Compound Weigh out to about 3 mg test tube of about 5 mg, and add each medium (water for injection, saline feed, 0.5% glucose solution) to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be ⁇ 1%. Measure and record the pH with 1% test solution.
  • Test Example 11 pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method) This is a separation method using capillary zone electrophoresis technology and free migration of each sample component in a buffer solution containing an electrolyte. After injecting a compound solution into a fused silica capillary filled with a buffer solution adjusted to pH 2.5 to 11.5 and then applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow).
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has excellent antifungal activity and is useful as an antifungal agent.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is excellent in safety and useful as an antifungal agent against Candida and Alpergillus.

Abstract

A compound represented by general formula (I) (wherein Z represents -CR1R2-; R1 and R2 independently represent a hydrogen atom, a halogen atom, a hydroxy group or the like, or independently form, together with an atom adjacent thereto, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring, or the like; G represents a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group or the like; and n represents an integer of 1 to 5) or a pharmaceutically acceptable salt thereof is useful as an anti-fungal agent.

Description

環状グアニジル基を有するチアゾール誘導体Thiazole derivatives having a cyclic guanidyl group
本発明は、抗真菌活性を有する新規な環状グアニジル基を有するチアゾール誘導体またはその塩、およびそれらを含有する抗真菌剤に関する。 The present invention relates to a thiazole derivative having a cyclic guanidyl group having antifungal activity or a salt thereof, and an antifungal agent containing them.
近年、致死率の高い難治性深在性真菌症が大きな問題となっている。深在性真菌症の増加背景の１つとして、医療の高度化にともなう易感染性患者の増加が挙げられる。高度救命医療や臓器移植などに用いられる抗菌薬、抗腫瘍薬及び免疫抑制薬の頻用に伴って、これら高度医療適用患者は免疫力が低下している場合が多く、その為、健常人においては感染・発症することのない内因性または外因性の日和見感染菌であるカンジダ属菌やアスペルギルス属菌などの真菌が起因菌となって重篤な感染症を発症することがある。例えば、AIDS（後天性免疫不全症候群）患者では口腔・食道カンジダ症、クリプトコッカス髄膜炎などの併発や、臓器移植や抗癌化学療法を受けている患者では、播種性カンジダ症、侵襲性アスペルギルス症などの発症頻度が高い（非特許文献１，２）。欧米先進国やわが国において重度の免疫不全の患者は、今後益々増加することが予想され、深在性真菌症の対策を講じることが重要である。
深在性真菌症の治療には、抗真菌化学療法が適用されている。アムホテリシンBはカンジダ属菌、アスペルギルス属菌に対して強い殺真菌効果を示すが、腎毒性の軽減のため現在では主にリポソーム製剤が使用されており、薬効の減少により有効な治療が実現できていない問題がある（非特許文献３）。カスポファンギンおよびミカファンギンは、カンジダ属菌に対して殺真菌活性を示して比較的安全性が高いことから、カンジダ症に対して多用されて良好な臨床効果を示している。しかしながら、これらの薬剤に対する低感受性菌種や耐性菌の増加が懸念されている（非特許文献４）。イトラコナゾールおよびボリコナゾールは，アスペルギルス属菌に対して殺真菌活性を示してアムホテリシンBより安全性が高いことから、アスペルギルス症に対して多用されて致死率の改善に大きく貢献している。しかしながら，薬物相互作用や肝毒性などの副作用により十分量の投与ができていない問題や（非特許文献５）、長期投与によるアゾール耐性菌の増加の問題がある（非特許文献６，７，８）。 
　そのため，これらの抗真菌剤以上の抗真菌活性を持ちながら、安全性および薬物相互作用が改善され、その結果として臨床治癒率や再発率が向上し、さらには既存薬の耐性菌に対しても効果を有する新系統の抗真菌剤が強く望まれている。 In recent years, refractory deep mycosis with a high mortality rate has become a major problem. One of the reasons for the increase in deep mycosis is the increase in the number of easily infectious patients as the medical advancement progresses. With the frequent use of antibacterial drugs, antitumor drugs and immunosuppressive drugs used in advanced lifesaving medical treatment and organ transplantation, these advanced medical treatment patients often have reduced immunity, so in healthy people Severe infections may be caused by fungi such as Candida and Aspergillus, which are endogenous or exogenous opportunistic infections that do not cause infection or onset. For example, patients with AIDS (acquired immunodeficiency syndrome) have concurrent oral and esophageal candidiasis, cryptococcal meningitis, etc. The onset frequency is high (Non-Patent Documents 1 and 2). It is expected that the number of severely immunocompromised patients in developed countries in Europe and the United States and Japan will increase in the future, and it is important to take measures against deep mycosis.
Antifungal chemotherapy has been applied to the treatment of deep mycosis. Amphotericin B has a strong fungicidal effect against Candida and Aspergillus spp., But currently, liposome preparations are mainly used to reduce nephrotoxicity. There is no problem (Non-Patent Document 3). Caspofungin and Micafungin have a fungicidal activity against Candida spp. And are relatively safe. Therefore, they are frequently used for candidiasis and have a good clinical effect. However, there is concern about an increase in low-sensitive bacterial species and resistant bacteria against these drugs (Non-patent Document 4). Itraconazole and voriconazole have fungicidal activity against Aspergillus spp. And are safer than amphotericin B. Therefore, itraconazole and voriconazole are frequently used for aspergillosis and contribute greatly to the improvement of mortality. However, there is a problem that a sufficient amount cannot be administered due to side effects such as drug interaction and hepatotoxicity (Non-patent Document 5), and an increase in azole-resistant bacteria due to long-term administration (Non-patent Documents 6, 7, and 8). ).
Therefore, while having antifungal activity higher than these antifungal agents, safety and drug interaction are improved. As a result, clinical cure rate and recurrence rate are improved. There is a strong desire for new antifungal agents that have efficacy.
　特許文献１～４には環状または非環状のグアニジル基を有するチアゾール誘導体が開示されているが、抗真菌作用に関する記載や示唆はない。また、特許文献５～９および非特許文献９、１０には抗真菌作用を有する環状グアニジル基を有するチアゾール誘導体が開示されているが、本発明の化合物またはその塩、およびそれらを含有する抗真菌剤は記載されていない。 Patent Documents 1 to 4 disclose thiazole derivatives having a cyclic or acyclic guanidyl group, but there is no description or suggestion regarding antifungal activity. Patent Documents 5 to 9 and Non-Patent Documents 9 and 10 disclose thiazole derivatives having a cyclic guanidyl group having an antifungal action. The compounds of the present invention or salts thereof, and antifungi containing them. The agent is not described.
特開平０３－１４１２７０号公報Japanese Patent Laid-Open No. 03-141270 国際公開第９６／０５１８７号International Publication No. 96/05187 特開平０２－７２１７７号公報Japanese Patent Laid-Open No. 02-72177 特開平０５－７８３５３号公報JP 05-78353 A 特開昭５８－２１６１８６号公報JP 58-216186 A 特開平０２－２７０８７０号公報Japanese Patent Laid-Open No. 02-270870 独国特許出願公開第３８３６１６０号明細書German Patent Application Publication No. 3836160 特開平０２－１６４８７９号公報JP 02-164879 A 独国特許出願公開第３８３６１６１号明細書German Patent Application Publication No. 3836161
　本発明の課題は、カンジダ属菌、アスペルギルス属菌をはじめとする病原性真菌や種々の耐性菌に対して優れた抗真菌活性を示し、医薬品として有用な新規化合物を提供することにある。 An object of the present invention is to provide a novel compound that exhibits excellent antifungal activity against pathogenic fungi such as Candida and Aspergillus and various resistant bacteria and is useful as a pharmaceutical.
　本発明は、少なくとも環状グアニジル基有するチアゾール誘導体を合成することにより、上記課題を解決し、以下の発明を提供する。 The present invention solves the above problems by synthesizing at least a thiazole derivative having a cyclic guanidyl group, and provides the following inventions.
（項目１）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000010
（式中、Ｚは－ＣＲ１Ｒ２－であり、
Ｒ１はそれぞれ独立して、
水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、ペンタハロゲノチオ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルであり、
隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレン、置換もしくは非置換のアルケニレン、または置換もしくは非置換のアルキニレンを形成するか、
Ｒ２はそれぞれ独立して、
水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、ペンタハロゲノチオ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルであるか、
同一炭素原子に結合するＲ１およびＲ２が、該炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成するか、
または、
同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソ、置換もしくは非置換のアルキルイミノ、置換もしくは非置換のアルケニルイミノ、置換もしくは非置換のアルキニルイミノ、置換もしくは非置換のアルキルカルボニルイミノ、置換もしくは非置換のアルケニルカルボニルイミノ、置換もしくは非置換のアルキニルカルボニルイミノ、置換もしくは非置換のアルキルオキシイミノ、置換もしくは非置換のアルケニルオキシイミノ、置換もしくは非置換のアルキニルオキシイミノ、または置換もしくは非置換のメチリデンを形成し、
Ｇは置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、または式（Ｉ－Ｇ１）：
Figure JPOXMLDOC01-appb-C000011
（式中、
Ｒ３およびＲ４については、
ａ）Ｒ３およびＲ４が隣接する原子と一緒になって、置換もしくは非置換の非芳香族炭素環、または置換もしくは非置換の非芳香族複素環を形成するか、または、
ｂ）Ｒ３およびＲ４が一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し、
Ｘ’はハロゲン、ヒドロキシ、カルボキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである。）
で示される基であり、
ｎは２～５の整数である。
ただし、
Ｇの炭素環式基がフェニルの場合、
ｉ）該フェニル基は少なくとも１つ以上の置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキルまたは置換もしくは非置換の複素環アルキルで置換されており、該フェニルはさらに置換されていてもよく、および／または
ｉｉ）該フェニル基の少なくとも１つのメタ位が置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシで置換されており、該フェニル基はさらに置換されていてもよく、かつ、
以下の化合物（Ａ－１）～（Ａ－３４）を除く。
Figure JPOXMLDOC01-appb-C000012

Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
）で示される化合物またはその製薬上許容される塩。 (Item 1) Formula (I):
Figure JPOXMLDOC01-appb-C000010
Wherein Z is —CR 1 R 2 —,
Each R 1 is independently
Hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, pentahalogenothio, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted Substituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Rubonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl Substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic compound Ring oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or substituted or unsubstituted non-aromatic heterocyclic A ring sulfonyl,
Neighboring two R 1 attached to a carbon atom which is not together form a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene or,
Each R 2 is independently
Hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, pentahalogenothio, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted Substituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Rubonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl Substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic compound Ring oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or substituted or unsubstituted non-aromatic heterocyclic A ring sulfonyl,
R 1 and R 2 bonded to the same carbon atom, together with the carbon atom, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
Or
R 1 and R 2 bonded to the same carbon atom are combined to form oxo, substituted or unsubstituted alkylimino, substituted or unsubstituted alkenylimino, substituted or unsubstituted alkynylimino, substituted or unsubstituted alkylcarbonyl Imino, substituted or unsubstituted alkenylcarbonylimino, substituted or unsubstituted alkynylcarbonylimino, substituted or unsubstituted alkyloxyimino, substituted or unsubstituted alkenyloxyimino, substituted or unsubstituted alkynyloxyimino, or substituted or Forming unsubstituted methylidene,
G is a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or formula (I-G1):
Figure JPOXMLDOC01-appb-C000011
(Where
For R 3 and R 4 ,
a) R 3 and R 4 together with adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, or
b) R 3 and R 4 together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
X ′ is halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy, substituted or Unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynyl Sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted Alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic A group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, Replacement or non- Substituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic carbocyclic alkyloxy, substituted or unsubstituted Aromatic heterocyclic alkyloxy, substituted or unsubstituted non-aromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic Heterocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or Unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl or substituted or unsubstituted non-aromatic heterocyclic sulfonyl. )
A group represented by
n is an integer of 2 to 5.
However,
When the carbocyclic group of G is phenyl,
i) The phenyl group is substituted with at least one or more substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl, or substituted or unsubstituted heterocyclic alkyl The phenyl may be further substituted, and / or ii) an aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic ring in which at least one meta position of the phenyl group is substituted or unsubstituted. Substituted with oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy, the phenyl group may be further substituted, and
The following compounds (A-1) to (A-34) are excluded.
Figure JPOXMLDOC01-appb-C000012

Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
Or a pharmaceutically acceptable salt thereof.
（項目２）Ｇが式（Ｉ－Ｇ１）：
Figure JPOXMLDOC01-appb-C000015
（式中、各記号は前記と同意義である。）で示される基
または式（Ｉ－Ｇ２）：
Figure JPOXMLDOC01-appb-C000016
（式中、
Ｙは炭素環または複素環であり、ｍは０～５であり、
Ｘはそれぞれ独立してハロゲン、ヒドロキシ、カルボキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである。）で示される基である、項目１記載の化合物またはその製薬上許容される塩。 (Item 2) G is the formula (I-G1):
Figure JPOXMLDOC01-appb-C000015
Wherein each symbol is as defined above, or a group represented by formula (IG2):
Figure JPOXMLDOC01-appb-C000016
(Where
Y is a carbocyclic or heterocyclic ring, m is 0-5,
X is independently halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamino Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Lucenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted Substituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic group, substituted Or an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic alkyl, Or unsubstituted non-aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted Non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic Carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted nonaromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted nonaromatic Carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic Heterocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, or substituted or unsubstituted non-aromatic heterocyclic sulfonyl. Or a pharmaceutically acceptable salt thereof.
（項目３）Ｇが式（Ｉ－Ｇ２）で示される基である、項目１記載の化合物またはその製薬上許容される塩。
（項目４）Ｙが複素環である、項目３記載の化合物またはその製薬上許容される塩。
（項目５）ｎが２または３である、項目１～４のいずれかに記載の化合物またはその製薬上許容される塩。
（項目６）ｎが３である、項目５記載の化合物またはその製薬上許容される塩。
（項目７）式：
Figure JPOXMLDOC01-appb-C000017
が、式：
Figure JPOXMLDOC01-appb-C000018
（式中、各定義は前記と同意義である。）
である、項目５記載の化合物またはその製薬上許容される塩。 (Item 3) The compound according to item 1, or a pharmaceutically acceptable salt thereof, wherein G is a group represented by the formula (IG2).
(Item 4) The compound according to item 3 or a pharmaceutically acceptable salt thereof, wherein Y is a heterocyclic ring.
(Item 5) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 4, wherein n is 2 or 3.
(Item 6) The compound according to item 5 or a pharmaceutically acceptable salt thereof, wherein n is 3.
(Item 7) Formula:
Figure JPOXMLDOC01-appb-C000017
But the formula:
Figure JPOXMLDOC01-appb-C000018
(In the formula, each definition is as defined above.)
6. The compound according to item 5, or a pharmaceutically acceptable salt thereof.
（項目８）Ｒ１がそれぞれ独立して、水素原子、ハロゲン、シアノ、置換もしくは非置換のアルキルであるか、隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレンを形成するか、Ｒ２がそれぞれ独立して、水素原子、ハロゲン、シアノ、置換もしくは非置換のアルキルであるか、同一炭素原子に結合するＲ１およびＲ２が隣接する原子と一緒になって置換もしくは非置換のシクロアルカンを形成するか、
または、同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソまたは置換もしくは非置換のメチリデンである、項目１～７のいずれかに記載の化合物またはその製薬上許容される塩。 (Item 8) Each R 1 is independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or two R 1 bonded to non-adjacent carbon atoms are combined to be substituted or unsubstituted. Each of R 2 is independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or R 1 and R 2 bonded to the same carbon atom together with adjacent atoms To form a substituted or unsubstituted cycloalkane,
Or the compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 7, wherein R 1 and R 2 bonded to the same carbon atom are together oxo or substituted or unsubstituted methylidene.
（項目９）Ｘがそれぞれ独立して、ハロゲン、シアノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換のもしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、または置換もしくは非置換の非芳香族複素環アルキルオキシである、項目２～８のいずれかに記載の化合物またはその製薬上許容される塩。 (Item 9) X is independently halogen, cyano, acyl, acyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aromatic carbocyclic alkyl, substituted or unsubstituted non-aromatic carbocyclic alkyl Substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic carbocyclic alkyloxy, substituted or unsubstituted Item 9. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 2 to 8, which is an aromatic heterocyclic alkyloxy, or a substituted or unsubstituted non-aromatic heterocyclic alkyloxy.
（項目１０）Ｘがそれぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換のもしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシであり、ｍが１または２である、項目２～８のいずれかに記載の化合物またはその製薬上許容される塩。 (Item 10) X is independently halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted aromatic carbocyclic group, Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or an unsubstituted aromatic carbocyclic alkyloxy, or a substituted or unsubstituted aromatic heterocyclic alkyloxy, and m is 1 or Is 2, the compound or a pharmaceutically acceptable salt thereof according to any of items 2-8.
（項目１１）Ｙが芳香族炭素環であり、ｍが２であり、Ｘがそれぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキル、置換もしくは非置換の複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシである、項目２、３、および５～１０のいずれかに記載の化合物またはその製薬上許容される塩。
（項目１２）
化合物Ｉ－０００４、Ｉ－００３４、Ｉ－００８４、Ｉ－０１５９、Ｉ－０１８３、Ｉ－０２５１、Ｉ－０３３２、Ｉ－０３５５、Ｉ－０３７６、Ｉ－０３８２、Ｉ－０４７４、Ｉ－０４７８、Ｉ－０６０９、Ｉ－０６１６、Ｉ－０６５０、Ｉ－０８２９、Ｉ－０８３０、Ｉ－０８４２、Ｉ－０８４５、Ｉ－０８５６、Ｉ－０８７４、Ｉ－０８９４、Ｉ－０９１１、Ｉ－０９３２、Ｉ－０９３７、Ｉ－０９５８、およびＩ－１０５２から選択される、項目１記載の化合物、またはその製薬上許容される塩。 (Item 11) Y is an aromatic carbocycle, m is 2, X is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic The compound according to any one of Items 2, 3, and 5 to 10, wherein the compound is an aromatic heterocyclic oxy, a substituted or unsubstituted aromatic carbocyclic alkyloxy, or a substituted or unsubstituted aromatic heterocyclic alkyloxy, or a compound thereof Pharmaceutically acceptable salt.
(Item 12)
Compounds I-0004, I-0034, I-0084, I-0159, I-0183, I-0251, I-0332, I-0355, I-0376, I-0382, I-0474, I-0478, I -0609, I-0616, I-0650, I-0929, I-0830, I-0842, I-0845, I-0856, I-0874, I-0894, I-0911, I-0932, I-0937 , I-0958, and I-1052, or a pharmaceutically acceptable salt thereof.
（項目１３）
項目１～１２のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
（項目１４）
抗真菌作用を有する、項目１３記載の医薬組成物。
（項目１５）
項目１～１２のいずれかに記載の化合物、またはその製薬上許容される塩を投与することを特徴とする、真菌感染に関連する疾患の治療またはその予防方法。
（項目１６）
真菌感染に関連する疾患を治療または予防するための、項目１～１２のいずれかに記載の化合物、またはその製薬上許容される塩。 (Item 13)
13. A pharmaceutical composition comprising the compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof.
(Item 14)
14. The pharmaceutical composition according to item 13, which has an antifungal action.
(Item 15)
A method for treating or preventing a disease associated with a fungal infection, which comprises administering the compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof.
(Item 16)
13. The compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease associated with a fungal infection.
（項目１０１）項目１～１０のいずれかに記載の化合物、またはその製薬上許容される塩を含有する、経口投与のための医薬組成物。
（項目１０２）錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤またはチンキ剤である、（項目１０１）記載の医薬組成物。
（項目１０３）糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠、口腔内崩壊錠、ドライシロップ、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤である、（項目１０２）記載の医薬組成物。
（項目１０４）項目１～１０のいずれかに記載の化合物、またはその製薬上許容される塩を含有する、非経口投与のための医薬組成物。
（項目１０５）経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳または膣内投与のための、（項目１０４）記載の医薬組成物。
（項目１０６）注射剤、点滴剤、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤または坐剤である、（項目１０４）または（項目１０５）記載の医薬組成物。
（項目１０７）項目１～１０のいずれかに記載の化合物、またはその製薬上許容される塩を含有する、小児用または高齢者用の医薬組成物。
（項目１０８）項目１～１０のいずれかに記載の化合物、またはその製薬上許容される塩と、ポリエン系化合物、ファンギン系化合物およびアゾール系化合物から選択される1つ以上の化合物との組み合わせからなる医薬組成物。
（項目１０９）項目１～１０のいずれかに記載の化合物、またはその製薬上許容される塩を含有する、ポリエン系化合物、１，３－βグルカンシンテース阻害剤またはエルゴステロール生合成阻害剤との併用療法のための医薬組成物。 (Item 101) A pharmaceutical composition for oral administration, comprising the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.
(Item 102) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, aromatic liquids, extracts, decoctions or tinctures The pharmaceutical composition according to (Item 101).
(Item 103) Sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, troche tablet, sublingual tablet, buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup, soft capsule, microcapsule or sustained-release capsule The pharmaceutical composition according to (Item 102), which is an agent.
(Item 104) A pharmaceutical composition for parenteral administration, comprising the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.
(Item 105) The pharmaceutical composition according to (Item 104), for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration .
(Item 106) Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellys The pharmaceutical composition according to (Item 104) or (Item 105), which is a cream, a patch, a patch, a powder for external use or a suppository.
(Item 107) A pharmaceutical composition for children or the elderly, comprising the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.
(Item 108) From a combination of the compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more compounds selected from a polyene compound, a fungine compound and an azole compound A pharmaceutical composition.
(Item 109) A polyene compound, a 1,3-β-glucan synthase inhibitor or an ergosterol biosynthesis inhibitor containing the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof A pharmaceutical composition for combination therapy.
　式（Ｉ）で示される化合物またはその製薬上許容される塩は、カンジダ属菌、アスペルギルス属菌または白癬属菌等に対して優れた抗真菌活性を有し、抗真菌剤として有用である。また、別の態様では、式（Ｉ）で示される化合物または製薬上許容される塩は、安全性、体内動態、溶解度、安定性等にも優れており医薬品として有用である。 The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has excellent antifungal activity against Candida, Aspergillus, or ringworm, and is useful as an antifungal agent. In another embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt is also excellent in safety, pharmacokinetics, solubility, stability, etc., and is useful as a pharmaceutical product.
　以下、本発明の実施の形態を説明する。本明細書の全体にわたり、単数形の表現（例えば、英語の場合は、「ａ」、「ａｎ」、「ｔｈｅ」など、他の言語において対応する冠詞、形容詞など）は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。また、本明細書において使用される用語は、特に言及しない限り、当該分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限り、本明細書中で使用されるすべての専門用語および化学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。以下に、本明細書において具体的に使用される用語について具体的な定義を記載する。
「からなる」という用語は、構成要件のみを有することを意味する。
「含む」という用語は、構成要件に限定されず、記載されていない要素を排除しないことを意味する。 Embodiments of the present invention will be described below. Throughout this specification, singular forms (e.g., “a”, “an”, “the” in the case of English, corresponding articles, adjectives, etc. in other languages) unless otherwise stated, It should be understood to include the plural concept. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and chemical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Hereinafter, specific definitions of terms specifically used in the present specification will be described.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.
　本明細書における各用語は、特に断りのない限り、単独または他の用語を組み合わされて、以下の通り定義される。 Unless otherwise specified, each term in the present specification is defined as follows, alone or in combination with other terms.
　「ハロゲン」とは、フッ素、塩素、臭素またはヨウ素を意味する。好ましくは、フッ素または塩素である。 “Halogen” means fluorine, chlorine, bromine or iodine. Preferred is fluorine or chlorine.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の炭素水素来を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－ヘプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デニル等が挙げられる。 “Alkyl” includes linear or branched carbon hydrogen atoms having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, Examples include isooctyl, n-nonyl, n-denyl and the like.
　「アルキル」の好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 Preferred examples of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖または分枝状の炭化水素来を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 “Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Including linear or branched hydrocarbons. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.
「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。さらに任意の位置に二重結合を有していてもよい。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。
「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
　「アルキレン」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の２価の炭化水素基を包含する。例えば、メチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、ペンタメチレン、ヘキサメチレン等が挙げられる。 “Alkylene” is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
　「アルケニレン」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の２価の炭化水素基を包含する。例えば、ビニレン、プロペニレン、ブテニレン、ペンテニレン等が挙げられる。 The term “alkenylene” refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group. For example, vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
　「アルキニレン」とは、任意の位置に１以上の三重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の２価の炭化水素基を包含する。さらに任意の位置に二重結合を有していてもよい。例えば、エチニレン、プロピニレン、ブチニレン、ペンチニレン、ヘキシニレン等が挙げられる。 “Alkynylene” refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position. A linear or branched divalent hydrocarbon group is included. Furthermore, you may have a double bond in arbitrary positions. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.
「芳香族炭素環式基」とは、単環または２環以上の環状芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
「芳香族炭素環式基」の好ましい態様として、フェニルが挙げられる。 “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の「非芳香族炭素環式基」は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000019
単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは、炭素数３～１２、さらに好ましくは炭素数３～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
２環以上の非芳香族炭素環式基としては、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000019
The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, still more preferably 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
「非芳香族炭素環」とは、上記「非芳香族炭素環式基」から導かれる環を意味する。 The “non-aromatic carbocycle” means a ring derived from the above “non-aromatic carbocyclic group”.
「シクロアルキル」とは、環状飽和炭化水素基を意味し、炭素数３～１６が好ましく、より好ましくは、炭素数３～１２、さらにこの好ましくは炭素数３～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル等が挙げられる。
「シクロアルキル」の好ましい態様としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルが挙げられる。 “Cycloalkyl” means a cyclic saturated hydrocarbon group, preferably having 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like can be mentioned.
Preferable embodiments of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
「シクロアルカン」とは、上記「シクロアルキル」から導かれる環を意味する。 “Cycloalkane” means a ring derived from the above “cycloalkyl”.
「炭素環式基」とは、上記「芳香族炭素環式基」および「非芳香族炭素環式基」を包含する。
「炭素環」とは、上記「炭素環式基」から導かれる環を意味する。 The “carbocyclic group” includes the above “aromatic carbocyclic group” and “non-aromatic carbocyclic group”.
“Carbocycle” means a ring derived from the above “carbocyclic group”.
「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。例えば、５員の単環の芳香族複素環式基としては、ピロリル、イミダゾリル、ピラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられ、６員の単環の芳香族複素環式基としては、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル等が挙げられる。
２環の芳香族複素環式基としては、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。
３環以上の芳香族複素環式基としては、例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do. The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. For example, the 5-membered monocyclic aromatic heterocyclic group includes pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like, and includes a 6-membered monocyclic aromatic group. Examples of group heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
Examples of the bicyclic aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
Examples of the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
「芳香族複素環」とは、上記「芳香族複素環式基」から導かれる環を意味する。 “Aromatic heterocycle” means a ring derived from the above “aromatic heterocyclic group”.
「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、環状非芳香族環式基を意味する。２環以上の非芳香族複素環式基は、単環または２環以上の非芳香族複素環式基に、上記「芳香族炭素環式基」、「非芳香族炭素環式基」、および／または「芳香族複素環式基」におけるそれぞれの環が縮合したものも包含する。
さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000020
単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジニル、ピペラジニル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル、アゼパン-1-イル等が挙げられる。
２環以上の非芳香族複素環式基としては、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル、オクタヒドロ－7H-ピラノ[2,3－c]ピリジン－7－イル、ヘキサヒドロ－2H－ピラノ[3,2－c]ピリジン-6(5H)-イル、7,8-ジヒドロピリド[4,3－d]ピリミジン-6(5H)－イル等が挙げられる。 “Non-aromatic heterocyclic group” means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group. The non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000020
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyryl, Thiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thiynyl, thiazinyl Azepan-1-yl and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include, for example, indolinyl, isoindolinyl, chromanyl, isochromanyl, octahydro-7H-pyrano [2,3-c] pyridin-7-yl, hexahydro-2H-pyrano [3, 2-c] pyridin-6 (5H) -yl, 7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl, and the like.
「非芳香族複素環」とは、上記「非芳香族複素環式基」から導かれる環を意味する。 The “non-aromatic heterocyclic ring” means a ring derived from the above “non-aromatic heterocyclic group”.
「複素環式基」とは、上記「芳香族複素環式基」および「非芳香族複素環式基」を包含する。 The “heterocyclic group” includes the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”.
「複素環」とは、上記「複素環式基」から導かれる環を意味する。 “Heterocycle” means a ring derived from the above “heterocyclic group”.
「アシル」とは、ホルミルおよび置換基を有するカルボニルを意味する。
「置換基を有するカルボニル」とは、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル等が挙げられる。 “Acyl” means formyl and substituted carbonyl.
“Substituted carbonyl” means substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl and the like can be mentioned.
「アルキルカルボニル」とは、上記「アルキル」がカルボニル基に結合した基を意味する。例えば、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ｔｅｒｔ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ペンチルカルボニル、イソペンチルカルボニル、へキシルカルボニル等が挙げられる。 “Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
　「アルキルカルボニル」の好ましい態様として、メチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニルが挙げられる。 Preferred examples of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
　「アルケニルカルボニル」とは、上記「アルケニル」がカルボニル基に結合した基を意味する。例えば、エチレニルカルボニル、プロペニルカルボニル等が挙げられる。 “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
　「アルキニルカルボニル」とは、上記「アルキニル」がカルボニル基に結合した基を意味する。例えば、エチニルカルボニル、プロピニルカルボニル等が挙げられる。 “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
「ヒドロキシアルキル」とは、１以上のヒドロキシ基が、上記「アルキル」の炭素原子に結合している水素原子と置き換わった基を意味する。例えば、ヒドロキシメチル、１－ヒドロキシエチル、２－ヒドロキシエチル、１－ヒドロキシプロピル、２－ヒドロキシプロピル、１，２－ヒドロキシエチル等が挙げられる。
「ヒドロキシアルキル」の好ましい態様として、ヒドロキシメチルが挙げられる。 “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
「アルキルオキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。例えば、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｎ－ブチルオキシ、ｔｅｒｔ－ブチルオキシ、イソブチルオキシ、ｓｅｃ－ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、ヘキシルオキシ等が挙げられる。
「アルキルオキシ」の好ましい態様として、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ヘキシルオキシ等が挙げられる。 “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, hexyloxy and the like.
「アルケニルオキシ」とは、上記「アルケニル」が酸素原子に結合した基を意味する。例えば、ビニルオキシ、アリルオキシ、１－プロペニルオキシ、２－ブテニルオキシ、２－ペンテニルオキシ、２－ヘキセニルオキシ、２－ヘプテニルオキシ、２－オクテニルオキシ等が挙げられる。 “Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
「アルキニルオキシ」とは、上記「アルキニル」が酸素原子に結合した基を意味する。
例えば、エチニルオキシ、１－プロピニルオキシ、２－プロピニルオキシ、２－ブチニルオキシ、２－ペンチニルオキシ、２－ヘキシニルオキシ、２－ヘプチニルオキシ、２－オクチニルオキシ等が挙げられる。 “Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
「ハロアルキル」とは、１以上の上記「ハロゲン」が上記「アルキル」に結合した基を意味する。例えば、モノフルオロメチル、モノフルオロエチル、モノフルオロプロピル、２，２，３，３，３－ペンタフルオロプロピル、モノクロロメチル、トリフルオロメチル、トリクロロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、１，２－ジブロモエチル、１，１，１－トリフルオロプロパン－２－イル等が挙げられる。
「ハロアルキル」の好ましい態様として、トリフルオロメチル、トリクロロメチルが挙げられる。 “Haloalkyl” means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
「ハロアルキルオキシ」とは、上記「ハロアルキル」が酸素原子に結合した基を意味する。例えば、モノフルオロメトキシ、モノフルオロエトキシ、トリフルオロメトキシ、トリクロロメトキシ、トリフルオロエトキシ、トリクロロエトキシ等が挙げられる。
「ハロアルキルオキシ」の好ましい態様として、トリフルオロメトキシ、トリクロロメトキシ等が挙げられる。 “Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Preferable embodiments of “haloalkyloxy” include trifluoromethoxy, trichloromethoxy and the like.
「アシルオキシ」とは、ホルミルオキシおよび置換基を有するカルボニルオキシを意味する。「置換基を有するカルボニルオキシ」とは、上記「置換基を有するカルボニル」が酸素原子に結合した基を意味する。例えば、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ等が挙げられる。 “Acyloxy” means formyloxy and carbonyloxy having a substituent. “Carbonyloxy having a substituent” means a group in which the above “carbonyl having a substituent” is bonded to an oxygen atom. For example, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted nonaromatic carbon Ring carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy and the like.
「アルキルカルボニルオキシ」とは、上記「アルキルカルボニル」が酸素原子に結合した基を意味する。例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ、イソブチルカルボニルオキシ、ｓｅｃ－ブチルカルボニルオキシ等が挙げられる。
「アルキルカルボニルオキシ」の好ましい態様としては、メチルカルボニルオキシ、エチルカルボニルオキシが挙げられる。 “Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. For example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
「アルケニルカルボニルオキシ」とは、上記「アルケニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチレニルカルボニルオキシ、プロペニルカルボニルオキシ等が挙げられる。 “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
「アルキニルカルボニルオキシ」とは、上記「アルキニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチニルカルボニルオキシ、プロピニルカルボニルオキシ等が挙げられる。 “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
「アルキルオキシアルキル」とは、上記「アルキルオキシ」が上記「アルキル」に結合した基を意味する。例えば、メトキシメチル、メトキシエチル、エトキシメチル等が挙げられる。 “Alkyloxyalkyl” means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
「アルキルオキシアルキルオキシ」とは、上記「アルキルオキシ」が上記「アルキルオキシ」に結合した基を意味する。例えば、メトキシメトキシ、メトキシエトキシ、エトキシメトキシ、エトキシエトキシ等が挙げられる。 “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
　「アルキルスルホニル」とは、上記「アルキル」がスルホニル基に結合した基を意味する。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ｔｅｒｔ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル等が挙げられる。
「アルキルスルホニル」の好ましい態様として、メチルスルホニル、エチルスルホニル等が挙げられる。 “Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Preferable embodiments of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like.
　「アルケニルスルホニル」とは、上記「アルケニル」がスルホニル基に結合した基を意味する。例えば、エチレニルスルホニル、プロペニルスルホニル等が挙げられる。 “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
　「アルキニルスルホニル」とは、上記「アルキニル」がスルホニル基に結合した基を意味する。例えば、エチニルスルホニル、プロピニルスルホニル等が挙げられる。 “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
　「モノアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルボニルアミノ、エチルカルボニルアミノ、プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ｔｅｒｔ－ブチルカルボニルアミノ、イソブチルカルボニルアミノ、ｓｅｃ－ブチルカルボニルアミノ等が挙げられる。 “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
　「モノアルキルカルボニルアミノ」の好ましい態様としては、メチルカルボニルアミノ、エチルカルボニルアミノが挙げられる。 Preferred embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
　「ジアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルカルボニル基は、同一でも異なっていてもよい。例えば、ジメチルカルボニルアミノ、ジエチルカルボニルアミノ、Ｎ，Ｎ－ジイソプロピルカルボニルアミノ等が挙げられる。 “Dialkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
　「ジアルキルカルボニルアミノ」の好ましい態様として、ジメチルカルボニルアミノ、ジエチルカルボニルアミノが挙げられる。 Preferred examples of “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
　「モノアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｓｅｃ－ブチルスルホニルアミノ等が挙げられる。 “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
　「モノアルキルスルホニルアミノ」の好ましい態様としては、メチルスルホニルアミノ、エチルスルホニルアミノが挙げられる。 Preferred embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
　「ジアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルスルホニル基は、同一でも異なっていてもよい。例えば、ジメチルスルホニルアミノ、ジエチルスルホニルアミノ、Ｎ，Ｎ－ジイソプロピルスルホニルアミノ等が挙げられる。 “Dialkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
　「ジアルキルカルボニルアミノ」の好ましい態様として、ジメチルスルホニルアミノ、ジエチルスルホニルアミノが挙げられる。 Preferred examples of “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
　「アルキルイミノ」とは、上記「アルキル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルイミノ、エチルイミノ、ｎ－プロピルイミノ、イソプロピルイミノ等が挙げられる。 “Alkylimino” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
　「アルケニルイミノ」とは、上記「アルケニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルイミノ、プロペニルイミノ等が挙げられる。 “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
　「アルキニルイミノ」とは、上記「アルキニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルイミノ、プロピニルイミノ等が挙げられる。 “Alkynylimino” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.
　「アルキルカルボニルイミノ」とは、上記「アルキルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えばメチルカルボニルイミノ、エチルカルボニルイミノ、ｎ－プロピルカルボニルイミノ、イソプロピルカルボニルイミノ等が挙げられる。 “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
　「アルケニルカルボニルイミノ」とは、上記「アルケニルカルボニル」がイミノ基の窒素原子と結合している水素原子を置き換わった基を意味する。例えば、エチレニルカルボニルイミノ、プロペニルカルボニルイミノ等が挙げられる。 “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” replaces the hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
「アルキニルカルボニルイミノ」とは、上記「アルキニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルカルボニルイミノ、プロピニルカルボニルイミノ等が挙げられる。 “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
「アルキルオキシイミノ」とは、上記「アルキルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルオキシイミノ、エチルオキシイミノ、ｎ－プロピルオキシイミノ、イソプロピルオキシイミノ等が挙げられる。 “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
「アルケニルオキシイミノ」とは、上記「アルケニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルオキシイミノ、プロペニルオキシイミノ等が挙げられる。 “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
「アルキニルオキシイミノ」とは、上記「アルキニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルオキシイミノ、プロピニルオキシイミノ等が挙げられる。 “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.
「アルキルオキシカルボニル」とは、上記「アルキルオキシ」がカルボニル基に結合した基を意味する。例えば、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル、イソブチルオキシカルボニル、ｓｅｃ－ブチルオキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、ヘキシルオキシカルボニル等が挙げられる。
「アルキルオキシカルボニル」の好ましい態様としては、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニルが挙げられる。 “Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like. .
Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
「アルケニルオキシカルボニル」とは、上記「アルケニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチレニルオキシカルボニル、プロペニルオキシカルボニル等が挙げられる。 “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
「アルキニルオキシカルボニル」とは、上記「アルキニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル等が挙げられる。 “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
「アルキルスルファニル」とは、上記「アルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル等が挙げられる。「アルキルスルファニル」の好ましい態様として、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル、ヘキシルスルファニル等が挙げられる。 “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned. Preferable embodiments of “alkylsulfanyl” include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, hexylsulfanyl and the like.
「アルケニルスルファニル」とは、上記「アルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルスルファニル、プロペニルスルファニル等が挙げられる。 “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
「アルキニルスルファニル」とは、上記「アルキニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルスルファニル、プロピニルスルファニル等が挙げられる。 “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
「ハロアルキルスルファニル」とは、上記「ハロアルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、モノフルオロメチルスルファニル、モノフルオロエチルスルファニル、トリフルオロメチルスルファニル、トリクロロメチルスルファニル、トリフルオロエチルスルファニル、トリクロロエチルスルファニル等が挙げられる。
「ハロアルキルスルファニル」の好ましい態様として、トリフルオロメチルスルファニル、トリクロロメチルスルファニル等が挙げられる。 “Haloalkylsulfanyl” means a group in which the above “haloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like can be mentioned.
Preferable embodiments of “haloalkylsulfanyl” include trifluoromethylsulfanyl, trichloromethylsulfanyl and the like.
「アルキルスルフィニル」とは、上記「アルキル」がスルフィニル気に結合した基を意味する。例えば、メチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル等が挙げられる。 “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
「アルケニルスルフィニル」とは、上記「アルケニル」がスルフィニル基に結合した基を意味する。例えば、エチレニルスルフィニル、プロペニルスルフィニル等が挙げられる。 “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
「アルキニルスルフィニル」とは、上記「アルキニル」がスルフィニル基に結合した基を意味する。例えば、エチニルスルフィニル、プロピニルスルフィニル等が挙げられる。 “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
「モノアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子の1個と置き換わった基を意味する。例えば、メチルカルバモイル、エチルカルバモイル等が挙げられる。 “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one of the hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
「ジアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子の2個と置き換わった基を意味する。2個のアルキル基は、同一でも異なっていても良い。例えば、ジメチルカルバモイル、エチルメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two of the hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. For example, dimethylcarbamoyl, ethylmethylcarbamoyl, diethylcarbamoyl and the like can be mentioned.
「モノアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子1個と置き換わった基を意味する。例えば、メチルスルファモイル、エチルスルファモイル等が挙げられる。 “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include methylsulfamoyl and ethylsulfamoyl.
「ジアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子2個と置き換わった基を意味する。2個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルスルファモイル、ジエチルスルファモイル等が挙げられる。 “Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. The two alkyl groups may be the same or different. Examples thereof include dimethylsulfamoyl and diethylsulfamoyl.
「トリアルキルシリル」とは、上記「アルキル」3個がケイ素原子に結合している基を意味する。3個のアルキル基は同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル等が挙げれれる。 “Trialkylsilyl” means a group in which three of the above “alkyl” are bonded to a silicon atom. The three alkyl groups may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
「ペンタハロゲノチオ」とは、上記「ハロゲン」５個が硫黄原子の結合している基を意味する。５個のハロゲンは同一でも異なっていても良い。該ハロゲンはフッ素または塩素が好ましい。例えば、ペンタフルオロチオ（－ＳＦ５）、モノクロロテトラフルオロチオ（－ＳＣｌＦ４）等が挙げられる。 “Pentahalogenothio” means a group in which the five “halogens” are bonded to a sulfur atom. The five halogens may be the same or different. The halogen is preferably fluorine or chlorine. For example, pentafluorothio (—SF 5 ), monochlorotetrafluorothio (—SCF 4 ) and the like can be mentioned.
「炭素環アルキル」、「芳香族炭素環アルキル」、「非芳香族炭素環アルキル」、「複素環アルキル」、「芳香族複素環アルキル」、「非芳香族複素環アルキル」、「炭素環アルキルオキシ」、「芳香族炭素環アルキルオキシ」、「非芳香族炭素環アルキルオキシ」、「複素環アルキルオキシ」、「芳香族複素環アルキルオキシ」、「非芳香族複素環アルキルオキシ」、「炭素環アルキルオキシカルボニル」、「芳香族炭素環アルキルオキシカルボニル」、「非芳香族炭素環アルキルオキシカルボニル」、「複素環アルキルオキシカルボニル」、「芳香族複素環オキシカルボニル」、「非芳香族複素環オキシカルボニル」、「炭素環アルキルオキシアルキル」、「芳香族炭素環アルキルオキシアルキル」、「非芳香族炭素環アルキルオキシアルキル」、「複素環アルキルオキシアルキル」、「芳香族複素環アルキルオキシアルキル」、「非芳香族複素環アルキルオキシアルキル」、「炭素環アルキルアミノ」、「芳香族炭素環アルキルアミノ」、「非芳香族炭素環アルキルアミノ」、「複素環アルキルアミノ」、「芳香族複素環アルキルアミノ」、および「非芳香族複素環アルキルアミノ」のアルキル部分も、上記「アルキル」と同様である。 “Carbocyclic alkyl”, “Aromatic carbocyclic alkyl”, “Non-aromatic carbocyclic alkyl”, “Heterocyclic alkyl”, “Aromatic heterocyclic alkyl”, “Non-aromatic heterocyclic alkyl”, “Carbocyclic alkyl” "Oxy", "aromatic carbocyclic alkyloxy", "non-aromatic carbocyclic alkyloxy", "heterocyclic alkyloxy", "aromatic heterocyclic alkyloxy", "non-aromatic heterocyclic alkyloxy", "carbon" Ring alkyloxycarbonyl "," aromatic carbocyclic alkyloxycarbonyl "," non-aromatic carbocyclic alkyloxycarbonyl "," heterocyclic alkyloxycarbonyl "," aromatic heterocyclic oxycarbonyl "," non-aromatic heterocyclic " "Oxycarbonyl", "carbocyclic alkyloxyalkyl", "aromatic carbocyclic alkyloxyalkyl", "non-aromatic carbocyclic alkyloxya" "Kil", "heterocyclic alkyloxyalkyl", "aromatic heterocyclic alkyloxyalkyl", "non-aromatic heterocyclic alkyloxyalkyl", "carbocyclic alkylamino", "aromatic carbocyclic alkylamino", "non The alkyl part of “aromatic carbocyclic alkylamino”, “heterocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “non-aromatic heterocyclic alkylamino” is the same as the above “alkyl”.
「芳香族炭素環アルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルを意味する。例えば、ベンジル、フェネチル、フェニルプロピル、ベンズヒドリル、トリチル、ナフチルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000021
等が挙げられる。
「芳香族炭素環アルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリル等が挙げられる。 “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below:
Figure JPOXMLDOC01-appb-C000021
Etc.
Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl, benzhydryl and the like.
「非芳香族炭素環アルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルを意味する。また、「非芳香族炭素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキル」も包含する。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000022
等が挙げられる。 “Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below:
Figure JPOXMLDOC01-appb-C000022
Etc.
「炭素環アルキル」とは、「芳香族炭素環アルキル」および「非芳香族炭素環アルキル」を包含する。「炭素環アルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリル、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000023
等が挙げられる。 “Carbocyclic alkyl” includes “aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyl”. Preferable embodiments of “carbocycle alkyl” include benzyl, phenethyl, benzhydryl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups shown below:
Figure JPOXMLDOC01-appb-C000023
Etc.
「芳香族複素環アルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルを意味する。また、「芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキル」も包含する。例えば、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000024
等が挙げられる。 “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
Figure JPOXMLDOC01-appb-C000024
Etc.
「非芳香族複素環アルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルを意味する。また、「非芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキル」も包含する。例えば、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000025
等が挙げられる。 “Non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000025
Etc.
「複素環アルキル」とは、「芳香族複素環アルキル」および「非芳香族複素環アルキル」を包含する。「複素環アルキル」の好ましい態様としては、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000026
等が挙げられる。 “Heterocyclic alkyl” includes “aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyl”. Preferred embodiments of “heterocyclic alkyl” include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, iso Pyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below:
Figure JPOXMLDOC01-appb-C000026
Etc.
「芳香族炭素環アルキルオキシ」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシを意味する。例えば、ベンジルオキシ、フェネチルオキシ、フェニルプロピルオキシ、ベンズヒドリルオキシ、トリチルオキシ、ナフチルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000027
等が挙げられる。 “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below:
Figure JPOXMLDOC01-appb-C000027
Etc.
　「非芳香族炭素環アルキルオキシ」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族炭素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロヘキシルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000028
等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below:
Figure JPOXMLDOC01-appb-C000028
Etc.
　「芳香族複素環アルキルオキシ」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシ」も包含する。例えば、ピリジルメチルオキシ、不らニルメチルオキシ、イミダゾリルメチルオキシ、インドリルメチルオキシ、ベンゾチオフェニルメチルオキシ、イソチアゾリルメチルオキシ、ピラゾリルメチルオキシ、イソピラゾリルメチルオキシ、ピロリジニルメチルオキシ、ベンズオキサゾリルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000029
等が挙げられる。 “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, nonylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxa Zolylmethyloxy, the group shown below:
Figure JPOXMLDOC01-appb-C000029
Etc.
　「非芳香族複素環アルキルオキシ」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシ」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000030
等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below:
Figure JPOXMLDOC01-appb-C000030
Etc.
　「芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル、フェニルプロピルオキシカルボニル、ベンズヒドリルオキシカルボニル、トリチルオキシカルボニル、ナフチルメチルオキシカルボニル、以下に示される基：
Figure JPOXMLDOC01-appb-C000031
等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below:
Figure JPOXMLDOC01-appb-C000031
Etc.
　「非芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族炭素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシカルボニル」も包含する。例えば、シクロプロピルメチルオキシカルボニル、シクロブチルメチルオキシカルボニル、シクロペンチルメチルオキシカルボニル、シクロヘキシルメチルオキシカルボニル、以下に示される基：
Figure JPOXMLDOC01-appb-C000032
等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below:
Figure JPOXMLDOC01-appb-C000032
Etc.
　「芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシカルボニル」も包含する。例えば、ピリジルメチルオキシカルボニル、フラニルメチルオキシカルボニル、イミダゾリルメチルオキシカルボニル、インドリルメチルオキシカルボニル、ベンゾチオフェニルメチルオキシカルボニル、オキサゾリルメチルオキシカルボニル、イソキサゾリルメチルオキシカルボニル、チアゾリルメチルオキシカルボニル、イソチアゾリルメチルオキシカルボニル、ピラゾリルメチルオキシカルボニル、イソピラゾリルメチルオキシカルボニル、ピロリジニルメチルオキシカルボニル、ベンズオキサゾリルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000033
等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000033
Etc.
　「非芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシカルボニル」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000034
等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000034
Etc.
　「芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。例えば、ベンジルオキシメチル、フェネチルオキシメチル、フェニルプロピルオキシメチル、ベンズヒドリルオキシメチル、トリチルオキシメチル、ナフチルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000035
等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000035
Etc.
　「非芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族炭素環アルキルオキシアルキル」は、非芳香族炭素環が結合しているアルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシアルキル」も包含する。例えば、シクロプロピルメチルオキシメチル、シクロブチルメチルオキシメチル、シクロペンチルメチルオキシメチル、シクロへキシルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000036
等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000036
Etc.
　「芳香族複素環アルキルオキシアルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「芳香族複素環アルキルオキシアルキル」は、芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシアルキル」も包含する。例えば、ピリジルメチルオキシメチル、フラニルメチルオキシメチル、イミダゾリルメチルオキシメチル、インドリルメチルオキシメチル、ベンゾチオフェニルメチルオキシメチル、オキサゾリルメチルオキシメチル、イソキサゾリルメチルオキシメチル、チアゾリルメチルオキシメチル、イソチアゾリルメチルオキシメチル、ピラゾリルメチルオキシメチル、イソピラゾリルメチルオキシメチル、ピロリジニルメチルオキシメチル、ベンズオキサゾリルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000037
等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000037
Etc.
　「非芳香族複素環アルキルオキシアルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族複素環アルキルオキシアルキル」は、非芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシアルキル」も包含する。例えば、テトラヒドロピラニルメチルオキシメチル、モルホリニルエチルオキシメチル、ピペリジニルメチルオキシメチル、ピペラジニルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000038
等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. The “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000038
Etc.
「芳香族炭素環アルキルアミノ」とは、上記「芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ベンジルアミノ、フェネチルアミノ、フェニルプロピルアミノ、ベンズヒドリルアミノ、トリチルアミノ、ナフチルメチルアミノ、ジベンジルアミノ等が挙げられる。 “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
「非芳香族炭素環アルキルアミノ」とは、上記「非芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルメチルアミノ、シクロブチルメチルアミノ、シクロペンチルメチルアミノ、シクロヘキシルメチルアミノ等が挙げられる。 “Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
「芳香族複素環アルキルアミノ」とは、上記「芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルメチルアミノ、フラニルメチルアミノ、イミダゾリルメチルアミノ、イソオキサゾリルメチルアミノ、チアゾリルメチルアミノ、イソチアゾリルメチルアミノ、ピラゾリルメチルアミノ、イソピラゾリルメチルアミノ、ピロリジニルメチルアミノ、ベンズオキサゾリルメチルアミノ等が挙げられる。 The “aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benz And oxazolylmethylamino.
「非芳香族複素環アルキルアミノ」とは、上記「非芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子1個または2個と置き換わった基を意味する。例えば、テトラヒドロピラニルメチル、モルホリニルエチルアミノ、ピペリジニルメチルアミノ、ピペラジニルメチルアミノ等が挙げられる。 The “non-aromatic heterocyclic alkylamino” means a group in which the “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethyl, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
「芳香族炭素環オキシ」「芳香族炭素環カルボニル」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環スルファニル」、「芳香族炭素環スルフィニル」および「芳香族炭素環スルホニル」の「芳香族炭素環」部分も、上記「芳香族炭素環式基」と同様である。 "Aromatic carbocyclic oxy" "aromatic carbocyclic carbonyl", "aromatic carbocyclic oxycarbonyl", "aromatic carbocyclic sulfanyl", "aromatic carbocyclic sulfinyl" and "aromatic carbocyclic sulfonyl" The “aromatic carbocyclic” moiety is the same as the above “aromatic carbocyclic group”.
　「芳香族炭素環オキシ」とは、上記「芳香族炭素環」が酸素原子に結合した基を意味する。例えば、フェニルオキシ、ナフチルオキシ等が挙げられる。 “Aromatic carbocyclic oxy” means a group in which the above “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
　「芳香族炭素環カルボニル」とは、上記「芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、ベンゾイル、ナフチルカルボニル等が挙げられる。 “Aromatic carbocyclic carbonyl” means a group in which the above “aromatic carbocycle” is bonded to a carbonyl group. Examples include benzoyl and naphthylcarbonyl.
「芳香族炭素環オキシカルボニル」とは、「芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、フェニルオキシカルボニル、ナフチルオキシカルボニル等が挙げられる。 “Aromatic carbocyclic oxycarbonyl” means a group in which “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
「芳香族炭素環スルファニル」とは、「芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、フェニルスルファニル、ナフチルスルファニル等が挙げられる。 “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
「芳香族炭素環スルフィニル」とは、「芳香族炭素環」がスルフィニル基に結合した基を意味する。例えば、フェニルスルフィニル、ナフチルスルフィニル等が挙げられる。 “Aromatic carbocyclic sulfinyl” means a group in which an “aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
「芳香族炭素環スルホニル」とは、「芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。 “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
「非芳香族炭素環オキシ」、「非芳香族炭素環カルボニル」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環スルファニル」、「非芳香族炭素環スルフィニル」、および「非芳香族炭素環スルホニル」の「非芳香族炭素環」部分も、上記「非芳香族炭素環式基」と同様である。 “Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfinyl”, and “non-aromatic The “non-aromatic carbocyclic” portion of the “aromatic carbocyclic sulfonyl” is the same as the above “non-aromatic carbocyclic group”.
「非芳香族炭素環オキシ」とは、上記「非芳香族炭素環」が酸素原子に結合した基を意味する。例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシ、シクロプロペニルオキシ、シクロブテニルオキシ、シクロペンテニルオキシ、シクロヘキセニルオキシ、シクロヘプテニルオキシ、シクロヘキサジエニルオキシ、インダニルオキシ、テトラヒドロナフチルオキシ、フルオレニルオキシ、アダマンチルオキシ等が挙げられる。 “Non-aromatic carbocyclic oxy” means a group in which the “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclohexadienyloxy , Indanyloxy, tetrahydronaphthyloxy, fluorenyloxy, adamantyloxy and the like.
　「非芳香族炭素環カルボニル」とは、上記「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロプロペニルカルボニル、インダニルカルボニル等が挙げられる。 “Non-aromatic carbocyclic carbonyl” means a group in which the above “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclopropenylcarbonyl, indanylcarbonyl and the like can be mentioned.
「非芳香族炭素環オキシカルボニル」とは、「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロヘキセニルカルボニル等が挙げられる。 “Non-aromatic carbocyclic oxycarbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. Examples thereof include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
「非芳香族炭素環オキシカルボニル」とは、上記「非芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロピルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロヘキセニルオキシカルボニル等が挙げられる。 The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
「非芳香族炭素環スルファニル」とは、上記「非芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロピルスルファニル、シクロブチルスルファニル、シクロペンチルスルファニル、シクロヘキシルスルファニル、シクロヘプチルスルファニル、シクロオクチルスルファニル、シクロプロペニルスルファニル、シクロブテニルスルファニル、シクロペンテニルスルファニル、シクロヘキセニルスルファニル、シクロヘプテニルスルファニル、シクロヘキサジエニルスルファニル、インダニルスルファニル、テトラヒドロナフチルスルファニル、フルオレニルスルファニル、アダマンチルスルファニル等が挙げられる。 The “non-aromatic carbocyclic sulfanyl” means a group in which the “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl, cyclopropenylsulfanyl, cyclobutenylsulfanyl, cyclopentenylsulfanyl, cyclohexenylsulfanyl, cycloheptenylsulfanyl, cyclohexadienylsulfanyl , Indanylsulfanyl, tetrahydronaphthylsulfanyl, fluorenylsulfanyl, adamantylsulfanyl and the like.
「非芳香族炭素環スルフィニル」とは、上記「非芳香族炭素環」がスルフィニル基に結合した基を意味する。例えば、シクロプロピルスルフィニル、シクロブチルスルフィニル、シクロペンチルスルフィニル、シクロヘキシルスルフィニル、シクロヘプチルスルフィニル、シクロヘキセニルスルフィニル、テトラヒドロナフチルスルフィニル、アダマンチルスルフィニル等が挙げられる。 The “non-aromatic carbocyclic sulfinyl” means a group in which the “non-aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclohexenylsulfinyl, tetrahydronaphthylsulfinyl, adamantylsulfinyl and the like.
「非芳香族炭素環スルホニル」とは、上記「非芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル等が挙げられる。 The “non-aromatic carbocycle sulfonyl” means a group in which the above “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
「芳香族複素環オキシ」、「芳香族複素環カルボニル」、「芳香族複素環オキシカルボニル」、「芳香族複素環スルファニル」、「芳香族複素環スルフィニル」、および「芳香族複素環スルホニル」の「芳香族複素環」部分も、上記「芳香族複素環式基」と同様である。 “Aromatic heterocyclic oxy”, “aromatic heterocyclic carbonyl”, “aromatic heterocyclic oxycarbonyl”, “aromatic heterocyclic sulfanyl”, “aromatic heterocyclic sulfinyl”, and “aromatic heterocyclic sulfonyl” The “aromatic heterocyclic ring” moiety is the same as the above “aromatic heterocyclic group”.
　「芳香族複素環オキシ」とは、上記「芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピリジルオキシ、オキサゾリルオキシ等が挙げられる。 “Aromatic heterocycle oxy” means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
　「芳香族複素環カルボニル」とは、上記「芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピロリルカルボニル、ピラゾリルカルボニル、ピリジルカルボニル、オキサゾリルカルボニル、インドリルカルボニル等が挙げられる。 “Aromatic heterocycle carbonyl” means a group in which the above “aromatic heterocycle” is bonded to a carbonyl group. For example, pyrrolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, oxazolylcarbonyl, indolylcarbonyl and the like can be mentioned.
「芳香族複素環オキシカルボニル」とは、上記「芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピリジルオキシカルボニル、オキサゾリルオキシカルボニル等が挙げられる。 “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
「芳香族複素環スルファニル」とは、上記「芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピリジルスルファニル、オキサゾリルスルファニル等が挙げられる。 “Aromatic heterocycle sulfanyl” means a group in which the above “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
「芳香族複素環スルフィニル」とは、上記「芳香族複素環」がスルフィニル基に結合した基を意味する。例えば、ピリジルスルフィニル、オキサゾリルスルフィニル等が挙げられる。 “Aromatic heterocycle sulfinyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group. For example, pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
「芳香族複素環スルホニル」とは、上記「芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピリジルスルホニル、オキサゾリルスルホニル等が挙げられる。 “Aromatic heterocycle sulfonyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
「非芳香族複素環オキシ」、「非芳香族複素環カルボニル」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環スルファニル」、「非芳香族複素環スルフィニル」、および「非芳香族複素環スルホニル」の「非芳香族複素環」部分も、上記「非芳香族複素環式基」と同様である。 “Non-aromatic heterocyclic oxy”, “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic sulfinyl”, and “Non-aromatic” The “non-aromatic heterocyclic” part of the “aromatic heterocyclic sulfonyl” is the same as the above “non-aromatic heterocyclic group”.
　「非芳香族複素環オキシ」とは、上記「非芳香族複素環」が酸素原子に結合した基を意味する。例えば、ジオキサニルオキシ、チイラニルオキシ、オキシラニルオキシ、オキセタニルオキシ、オキサチオラニルオキシ、アゼチジニルオキシ、チアニルオキシ、チアゾリジニルオキシ、ピロリジニルオキシ、ピロリニルオキシ、イミダゾリジニルオキシ、イミダゾリニルオキシ、ピラゾリジニルオキシ、ピラゾリニルオキシ、ピペリジルオキシ、ピペラジニルオキシ、モルホリニルオキシ、インドリニルオキシ、クロマニルオキシ等が挙げられる。 “Non-aromatic heterocyclic oxy” means a group in which the above “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, dioxanyloxy, thiranyloxy, oxiranyloxy, oxetanyloxy, oxathiolanyloxy, azetidinyloxy, thianyloxy, thiazolidinyloxy, pyrrolidinyloxy, pyrrolinyloxy, imidazolidinyloxy, imidazo Examples include linyloxy, pyrazolidinyloxy, pyrazolinyloxy, piperidyloxy, piperazinyloxy, morpholinyloxy, indolinyloxy, chromanyloxy and the like.
「非芳香族複素環カルボニル」とは、上記「非芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ジオキサニルカルボニル、オキセタニルカルボニル、ピラゾリニルカルボニル、モルホリノカルボニル、モルホリニルカルボニル、インドリニルカルボニル等が挙げられる。 The “non-aromatic heterocyclic carbonyl” means a group in which the above “non-aromatic heterocyclic” is bonded to a carbonyl group. Examples include dioxanylcarbonyl, oxetanylcarbonyl, pyrazolinylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl, indolinylcarbonyl and the like.
「非芳香族複素環オキシカルボニル」とは、上記「非芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピペリジニルオキシカルボニル、テトラヒドロフリルオキシカルボニル等が挙げられる。 The “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
「非芳香族複素環スルファニル」とは、上記「非芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ジオキサニルスルファニル、チイラニルスルファニル、オキシラニルスルファニル、オキセタニルスルファニル、オキサチオラニルスルファニル、アゼチジニルスルファニル、チアニルスルファニル、チアゾリジニルスルファニル、ピロリジニルスルファニル、ピロリニルスルファニル、イミダゾリジニルスルファニル、イミダゾリニルスルファニル、ピラゾリジニルスルファニル、ピラゾリニルスルファニル、ピペリジルスルファニル、ピペラジニルスルファニル、モルホリニルスルファニル、インドリニルスルファニル、クロマニルスルファニル等が挙げられる。 “Non-aromatic heterocyclic sulfanyl” means a group in which the “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, dioxanylsulfanyl, thiylylsulfanyl, oxiranylsulfanyl, oxetanylsulfanyl, oxathiolanylsulfanyl, azetidinylsulfanyl, thianylsulfanyl, thiazolidinylsulfanyl, pyrrolidinylsulfanyl, pyrrolinylsulfanyl, imidazolidinini Examples include sulfanyl, imidazolinylsulfanyl, pyrazolidinylsulfanyl, pyrazolinylsulfanyl, piperidylsulfanyl, piperazinylsulfanyl, morpholinylsulfanyl, indolinylsulfanyl, chromanylsulfanyl and the like.
「非芳香族複素環スルフィニル」とは、上記「非芳香族複素環」がスルフィニル基に結合した基を意味する。例えば、ピペリジニルスルフィニル、テトラヒドロフリルスルフィニル等が挙げられる。 The “non-aromatic heterocyclic sulfinyl” means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfinyl group. For example, piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
「非芳香族複素環スルホニル」とは、上記「非芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。 The “non-aromatic heterocyclic sulfonyl” means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
　「炭素環オキシ」とは、上記「炭素環」が酸素原子に結合した基を意味する。すなわち、非芳香族炭素環オキシおよび芳香族炭素環オキシを包含する。 “Carbocyclic oxy” means a group in which the above “carbocycle” is bonded to an oxygen atom. That is, non-aromatic carbocyclic oxy and aromatic carbocyclic oxy are included.
　「複素環オキシ」とは、上記「複素環」が酸素原子に結合した基を意味する。すなわち、非芳香族複素環オキシおよび芳香族複素環オキシを包含する。 “Heterocyclic oxy” means a group in which the above “heterocycle” is bonded to an oxygen atom. That is, non-aromatic heterocyclic oxy and aromatic heterocyclic oxy are included.
　「置換もしくは非置換のアルキル」、「置換もしくは非置換のアルケニル」、「置換もしくは非置換のアルキニル」、「置換もしくは非置換のアルキルオキシ」、「置換もしくは非置換のアルケニルオキシ」、「置換もしくは非置換のアルキニルオキシ」、「置換もしくは非置換のアルキルカルボニル」、「置換もしくは非置換のアルケニルカルボニル」、「置換もしくは非置換のアルキニルカルボニル」、「置換もしくは非置換のアルキルスルホニル」、「置換もしくは非置換のアルケニルスルホニル」、「置換もしくは非置換のアルキニルスルホニル」、「置換もしくは非置換のアルキルイミノ」、「置換もしくは非置換のアルケニルイミノ」、「置換もしくは非置換のアルキニルイミノ」、「置換もしくは非置換のアルキルカルボニルイミノ」、「置換もしくは非置換のアルケニルカルボニルイミノ」、「置換もしくは非置換のアルキニルカルボニルイミノ」、「置換もしくは非置換のアルキルオキシイミノ」、「置換もしくは非置換のアルケニルオキシイミノ」、「置換もしくは非置換のアルキニルオキシイミノ」、「置換もしくは非置換のアルキルカルボニルオキシ」、「置換もしくは非置換のアルケニルカルボニルオキシ」、「置換もしくは非置換のアルキニルカルボニルオキシ」、「置換もしくは非置換のアルキルオキシカルボニル」、「置換もしくは非置換のアルケニルオキシカルボニル」、「置換もしくは非置換のアルキニルオキシカルボニル」、「置換もしくは非置換のアルキルスルファニル」、「置換もしくは非置換のアルケニルスルファニル」、「置換もしくは非置換のアルキニルスルファニル」、「置換もしくは非置換のアルキルスルフィニル」、「置換もしくは非置換のアルケニルスルフィニル」、「置換もしくは非置換のアルキニルスルフィニル」、「置換もしくは非置換のアルキレン」、「置換もしくは非置換のアルケニレン」、および「置換もしくは非置換のアルキニレン」の置換基としては、次の置換基群Ａが挙げられる。任意の位置の炭素原子が次の置換基群Ａから選択される１以上の基と結合していてもよい。好ましい置換基としては、置換基群Ｇが挙げられる。より好ましくは、置換基群Ｋが挙げられる。 “Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted or "Unsubstituted alkynyloxy", "substituted or unsubstituted alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted alkylsulfonyl", "substituted or "Unsubstituted alkenylsulfonyl", "substituted or unsubstituted alkynylsulfonyl", "substituted or unsubstituted alkylimino", "substituted or unsubstituted alkenylimino", "substituted or unsubstituted alkynylimino", "substituted or Unsubstituted alkylcarbonyl "Imino", "substituted or unsubstituted alkenylcarbonylimino", "substituted or unsubstituted alkynylcarbonylimino", "substituted or unsubstituted alkyloxyimino", "substituted or unsubstituted alkenyloxyimino", "substituted or "Unsubstituted alkynyloxyimino", "substituted or unsubstituted alkylcarbonyloxy", "substituted or unsubstituted alkenylcarbonyloxy", "substituted or unsubstituted alkynylcarbonyloxy", "substituted or unsubstituted alkyloxycarbonyl" ”,“ Substituted or unsubstituted alkenyloxycarbonyl ”,“ substituted or unsubstituted alkynyloxycarbonyl ”,“ substituted or unsubstituted alkylsulfanyl ”,“ substituted or unsubstituted alkenylsulfanyl ”,“ substituted ” Or “substituted alkynylsulfinyl”, “substituted or unsubstituted alkylsulfinyl”, “substituted or unsubstituted alkenylsulfinyl”, “substituted or unsubstituted alkynylsulfinyl”, “substituted or unsubstituted alkylene”, “substituted” Examples of the substituent of “unsubstituted alkenylene” and “substituted or unsubstituted alkynylene” include the following substituent group A. The carbon atom at any position may be bonded to one or more groups selected from the following substituent group A. Preferred examples of the substituent include the substituent group G. More preferably, the substituent group K is mentioned.
置換基群Ａ：ハロゲン、ヒドロキシ、カルボキシ、イミノ、ヒドロキシアミノ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルシリル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルオキシ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルオキシ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルオキシ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルスルホニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルスルホニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルスルホニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルカルボニルイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルカルボニルイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルカルボニルイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルオキシイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルオキシイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルオキシイミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルカルボニルオキシ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルカルボニルオキシ、アルキニルカルボニルオキシ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルオキシカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルオキシカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルオキシカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルスルファニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルスルファニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルスルファニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルスルフィニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルスルフィニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルスルフィニル、非置換もしくは置換基群Ｃから選択される１または２つの基で置換されたアミノ、非置換もしくは置換基群Ｃから選択される１または２つの基で置換されたカルバモイル、非置換もしくは置換基群Ｃから選択される１または２つの基で置換されたスルファモイル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環スルホニル。 Substituent group A: halogen, hydroxy, carboxy, imino, hydroxyamino, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, azide, Hydrazino, ureido, amidino, guanidino, alkylsilyl substituted with one or more groups selected from unsubstituted or substituted group G, alkyl substituted with one or more groups selected from unsubstituted or substituted group G Oxy, unsubstituted or alkenyloxy substituted with one or more groups selected from substituent group G, alkynyloxy substituted with one or more groups selected from unsubstituted or substituent group G, unsubstituted or substituted Alkyl substituted with one or more groups selected from group G Rubonyl, alkenylcarbonyl substituted with one or more groups selected from unsubstituted or substituted group G, alkynylcarbonyl substituted with one or more groups selected from unsubstituted or substituted group G, unsubstituted or substituted Selected from alkylsulfonyl substituted with one or more groups selected from group G, alkenylsulfonyl substituted with one or more groups selected from unsubstituted or substituent group G, unsubstituted or substituted group G An alkynylsulfonyl substituted with one or more groups, an alkylimino substituted with one or more groups selected from unsubstituted or substituted group G, and one or more groups selected from unsubstituted or substituted group G Substituted alkenylimino, unsubstituted or substituted with one or more groups selected from substituent group G, alkynylimino, unsubstituted or substituted group G? Alkylcarbonylimino substituted with one or more selected groups, alkenylcarbonylimino substituted with one or more groups selected from unsubstituted or substituted group G, 1 selected from unsubstituted or substituted group G Alkynylcarbonylimino substituted with the above groups, alkyloxyimino substituted with one or more groups selected from unsubstituted or substituent group G, one or more groups selected from unsubstituted or substituent group G Substituted alkenyloxyimino, unsubstituted or substituted with one or more groups selected from substituent group G, alkynyloxyimino, unsubstituted or substituted with one or more groups selected from substituent group G Carbonyloxy, unsubstituted or alkenylcarbonyloxy substituted with one or more groups selected from substituent group G, alkynylcarbonyl Ruoxy, unsubstituted or substituted with one or more groups selected from substituent group G, unsubstituted or substituted alkenyloxycarbonyl with one or more groups selected from substituent group G, unsubstituted Or alkynyloxycarbonyl substituted with one or more groups selected from substituent group G, alkylsulfanyl substituted with one or more groups selected from unsubstituted or substituent group G, unsubstituted or substituent group G One or more selected from alkenylsulfanyl substituted with one or more groups selected from: alkynylsulfanyl substituted with one or more groups selected from unsubstituted or substituted group G, unsubstituted or substituted group G Alkylsulfinyl substituted with one or more groups, unsubstituted or alkenyl substituted with one or more groups selected from substituent group G Finyl, unsubstituted or substituted with one or more groups selected from substituent group G, alkynylsulfinyl, unsubstituted or substituted with one or two groups selected from substituent group C, unsubstituted or substituted Selected from carbamoyl substituted with one or two groups selected from group C, unsubstituted or substituted sulfamoyl substituted with one or two groups selected from group C, unsubstituted or substituted group E An aromatic carbocyclic group substituted with one or more groups, unsubstituted or substituted with one or more groups selected from substituent group E, unsubstituted or substituted group E An aromatic heterocyclic group substituted with one or more groups selected from: unsubstituted or non-aromatic heterocyclic group substituted with one or more groups selected from substituent group E, unsubstituted or substituted Group E Aromatic carbocyclic oxy substituted with one or more selected groups, non-aromatic carbocyclic oxy, unsubstituted or substituted with one or more groups selected from substituent group E Aromatic heterocyclic oxy substituted with one or more groups selected from the following: Non-aromatic heterocyclic oxy substituted with one or more groups selected from the unsubstituted or substituted group E, unsubstituted or substituted groups Aromatic carbocyclic carbonyl substituted with one or more groups selected from E, unsubstituted or non-aromatic carbocyclic carbonyl substituted with one or more groups selected from substituent group E, unsubstituted or substituted Aromatic heterocyclic carbonyl substituted with one or more groups selected from group E, unsubstituted or non-aromatic heterocyclic carbonyl substituted with one or more groups selected from substituent group E, unsubstituted or substituted 1 selected from the group E Aromatic carbocyclic oxycarbonyl substituted with the above groups, non-aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group E, aromatic heterocyclic oxycarbonyl, unsubstituted Or non-aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from substituent group E, aromatic carbocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituent group E A non-aromatic carbocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituted group E, an aromatic complex substituted with one or more groups selected from unsubstituted or substituted group E Ring alkyloxy, unsubstituted or substituted with one or more groups selected from non-aromatic heterocyclic alkyloxy, unsubstituted or substituted group E selected from substituent group E 1 or more selected from non-aromatic carbocyclic alkyloxycarbonyl, unsubstituted or substituted group E, substituted with one or more groups selected from aromatic or carbocyclic alkyloxycarbonyl, unsubstituted or substituted group E An aromatic heterocyclic alkyloxycarbonyl substituted with a group of the following: a non-aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from the unsubstituted or substituted group E, an unsubstituted or substituted group E Aromatic carbocyclic sulfanyl substituted with one or more selected groups, non-substituted or non-aromatic carbocyclic sulfanyl substituted with one or more selected from substituent group E, unsubstituted or substituted group E Aromatic heterocyclic sulfanyl substituted with one or more groups selected from: unsubstituted or substituted with one or more groups selected from substituent group E A non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from fanyl, unsubstituted or substituted group E, an aromatic carbon substituted with one or more groups selected from unsubstituted or substituted group E Ring sulfonyl, aromatic heterocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group E, and non-aromatic substituted with one or more groups selected from unsubstituted or substituted group E Group heterocyclic sulfonyl.
　　「置換もしくは非置換の芳香族炭素環式基」、「置換もしくは非置換の非芳香族炭素環式基」、「置換もしくは非置換の芳香族複素環式基」、「置換もしくは非置換の非芳香族複素環式基」、「置換もしくは非置換の芳香族炭素環オキシ」、「置換もしくは非置換の非芳香族炭素環オキシ」、「置換もしくは非置換の芳香族複素環オキシ」、「置換もしくは非置換の非芳香族複素環オキシ」、「置換もしくは非置換の芳香族炭素環カルボニル」、「置換もしくは非置換の非芳香族炭素環カルボニル」、「置換もしくは非置換の芳香族複素環カルボニル」、「置換もしくは非置換の非芳香族複素環カルボニル」、「置換もしくは非置換の芳香族炭素環オキシカルボニル」、「置換もしくは非置換の非芳香族炭素環オキシカルボニル」、「置換もしくは非置換の芳香族複素環オキシカルボニル」、「置換もしくは非置換の非芳香族複素環オキシカルボニル」、「置換もしくは非置換の芳香族炭素環スルファニル」、「置換もしくは非置換の非芳香族炭素環スルファニル」、「置換もしくは非置換の芳香族複素環スルファニル」、「置換もしくは非置換の非芳香族複素環スルファニル」、「置換もしくは非置換の芳香族炭素環スルフィニル」、「置換もしくは非置換の非芳香族炭素環スルフィニル」、「置換もしくは非置換の芳香族複素環スルフィニル」、「置換もしくは非置換の非芳香族複素環スルフィニル」、「置換もしくは非置換の芳香族炭素環スルホニル」、「置換もしくは非置換の非芳香族炭素環スルホニル」、「置換もしくは非置換の芳香族複素環スルホニル」、「置換もしくは非置換の非芳香族複素環スルホニル」、「置換もしくは非置換の炭素環式基」、「置換もしくは非置換の複素環式基」、「置換もしくは非置換の炭素環アルキル」、「置換もしくは非置換の複素環アルキル」、「置換もしくは非置換の炭素環アルキルオキシ」、「置換もしくは非置換の複素環アルキルオキシ」、「置換もしくは非置換の芳香族炭素環アルキル」、「置換もしくは非置換の非芳香族炭素環アルキル」、「置換もしくは非置換の芳香族複素環アルキル」、「置換もしくは非置換の非芳香族複素環アルキル」、「置換もしくは非置換の芳香族炭素環アルキルオキシ」、「置換もしくは非置換の非芳香族炭素環アルキルオキシ」、「置換もしくは非置換の芳香族複素環アルキルオキシ」、「置換もしくは非置換の非芳香族複素環アルキルオキシ」、「置換もしくは非置換の芳香族炭素環アルキルオキシカルボニル」、「置換もしくは非置換の非芳香族炭素環アルキルオキシカルボニル」、「置換もしくは非置換の芳香族複素環アルキルオキシカルボニル」、「置換もしくは非置換の非芳香族複素環アルキルオキシカルボニル」、「置換もしくは非置換の芳香族炭素環アルキルオキシアルキル」、「置換もしくは非置換の非芳香族炭素環アルキルオキシアルキル」、「置換もしくは非置換の芳香族複素環アルキルオキシアルキル」、および「置換もしくは非置換の非芳香族複素環アルキルオキシアルキル」における「炭素環」、「複素環」、「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、および「非芳香族複素環」の環上の置換基としては、次の置換基群Ｂが挙げられる。環上の任意の位置の原子が次の置換基群Ｂから選択される１以上の基と結合していてもよい。好ましい置換基としては、置換基群Ｅが挙げられる。より好ましくは、置換基群Ｆが挙げられる。さらに好ましくは置換基群Ｆが挙げられる。別の好ましい態様としては、置換基群Ｉが挙げられる。 "Substituted or unsubstituted aromatic carbocyclic group", "Substituted or unsubstituted nonaromatic carbocyclic group", "Substituted or unsubstituted aromatic heterocyclic group", "Substituted or unsubstituted non-substituted aromatic carbocyclic group" "Aromatic heterocyclic group", "Substituted or unsubstituted aromatic carbocyclic oxy", "Substituted or unsubstituted non-aromatic carbocyclic oxy", "Substituted or unsubstituted aromatic heterocyclic oxy", "Substituted Or “unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted aromatic carbocyclic carbonyl”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted aromatic heterocyclic carbonyl” ”,“ Substituted or unsubstituted non-aromatic heterocyclic carbonyl ”,“ substituted or unsubstituted aromatic carbocyclic oxycarbonyl ”,“ substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl ”,“ Or “unsubstituted aromatic heterocyclic oxycarbonyl”, “substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl”, “substituted or unsubstituted aromatic carbocyclic sulfanyl”, “substituted or unsubstituted non-aromatic carbon” ”Ring sulfanyl”, “substituted or unsubstituted aromatic heterocyclic sulfanyl”, “substituted or unsubstituted non-aromatic heterocyclic sulfanyl”, “substituted or unsubstituted aromatic carbocyclic sulfinyl”, “substituted or unsubstituted "Non-aromatic carbocyclic sulfinyl", "substituted or unsubstituted aromatic heterocyclic sulfinyl", "substituted or unsubstituted non-aromatic heterocyclic sulfinyl", "substituted or unsubstituted aromatic carbocyclic sulfonyl", "substituted Or “unsubstituted non-aromatic carbocyclic sulfonyl”, “substituted or unsubstituted aromatic heterocyclic sulfonyl”, “substituted Or unsubstituted non-aromatic heterocyclic sulfonyl ”,“ substituted or unsubstituted carbocyclic group ”,“ substituted or unsubstituted heterocyclic group ”,“ substituted or unsubstituted carbocyclic alkyl ”,“ substituted ” Or "unsubstituted heterocyclic alkyl", "substituted or unsubstituted carbocyclic alkyloxy", "substituted or unsubstituted heterocyclic alkyloxy", "substituted or unsubstituted aromatic carbocyclic alkyl", "substituted or unsubstituted "Substituted non-aromatic carbocyclic alkyl", "Substituted or unsubstituted aromatic heterocyclic alkyl", "Substituted or unsubstituted non-aromatic heterocyclic alkyl", "Substituted or unsubstituted aromatic carbocyclic alkyloxy" , “Substituted or unsubstituted non-aromatic carbocyclic alkyloxy”, “substituted or unsubstituted aromatic heterocyclic alkyloxy”, “substituted or unsubstituted non-aromatic heterocyclic” Ring alkyloxy "," substituted or unsubstituted aromatic carbocyclic alkyloxycarbonyl "," substituted or unsubstituted nonaromatic carbocyclic alkyloxycarbonyl "," substituted or unsubstituted aromatic heterocyclic alkyloxycarbonyl " , “Substituted or unsubstituted non-aromatic heterocyclic alkyloxycarbonyl”, “substituted or unsubstituted aromatic carbocyclic alkyloxyalkyl”, “substituted or unsubstituted non-aromatic carbocyclic alkyloxyalkyl”, “substituted Or “carbocyclic”, “heterocycle”, “aromatic carbocycle”, “non-aromatic” in “unsubstituted aromatic heterocyclic alkyloxyalkyl” and “substituted or unsubstituted non-aromatic heterocyclic alkyloxyalkyl”. The substituents on the ring of “aromatic carbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” include the following substituents: B, and the like. The atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Preferred examples of the substituent include Substituent Group E. More preferably, the substituent group F is mentioned. More preferably, the substituent group F is mentioned. Another preferred embodiment includes substituent group I.
置換基群Ｂ：オキソ、ハロゲン、ヒドロキシ、カルボキシ、イミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルシリル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルオキシ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルオキシ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルオキシ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルカルボニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルカルボニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルカルボニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルスルホニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルスルホニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルスルホニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルカルボニルイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルカルボニルイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルカルボニルイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルオキシイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルオキシイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルオキシイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルオキシアルキルオキシイミノ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたメチリデン、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルカルボニルオキシ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルカルボニルオキシ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルカルボニルオキシ、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルオキシカルボニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルオキシカルボニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルオキシカルボニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルスルファニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルスルファニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルスルファニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキルスルフィニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルケニルスルフィニル、非置換もしくは置換基群Ａから選択される1以上の基で置換されたアルキニルスルフィニル、非置換もしくは置換基群Ｃから選択される1または２つの基で置換されたアミノ、非置換もしくは置換基群Ｃから選択される１または２つの基で置換されたカルバモイル、非置換または置換基群Ｃから選択される１または２つの基で置換されたスルファモイル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルケニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルケニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシアルキルオキシ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環オキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環オキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環オキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環スルファニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｅから選択される1以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｅから選択される1以上の基で置換された非芳香族複素環スルホニル。 Substituent group B: oxo, halogen, hydroxy, carboxy, imino, hydroxyimino, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, Azido, hydrazino, ureido, amidino, guanidino, unsubstituted or substituted by one or more groups selected from substituent group G, unsubstituted or substituted by one or more groups selected from substituent group A Alkyl, alkenyl substituted with one or more groups selected from unsubstituted or substituted group A, alkynyl substituted with one or more groups selected from unsubstituted or substituted group A, unsubstituted or substituted Alkyloxy substituted with one or more groups selected from group A, non- Alkenyloxy substituted with one or more groups selected from substituted or substituent group A, alkynyloxy substituted with one or more groups selected from unsubstituted or substituent group A, unsubstituted or substituted group A Alkylcarbonyl substituted with one or more groups selected from: alkenylcarbonyl substituted with one or more groups selected from unsubstituted or substituent group A, one or more selected from unsubstituted or substituent group A Substituted with one or more groups selected from unsubstituted or substituted group A, alkynylcarbonyl substituted with one or more groups selected from unsubstituted or substituted group A Alkenylsulfonyl, alkynylsulfonyl substituted with one or more groups selected from unsubstituted or substituent group A, selected from unsubstituted or substituent group A Alkylimino substituted with one or more groups, unsubstituted or alkenylimino substituted with one or more groups selected from substituent group A, unsubstituted or substituted with one or more groups selected from substituent group A Alkynylimino substituted, alkylcarbonylimino unsubstituted or substituted with one or more groups selected from substituent group A, alkenylcarbonylimino substituted with one or more groups selected from unsubstituted or substituent group A An alkynylcarbonylimino substituted with one or more groups selected from unsubstituted or substituent group A, an alkyloxyimino substituted with one or more groups selected from unsubstituted or substituent group A, unsubstituted or Alkenyloxyimino substituted with one or more groups selected from Substituent Group A, unsubstituted or substituted with one or more groups selected from Substituent Group A Alkynyloxyimino, alkyloxyalkyloxyimino substituted with one or more groups selected from unsubstituted or substituted group A, substituted with one or more groups selected from unsubstituted or substituted group A Methylidene, alkylcarbonyloxy substituted with one or more groups selected from unsubstituted or substituted group A, alkenylcarbonyloxy substituted with one or more groups selected from unsubstituted or substituted group A, unsubstituted Or alkynylcarbonyloxy substituted with one or more groups selected from substituent group A, alkyloxycarbonyl substituted with one or more groups selected from unsubstituted or substituent group A, unsubstituted or substituent groups Alkenyloxycarbonyl substituted with one or more groups selected from A, one or more selected from unsubstituted or substituent group A Alkynyloxycarbonyl substituted with a group, alkylsulfanyl substituted with one or more groups selected from unsubstituted or substituent group A, substituted with one or more groups selected from unsubstituted or substituent group A Alkenylsulfanyl, unsubstituted or substituted with one or more groups selected from substituent group A, alkynylsulfanyl, unsubstituted or substituted alkylsulfinyl with one or more groups selected from substituent group A, unsubstituted or Selected from alkenylsulfinyl substituted with one or more groups selected from substituent group A, unsubstituted or alkynylsulfinyl substituted with one or more groups selected from substituent group A, unsubstituted or substituted group C Substituted with one or two groups selected from amino, unsubstituted or substituted group C Carbamoyl, unsubstituted or substituted with one or two groups selected from substituent group C, sulfamoyl substituted with one or more groups selected from unsubstituted or substituted group E A non-aromatic carbocyclic group substituted with one or more groups selected from the group, unsubstituted or substituted group E, aromatic substituted with one or more groups selected from unsubstituted or substituted group E Substituted with one or more groups selected from heterocyclic groups, unsubstituted or substituted with one or more groups selected from substituent group E, unsubstituted or substituted with substituent groups E Substituted with one or more groups selected from non-aromatic carbocyclic oxy, unsubstituted or substituted group E, unsubstituted or substituted with one or more groups selected from substituent group E Aromatic heterocyclic oxy, unsubstituted or substituted Non-aromatic heterocyclic oxy substituted with one or more groups selected from group E, unsubstituted or aromatic carbocyclic carbonyl substituted with one or more groups selected from substituent group E, unsubstituted or Non-aromatic carbocyclic carbonyl substituted with one or more groups selected from substituent group E, unsubstituted or aromatic heterocyclic carbonyl substituted with one or more groups selected from substituent group E, unsubstituted Or a non-aromatic heterocyclic carbonyl substituted with one or more groups selected from substituent group E, an aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from unsubstituted or substituent group E, Non-aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group E, Aromatic heterocyclic ring substituted with one or more groups selected from unsubstituted or substituted group E Oxycarbonyl, Non-aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group E, Aromatic carbocycle substituted with one or more groups selected from unsubstituted or substituted group E A non-aromatic carbocyclic alkyl substituted with one or more groups selected from alkyl, unsubstituted or substituted group E, an aromatic complex substituted with one or more groups selected from unsubstituted or substituted group E Ring alkyl, unsubstituted or substituted with one or more groups selected from substituent group E, non-aromatic heterocyclic alkyl, substituted with one or more groups selected from unsubstituted or substituent group E Non-aromatic carbocyclic alkenyl, unsubstituted or substituted with one or more groups selected from substituent group E, unsubstituted or substituted with one or more groups selected from substituent group E Group carbocyclic alkylo A non-aromatic carbocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituted group E, an aromatic substituted with one or more groups selected from unsubstituted or substituted group E Heterocyclic alkyloxy, unsubstituted or substituted with one or more groups selected from non-aromatic heterocyclic alkyloxy, unsubstituted or substituted group E selected from substituent group E Aromatic carbocyclic alkyloxyalkyloxy, unsubstituted or substituted with one or more groups selected from substituent group E. One or more selected from aromatic carbocyclic oxyalkyloxy, unsubstituted or substituted group E Aromatic carbocyclic alkyloxycarbonyl substituted with a group of the above, non-aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from unsubstituted or substituent group E, unsubstituted Or aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group E, unsubstituted or non-aromatic heterocyclic ring substituted with one or more groups selected from substituent group E An alkyloxycarbonyl, an aromatic carbocyclic oxyalkyl which is unsubstituted or substituted with one or more groups selected from substituent group E, an unsubstituted or substituted non-substituted with one or more groups selected from substituent group E Aromatic carbocyclic oxyalkyl, unsubstituted or substituted with one or more groups selected from aromatic heterocyclic oxyalkyl, unsubstituted or substituted group E selected from substituent group E Selected from aromatic carbocyclic alkyloxyalkyl substituted with one or more groups selected from non-aromatic heterocyclic oxyalkyl, unsubstituted or substituted group E, unsubstituted or substituted group E Non-aromatic carbocyclic alkyloxyalkyl substituted with one or more groups, aromatic heterocyclic alkyloxyalkyl substituted with one or more groups selected from unsubstituted or substituted group E, unsubstituted or substituted Non-aromatic heterocyclic alkyloxyalkyl substituted with one or more groups selected from group E, unsubstituted or aromatic carbocyclic oxyimino substituted with one or more groups selected from substituent group E, unsubstituted Or a non-aromatic carbocyclic oximino substituted with one or more groups selected from substituent group E, an aromatic carbocyclic sulfanyl substituted with one or more groups selected from unsubstituted or substituent group E, non- Non-aromatic carbocyclic sulfanyl substituted with one or more groups selected from substituted or substituent group E, Aromatic heterocycles substituted with one or more groups selected from unsubstituted or substituent group E Non-aromatic heterocyclic sulfanyl substituted with one or more groups selected from rufanyl, unsubstituted or substituted group E, non-aromatic substituted with one or more groups selected from unsubstituted or substituted group E Aromatic carbocyclic sulfonyl, substituted with one or more groups selected from unsubstituted or substituted group E, Aromatic carbocyclic sulfonyl, substituted with one or more groups selected from unsubstituted or substituted group E Heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituent group E.
　「置換もしくは非置換の炭素環式基」、「置換もしくは非置換の複素環式基」、「置換もしくは非置換の炭素環アルキル」および「置換もしくは非置換の複素環アルキル」の「炭素環」および「複素環」の環上の置換基としても、置換基群Ｂが挙げられる。環上の任意の位置の原子が置換基群Ｂから選択される１以上の基と結合していてもよい。該置換基が２つ以上存在する場合は同一でも異なっていても良い。好ましい置換基としては、置換基群Ｅが挙げられる。より好ましくは、置換基群Ｆが挙げられる。さらに好ましくは置換基群Ｆが挙げられる。別の好ましい態様としては、置換基群Ｉが挙げられる。 “Carbocycle” of “substituted or unsubstituted carbocyclic group”, “substituted or unsubstituted heterocyclic group”, “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl” Substituent group B is also included as a substituent on the ring of “heterocycle”. The atom at any position on the ring may be bonded to one or more groups selected from the substituent group B. When two or more substituents are present, they may be the same or different. Preferred examples of the substituent include Substituent Group E. More preferably, the substituent group F is mentioned. More preferably, the substituent group F is mentioned. Another preferred embodiment includes substituent group I.
　「置換もしくは非置換のアルキルアミノ」、「置換もしくは非置換のモノアルキルアミノ」、「置換もしくは非置換のジアルキルアミノ」、「置換もしくは非置換のモノアルキルアミノカルボニル」、「置換もしくは非置換のジアルキルアミノカルボニル」、「置換もしくは非置換のモノアルキルアミノスルホニル」、「置換もしくは非置換のジアルキルアミノスルホニル」、「置換もしくは非置換のモノアルキルカルバモイル」、「置換もしくは非置換のジアルキルカルバモイル」、「置換もしくは非置換のモノアルキルスルファモイル」、「置換もしくは非置換のジアルキルスルファモイル」、「置換もしくは非置換の炭素環アルキル」、「置換もしくは非置換の複素環アルキル」、「置換もしくは非置換の芳香族炭素環アルキル」、「置換もしくは非置換の非芳香族炭素環アルキル」、「置換もしくは非置換の芳香族複素環アルキル」、「置換もしくは非置換の非芳香族複素環アルキル」、「置換もしくは非置換の芳香族炭素環アルキルオキシ」、「置換もしくは非置換の非芳香族炭素環アルキルオキシ」、「置換もしくは非置換の芳香族複素環アルキルオキシ」、「置換もしくは非置換の非芳香族複素環アルキルオキシ」、「置換もしくは非置換の芳香族炭素環アルキルオキシカルボニル」、「置換もしくは非置換の非芳香族炭素環アルキルオキシカルボニル」、「置換もしくは非置換の芳香族複素環アルキルオキシカルボニル」、「置換もしくは非置換の非芳香族複素環アルキルオキシカルボニル」、「置換もしくは非置換の芳香族炭素環アルキルオキシアルキル」、「置換もしくは非置換の非芳香族炭素環アルキルオキシアルキル」、「置換もしくは非置換の芳香族複素環アルキルオキシアルキル」、および「置換もしくは非置換の非芳香族複素環アルキルオキシアルキル」の「アルキル」上の置換基としても、置換基群Ａが挙げられる。アルキル上の任意の位置に置換基群Ａから選択される１以上の基と結合していてもよい。該置換基が２つ以上存在する場合は同一でも異なっていても良い。好ましい置換基としては、置換基群Ｇが挙げられる。より好ましくは、置換基群Ｋが挙げられる。 "Substituted or unsubstituted alkylamino", "Substituted or unsubstituted monoalkylamino", "Substituted or unsubstituted dialkylamino", "Substituted or unsubstituted monoalkylaminocarbonyl", "Substituted or unsubstituted dialkyl “Aminocarbonyl”, “substituted or unsubstituted monoalkylaminosulfonyl”, “substituted or unsubstituted dialkylaminosulfonyl”, “substituted or unsubstituted monoalkylcarbamoyl”, “substituted or unsubstituted dialkylcarbamoyl”, “substituted” Or “unsubstituted monoalkylsulfamoyl”, “substituted or unsubstituted dialkylsulfamoyl”, “substituted or unsubstituted carbocyclic alkyl”, “substituted or unsubstituted heterocyclic alkyl”, “substituted or unsubstituted” Aromatic carbocyclic alkyl ", Substituted or unsubstituted non-aromatic carbocyclic alkyl "," substituted or unsubstituted aromatic heterocyclic alkyl "," substituted or unsubstituted non-aromatic heterocyclic alkyl "," substituted or unsubstituted aromatic carbocyclic ring " Alkyloxy "," substituted or unsubstituted non-aromatic carbocyclic alkyloxy "," substituted or unsubstituted aromatic heterocyclic alkyloxy "," substituted or unsubstituted non-aromatic heterocyclic alkyloxy "," substituted Or “unsubstituted aromatic carbocyclic alkyloxycarbonyl”, “substituted or unsubstituted nonaromatic carbocyclic alkyloxycarbonyl”, “substituted or unsubstituted aromatic heterocyclic alkyloxycarbonyl”, “substituted or unsubstituted “Non-aromatic heterocyclic alkyloxycarbonyl”, “substituted or unsubstituted aromatic carbocyclic alkyloxyalkyl”, "Alkyl" of "Substituted or unsubstituted non-aromatic carbocyclic alkyloxyalkyl", "Substituted or unsubstituted aromatic heterocyclic alkyloxyalkyl", and "Substituted or unsubstituted non-aromatic heterocyclic alkyloxyalkyl" As the above substituent, the substituent group A can be mentioned. One or more groups selected from the substituent group A may be bonded to any position on the alkyl. When two or more substituents are present, they may be the same or different. Preferred examples of the substituent include the substituent group G. More preferably, the substituent group K is mentioned.
　「置換もしくは非置換のアミノ」、「置換もしくは非置換のカルバモイル」、「置換もしくは非置換のスルファモイル」、「置換もしくは非置換のアルキルアミノ」、「置換もしくは非置換のモノアルキルアミノ」、「置換もしくは非置換のジアルキルアミノ」、「置換もしくは非置換のモノアルキルアミノカルボニル」、「置換もしくは非置換のジアルキルアミノカルボニル」、「置換もしくは非置換のモノアルキルアミノスルホニル」、「置換もしくは非置換のジアルキルアミノスルホニル」、「置換もしくは非置換のモノアルキルカルバモイル」、「置換もしくは非置換のジアルキルカルバモイル」、「置換もしくは非置換のモノアルキルスルファモイル」、および「置換もしくは非置換のジアルキルスルファモイル」における「アミノ」上の置換基としては、次の置換基群Ｃが挙げられる。該置換基が２つ存在する場合は同一でも異なっていてもよい。好ましい置換基としては、置換基群Ｈが挙げられる。より好ましくは、置換基群Ｊが挙げられる。 "Substituted or unsubstituted amino", "Substituted or unsubstituted carbamoyl", "Substituted or unsubstituted sulfamoyl", "Substituted or unsubstituted alkylamino", "Substituted or unsubstituted monoalkylamino", "Substituted Or “unsubstituted dialkylamino”, “substituted or unsubstituted monoalkylaminocarbonyl”, “substituted or unsubstituted dialkylaminocarbonyl”, “substituted or unsubstituted monoalkylaminosulfonyl”, “substituted or unsubstituted dialkyl” “Aminosulfonyl”, “substituted or unsubstituted monoalkylcarbamoyl”, “substituted or unsubstituted dialkylcarbamoyl”, “substituted or unsubstituted monoalkylsulfamoyl”, and “substituted or unsubstituted dialkylsulfamoyl” "A" The substituent on Bruno "include the following substituent group C. When two substituents are present, they may be the same or different. Preferred examples of the substituent include substituent group H. More preferably, the substituent group J is mentioned.
置換基群Ｃ：ヒドロキシ、アミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルシリル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルスルホニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルスルホニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルスルホニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキルオキシカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルケニルオキシカルボニル、非置換もしくは置換基群Ｇから選択される1以上の基で置換されたアルキニルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環スルホニル。 Substituent group C: hydroxy, amino, unsubstituted or alkylsilyl substituted with one or more groups selected from substituent group G, unsubstituted or substituted with one or more groups selected from substituent group G Alkyl, alkenyl substituted with one or more groups selected from unsubstituted or substituted group G, alkynyl substituted with one or more groups selected from unsubstituted or substituted group G, unsubstituted or substituted groups Alkylcarbonyl substituted with one or more groups selected from G, alkenylcarbonyl substituted with one or more groups selected from unsubstituted or substituent group G, 1 selected from unsubstituted or substituent group G Alkynylcarbonyl, monoalkylamino, dialkylamino, unsubstituted or substituted with one or more groups selected from substituent group G substituted with the above groups Nyl, alkenylsulfonyl substituted with one or more groups selected from unsubstituted or substituted group G, alkynylsulfonyl substituted with one or more groups selected from unsubstituted or substituted group G, unsubstituted or substituted From alkyloxycarbonyl substituted with one or more groups selected from group G, unsubstituted or alkenyloxycarbonyl substituted with one or more groups selected from substituent group G, from unsubstituted or substituent group G Selected from alkynyloxycarbonyl substituted with one or more selected groups, unsubstituted or aromatic carbocyclic group substituted with one or more groups selected from substituent group E, unsubstituted or substituted group E A non-aromatic carbocyclic group substituted with one or more groups selected from the above, an unsubstituted or aromatic heterocyclic group substituted with one or more groups selected from substituent group E, non-substituted Or a non-aromatic heterocyclic group substituted with one or more groups selected from substituent group E, an aromatic carbocyclic oxy substituted with one or more groups selected from unsubstituted or substituent group E, Non-aromatic carbocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group E, Aromatic heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group E A non-aromatic heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group E, an aromatic carbocycle substituted with one or more groups selected from unsubstituted or substituted group E A non-aromatic carbocyclic carbonyl substituted with one or more groups selected from carbonyl, unsubstituted or substituted group E, an aromatic complex substituted with one or more groups selected from unsubstituted or substituted group E Ring carbonyl, unsubstituted or A non-aromatic heterocyclic carbonyl substituted with one or more groups selected from substituent group E, an aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group E, non- Non-aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from substituted or substituent group E, Aromatic heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituent group E Non-aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from carbonyl, unsubstituted or substituted group E, aromatic substituted with one or more groups selected from unsubstituted or substituted group E Carbocyclic alkyl, non-aromatic substituted with one or more groups selected from unsubstituted or substituted group E, aromatic substituted with one or more groups selected from unsubstituted or substituted group E Aromatic heterocyclic alkyl, unsubstituted or substituted with one or more groups selected from substituent group E, non-aromatic heterocyclic alkyl, unsubstituted or substituted with one or more groups selected from substituent group E Aromatic carbocyclic alkyloxy, one or more groups selected from non-aromatic carbocyclic alkyloxy, unsubstituted or substituted group E, unsubstituted or substituted with one or more groups selected from substituent group E 1 or more selected from substituted or non-aromatic heterocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituted group E Aromatic carbocyclic alkyloxycarbonyl substituted with a group of the above, unsubstituted or nonaromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group E, unsubstituted Is an aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group E, unsubstituted or non-aromatic heterocyclic alkyl substituted with one or more groups selected from substituent group E Oxycarbonyl, an unsubstituted or substituted aromatic carbocyclic alkyloxyalkyl substituted with one or more groups selected from substituent group E, unsubstituted or substituted with one or more groups selected from substituent group E Aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl substituted with one or more groups selected from unsubstituted or substituted group E, one or more groups selected from unsubstituted or substituted group E A non-aromatic heterocyclic alkyloxyalkyl substituted with a non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group E Or an aromatic carbocyclic sulfonyl substituted with one or more groups selected from Substituent Group E, an aromatic heterocyclic sulfonyl substituted with one or more groups selected from unsubstituted or Substituent Group E, and non A non-aromatic heterocyclic sulfonyl substituted or substituted with one or more groups selected from Substituent Group E.
　「置換もしくは非置換のメチリデン」および「置換もしくは非置換のヒドロキシイミノ」の置換基としては、置換基群Ｃが挙げられる。好ましくは、置換基群Ｈである。 As substituents of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino”, substituent group C can be mentioned. Substituent group H is preferable.
　「置換基を有するカルボニル」および「置換基を有するカルボニルオキシ」の置換基としては、次の置換基群Ｄが挙げられる。
置換基群Ｄ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環アルケニル、置換もしくは非置換の非芳香族炭素環アルケニル、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環アルキルオキシアルキルオキシ、置換もしくは非置換の芳香族炭素環オキシアルキルオキシ、置換もしくは非置換の芳香族炭素環オキシアルキル、置換もしくは非置換の非芳香族炭素環オキシアルキル、置換もしくは非置換の芳香族複素環オキシアルキル、置換もしくは非置換の非芳香族複素環オキシアルキル、置換もしくは非置換の芳香族炭素環アルキルオキシアルキル、置換もしくは非置換の非芳香族炭素環アルキルオキシアルキル、置換もしくは非置換の芳香族複素環アルキルオキシアルキル、および置換もしくは非置換の非芳香族複素環アルキルオキシアルキル。 Examples of the substituent of “carbonyl having a substituent” and “carbonyloxy having a substituent” include the following substituent group D.
Substituent group D: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, Substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or Unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or Unsubstituted aromatic carbocyclic oxy, substituted or Substituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted non-aromatic Aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic alkenyl, substituted or unsubstituted non-aromatic carbocyclic alkenyl Substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted nonaromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted nonaromatic heterocyclic alkyloxy Substituted or unsubstituted aromatic carbocyclic alkyloxyalkyloxy, substituted or unsubstituted aromatic carbocyclic o Cialkyloxy, substituted or unsubstituted aromatic carbocyclic oxyalkyl, substituted or unsubstituted nonaromatic carbocyclic oxyalkyl, substituted or unsubstituted aromatic heterocyclic oxyalkyl, substituted or unsubstituted nonaromatic hetero Ring oxyalkyl, substituted or unsubstituted aromatic carbocyclic alkyloxyalkyl, substituted or unsubstituted non-aromatic carbocyclic alkyloxyalkyl, substituted or unsubstituted aromatic heterocyclic alkyloxyalkyl, and substituted or unsubstituted Non-aromatic heterocyclic alkyloxyalkyl.
置換基群Ｅ：オキソ、ハロゲン、ヒドロキシ、カルボキシ、イミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニル、アルキニル、ハロアルキル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニルオキシ、アルキニルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたハロアルキルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルオキシアルキル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルオキシアルキルオキシ、ヒドロキシアルキニル、アルキルオキシアルキルオキシアルキルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、ハロアルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルオキシアルキルオキシイミノ、メチリデン、アルキルメチリデン、アルキルオキシカルボニルメチリデン、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルオキシアルキルオキシアルキルオキシ、非置換もしくは置換基群Ｊから選択される１または２つの基で置換されたカルバモイルアルキルオキシ、アルキルスルホニルアミノアルキルオキシ、非置換もしくは置換基群Ｊから選択される１または２つの基で置換されたスルファモイルアルキルオキシ、非置換もしくは置換基群Ｊから選択される１または２つの基で置換されたアミノアルキルオキシ、非置換もしくは置換基群Ｈから選択される1または２つの基で置換されたアミノ、非置換もしくは置換基群Ｈから選択される１または２つの基で置換されたカルバモイル、非置換または置換基群Ｈから選択される１または２つの基で置換されたスルファモイル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環アルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環アルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環アルケニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環アルケニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキルオキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環オキシアルキルオキシ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環オキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環オキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環オキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環オキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環スルファニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環スルファニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環スルファニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環スルファニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｆから選択される1以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｆから選択される1以上の基で置換された非芳香族複素環スルホニル。 Substituent group E: oxo, halogen, hydroxy, carboxy, imino, hydroxyimino, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, One or more groups selected from azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl substituted by one or more groups selected from unsubstituted or substituted group K, unsubstituted or substituted group K Substituted with one or more groups selected from unsubstituted or substituted group K, substituted with alkenyl, alkynyl, haloalkyl, substituted or substituted with one or more groups selected from substituted group K Alkenyloxy, alkynyloxy, unsubstituted Or haloalkyloxy substituted with one or more groups selected from substituent group K, alkyloxyalkyl substituted with one or more groups selected from unsubstituted or substituent group K, unsubstituted or substituted groups Alkyloxyalkyloxy, hydroxyalkynyl, alkyloxyalkyloxyalkyloxy substituted with one or more groups selected from K, unsubstituted or substituted with one or more groups selected from substituent group K, Alkenylcarbonyl, alkynylcarbonyl, alkylsulfonyl substituted with one or more groups selected from unsubstituted or substituted group K, alkenylsulfonyl, alkynylsulfonyl, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino , Archi Rucarbonylimino, alkyloxyimino, haloalkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkyloxyalkyloxyimino, methylidene, alkylmethylidene, alkyloxycarbonylmethylidene, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkyl substituted with one or more groups selected from unsubstituted or substituted group K Oxyalkyloxyalkyloxy, unsubstituted or selected from substituent group J Or carbamoylalkyloxy, alkylsulfonylaminoalkyloxy substituted with two groups, sulfamoylalkyloxy substituted with one or two groups selected from unsubstituted or substituted group J, unsubstituted or substituted groups Selected from aminoalkyloxy substituted with one or two groups selected from J, amino substituted with one or two groups selected from unsubstituted or substituted group H, unsubstituted or substituted group H One or more groups selected from carbamoyl substituted with one or two groups, unsubstituted or substituted sulfamoyl substituted with one or two groups selected from substituent group H, A substituted aromatic carbocyclic group, a non-aromatic carbocyclic group that is unsubstituted or substituted with one or more groups selected from substituent group F; Aromatic heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group F, Non-aromatic heterocyclic ring substituted with one or more groups selected from unsubstituted or substituted group F Aromatic carbocyclic oxy substituted with one or more groups selected from the formula group, unsubstituted or substituted group F, non-aromatic substituted with one or more groups selected from unsubstituted or substituted group F Aromatic heterocyclic oxy substituted with one or more groups selected from carbocyclic oxy, unsubstituted or substituted group F, non-aromatic substituted with one or more groups selected from unsubstituted or substituted group F Aromatic heterocyclic oxy, unsubstituted or substituted with one or more groups selected from substituent group F, non-substituted or substituted with one or more groups selected from substituent group F Aromatic carbocyclic carbonyl, unsubstituted or substituted group F Aromatic heterocyclic carbonyl substituted with one or more groups selected from the above, non-aromatic heterocyclic carbonyl substituted with one or more groups selected from unsubstituted or substituted group F, unsubstituted or substituted groups Aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from F, unsubstituted or non-aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from substituent group F, unsubstituted or An aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from Substituent Group F, an unsubstituted or non-aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from Substituent Group F, Aromatic carbocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted group F, Non-aromatic carbocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted group F , Non An aromatic heterocyclic alkyl substituted with one or more groups selected from substituted or substituent group F, a non-aromatic heterocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted group F, Aromatic carbocyclic alkenyl substituted with one or more groups selected from unsubstituted or substituted group F, Non-aromatic carbocyclic alkenyl substituted with one or more groups selected from unsubstituted or substituted group F An aromatic carbocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituted group F, a non-aromatic carbon substituted with one or more groups selected from unsubstituted or substituted group F Aromatic heterocyclic alkyloxy substituted with one or more groups selected from ring alkyloxy, unsubstituted or substituted group F, non-substituted substituted with one or more groups selected from unsubstituted or substituted group F Aromatic heterocyclic ring Aromatic carbocyclic alkyloxyalkyloxy substituted with one or more groups selected from killoxy, unsubstituted or substituted group F, aromatic substituted with one or more groups selected from unsubstituted or substituted group F An aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from an unsubstituted or substituted group F, or one or more groups selected from an unsubstituted or substituted group F Selected from substituted non-aromatic carbocyclic alkyloxycarbonyl, unsubstituted heterocyclic alkyloxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group F, unsubstituted or substituted group F Non-aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups, unsubstituted or substituted aromatic carbocycle with one or more groups selected from substituent group F Non-aromatic carbocyclic oxyalkyl substituted with one or more groups selected from oxyalkyl, unsubstituted or substituted group F, fragrance substituted with one or more groups selected from unsubstituted or substituted group F Aromatic heterocyclic oxyalkyl, unsubstituted or substituted with one or more groups selected from non-aromatic heterocyclic oxyalkyl, unsubstituted or substituted group F selected from substituent group F Aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl substituted with one or more groups selected from unsubstituted or substituted group F, unsubstituted or substituted 1 Aromatic heterocyclic alkyloxyalkyl substituted with the above groups, non-aromatic heterocyclic alkyloxyalkyl substituted with one or more groups selected from unsubstituted or substituent group F, non-substituted An aromatic carbocyclic oxyimino substituted with one or more groups selected from substituted or substituent group F, a non-aromatic carbocyclic oxyimino substituted with one or more groups selected from unsubstituted or substituted group F, Aromatic carbocyclic sulfanyl substituted with one or more groups selected from unsubstituted or substituted group F, Non-aromatic carbocyclic sulfanyl substituted with one or more groups selected from unsubstituted or substituted group F , An aromatic heterocyclic sulfanyl substituted with one or more groups selected from unsubstituted or substituted group F, a non-aromatic heterocyclic ring substituted with one or more groups selected from unsubstituted or substituted group F Sulfanyl, non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group F, aromatic carbon substituted with one or more groups selected from unsubstituted or substituted group F ring Sulfonyl, aromatic heterocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group F, and non-aromatic substituted with one or more groups selected from unsubstituted or substituted group F Heterocyclic sulfonyl.
置換基群Ｆ：オキソ、ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、シアノアルキル、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、ハロアルケニルオキシ、ヒドロキシアルキルオキシ、カルボキシアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、ヒドロキシアルキル、ヒドロキシアルケニル、ヒドロキシアルキニル、アルキルオキシアルキル、アルキルオキシアルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、ハロアルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルオキシアルキルオキシイミノ、メチリデン、アルキルメチリデン、アルキルオキシカルボニルメチリデン、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルオキシカルボニルアルキルオキシ、アルキルオキシカルボニルアルキル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルケニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルケニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシアルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環オキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された香族炭素環スルファモイル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環スルファモイル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環スルファモイル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環スルファモイル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルスルファモイル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルアミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルアミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルアミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環スルホニル。 Substituent group F: oxo, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, penta Halogenothio, cyano, cyanoalkyl, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, haloalkenyloxy, Hydroxyalkyloxy, carboxyalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, hydroxyalkyl, Roxyalkenyl, hydroxyalkynyl, alkyloxyalkyl, alkyloxyalkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino , Monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, haloalkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkyloxyalkyl Oximino, methylide , Alkylmethylidene, alkyloxycarbonylmethylidene, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxycarbonylalkyloxy, alkyloxycarbonylalkyl, alkylsulfanyl, alkenyl Sulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, unsubstituted or substituted with one or more groups selected from substituent group I An aromatic carbocyclic group, one or more groups selected from unsubstituted or substituent group I A substituted non-aromatic carbocyclic group, unsubstituted or substituted with one or more groups selected from substituent group I, one or more selected from unsubstituted or substituted group I A non-aromatic heterocyclic group substituted with a group of the above, an aromatic carbocyclic oxy substituted with one or more groups selected from an unsubstituted or a substituent group I, selected from an unsubstituted or a substituent group I Selected from non-aromatic carbocyclic oxy substituted with one or more groups, unsubstituted heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I Selected from non-aromatic heterocyclic oxy substituted with one or more groups, aromatic carbocyclic carbonyl substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I Non-aromatic carbocyclic carbons substituted with one or more selected groups , Aromatic heterocyclic carbonyl substituted with one or more groups selected from unsubstituted or substituted group I, non-aromatic heterocyclic substituted with one or more groups selected from unsubstituted or substituted group I Aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from ring carbonyl, unsubstituted or substituted group I, non-aromatic substituted with one or more groups selected from unsubstituted or substituted group I Substituted with one or more groups selected from aromatic heterocyclic oxycarbonyl, unsubstituted or substituted group I, unsubstituted or substituted with one or more groups selected from substituent group I A non-aromatic heterocyclic oxycarbonyl group, an aromatic carbocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted group I, and one or more groups selected from unsubstituted or substituted group I Replaced A non-aromatic carbocyclic alkyl, an unsubstituted or substituted aromatic heterocyclic alkyl substituted with one or more groups selected from Substituent Group I, an unsubstituted or substituted with one or more groups selected from Substituent Group I A non-aromatic heterocyclic alkyl, an aromatic carbocyclic alkenyl substituted with one or more groups selected from unsubstituted or substituent group I, one or more groups selected from unsubstituted or substituent group I One or more aromatic carbocyclic alkyloxy substituted with one or more groups selected from substituted non-aromatic carbocyclic alkenyl, unsubstituted or substituent group I, one or more selected from unsubstituted or substituent group I Selected from non-aromatic carbocyclic alkyloxy substituted with one or more groups, aromatic heterocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I 1 or more groups Selected from substituted or non-aromatic heterocyclic alkyloxy, unsubstituted or substituted carbocyclic alkyloxyalkyloxy substituted with one or more groups selected from substituent group I Aromatic carbocyclic oxyalkyloxy substituted with one or more groups, unsubstituted or substituted carbocyclic alkyloxycarbonyl with one or more groups selected from substituent group I, unsubstituted or substituent group I Non-aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from: unsubstituted or substituted aromatic heterocyclic alkyloxycarbonyl with one or more groups selected from substituent group I, unsubstituted Or a non-aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group I, one or more selected from unsubstituted or substituent group I Aromatic carbocyclic oxyalkyl substituted with a group of the following: selected from non-aromatic carbocyclic oxyalkyl substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I Aromatic heterocyclic oxyalkyl substituted with one or more groups, non-aromatic heterocyclic oxyalkyl substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I Aromatic carbocyclic alkyloxyalkyl substituted with one or more groups selected from: unsubstituted or non-aromatic carbocyclic alkyloxyalkyl substituted with one or more groups selected from Substituent Group I, unsubstituted Or an aromatic heterocyclic alkyloxyalkyl substituted with one or more groups selected from Substituent Group I, non-aromatic heterocyclic substituted with one or more groups selected from unsubstituted or Substituent Group I Alkyloxyalkyl, an aromatic carbocyclic oxyimino substituted with one or more groups selected from unsubstituted or substituted group I, a non-aromatic substituted with one or more groups selected from unsubstituted or substituted group I Aromatic carbocyclic sulfamoyl substituted with one or more groups selected from the group carbocyclic oxyimino, unsubstituted or substituted group I, non-substituted or substituted with one or more groups selected from substituent group I Aromatic carbocyclic sulfamoyl, unsubstituted or substituted by one or more groups selected from substituent group I, substituted or unsubstituted aromatic heterocyclic sulfamoyl, unsubstituted or substituted by substituent group I Non-aromatic heterocyclic sulfamoyl, unsubstituted or substituted with one or more groups selected from Substituent Group I, unsubstituted carbocyclic alkyl sulfamoyl, unsubstituted or Substituent Group I Aromatic carbocyclic alkylamino substituted with one or more selected groups, unsubstituted or non-aromatic carbocyclic alkylamino substituted with one or more groups selected from substituent group I, unsubstituted or substituted Aromatic heterocyclic alkylamino substituted with one or more groups selected from group I, non-aromatic heterocyclic alkylamino substituted or unsubstituted with one or more groups selected from substituent group I, aromatic Carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituent group I, An aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group I, an aromatic compound substituted with one or more groups selected from unsubstituted or substituted group I Non-aromatic heterocyclic sulfonyl substituted with one or more groups selected from a ring sulfonyl, and unsubstituted or substituted Group I.
置換基群Ｇ：ハロゲン、ヒドロキシ、カルボキシ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、ペンタハロゲノチオ、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニルオキシ、アルキニルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルカルボニル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニルカルボニル、アルキニルカルボニル、非置換もしくは置換基群Ｊから選択される1または２つの基で置換されたアミノ、非置換もしくは置換基群Ｊから選択される1または２つのの基で置換されたカルバモイル、非置換もしくは置換基群Ｊから選択される1または２つの基で置換されたスルファモイル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルスルホニル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニルスルホニル、アルキニルスルホニル、モノアルキルアミノカルボニル、ジアルキルアミノカルボニル、モノアルキルアミノスルホニル、ジアルキルアミノスルホニル、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルカルボニルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニルカルボニルオキシ、アルキニルカルボニルオキシ、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルキルオキシカルボニル、非置換もしくは置換基群Ｋから選択される1以上の基で置換されたアルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルアミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環スルホニル。 Substituent group G: halogen, hydroxy, carboxy, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, pentahalogenothio, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano , Nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, unsubstituted or substituted with one or more groups selected from substituent group K, selected from unsubstituted or substituted group K Selected from alkenyloxy, alkynyloxy, unsubstituted or substituted with one or more groups selected from unsubstituted or substituted group K, 1 Substituted with more groups Substituted alkenylcarbonyl, alkynylcarbonyl, unsubstituted or substituted with 1 or 2 groups selected from substituent group J, substituted with 1 or 2 groups selected from unsubstituted or substituted group J Carbamoyl, sulfamoyl substituted with one or two groups selected from unsubstituted or substituent group J, alkylsulfonyl substituted with one or more groups selected from unsubstituted or substituent group K, unsubstituted or Alkenylsulfonyl, alkynylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylimino, alkenylimino, alkynylimino, alkyl substituted with one or more groups selected from substituent group K Carbonylimino, alkeni From carbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy substituted with one or more groups selected from unsubstituted or substituent group K, unsubstituted or substituted group K From alkenylcarbonyloxy, alkynylcarbonyloxy substituted with one or more selected groups, alkyloxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group K, unsubstituted or substituted group K Alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, unsubstituted, substituted with one or more selected groups Is an aromatic carbocyclic group substituted with one or more groups selected from substituent group I, unsubstituted or a non-aromatic carbocyclic group substituted with one or more groups selected from substituent group I , An aromatic heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group I, a non-aromatic complex substituted with one or more groups selected from unsubstituted or substituted group I Aromatic carbocyclic oxy substituted with one or more groups selected from a cyclic group, unsubstituted or substituted group I, Non-aromatic substituted with one or more groups selected from unsubstituted or substituted group I Aromatic heterocyclic oxy, unsubstituted or substituted with one or more groups selected from substituent group I, unsubstituted or substituted with one or more groups selected from substituent group I One or more groups selected from aromatic heterocyclic oxy, unsubstituted or substituted group I One or more groups selected from a substituted aromatic carbocyclic carbonyl, unsubstituted or substituted with one or more groups selected from substituent group I, non-aromatic carbocyclic carbonyl, unsubstituted or substituted group I 1 or more selected from the non-aromatic heterocyclic carbonyl substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted with substituent group I Aromatic carbocyclic oxycarbonyl substituted with a group, selected from non-aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from unsubstituted or substituent group I, unsubstituted or substituted group I An aromatic heterocyclic oxycarbonyl substituted with one or more groups, a non-aromatic heterocyclic oxycarbonyl, an unsubstituted or substituted aromatic carbocyclic alkyl substituted with one or more groups selected from Substituent Group I A non-aromatic carbocyclic alkyloxy substituted with one or more groups selected from xy, unsubstituted or substituted group I, an aromatic substituted with one or more groups selected from unsubstituted or substituted group I Heterocyclic alkyloxy, unsubstituted or substituted with one or more groups selected from substituent group I, non-aromatic heterocyclic alkyloxy, unsubstituted or substituted with one or more groups selected from substituent group I 1 or more selected from non-aromatic carbocyclic alkyloxycarbonyl, unsubstituted or substituted group I, substituted with one or more groups selected from aromatic carbocyclic alkyloxycarbonyl, unsubstituted or substituted group I Aromatic heterocyclic alkyloxycarbonyl substituted with a group of the above, unsubstituted or nonaromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group I, unsubstituted Or an aromatic carbocyclic alkylamino substituted with one or more groups selected from substituent group I, a non-aromatic carbocyclic alkylamino substituted with one or more groups selected from unsubstituted or substituent group I , Aromatic heterocyclic alkylamino, unsubstituted or substituted with one or more groups selected from substituent group I, nonaromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, nonaromatic carbocyclic sulfanyl, aromatic Heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituent group I, one or more selected from unsubstituted or substituent group I An aromatic carbocyclic sulfonyl substituted with one or more groups, an unsubstituted or substituted heterocyclic sulfonyl substituted with one or more groups selected from Substituent Group I, and unsubstituted or substituted Non-aromatic heterocyclic sulfonyl substituted with one or more groups selected from Group I.
置換基群Ｈ：ヒドロキシ、アミノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、ヒドロキシアルキル、アルキルオキシアルキル、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環オキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシカルボニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環アルキルオキシアルキル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族炭素環スルホニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族炭素環スルホニル、非置換もしくは置換基群Ｉから選択される1以上の基で置換された芳香族複素環スルホニル、および非置換もしくは置換基群Ｉから選択される1以上の基で置換された非芳香族複素環スルホニル。 Substituent group H: hydroxy, amino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, Selected from alkynylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aromatic carbocyclic group substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I A non-aromatic carbocyclic group substituted with one or more groups selected from the above, an aromatic heterocyclic group substituted with one or more groups selected from unsubstituted or a substituent group I, unsubstituted or substituted groups 1 or more selected from I A non-aromatic heterocyclic group substituted with a group of the above, an aromatic carbocyclic oxy substituted with one or more groups selected from an unsubstituted or a substituent group I, selected from an unsubstituted or a substituent group I Selected from non-aromatic carbocyclic oxy substituted with one or more groups, unsubstituted heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I Selected from non-aromatic heterocyclic oxy substituted with one or more groups, aromatic carbocyclic carbonyl substituted with one or more groups selected from unsubstituted or substituted group I, unsubstituted or substituted group I A non-aromatic carbocyclic carbonyl substituted with one or more groups selected from the above, an aromatic heterocyclic carbonyl substituted with one or more groups selected from the unsubstituted or substituent group I, unsubstituted or substituted from the substituent group I Non-substituted with one or more selected groups Aromatic heterocyclic carbonyl, unsubstituted or substituted with one or more groups selected from an aromatic carbocyclic oxycarbonyl, unsubstituted or substituted group I selected from substituent group I One or more groups selected from non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, unsubstituted or substituted by substituent group I, unsubstituted or substituted by substituent group I A non-aromatic heterocyclic oxycarbonyl substituted with, an aromatic carbocyclic alkyl substituted with one or more groups selected from unsubstituted or substituent group I, one or more selected from unsubstituted or substituent group I A non-aromatic carbocyclic alkyl substituted with a group of the above, an aromatic heterocyclic alkyl substituted with one or more groups selected from an unsubstituted or a substituent group I, 1 selected from an unsubstituted or a substituent group I Less than A non-aromatic heterocyclic alkyl substituted with a group of the above, an aromatic carbocyclic alkyloxy substituted with one or more groups selected from an unsubstituted or a substituent group I, selected from an unsubstituted or a substituent group I A non-aromatic carbocyclic alkyloxy substituted with one or more groups, an aromatic heterocyclic alkyloxy, a non-aromatic heterocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituent group I; Aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group I, Non-aromatic carbon substituted with one or more groups selected from unsubstituted or substituted group I An aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from a ring alkyloxycarbonyl, unsubstituted or substituted group I, one or more selected from unsubstituted or substituted group I A non-aromatic heterocyclic alkyloxycarbonyl substituted with a group of the following: an aromatic carbocyclic alkyloxyalkyl substituted with one or more groups selected from an unsubstituted or substituted group I, an unsubstituted or substituted group I A non-aromatic carbocyclic alkyloxyalkyl substituted with one or more selected groups, an unsubstituted or heterocyclic alkyloxyalkyl substituted with one or more groups selected from substituent group I, unsubstituted or Non-aromatic heterocyclic alkyloxyalkyl substituted with one or more groups selected from substituent group I, Non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituent group I Substituted with one or more groups selected from unsubstituted or substituted group I, aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group I Aromatic heterocyclic sulfonyl, and unsubstituted or non-aromatic heterocyclic sulfonyl substituted with one or more groups selected from Substituent Group I.
置換基群Ｉ：オキソ、ハロゲン、シアノ、アルキル、ハロアルキル、ヒドロキシ、アルキルオキシ、ハロアルキルオキシ、アルキルオキシアルキル、ヒドロキシアルキル、非置換もしくは置換基群Ｊから選択される1または２つの基で置換されたアミノ、非置換もしくは置換基群Ｊから選択される1または２つの基で置換されたカルバモイル、および非置換もしくは置換基群Ｊから選択される1または２つの基で置換されたスルファモイル。 Substituent group I: oxo, halogen, cyano, alkyl, haloalkyl, hydroxy, alkyloxy, haloalkyloxy, alkyloxyalkyl, hydroxyalkyl, unsubstituted or substituted with one or two groups selected from substituent group J Carbamoyl substituted with 1 or 2 groups selected from amino, unsubstituted or substituted group J, and sulfamoyl substituted with 1 or 2 groups selected from unsubstituted or substituted group J.
置換基群Ｊ：アルキル、ハロアルキル、ヒドロキシアルキル、カルボキシアルキル、カルバモイル、アルキルカルボニル、ハロアルキルカルボニル、アルキルスルホニル、およびハロアルキルスルホニル。 Substituent group J: alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, carbamoyl, alkylcarbonyl, haloalkylcarbonyl, alkylsulfonyl, and haloalkylsulfonyl.
置換基群Ｋ：シアノ、ハロゲン、ヒドロキシ、カルボキシ、アルキルオキシ、ハロアルキルオキシ、アルケニルオキシ、ハロアルケニルオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、スルファモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、アルキルカルボニル、ハロアルキルカルボニル、アルキルカルボニルオキシ、アルキルオキシカルボニル、アルキルカルボニルアミノ、アルキルスルホニル、およびアルキルスルホニルアミノ。 Substituent group K: cyano, halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, haloalkenyloxy, amino, alkylamino, dialkylamino, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkylcarbonyl, Haloalkylcarbonyl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonylamino, alkylsulfonyl, and alkylsulfonylamino.
また、「置換もしくは非置換の非芳香族炭素環式基」および「置換もしくは非置換の非芳香族複素環式基」は「オキソ」で置換されていてもよい。この場合、以下のように炭素原子上の2個の水素原子が置換もしくは非置換のされている基を意味する。
Figure JPOXMLDOC01-appb-C000039
　上記、「置換もしくは非置換の非芳香族炭素環オキシ」、「置換もしくは非置換の非芳香族複素環オキシ」、「置換もしくは非置換の非芳香族炭素環カルボニル」、「置換もしくは非置換の非芳香族複素環カルボニル」、「置換もしくは非置換の非芳香族炭素環オキシカルボニル」、「置換もしくは非置換の非芳香族複素環オキシカルボニル」、「置換もしくは非置換の非芳香族炭素環スルファニル」、「置換もしくは非置換の非芳香族複素環スルファニル」、「置換もしくは非置換の非芳香族炭素環スルフィニル」、「置換もしくは非置換の非芳香族複素環スルフィニル」、「置換もしくは非置換の非芳香族炭素環スルホニル」、および「置換もしくは非置換の非芳香族複素環スルホニル」の非芳香族炭素環、および非芳香族複素環部分も上記と同様に「オキソ」で置換されていてもよい。 Further, the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted or unsubstituted as follows.
Figure JPOXMLDOC01-appb-C000039
The above-mentioned “substituted or unsubstituted non-aromatic carbocyclic oxy”, “substituted or unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted "Non-aromatic heterocyclic carbonyl", "Substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl", "Substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl", "Substituted or unsubstituted non-aromatic carbocyclic sulfanyl" ”,“ Substituted or unsubstituted non-aromatic heterocyclic sulfanyl ”,“ substituted or unsubstituted non-aromatic carbocyclic sulfinyl ”,“ substituted or unsubstituted non-aromatic heterocyclic sulfinyl ”,“ substituted or unsubstituted Non-aromatic carbocyclic sulfonyl "and non-aromatic carbocyclic and non-aromatic heterocyclic moieties of" substituted or unsubstituted non-aromatic heterocyclic sulfonyl " Serial and may be substituted Similarly, in "oxo".
「置換もしくは非置換のメチリデン」および「置換もしくは非置換のヒドロキシイミノ」の置換基としては、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基等が挙げられる。複数の置換基で置換される場合は、置換基は同一でも異なっていても良い。 Examples of the substituent of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino” include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, etc. are mentioned. When substituted with a plurality of substituents, the substituents may be the same or different.
「脱離基」としては、たとえば、ハロゲン、Ｃ１－６アルキルスルホニルオキシまたはアリールスルホニルオキシが挙げられる。 Examples of the “leaving group” include halogen, C 1-6 alkylsulfonyloxy or arylsulfonyloxy.
式（Ｉ）で示される化合物における、Ｒ１，Ｒ２，Ｒ３，Ｒ４、Ｘ，Ｘ’，Ｚ，Ｇ，Ｙ，ｍ，およびｎの好ましい態様を以下に示す。 下記の可能な組み合わせの化合物が好ましい。 Preferred embodiments of R 1 , R 2 , R 3 , R 4 , X, X ′, Z, G, Y, m, and n in the compound represented by the formula (I) are shown below. The following possible combinations of compounds are preferred:
Ｒ１およびＲ２は、好ましくは、
それぞれ独立して、水素原子、ハロゲン、ヒドロキシ、アシル、アシルオキシ、スルファニル、シアノ、ニトロ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環スルファニル、または置換もしくは非置換の非芳香族複素環スルファニルであるか、
隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレンを形成するか、
同一炭素原子に結合するＲ１およびＲ２が隣接する原子と一緒になって置換もしくは非置換の非芳香族炭素環を形成するか、
または同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソまたは置換もしくは非置換のメチリデンを形成する。
Ｒ１およびＲ２は、より好ましくは、
それぞれ独立して、水素原子、ハロゲン、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基であるか、
隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレンを形成するか、
同一炭素原子に結合するＲ１およびＲ２が隣接する原子と一緒になって置換もしくは非置換のシクロアルカンを形成するか、
または同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソまたは置換もしくは非置換のメチリデンである。
Ｒ１およびＲ２は、さらに好ましくは、
Ｒ１が、それぞれ独立して、水素原子、ハロゲン、シアノ、アルキル、ハロアルキル、アルケニル、アルキニル、アルキルオキシ、ハロアルキルオキシ、アルキルスルファニル、または、シクロアルキルであり、かつ、Ｒ２が、水素原子、ハロゲン、またはアルキルであるか、
隣接しない炭素原子に結合する２つのＲ１が一緒になって、アルキレンを形成し、かつＲ２が水素原子であるか、
同一炭素原子に結合するＲ１およびＲ２が、隣接する原子と一緒になって非置換またはハロゲンで置換されたシクロアルカンを形成するか、
または、同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソまたはメチリデンである。
Ｒ１およびＲ２が、それぞれ独立した基である場合、特に好ましい態様としては、（Ｒ１，Ｒ２）が、それぞれ独立して、（水素原子、水素原子）、（水素原子、メチル）、（メチル、水素原子）、（メチル、メチル）、（水素原子、ハロゲン）、（ハロゲン、水素原子）または（ハロゲン、ハロゲン）である。さらに好ましい態様としては、（Ｒ１，Ｒ２）が、それぞれ独立して、（水素原子、水素原子）、（水素原子、メチル）、（メチル、水素原子）、（メチル、メチル）、（水素原子、フッ素原子）、（フッ素原子、水素原子）または（フッ素原子）である。 R 1 and R 2 are preferably
Each independently a hydrogen atom, halogen, hydroxy, acyl, acyloxy, sulfanyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted nonaromatic carbon Cyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbon Ring sulfanyl, or substituted or Or a non-aromatic heterocyclic sulfanyl unsubstituted,
Two R 1 bonded to non-adjacent carbon atoms together form a substituted or unsubstituted alkylene,
R 1 and R 2 bonded to the same carbon atom, together with adjacent atoms, form a substituted or unsubstituted non-aromatic carbocycle;
Or R 1 and R 2 bonded to the same carbon atom together form oxo or substituted or unsubstituted methylidene.
R 1 and R 2 are more preferably
Each independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfanyl, substituted Or an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group,
Two R 1 bonded to non-adjacent carbon atoms together form a substituted or unsubstituted alkylene,
R 1 and R 2 bonded to the same carbon atom together with adjacent atoms form a substituted or unsubstituted cycloalkane,
Or, R 1 and R 2 bonded to the same carbon atom together are oxo or substituted or unsubstituted methylidene.
R 1 and R 2 are more preferably
Each R 1 is independently a hydrogen atom, halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, alkyloxy, haloalkyloxy, alkylsulfanyl, or cycloalkyl, and R 2 is a hydrogen atom, halogen, Or alkyl,
Two R 1 bonded to non-adjacent carbon atoms together form an alkylene and R 2 is a hydrogen atom,
R 1 and R 2 bonded to the same carbon atom, together with adjacent atoms, form an unsubstituted or halogen-substituted cycloalkane,
Or, R 1 and R 2 bonded to the same carbon atom together are oxo or methylidene.
When R 1 and R 2 are each an independent group, as a particularly preferred embodiment, (R 1 , R 2 ) are each independently (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (Methyl, hydrogen atom), (methyl, methyl), (hydrogen atom, halogen), (halogen, hydrogen atom) or (halogen, halogen). In a more preferred embodiment, (R 1 , R 2 ) are each independently (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (methyl, hydrogen atom), (methyl, methyl), (hydrogen Atom, fluorine atom), (fluorine atom, hydrogen atom) or (fluorine atom).
　Ｒ１および／またはＲ２が置換基を有する場合、Ｒ１またはＲ２の好ましい置換基は、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、スルファモイル、スルファニル、スルフィノ、シアノ、ニトロ、トリアルキルシリル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、アルキルスルファニル、アルケニルスルファニルおよびアルキニルスルファニルから選択される１以上の基である。より好ましい置換基は、ハロゲン、シアノ、ニトロ、アルキルオキシ、ハロアルキルオキシ、ジアルキルアミノおよびアルキルスルホニルから選択される１以上の基である。 When R 1 and / or R 2 has a substituent, preferred substituents for R 1 or R 2 are halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfanyl, sulfino, cyano, nitro, trialkylsilyl, alkyl One or more groups selected from oxy, alkenyloxy, alkynyloxy, haloalkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfanyl, alkenylsulfanyl and alkynylsulfanyl. More preferred substituents are one or more groups selected from halogen, cyano, nitro, alkyloxy, haloalkyloxy, dialkylamino and alkylsulfonyl.
「隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレン、置換もしくは非置換のアルケニレン、または置換もしくは非置換のアルキニレンを形成する」としては、例えば以下のような基：
Figure JPOXMLDOC01-appb-C000040
（式中、Ｒ５は置換もしくは非置換のアルキニレン、置換もしくは非置換のアルケニレン、または置換もしくは非置換のアルキニレンであり、その他の各定義は上記を同意義である。）
等を含有する。 “Two R 1 bonded to non-adjacent carbon atoms together form a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene”. For example, Base:
Figure JPOXMLDOC01-appb-C000040
(In the formula, R 5 is substituted or unsubstituted alkynylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, and the other definitions are the same as above.)
Etc.
Ｒ５は、好ましくは置換もしくは非置換のアルキニレンであり、より好ましくは非置換もしくはハロゲンで置換されたアルキニレンである。該アルキニレンの炭素数は、好ましくは１～４、より好ましくは１～３である。 R 5 is preferably a substituted or unsubstituted alkynylene, more preferably an unsubstituted or halogen-substituted alkynylene. The alkynylene preferably has 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms.
「同一炭素原子に結合するＲ１およびＲ２が一緒になって、置換もしくは非置換のメチリデンを形成する」および「Ｒ３およびＲ４が一緒になって、置換もしくは非置換のメチリデンを形成する」とは、式：
Figure JPOXMLDOC01-appb-C000041
（Ｒ６およびＲ７は、それぞれ独立して上記の「置換もしくは非置換のメチリデン」の置換基と同意義である。）
で示される基を意味する。
Ｒ６およびＲ７は、好ましくは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基である。より好ましくは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基、または置換もしくは非置換の非芳香族複素環式基である。さらに好ましくは、水素原子、非置換またはハロゲンで置換されたアルキル、または非置換またはハロゲンで置換されたシクロアルキルである。特に好ましくは、水素原子である。 “R 1 and R 2 bonded to the same carbon atom together form a substituted or unsubstituted methylidene” and “R 3 and R 4 together form a substituted or unsubstituted methylidene. Is the formula:
Figure JPOXMLDOC01-appb-C000041
(R 6 and R 7 are each independently the same as the substituent of the above-mentioned “substituted or unsubstituted methylidene”.)
Means a group represented by
R 6 and R 7 are preferably each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group or substituted Or it is an unsubstituted heterocyclic group. More preferably, they are a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group. More preferably, they are a hydrogen atom, an unsubstituted or halogen-substituted alkyl, or an unsubstituted or halogen-substituted cycloalkyl. Particularly preferred is a hydrogen atom.
ｎは、好ましくは２～４、より好ましくは２または３、特に好ましくは３である。 n is preferably 2 to 4, more preferably 2 or 3, particularly preferably 3.
　式：
Figure JPOXMLDOC01-appb-C000042
の好ましい態様としては、式：
Figure JPOXMLDOC01-appb-C000043
（式中、各定義は前記と同意義である。）
が挙げられる。
より好ましい態様としては、式：
Figure JPOXMLDOC01-appb-C000044
（式中、各定義は前記と同意義である。）
が挙げられる。 formula:
Figure JPOXMLDOC01-appb-C000042
In a preferred embodiment of the formula:
Figure JPOXMLDOC01-appb-C000043
(In the formula, each definition is as defined above.)
Is mentioned.
In a more preferred embodiment, the formula:
Figure JPOXMLDOC01-appb-C000044
(In the formula, each definition is as defined above.)
Is mentioned.
Ｇは、好ましくは、置換されたフェニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の複素環式基、または式（Ｉ－Ｇ１）：
Figure JPOXMLDOC01-appb-C000045
（式中、各定義は前記と同意義である。）
で示される基ある。
好ましくは、置換もしくは非置換の２環の非芳香族炭素環式基、置換もしくは非置換の複素環式基、または式（Ｉ－Ｇ１）で示される基である。
より好ましくは、置換もしくは非置換の複素環式基、または式（Ｉ－Ｇ１）で示される基である。
さらに好ましくは、置換もしくは非置換の単環の芳香族複素環式基、置換もしくは非置換の単環または２環の非芳香族複素環式基、または式（Ｉ－Ｇ１）で示される基である。
Ｇが置換基を有する場合、該置換基の好ましい態様は、置換基群Ｂから選択される１以上の基である。より好ましい態様としては、置換基群Ｅから選択される1以上の基である。該置換基が複数存在する場合は、同一でも異なっていても良い。
別の好ましい置換基の態様としては、オキソ、ハロゲン、ヒドロキシ、アミノ、シアノ、シアノアルキル、アルキル、アルケニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、ヒドロキシアルキルオキシ、アルキルオキシアルキルオキシ、ヒドロキシアルキル、ヒドロキシアルキニル、シアノアルキル、アルキルオキシアルキル、アルキルオキシアルキルオキシ、アルキルオキシアルキルオキシアルキルオキシ、アルキルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、モノアルキルスルホニルアミノ、アルキルオキシイミノ、ハロアルキルオキシイミノ、アルキルオキシアルキルオキシイミノ、メチリデン、アルキルメチリデン、アルキルオキシカルボニルメチリデン、アルキルオキシカルボニル、アルキルオキシカルボニルアルキルオキシ、アルキルオキシカルボニルアルキル、アルキルスルファニル、アルキルスルフィニル、モノアルキルスルファモイル、ジアルキルスルファモイル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環式基、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環式基、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族複素環式基、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族複素環式基、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環オキシ、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環オキシ、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族複素環オキシ、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族複素環オキシ、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族複素環カルボニル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環アルキル、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環アルキル、非置換置換基群Ｂから選択される1以上の基で置換された非芳香族複素環アルキル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族複素環アルキル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環アルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環アルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族複素環アルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族複素環アルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環アルキルオキシアルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環オキシアルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環オキシアルキル、置換基群Ｂから選択される1以上の基で置換された芳香族炭素環オキシアルキル、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環オキシイミノ、非置換または置換基群Ｂから選択される1以上の基で置換されたアルキルオキシ芳香族炭素環アルキルオキシ、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環スルファモイル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環アルキルスルファモイル、非置換または置換基群Ｂから選択される1以上の基で置換された芳香族炭素環スルファニル、非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族炭素環スルホニル、および非置換または置換基群Ｂから選択される1以上の基で置換された非芳香族複素環スルホニルから選択される１以上の基である。該置換基が複数存在する場合は、同一でも異なっていても良い。好ましい置換基の数としては、０～８であり、より好ましくは０～５、さらに好ましくは０～３である。
Ｇの非芳香族炭素環式基としては、シクロプロピル、インダニル（特に好ましくは、インダン－４－イル）等が挙げられる。
Ｇの複素環式基としては、チエニル（特に好ましくは、チオフェン－２－イルまたはチオフェン－３－イル）、フリル（特に好ましくは、フラン－３－イル）、チアゾール（特に好ましくは、チアゾール－４－イル）、ピロリル（特に好ましくは、ピロール－２－イル）、イミダゾリル（特に好ましくは、イミダゾール－２－イル）、ピリジル（特に好ましくは、ピリジン－２－イル、ピリジン－３－イル、ピリジン－４－イル）、ピリミジニル（特に好ましくは、ピリミジン－２－イル、ピリミジン－４－イル、ピリミジン－５－イル）、ピラジニル（特に好ましくは、ピラジン－２－イル）、ピペリジニル（特に好ましくは、ピペリジン－３－イル、ピペリジン－４－イル）、ピペラジニル（特に好ましくは、ピペラジン－１―イル）、チオモルホリニル（特に好ましくは、チオモルホリン－２－イル）、アゼパン-1-イル、オクタヒドロ－7H-ピラノ[2,3－c]ピリジン－7－イル、ヘキサヒドロ－2H－ピラノ[3,2－c]ピリジン-6(5H)-イル、7,8-ジヒドロピリド[4,3－d]ピリミジン-6(5H)－イル、インドリル（特に好ましくは、１－インドリル、インドール－２－イル、インドール－４－イル、インドール－３－イル）、ベンゾフリル（特に好ましくは、ベンゾフリル－３－イル、ベンゾフリル－７－イル、ベンゾフリル－４－イル）、ベンゾチエニル（特に好ましくは、ベンゾチオフェン－３－イル、ベンゾチオフェン－４－イル）、キノリル（特に好ましくは、キノリン－５－イル）、イソキノリル（特に好ましくは、イソキノリン）、ベンズチアゾリル（特に好ましくは、ベンズチアゾール－４－イル、ベンズチアゾール－５－イル）、テトラヒドロイソキノリル（特に好ましくは、１，２，３，４－テトラヒドロイソキノリン－５－イル）、ジベンゾフリル（特に好ましくは、ジベンゾ［ｂ、ｄ］フラン－４－イル）等が挙げられる。 G is preferably substituted phenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted heterocyclic group, or formula (I-G1):
Figure JPOXMLDOC01-appb-C000045
(In the formula, each definition is as defined above.)
There is a group represented by
A substituted or unsubstituted bicyclic non-aromatic carbocyclic group, a substituted or unsubstituted heterocyclic group, or a group represented by the formula (I-G1) is preferable.
More preferably, it is a substituted or unsubstituted heterocyclic group, or a group represented by the formula (I-G1).
More preferably, a substituted or unsubstituted monocyclic aromatic heterocyclic group, a substituted or unsubstituted monocyclic or bicyclic nonaromatic heterocyclic group, or a group represented by the formula (I-G1) is there.
When G has a substituent, a preferred embodiment of the substituent is one or more groups selected from the substituent group B. A more preferred embodiment is one or more groups selected from the substituent group E. When a plurality of the substituents are present, they may be the same or different.
Other preferred substituent embodiments include oxo, halogen, hydroxy, amino, cyano, cyanoalkyl, alkyl, alkenyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, Hydroxyalkyl, hydroxyalkynyl, cyanoalkyl, alkyloxyalkyl, alkyloxyalkyloxy, alkyloxyalkyloxyalkyloxy, alkylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, monoalkylsulfonylamino, alkyloxyimino, haloalkyloxyimino , Alkyloxyalkyloxyimino, methylidene, alkylmethylidene, alkyloxycarbonylmethyl One or more groups selected from the group consisting of redene, alkyloxycarbonyl, alkyloxycarbonylalkyloxy, alkyloxycarbonylalkyl, alkylsulfanyl, alkylsulfinyl, monoalkylsulfamoyl, dialkylsulfamoyl, unsubstituted or substituent group B One or more selected from a substituted aromatic carbocyclic group, unsubstituted or substituted with one or more groups selected from Substituent Group B, unsubstituted aromatic carbocyclic group, unsubstituted or substituted Group B Selected from the group consisting of an aromatic heterocyclic group substituted with one of the following groups, a non-aromatic heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group B, and an unsubstituted or substituted group B An aromatic carbocyclic oxy substituted with one or more groups, a non-aromatic carbocyclic oxy unsubstituted or substituted with one or more groups selected from substituent group B, Aromatic heterocyclic oxy substituted with one or more groups selected from substituted or substituent group B, non-aromatic heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituent group B, Non-aromatic heterocyclic carbonyl substituted with one or more groups selected from unsubstituted or substituted group B, Aromatic carbocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted group B A non-aromatic carbocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted group B, a non-aromatic heterocyclic ring substituted with one or more groups selected from unsubstituted substituent group B An aromatic heterocyclic ring substituted with one or more groups selected from alkyl, unsubstituted or substituted group B, an aromatic carbocycle substituted with one or more groups selected from unsubstituted or substituted group B Selected from alkyloxy, unsubstituted or substituent group B A non-aromatic carbocyclic alkyloxy substituted with one or more groups, an aromatic heterocyclic alkyloxy substituted with one or more groups selected from unsubstituted or substituted group B, an unsubstituted or substituted group B Non-aromatic heterocyclic alkyloxy substituted with one or more groups selected from: unsubstituted or aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group B, unsubstituted or Aromatic carbocyclic alkyloxyalkyloxy substituted with one or more groups selected from Substituent Group B, Aromatic carbocyclic oxyalkyl unsubstituted or substituted with one or more groups selected from Substituent Group B Aromatic carbocyclic oxyalkyl substituted with one or more groups selected from substituent group B, Aromatic carbocyclic oxyalkyl substituted with one or more groups selected from oxy, unsubstituted or substituent group B , Non-aromatic carbocyclic oxyimino substituted with one or more groups selected from unsubstituted or substituted group B, alkyloxy aromatic carbon substituted with one or more groups selected from unsubstituted or substituted group B Ring alkyloxy, unsubstituted or substituted with one or more groups selected from substituent group B, non-aromatic carbocyclic sulfamoyl, unsubstituted or substituted with one or more groups selected from substituent group B Aromatic carbocyclic sulfanyl substituted with one or more groups selected from unsubstituted or substituted group B, substituted with one or more groups selected from unsubstituted or substituted group B And one or more groups selected from a non-aromatic heterocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group B. When a plurality of the substituents are present, they may be the same or different. The number of substituents is preferably 0 to 8, more preferably 0 to 5, and still more preferably 0 to 3.
Examples of the non-aromatic carbocyclic group for G include cyclopropyl and indanyl (particularly preferably, indan-4-yl).
The heterocyclic group of G includes thienyl (particularly preferably thiophen-2-yl or thiophen-3-yl), furyl (particularly preferably furan-3-yl), thiazole (particularly preferably thiazole-4 -Yl), pyrrolyl (particularly preferably pyrrol-2-yl), imidazolyl (particularly preferably imidazol-2-yl), pyridyl (particularly preferably pyridin-2-yl, pyridin-3-yl, pyridine- 4-yl), pyrimidinyl (particularly preferably pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), pyrazinyl (particularly preferably pyrazin-2-yl), piperidinyl (particularly preferred piperidin -3-yl, piperidin-4-yl), piperazinyl (particularly preferably piperazin-1-yl), Omorpholinyl (particularly preferably, thiomorpholin-2-yl), azepan-1-yl, octahydro-7H-pyrano [2,3-c] pyridin-7-yl, hexahydro-2H-pyrano [3,2-c] Pyridin-6 (5H) -yl, 7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl, indolyl (particularly preferably 1-indolyl, indol-2-yl, indol-4- Yl, indol-3-yl), benzofuryl (particularly preferred, benzofuryl-3-yl, benzofuryl-7-yl, benzofuryl-4-yl), benzothienyl (particularly preferred, benzothiophen-3-yl, benzothiophene) -4-yl), quinolyl (particularly preferred, quinolin-5-yl), isoquinolyl (particularly preferred, isoquinoline), benzthiazolyl (particularly preferred benzthiazole) -4-yl, benzthiazol-5-yl), tetrahydroisoquinolyl (particularly preferably 1,2,3,4-tetrahydroisoquinolin-5-yl), dibenzofuryl (particularly preferably dibenzo [b, d Furan-4-yl) and the like.
「Ｇの炭素環式基がフェニルの場合、ｉ）該フェニル基は少なくとも１つ以上の置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキルまたは置換もしくは非置換の複素環アルキルで置換されており、該フェニルはさらに置換されていてもよく」の該フェニルにさらに置換される置換基としては、置換基群Ｂから選択される基が挙げられる。好ましくは、置換基群Ｉから選択される基が挙げられる。より好ましくは、ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。置換基が複数存在する場合は、該置換基は同一でも異なっていても良い。該フェニルにさらに置換される置換基の数としては、０～４であり、好ましくは０～２、より好ましくは０または１である。「置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキルまたは置換もしくは非置換の複素環アルキル」の好ましい置換位置としては、オルト位またはメタ位であり、より好ましくはメタ位である。該フェニルにさらに置換される置換基の好ましい置換位置としては、オルト位またはメタ位であり、より好ましくは、オルト位である。好ましい態様としては、Ｇが下式：
Figure JPOXMLDOC01-appb-C000046
（式中、Ｒ１１は置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキルまたは置換もしくは非置換の複素環アルキルであり、Ｒ１２は水素原子または置換基群Ｂから選択される基が挙げられる）
で示される基である。
Ｒ１１は、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基が好ましく、より好ましくは、置換もしくは非置換の単環または二環の芳香族炭素環式基または置換もしくは非置換の単環または二環の芳香族複素環式基である。Ｒ１１の置換基としては、置換基群Ｂから選択される1以上の基が挙げられる。好ましくは、置換基群Ｉから選択される基が挙げられる。より好ましくは、ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。置換基が複数存在する場合は、同一でも異なっていても良い。該置換基の数は、０～５であり、好ましくは０～３、より好ましくは０～２である。該置換基は、少なくとも１つのオルト位に置換されているのが好ましい。
Ｒ１２は、好ましくは水素原子または置換基群Ｉから選択される基であり、より好ましくはハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。 "When the carbocyclic group of G is phenyl, i) the phenyl group is at least one or more substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocycle The substituent further substituted on the phenyl ”substituted with alkyl or substituted or unsubstituted heterocyclic alkyl, and the phenyl may be further substituted” includes a group selected from the substituent group B. Can be mentioned. Preferably, the group selected from the substituent group I is mentioned. More preferably, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned. When a plurality of substituents are present, the substituents may be the same or different. The number of substituents further substituted on the phenyl is 0 to 4, preferably 0 to 2, more preferably 0 or 1. The preferred substitution position of “substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl or substituted or unsubstituted heterocyclic alkyl” is ortho-position or meta. The meta position is more preferable. A preferred substitution position of the substituent further substituted on the phenyl is an ortho position or a meta position, and more preferably an ortho position. In a preferred embodiment, G is represented by the following formula:
Figure JPOXMLDOC01-appb-C000046
Wherein R 11 is a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic alkyl or a substituted or unsubstituted heterocyclic alkyl, and R 12 is And a group selected from a hydrogen atom or a substituent group B)
It is group shown by these.
R 11 is preferably a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, more preferably a substituted or unsubstituted monocyclic or bicyclic aromatic carbocyclic group. A group or a substituted or unsubstituted monocyclic or bicyclic aromatic heterocyclic group. Examples of the substituent for R 11 include one or more groups selected from the substituent group B. Preferably, the group selected from the substituent group I is mentioned. More preferably, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned. When there are a plurality of substituents, they may be the same or different. The number of the substituent is 0 to 5, preferably 0 to 3, and more preferably 0 to 2. The substituent is preferably substituted at at least one ortho position.
R 12 is preferably a hydrogen atom or a group selected from Substituent Group I, more preferably halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
「Ｇの炭素環式基がフェニルの場合、ｉｉ）該フェニル基の少なくとも１つのメタ位が置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシで置換されており、該フェニル基はさらに置換されていてもよく、」の該フェニルにさらに置換される置換基としては、置換基群Ｂから選択される基が挙げられる。好ましくは、置換基群Ｉから選択される基が挙げられる。より好ましくは、ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。置換基が複数存在する場合は、該置換基は同一でも異なっていても良い。該置換基の置換位置としては、オルト位またはパラ位が好ましく、オルト位がより好ましい。該フェニルにさらに置換される置換基の数としては、０～４であり、好ましくは０～２、より好ましくは０または１である。好ましい態様としては、Ｇが下式：
Figure JPOXMLDOC01-appb-C000047
（式中、Ｒ１３は置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシであり、Ｒ１４は水素原子または置換基群Ｂから選択される基である）
で示される基である。
Ｒ１３は、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシが好ましく、より好ましくは、置換もしくは非置換の単環の芳香族炭素環オキシ、置換もしくは非置換の単環の芳香族複素環オキシ、または置換もしくは非置換の単環の芳香族炭素環アルキルオキシである。Ｒ１３の置換基としては、置換基群Ｂから選択される1以上の基が挙げられる。好ましくは、置換基群Ｉから選択される基が挙げられる。より好ましくは、ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。置換基が複数存在する場合は、同一でも異なっていても良い。該置換基の数は、０～５であり、好ましくは０～３、より好ましくは０～２である。該置換基は、少なくとも１つのオルト位に置換されているのが好ましい。
Ｒ１３は、好ましくは水素原子または置換基群Ｉから選択される基であり、より好ましくはハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ等が挙げられる。 “When the carbocyclic group of G is phenyl, ii) at least one meta position of the phenyl group is substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted Substituted with a substituted or unsubstituted aromatic heterocyclic alkyloxy, and the phenyl group may be further substituted. Includes a group selected from Substituent Group B. Preferably, the group selected from the substituent group I is mentioned. More preferably, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned. When a plurality of substituents are present, the substituents may be the same or different. The substitution position of the substituent is preferably the ortho position or the para position, and more preferably the ortho position. The number of substituents further substituted on the phenyl is 0 to 4, preferably 0 to 2, more preferably 0 or 1. In a preferred embodiment, G is represented by the following formula:
Figure JPOXMLDOC01-appb-C000047
(Wherein R 13 represents substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic Ring alkyloxy, and R 14 is a hydrogen atom or a group selected from substituent group B)
It is group shown by these.
R 13 represents substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy. And more preferably, a substituted or unsubstituted monocyclic aromatic carbocyclic oxy, a substituted or unsubstituted monocyclic aromatic heterocyclic oxy, or a substituted or unsubstituted monocyclic aromatic carbocyclic alkyloxy It is. Examples of the substituent for R 13 include one or more groups selected from the substituent group B. Preferably, the group selected from the substituent group I is mentioned. More preferably, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned. When there are a plurality of substituents, they may be the same or different. The number of the substituent is 0 to 5, preferably 0 to 3, and more preferably 0 to 2. The substituent is preferably substituted at at least one ortho position.
R 13 is preferably a hydrogen atom or a group selected from Substituent Group I, more preferably halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
　Ｒ３およびＲ４が「ａ）Ｒ３およびＲ４が隣接する原子と一緒になって、置換もしくは非置換の非芳香族炭素環、または置換もしくは非置換の非芳香族複素環を形成する」場合、好ましくは、置換もしくは非置換の単環の非芳香族炭素環、置換もしくは非置換の架橋構造もしくはスピロ構造を有する非芳香族炭素環、置換もしくは非置換の単環の非芳香族複素環または置換もしくは非置換の架橋構造もしくはスピロ構造を有する非芳香族複素環である。該環は、好ましくは３～８員の環であり、より好ましくは３～５員の環である。 R 3 and R 4 “a) R 3 and R 4 together with the adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle” Preferably a substituted or unsubstituted monocyclic non-aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring having a bridged structure or a spiro structure, a substituted or unsubstituted monocyclic non-aromatic heterocyclic ring Alternatively, it is a non-aromatic heterocyclic ring having a substituted or unsubstituted bridged structure or spiro structure. The ring is preferably a 3- to 8-membered ring, more preferably a 3- to 5-membered ring.
　Ｒ３およびＲ４が「一緒になって、置換もしくは非置換のヒドロキシイミノを形成する」とは、式：
Figure JPOXMLDOC01-appb-C000048
（式中、Ｒ８は上記「置換もしくは非置換のヒドロキシイミノ」の置換基と同意義である。ここで、窒素原子と酸素原子との間の波線は、シス結合、トランス結合またはその混合であることを意味する。）
で示される基である。
Ｒ８は好ましくは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基である。より好ましくは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基、または置換もしくは非置換の非芳香族複素環式基である。さらに好ましくは、非置換またはハロゲンで置換されたアルキル、または非置換またはハロゲンで置換されたシクロアルキルである。 R 3 and R 4 are taken together to form a substituted or unsubstituted hydroxyimino.
Figure JPOXMLDOC01-appb-C000048
(In the formula, R 8 has the same meaning as the substituent of the above-mentioned “substituted or unsubstituted hydroxyimino”. Here, the wavy line between the nitrogen atom and the oxygen atom is a cis bond, a trans bond or a mixture thereof. It means that there is.)
It is group shown by these.
R 8 is preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group. is there. More preferably, they are a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group. More preferred is unsubstituted or halogen-substituted alkyl, or unsubstituted or halogen-substituted cycloalkyl.
　Ｒ３およびＲ４が「一緒になって、置換もしくは非置換のメチリデンを形成する」とは、式：
Figure JPOXMLDOC01-appb-C000049
（式中、Ｒ９およびＲ１０は上記「置換もしくは非置換のメチリデン」の置換基と同意義である。）
で示される基である。
Ｒ９およびＲ１０は好ましくは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基である。より好ましくは、水素原子または置換もしくは非置換のアルキルである。さらに好ましくは、ともに水素原子である。 R 3 and R 4 together form a substituted or unsubstituted methylidene
Figure JPOXMLDOC01-appb-C000049
(Wherein R 9 and R 10 have the same meanings as the substituents of the above-mentioned “substituted or unsubstituted methylidene”.)
It is group shown by these.
R 9 and R 10 are preferably each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted An unsubstituted heterocyclic group. More preferably, they are a hydrogen atom or substituted or unsubstituted alkyl. More preferably, both are hydrogen atoms.
　Ｘ’は、好ましくは、ハロゲン、シアノ、アシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環オキシ、置換もしくは非置換の複素環オキシ、置換もしくは非置換の炭素環アルキルオキシ、または置換もしくは非置換の複素環アルキルオキシである。より好ましくは、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシである。さらに好ましくは、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシである。
Ｘ’の置換基としては、置換基群Ｆから選択される基が挙げられる。好ましくは、非置換もしくは置換基群Ｉから選択される１以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される１以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｉから選択される１以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｉから選択される１以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｉから選択される１以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される１以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される１以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｉから選択される１以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｉから選択される１以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｉから選択される１以上の基で置換された芳香族複素環アルキルオキシ、および置換基群Ｉから選択される基等が挙げられる。より好ましくは、ハロゲン、シアノ、非置換もしくは置換基群Ｋから選択される１以上の基で置換された芳香族炭素環式基、および非置換もしくは置換基群Ｋから選択される１以上の基で置換された芳香族複素環式基等が挙げられる。 X ′ is preferably halogen, cyano, acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted amino, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group Substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted carbocyclic alkyloxy, or substituted or unsubstituted heterocyclic alkyloxy. More preferably, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, Substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy. More preferably, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted aromatic heterocyclic oxy, Substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy.
Examples of the substituent for X ′ include a group selected from the substituent group F. Preferably, an aromatic carbocyclic group substituted with one or more groups selected from unsubstituted or substituted group I, an aromatic group substituted with one or more groups selected from unsubstituted or substituted group I Substituted with one or more groups selected from heterocyclic groups, unsubstituted or substituted with one or more groups selected from substituent group I, non-aromatic carbocyclic groups, unsubstituted or substituted with group I A non-aromatic heterocyclic group, an aromatic or carbocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group I, or one or more groups selected from unsubstituted or substituted group I One or more groups selected from a substituted aromatic heterocyclic oxy, non-aromatic carbocyclic oxy, unsubstituted or substituted or group I selected from one or more groups selected from substituent or group I A non-aromatic heterocyclic oxy substituted with an unsubstituted or An aromatic carbocyclic alkyloxy substituted with one or more groups selected from the substituent group I, an aromatic heterocyclic alkyloxy unsubstituted or substituted with one or more groups selected from the substituent group I, and Examples include groups selected from Substituent Group I. More preferably, an aromatic carbocyclic group substituted with one or more groups selected from halogen, cyano, unsubstituted or substituent group K, and one or more groups selected from unsubstituted or substituent group K And aromatic heterocyclic groups substituted with.
Ｙは、好ましくは、ベンゼンまたは複素環である。より好ましくは、ベンゼン、単環の芳香族複素環もしくは非芳香族複素環、または２環もしくは３環の非芳香族複素環である。２環もしくは３環の非芳香族複素環は架橋構造および／またはスピロ構造を有していてもよい。特に好ましくは、５～６員の芳香族複素環または９～１０員の非芳香族複素環である。 Y is preferably benzene or a heterocyclic ring. More preferably, it is benzene, a monocyclic aromatic heterocycle or a non-aromatic heterocycle, or a bicyclic or tricyclic nonaromatic heterocycle. The bicyclic or tricyclic non-aromatic heterocyclic ring may have a bridge structure and / or a spiro structure. Particularly preferred is a 5- to 6-membered aromatic heterocyclic ring or a 9- to 10-membered non-aromatic heterocyclic ring.
　Ｘは、好ましくは、それぞれ独立して、ハロゲン、シアノ、アシル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、または置換もしくは非置換の芳香族炭素環スルホニルである。
より好ましくは、それぞれ独立して、ハロゲン、シアノ、アシル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、または置換もしくは非置換の芳香族炭素環スルホニルである。
Ｘの別の好ましい態様としては、それぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環オキシアルキル、置換もしくは非置換の非芳香族炭素環オキシアルキル、置換もしくは非置換の芳香族複素環オキシアルキル、置換もしくは非置換の非芳香族複素環オキシアルキル、置換もしくは非置換の芳香族炭素環アルキルオキシアルキル、置換もしくは非置換の非芳香族炭素環アルキルオキシアルキル、置換もしくは非置換の芳香族複素環アルキルオキシアルキル、置換もしくは非置換の非芳香族複素環アルキルオキシアルキル、置換もしくは非置換の芳香族炭素カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、または置換もしくは非置換の芳香族炭素環スルホニルである。
Ｘのより好ましい態様としては、それぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族複素環オキシアルキル、置換もしくは非置換の芳香族複素環アルキルオキシアルキル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、または置換もしくは非置換の芳香族炭素環スルホニルである。 X is preferably each independently halogen, cyano, acyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted Or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or substituted Ku is unsubstituted aromatic carbocyclic sulfonyl.
More preferably, each independently, halogen, cyano, acyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic ring Oxy or substituted or unsubstituted aromatic carbocyclic sulfonyl.
Another preferred embodiment of X is independently halogen, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted non-aromatic carbocyclic alkyl, substituted or unsubstituted aromatic Heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic charcoal Ring oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, Substituted or unsubstituted non-aromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted non-aromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic carbocyclic oxyalkyl, Substituted or unsubstituted non-aromatic carbocyclic oxyalkyl, substituted or unsubstituted aromatic heterocyclic oxyalkyl, substituted or unsubstituted non-aromatic heterocyclic oxyalkyl, substituted or unsubstituted aromatic carbocyclic alkyloxyalkyl Substituted or unsubstituted non-aromatic carbocyclic alkyloxyalkyl, substituted or unsubstituted aromatic Heterocyclic alkyloxyalkyl, substituted or unsubstituted non-aromatic heterocyclic alkyloxyalkyl, substituted or unsubstituted aromatic carbon carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic hetero A ring carbonyl, a substituted or unsubstituted non-aromatic heterocyclic carbonyl, or a substituted or unsubstituted aromatic carbocyclic sulfonyl;
As more preferred embodiments of X, each independently, halogen, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-substituted Aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic ring Oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic Aromatic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted nonaromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic oxyalkyl, substituted or unsubstituted aromatic heterocyclic Ring alkyloxyalkyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, or substituted or unsubstituted aromatic carbocyclic sulfonyl.
　Ｘが環式基を有する場合、該環の好ましい態様としては、単環の置換もしくは非置換の芳香族炭素環、単環もしくは２環の置換もしくは非置換の芳香族複素環、または単環もしくは２環の置換もしくは非置換の非芳香族複素環である。より好ましい態様としては、６員の置換もしくは非置換の芳香族炭素環、５～６員の単環もしくは９～１０員の２環の置換もしくは非置換の芳香族複素環、または５～６員の単環もしくは９～１０員の２環の置換もしくは非置換の非芳香族複素環である。
Ｘの芳香族炭素環式基としては、ベンジル、ナフチル（特に好ましくは、ナフタレン－２－イル）等が挙げられる。
Ｘの非芳香族炭素環式基としては、下式：
Figure JPOXMLDOC01-appb-C000050
 で示される基等が挙げられる。特に好ましくは、下式：
Figure JPOXMLDOC01-appb-C000051
で示される基等が挙げられる。
Ｘの芳香族複素環式基としては、ピラゾリル、オキサゾリル、イソオキサゾリル、フリル、イミダゾリル、チエニル、チアゾリル、ピロリル、ピリジル、ピリミジル、ピリダジニル、インドリル、キノリル、イソキノリル、ベンゾフリル、ベンゾチエニル、キナゾリル等が挙げられる。特に好ましくは、下式：
Figure JPOXMLDOC01-appb-C000052
 で示される基が挙げられる。 When X has a cyclic group, preferred embodiments of the ring include monocyclic substituted or unsubstituted aromatic carbocyclic ring, monocyclic or bicyclic substituted or unsubstituted aromatic heterocyclic ring, or monocyclic or It is a bicyclic substituted or unsubstituted non-aromatic heterocycle. In a more preferred embodiment, a 6-membered substituted or unsubstituted aromatic carbocyclic ring, a 5 to 6-membered monocyclic ring or a 9 to 10-membered bicyclic substituted or unsubstituted aromatic heterocyclic ring, or a 5 to 6-membered ring is used. Or a 9 to 10-membered bicyclic substituted or unsubstituted non-aromatic heterocyclic ring.
Examples of the aromatic carbocyclic group of X include benzyl and naphthyl (particularly preferably naphthalen-2-yl).
As the non-aromatic carbocyclic group of X, the following formula:
Figure JPOXMLDOC01-appb-C000050
 Group etc. which are shown by these, etc. are mentioned. Particularly preferably, the following formula:
Figure JPOXMLDOC01-appb-C000051
Group etc. which are shown by these, etc. are mentioned.
Examples of the aromatic heterocyclic group of X include pyrazolyl, oxazolyl, isoxazolyl, furyl, imidazolyl, thienyl, thiazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, quinazolyl and the like. Particularly preferably, the following formula:
Figure JPOXMLDOC01-appb-C000052
 The group shown by these is mentioned.
　Ｘの非芳香族複素環式基としては、下式：
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000054
 で示される基等が挙げられる。特に好ましくは、下式：
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000056
で示される基等が挙げられる。 As the non-aromatic heterocyclic group of X, the following formula:
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000054
 Group etc. which are shown by these, etc. are mentioned. Particularly preferably, the following formula:
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000056
Group etc. which are shown by these, etc. are mentioned.
　Ｘの別の好ましい態様としては、下式：
Figure JPOXMLDOC01-appb-C000057
（式中、環上にさらに１以上の置換基を有していても良い。該置換基としては、下記の置換基等が挙げられる）
で示される基等が挙げられる。 In another preferred embodiment of X, the following formula:
Figure JPOXMLDOC01-appb-C000057
(In the formula, one or more substituents may be further present on the ring. Examples of the substituent include the following substituents)
Group etc. which are shown by these, etc. are mentioned.
Ｘが置換基を有する場合、該置換基は置換基群Ａ、置換基群Ｂ、置換基群Ｃ、または置換基群Ｄ等が挙げられる。好ましくは、置換基群Ｇ、置換基群Ｅまたは置換基群Ｈ等が挙げられ、より好ましくは、置換基群Ｋ、置換基群Ｆ、または置換基群Ｊ等が挙げられる。該置換基の好ましい態様としては、オキソ、ハロゲン、ヒドロキシ、非置換もしくは置換基群Ｃから選択される１以上の基で置換されたアミノ、非置換もしくは置換基群Ｃから選択される１以上の基で置換されたカルバモイル、シアノ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルケニル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルオキシ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルケニルオキシ、アルキニルオキシ、ヒドロキシアルキニル、シアノアルキル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルオキシアルキルオキシアルキルオキシ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルカルボニル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルスルホニル、ハロアルキルオキシイミノ、アルキルオキシアルキルオキシイミノ、メチリデン、アルキルメチリデン、アルキルオキシカルボニルメチリデン、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルオキシカルボニル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルオキシカルボニルアルキル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルスルファニル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルスルフィニル、非置換もしくは置換基群Ｃから選択される１以上の基で置換されたスルファモイル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシアルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシアルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシアルキル、非芳香族炭素環オキシイミノ、アルキルオキシ芳香族炭素環アルキルオキシ、非芳香族炭素環スルファモイル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルスルファモイル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環スルファニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環スルホニル、および非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環スルホニルから選択される１以上の基である。該置換基が複数存在する場合は、同一でも異なっていても良い。
より好ましくは、オキソ、ハロゲン、ヒドロキシ、シアノ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルケニル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルオキシ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルケニルオキシ、アルキニルオキシ、ヒドロキシアルキル、シアノアルキル、アルキルオキシアルキル、アルキルオキシアルキルオキシ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルオキシアルキルオキシアルキルオキシ、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルカルボニル、非置換もしくは置換基群Ｈから選択される１以上の基で置換されたアミノ、非置換もしくは置換基群Ｈから選択される１以上の基で置換されたカルバモイル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたスルファモイル、非置換もしくは置換基群Ｇから選択される１以上の基で置換されたアルキルスルホニル、アルキルオキシカルボニルメチリデン、非置換もしくは置換基群Ｆから選択される１以上の基で置換されたアルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環式基、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族複素環オキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環カルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族複素環アルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルオキシカルボニル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシアルキルオキシ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環オキシアルキル、非芳香族炭素環オキシイミノ、非置換もしくは置換基群Ｅから選択される１以上の基で置換された非芳香族炭素環スルファモイル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環アルキルスルファモイル、非置換もしくは置換基群Ｅから選択される１以上の基で置換された芳香族炭素環スルファニル、および非芳香族複素環スルホニルである。 When X has a substituent, examples of the substituent include Substituent Group A, Substituent Group B, Substituent Group C, and Substituent Group D. Preferably, the substituent group G, the substituent group E, the substituent group H, etc. are mentioned, More preferably, the substituent group K, the substituent group F, or the substituent group J etc. are mentioned. Preferred examples of the substituent include one or more selected from oxo, halogen, hydroxy, unsubstituted or substituted with one or more groups selected from substituent group C, unsubstituted or substituent group C Carbamoyl substituted with a group, cyano, alkyl substituted with one or more groups selected from unsubstituted or substituent group G, alkenyl substituted with one or more groups selected from unsubstituted or substituent group G Alkyloxy substituted with one or more groups selected from unsubstituted or substituted group G, alkenyloxy substituted with one or more groups selected from unsubstituted or substituted group G, alkynyloxy, hydroxyalkynyl Alkyloxyalkyloxyalkyloxy substituted with one or more groups selected from cyanoalkyl, unsubstituted or substituted group G Alkylcarbonyl substituted with one or more groups selected from unsubstituted or substituted group G, alkylsulfonyl substituted with one or more groups selected from unsubstituted or substituted group G, haloalkyloxyimino, alkyloxy Alkyloxyimino, methylidene, alkylmethylidene, alkyloxycarbonylmethylidene, alkyloxycarbonyl substituted with one or more groups selected from unsubstituted or substituted group G, selected from unsubstituted or substituted group G Alkyloxycarbonylalkyl substituted with one or more groups, alkylsulfanyl substituted with one or more groups selected from unsubstituted or substituent group G, one or more groups selected from unsubstituted or substituent group G An alkylsulfinyl substituted with an unsubstituted or substituted group C Selected from sulfamoyl substituted with one or more groups selected from, an aromatic carbocyclic group substituted with one or more groups selected from unsubstituted or substituent group E, 1 selected from unsubstituted or substituent group E Selected from a non-aromatic carbocyclic group substituted with the above groups, an aromatic heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group E, unsubstituted or substituted group E A non-aromatic heterocyclic group substituted with one or more groups, an aromatic or carbocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group E, an unsubstituted or substituted group E A non-aromatic carbocyclic oxy substituted with one or more groups selected from: an aromatic heterocyclic oxy substituted with one or more groups selected from unsubstituted or substituted group E, an unsubstituted or substituted group Homogen substituted with one or more groups selected from E Substituted with one or more groups selected from aromatic heterocyclic oxy, unsubstituted or substituted with one or more groups selected from substituent group E, non-aromatic heterocyclic carbonyl, unsubstituted or substituted group E Substituted with one or more groups selected from non-aromatic carbocyclic alkyl, unsubstituted or substituted group E, unsubstituted or substituted with one or more groups selected from substituent group E A non-aromatic heterocyclic alkyl substituted with one or more groups selected from unsubstituted or substituted substituent E, one or more groups selected from unsubstituted or substituted group E 1 or more selected from the non-aromatic carbocyclic alkyloxy substituted with one or more groups selected from the substituted aromatic carbocyclic alkyloxy, unsubstituted or substituted group E, unsubstituted or substituted group E Set by 1 or more selected from an aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from substituted or non-aromatic heterocyclic alkyloxy, unsubstituted or substituted group E From an aromatic carbocyclic alkyloxyalkyloxy substituted with one or more groups, an aromatic carbocyclic oxyalkyloxy substituted with one or more groups selected from unsubstituted or substituted group E, from unsubstituted or substituted group E Selected from aromatic carbocyclic oxyalkyl, non-aromatic carbocyclic oxyimino, alkyloxy aromatic carbocyclic alkyloxy, non-aromatic carbocyclic sulfamoyl, unsubstituted or substituted group E, substituted with one or more selected groups An aromatic carbocyclic alkylsulfamoyl substituted with one or more groups selected from: unsubstituted or substituted with one or more groups selected from substituent group E One or more selected from unsubstituted aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from unsubstituted or substituted group E, and unsubstituted or substituted group E One or more groups selected from a non-aromatic heterocyclic sulfonyl substituted with a group. When a plurality of the substituents are present, they may be the same or different.
More preferably, oxo, halogen, hydroxy, cyano, unsubstituted or substituted with one or more groups selected from substituent group G, unsubstituted or substituted with one or more groups selected from substituent group G Alkenyl substituted with one or more groups selected from unsubstituted or substituted group G, alkenyloxy substituted with one or more groups selected from unsubstituted or substituted group G, alkynyloxy , Hydroxyalkyl, cyanoalkyl, alkyloxyalkyl, alkyloxyalkyloxy, unsubstituted or substituted with one or more groups selected from substituent group G, from unsubstituted or substituted group G Alkylcarbonyl, unsubstituted or substituted group H substituted with one or more selected groups One or more groups selected from one or more groups selected from amino, unsubstituted or substituted carbamoyl selected from one or more groups selected from substituent group H One or more groups selected from alkylsulfonyl, alkyloxycarbonylmethylidene, unsubstituted or substituent group F, substituted with one or more groups selected from unsubstituted or substituted group G Substituted alkyloxycarbonyl, unsubstituted or substituted with one or more groups selected from substituent group E, substituted with one or more groups selected from unsubstituted or substituted group E Selected from non-aromatic carbocyclic groups, unsubstituted or substituted with one or more groups selected from unsubstituted or substituted group E, unsubstituted or substituted group E Aromatic carbocyclic oxy substituted with one or more groups selected from non-aromatic carbocyclic oxy, unsubstituted or substituted group E selected from one or more groups selected from unsubstituted or substituted group E A non-aromatic heterocyclic carbonyl substituted with one or more groups selected from an aromatic heterocyclic oxy substituted with one or more groups, unsubstituted or substituted group E, an unsubstituted or substituted group E Aromatic carbocyclic alkyl substituted with one or more selected groups, unsubstituted or non-aromatic heterocyclic alkyl substituted with one or more groups selected from substituent group E, unsubstituted or substituted group E Aromatic carbocyclic alkyloxy substituted with one or more groups selected from, unsubstituted or non-aromatic carbocyclic alkyloxy substituted with one or more groups selected from substituent group E, unsubstituted or substituted Selected from group E Non-aromatic heterocyclic alkyloxy substituted with one or more selected groups, unsubstituted or aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from substituent group E, unsubstituted or substituted Aromatic carbocyclic oxyalkyloxy substituted with one or more groups selected from group E, unsubstituted or aromatic carbocyclic oxyalkyl substituted with one or more groups selected from substituent group E, non Aromatic carbocyclic oxyimino, unsubstituted or substituted with one or more groups selected from substituent group E, non-aromatic carbocyclic sulfamoyl, unsubstituted or substituted with one or more groups selected from substituent group E An aromatic carbocyclic alkylsulfamoyl, an unsubstituted or substituted aromatic carbocyclic sulfanyl with one or more groups selected from substituent group E, and a non-aromatic heterocyclic sulfo Is Le.
　ｍは、好ましくは、０～３であり、より好ましくは０～２である。 M is preferably 0 to 3, more preferably 0 to 2.
式（Ｉ）：
Figure JPOXMLDOC01-appb-I000058

の好ましい態様は、式（Ｉ－Ａ）：
Figure JPOXMLDOC01-appb-C000059
（式中、Ｕは、単結合、－Ｏ－、－ＮＲ１５－、置換もしくは非置換のアルキレン、置換もしくは非置換のアルケニレン、または任意の位置で１以上の酸素原子および／または窒素原子を介在している置換もしくは非置換のアルキレンであり、Ｒ１５は水素原子または置換もしくは非置換のアルキルであり、Ｗは置換もしくは非置換の炭素環または置換もしくは非置換の複素環であり、Ｘ１Ａは、それぞれ独立してハロゲン、ヒドロキシ、カルボキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルであり、ｋは０～５であり、その他の定義は上記と同意義である）
で示される化合物、または、式（Ｉ－Ｂ）：
Figure JPOXMLDOC01-appb-C000060
（式中、各記号は前記と同意義である）
で示される化合物が挙げられる。各定義の好ましい態様は上記の通りである。
Ｕは、好ましくは、単結合、－Ｏ－、－ＮＲ１５－、置換もしくは非置換のアルキレン、置換もしくは非置換のアルケニレン、－Ｏ－（ＣＲ１６Ｒ１７）ｅ－、－Ｏ－（ＣＲ１６Ｒ１７）ｅ－Ｏ－、－（ＣＲ１６Ｒ１７）ｅ－Ｏ－、－（ＣＲ１６Ｒ１７）ｅ－Ｏ－（ＣＲ１６Ｒ１７）ｅ－、－ＮＲ１５－（ＣＲ１６Ｒ１７）ｅ－、－（ＣＲ１６Ｒ１７）ｅ－ＮＲ１５－、－ＮＲ１５－（ＣＲ１６Ｒ１７）ｅ－Ｏ－、－Ｏ－（ＣＲ１６Ｒ１７）ｅ－ＮＲ１５－、または－（ＣＲ１６Ｒ１７）ｅ－ＮＲ１５－（ＣＲ１６Ｒ１７）ｅ－、である。ここで、Ｒ１６およびＲ１７は、それぞれ独立して水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のシクロアルキルであるか、Ｒ１６およびＲ１７が一緒になってオキソを形成していてもよい。ｅは１～４である。
Ｗは、好ましくは、芳香族炭素環、非芳香族炭素環、芳香族複素環、または非芳香族複素環である。より好ましくは、ベンゼン、ナフタレン、単環または多環の非芳香族炭素環
、単環の芳香族複素環もしくは非芳香族複素環、または２環もしくは３環の非芳香族複素環である。多環の非芳香族炭素環および２環もしくは３環の非芳香族複素環は、架橋構造および／またはスピロ構造を有していてもよい。
Ｘ１Ａは、好ましくは、それぞれ独立して、ハロゲン、シアノ、アシル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、または置換もしくは非置換の芳香族炭素環スルホニルである。
より好ましくは、それぞれ独立して、ハロゲン、シアノ、アシル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、または置換もしくは非置換の芳香族炭素環スルホニルである。
Ｘ１Ａの別の好ましい態様としては、それぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環オキシアルキル、置換もしくは非置換の非芳香族炭素環オキシアルキル、置換もしくは非置換の芳香族複素環オキシアルキル、置換もしくは非置換の非芳香族複素環オキシアルキル、置換もしくは非置換の芳香族炭素環アルキルオキシアルキル、置換もしくは非置換の非芳香族炭素環アルキルオキシアルキル、置換もしくは非置換の芳香族複素環アルキルオキシアルキル、置換もしくは非置換の非芳香族複素環アルキルオキシアルキル、置換もしくは非置換の芳香族炭素カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、または置換もしくは非置換の芳香族炭素環スルホニルである。
Ｘ１Ａのより好ましい態様としては、それぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族複素環オキシアルキル、置換もしくは非置換の芳香族複素環アルキルオキシアルキル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、または置換もしくは非置換の芳香族炭素環スルホニルである。 Formula (I):
Figure JPOXMLDOC01-appb-I000058

A preferred embodiment of formula (IA):
Figure JPOXMLDOC01-appb-C000059
(In the formula, U is a single bond, —O—, —NR 15 —, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or one or more oxygen atoms and / or nitrogen atoms at any position. Substituted or unsubstituted alkylene, R 15 is a hydrogen atom or substituted or unsubstituted alkyl, W is a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and X 1A is Each independently halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy, Substituted or unsubstituted amino, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted Lucinylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocycle Group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted non-aromatic carbocyclic alkyl Substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted non-aromatic heterocyclic alkyloxy, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic ring Sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or Is an unsubstituted aromatic heterocyclic sulfonyl, or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl, k is 0 to 5, and other definitions are as defined above)
Or a compound of formula (IB):
Figure JPOXMLDOC01-appb-C000060
(Wherein each symbol is as defined above)
The compound shown by these is mentioned. Preferred embodiments of each definition are as described above.
U is preferably a single bond, —O—, —NR 15 —, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, —O— (CR 16 R 17 ) e —, —O— (CR 16 R 17 ) e —O—, — (CR 16 R 17 ) e —O—, — (CR 16 R 17 ) e —O— (CR 16 R 17 ) e —, —NR 15 — (CR 16 R 17 ) e -, - (CR 16 R 17) e -NR 15 -, - NR 15 - (CR 16 R 17) e -O -, - O- (CR 16 R 17) e -NR 15 -, or - (CR 16 R 17) e -NR 15 - (CR 16 R 17) e -, it is. Here, R 16 and R 17 are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted cycloalkyl, or R 16 and R 17 together may form an oxo. e is 1 to 4.
W is preferably an aromatic carbocycle, a non-aromatic carbocycle, an aromatic heterocycle, or a non-aromatic heterocycle. More preferred are benzene, naphthalene, monocyclic or polycyclic non-aromatic carbocycle, monocyclic aromatic heterocycle or nonaromatic heterocycle, or bicyclic or tricyclic nonaromatic heterocycle. The polycyclic non-aromatic carbocyclic ring and the bicyclic or tricyclic non-aromatic heterocyclic ring may have a bridge structure and / or a spiro structure.
X 1A is preferably each independently halogen, cyano, acyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic A group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or Substituted or unsubstituted aromatic carbocyclic sulfonyl.
More preferably, each independently, halogen, cyano, acyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic ring Oxy or substituted or unsubstituted aromatic carbocyclic sulfonyl.
As another preferred embodiment of X 1A , each independently represents halogen, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted non-aromatic carbocyclic alkyl, substituted or unsubstituted Aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic Aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyl Oxy, substituted or unsubstituted non-aromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted non-aromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic carbocyclic oxy Alkyl, substituted or unsubstituted non-aromatic carbocyclic oxyalkyl, substituted or unsubstituted aromatic heterocyclic oxyalkyl, substituted or unsubstituted non-aromatic heterocyclic oxyalkyl, substituted or unsubstituted aromatic carbocyclic alkyl Oxyalkyl, substituted or unsubstituted non-aromatic carbocyclic alkyloxyalkyl, substituted or unsubstituted Aromatic heterocyclic alkyloxyalkyl, substituted or unsubstituted non-aromatic heterocyclic alkyloxyalkyl, substituted or unsubstituted aromatic carbon carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic An aromatic heterocyclic carbonyl, a substituted or unsubstituted non-aromatic heterocyclic carbonyl, or a substituted or unsubstituted aromatic carbocyclic sulfonyl;
As a more preferred embodiment of X 1A , each independently represents halogen, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic Ring oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic Aromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted nonaromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic oxyalkyl, substituted or unsubstituted aromatic A heterocyclic alkyloxyalkyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted non-aromatic heterocyclic carbonyl, or a substituted or unsubstituted aromatic carbocyclic sulfonyl.
抗真菌剤とは、病原性真菌に作用して、その生育を抑制または殺菌する能力を持つ物質を意味する。真菌の繁殖を抑えたり、一部の真菌を殺してその数を減少させたりするようなものでもよい。  An antifungal agent means a substance that acts on a pathogenic fungus and has the ability to suppress or sterilize its growth. It may be something that suppresses fungal growth or kills some fungi to reduce their number.
病原性真菌とは、例えば酵母様真菌、糸状真菌、接合菌などを挙げることができる。酵母様真菌として、例えば、カンジダ属（カンジダ・アルビカンス、カンジダ・グラブラータ、カンジダ・ギリエルモンディ、カンジダ・クルセイ、カンジダ・パラプシローシス、カンジダ・トロピカリスなど）、クリプトコッカス属（クリプトコッカス・ネオフォルマンスなど）、マラセチア属（マラセチア・フルフルなど）、トリコスポロン属（トリコスポロン・アサヒなど）が挙げられる。糸状真菌として、例えば、アスペルギルス属（アスペルギルス・フミガーツス、アスペルギルス・テレウス、アスペルギルス・ニゲール、アスペルギルス・フラバスなど）、白癬菌属（トリコフィトン・ルブルム、トリコフィトン・メンタグロファィテス、トリコフィトン・トンズランスなど）、フサリウム属（フサリウム・ソラニなど）、セドスポリウム属（セドスポリウム・アピオスペルマムなど）、小胞子菌（ミクロスポルム・カニスなど）が挙げられる。接合菌として、例えば、ムコール属（ムコール・プルムベウスなど）、リゾプス属（リゾプス・オリゼなど）、アブシディア属（アブシディア・コリンビフェラなど）が挙げられる。
本発明の抗真菌剤は、カンジダ属菌、アスペルギルス属菌およびクリプトコッカス属菌などの菌種に対して優れた抗真菌作用を示し、アスペルギルス属菌に対してより優れた抗真菌作用を示す。
また、別の態様では、本発明の抗真菌剤は、カンジダ・アルビカンス、アスペルギルス・フミガーツス、アスペルギルス・フラバスおよびクリプトコッカス・ネオフォルマンスなどの菌種に対して優れた抗真菌作用を示す。
また、別の態様では、本発明の抗真菌剤は、種々の耐性菌に対して優れた抗真菌作用を示す。  Examples of pathogenic fungi include yeast-like fungi, filamentous fungi, zygomycetes, and the like. Examples of yeast-like fungi include Candida genus (Candida albicans, Candida glabrata, Candida giermondii, Candida crusei, Candida parapsilosis, Candida tropicalis, etc.), Cryptococcus genus (such as Cryptococcus neoformans), Examples include the genus Malassezia (such as Malassezia fullfur) and the genus Trichosporon (such as Trichosporon and Asahi). As the filamentous fungi, for example, Aspergillus genus (Aspergillus fumigatus, Aspergillus tereus, Aspergillus niguel, Aspergillus flavus, etc.), Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonlances, etc. Genus Fusarium (such as Fusarium solani), genus Sedsporium (such as Sedosporum / Apiospermum), and microspores (such as Microsporum canis). Examples of the zygomycete include a genus Mucor (mucor, plumbeus, etc.), a genus Rhizopus (eg, Rhizopus oryzae), and a genus Absidia (eg, Absidia cholinebifera).
The antifungal agent of the present invention exhibits an excellent antifungal action against bacterial species such as Candida, Aspergillus, and Cryptococcus, and more excellent antifungal action against Aspergillus.
In another aspect, the antifungal agent of the present invention exhibits excellent antifungal activity against bacterial species such as Candida albicans, Aspergillus fumigatus, Aspergillus flavus and Cryptococcus neoformans.
In another aspect, the antifungal agent of the present invention exhibits excellent antifungal activity against various resistant bacteria.
式（Ｉ）で表される化合物またはその製薬上許容される塩は、優れた安全性を示す。安全性は、種々の試験によって評価されるが、たとえば、細胞毒性試験、ｈＥＲＧ試験、反復投与毒性試験、シトクロムＰ４５０（ＣＹＰ）活性阻害試験、代謝依存性阻害試験、インビボ（in vivo）マウス小核試験およびインビボ（in vivo）ラット肝ＵＤＳ試験などから選ばれる各種安全性試験などで評価することができる。  The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof exhibits excellent safety. Safety is evaluated by various tests, for example, cytotoxicity test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse micronucleus It can be evaluated by various safety tests selected from a test and an in vivo rat liver UDS test.
　式（Ｉ）の化合物の製薬上許容される塩としては、通常知られているアミノ基などの塩基性基またはヒドロキシもしくはカルボキシ基などの酸性基における塩を挙げることができる。  Examples of the pharmaceutically acceptable salt of the compound of the formula (I) include salts that are generally known in basic groups such as amino groups or acidic groups such as hydroxy or carboxy groups.
塩基性基における塩としては、たとえば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩；ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩；ならびにメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。  Examples of salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
酸性基における塩としては、たとえば、ナトリウムおよびカリウムなどのアルカリ金属との塩；カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ、Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ－ベンジル－β－フェネチルアミン、１－エフェナミンおよびＮ、Ｎ'－ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。 
好ましい塩としては、薬理学的に許容される塩が挙げられる。  Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
Preferred salts include pharmacologically acceptable salts.
式（Ｉ）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等）との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid, Stone acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Of the salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
式（Ｉ）で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等）、ラセミ体またはそれらの混合物を含む。例えば、式（Ｉ）で示される化合物は、以下のような互変異体を包含する。
Figure JPOXMLDOC01-appb-C000061
 The compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof. For example, the compound represented by the formula (I) includes the following tautomers.
Figure JPOXMLDOC01-appb-C000061
　式（Ｉ）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、該「放射性標識体」は、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). In addition, a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
　式（Ｉ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。トリチウム標識化合物を調製するための他の適切な方法は、“Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）”を参照することができる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）、共結晶、および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物、共結晶および結晶多形も包含する。「溶媒和物」は、式（Ｉ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）で示される化合物またはその製薬上許容される塩を、再結晶することで結晶多形を形成する場合がある。「共結晶」は、式（Ｉ）で示される化合物または塩とカウンター分子が同一結晶格子内に存在することを意味し、任意の数のカウンター分子を含んでいても良い。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal, and / or a crystal polymorph. The invention also encompasses such various solvates, co-crystals and polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えば “Ｄｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ，　１９８５”に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. A method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
　式（Ｉ）で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent. For example, CH 3 COO—, C 2 H 5 COO—, tert-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3- , PhSO 3- , p-CH 3 PhSO 3 -can be mentioned.
本発明の式（Ｉ）の化合物またはその製薬上許容される塩を医薬として用いる場合、通常、製剤化に使用される賦形剤、単体および希釈剤などの製剤補助剤を適宜混合してもよい。これらは、常法にしたがって、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、紛体製剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤または注射剤などの形態で、経口または非経口で投与することができる。また、投与方法、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択することができる。通常、成人に対しては、経口または非経口投与（たとえば、注射、点滴および直腸部位への投与など）により、１日、０．０１～１０００ｍｇ／ｋｇを１回から数回に分割して投与すればよい。 When the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical, formulation adjuvants such as excipients, simple substances and diluents usually used in the formulation may be appropriately mixed. Good. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dose, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, 0.01 to 1000 mg / kg is administered in 1 to several divided doses a day by oral or parenteral administration (eg, injection, infusion, and administration to the rectal site) do it.
　本発明化合物は、各種真菌に対する高い抗真菌作用を有するため、抗真菌剤、特に深在性真菌症の治療剤及び／又は予防剤として有用である。さらに、本発明化合物は、血清添加条件下における各種真菌に対しても、優れた抗真菌活性を有するため、医薬品としての有用性を備えている。 Since the compound of the present invention has a high antifungal activity against various fungi, it is useful as an antifungal agent, particularly a therapeutic and / or prophylactic agent for deep mycosis. Furthermore, since the compound of the present invention has excellent antifungal activity against various fungi under serum-added conditions, it has utility as a pharmaceutical product.
　本発明化合物は、抗真菌作用のみならず、以下のいずれか１つ以上の特徴を有している点で医薬品としての有用性を備えている。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
ｂ）血中濃度が高い、経口吸収性が高い、効果持続時間が長い、適度なクリアランスを有する、適度なタンパク結合率を有する、適度な組織移行性を有する等の良好な薬物動態を示す。
ｃ）代謝安定性（例えば、ラットおよび／またはヒトの代謝酵素に対する安定性）が高い。
ｄ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、本明細書に記載する測定条件の濃度範囲内で不可逆的阻害作用を示さない。
ｅ）変異原性を有さない。
ｆ）心血管系のリスクが低い。
ｇ）化合物の安定性および／または水に対する溶解性が高い。
ｈ）薬物相互作用を示さない。
ｉ）肝毒性、腎毒性等の毒性を示さない。
ｊ）生体内への投与後に、発熱や痙攣などの副作用を示さない。 The compound of the present invention has utility as a pharmaceutical in that it has not only an antifungal action but also one or more of the following characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) It shows good pharmacokinetics such as high blood concentration, high oral absorption, long duration of effect, moderate clearance, moderate protein binding rate, and moderate tissue migration.
c) High metabolic stability (eg stability to rat and / or human metabolic enzymes).
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High compound stability and / or solubility in water.
h) No drug interaction is shown.
i) No toxicity such as hepatotoxicity or nephrotoxicity.
j) No side effects such as fever and convulsions are shown after administration in vivo.
　本発明の医薬組成物は、経口的、非経口的のいずれの方法でも投与することができる。非経口投与の方法としては、経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳、膣内投与等が挙げられる。 The pharmaceutical composition of the present invention can be administered either orally or parenterally. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
　経口投与の場合は常法に従って、内用固形製剤（例えば、錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤等）、内用液剤（例えば、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤、チンキ剤等）等の通常用いられるいずれの剤型に調製して投与すればよい。錠剤は、糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠または口腔内崩壊錠であってもよく、散剤および顆粒剤はドライシロップであってもよく、カプセル剤は、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤であってもよい。 In the case of oral administration, solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.) and liquids for internal use (eg, suspensions, emulsions, elixirs, syrups) Preparations, limonade agents, spirits, fragrances, extracts, decoctions, tinctures, etc.), etc. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups. Alternatively, the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
　非経口投与の場合は、注射剤、点滴剤、外用剤（例えば、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤、坐剤等）等の通常用いられるいずれの剤型でも好適に投与することができる。注射剤は、Ｏ／Ｗ、Ｗ／Ｏ、Ｏ／Ｗ／Ｏ、Ｗ／Ｏ／Ｗ型等のエマルジョンであってもよい。 In the case of parenteral administration, injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas, Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered. The injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。さらに、該医薬組成物は、本発明化合物の有効量、剤型および／または各種医薬用添加剤を適宜変更することにより、小児用、高齢者用、重症患者用または手術用の医薬組成物とすることもできる。小児用医薬組成物は、１２歳または１５歳未満の患者に投与するのが好ましい。また、小児用医薬組成物は、出生後２７日未満、出生後２８日～２３か月、２歳～１１歳または１２歳～１６歳もしくは１８歳の患者に投与されうる。高齢者用医薬組成物は、６５歳以上の患者に投与するのが好ましい。 Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. Furthermore, the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also The pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. Also, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old. The elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
　本発明化合物は、該化合物の作用の増強または該化合物の投与量の低減等を目的として、ポリエン系の薬剤、ファンギン系の薬剤、またはアゾール系の薬剤等（以下、併用薬剤と称する）と組み合わせて用いることができる。この際、本発明化合物と併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。さらに、本発明化合物と併用薬剤とは、それぞれの活性成分を含む２種類の製剤として投与されてもよいし、両方の活性成分を含む単一の製剤として投与されてもよい。 The compound of the present invention is combined with a polyene drug, a fungine drug, an azole drug or the like (hereinafter referred to as a concomitant drug) for the purpose of enhancing the action of the compound or reducing the dose of the compound. Can be used. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
　併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明化合物１重量部に対し、併用薬剤を０．０１～１００重量部用いればよい。 The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
次に、本発明化合物の製造法について説明する。
本発明化合物は、自体公知の方法を組み合わせることにより製造されるが、たとえば、次に示す製造法にしたがって製造することができる。 Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
（製法Ａ）
Figure JPOXMLDOC01-appb-C000062
（式中、P1はアミノ保護基であり、その他の記号は前記と同意義であり、P1はProtective Groups in Organic Synthesis, Theodora W Green(John Wiley & Sons)等に記載の方法で保護および／または脱保護できる基であればよく、例えばP1はアルキルオキシカルボニルやｔｅｒｔ―ブチル等である。）
工程１：
式［２ａ］で示される化合物とグアニジン塩酸塩を反応させ、式［３ａ］で示される化合物を製造する工程である。
式［２ａ］で示される化合物としては，たとえば，１，３－プロパンジアミン，１，２－エタンジアミン等が挙げられる．
反応温度としては０～１５０℃で、反応時間としては０．５～４８時間で反応させればよい。 (Manufacturing method A)
Figure JPOXMLDOC01-appb-C000062
(Wherein, P 1 is an amino protecting group, and other symbols are as defined above, P 1 is protected and in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) method described in such as And / or any group that can be deprotected, for example, P 1 is alkyloxycarbonyl, tert-butyl, etc.)
Step 1:
In this step, the compound represented by the formula [2a] is reacted with guanidine hydrochloride to produce the compound represented by the formula [3a].
Examples of the compound represented by the formula [2a] include 1,3-propanediamine, 1,2-ethanediamine and the like.
The reaction temperature may be 0 to 150 ° C., and the reaction time may be 0.5 to 48 hours.
工程２：
式［３ａ］で示される化合物と式［４ａ］で示される化合物を反応させ、式［５ａ］で示される化合物を製造する方法である。
反応溶媒としては、上記工程を効率よく進行させるものであれば特に限定されない。例えば、アルコール系溶媒（例：メタノール、エタノール、イソプロパノール等）、アミド系溶媒（例：Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、１，３－ジメチルー２－イミダゾリジノン等）、酢酸エステル系溶媒（例：酢酸エチル、酢酸プロピル等）、炭化水素系溶媒（例：トルエン、ベンゼン、ヘキサン等）、エーテル系溶媒（例：シクロペンチルメチルエーテル、テトラヒドロフラン、２－メチルテトラヒドロフラン、１，２－ジメトキシエタン、アニソール等）、ニトリル系溶媒（例：アセトニトリル、プロピオニトリル等）、ハロゲン系溶媒（例、ジクロロメタン、クロロホルム等）、ケトン系溶媒（例：アセトン、メチルエチルケトン等）、ジメチルスルホキシド、水等から選ばれる１以上を用いることができる。溶媒は、必要に応じて水との２層溶媒や含水溶媒として用いることができる。好ましくはエーテル系溶媒，ケトン系溶媒である。
反応温度としては０～１２０℃で、反応時間としては０．５～２４時間で反応させればよい。 Step 2:
In this method, the compound represented by the formula [3a] is reacted with the compound represented by the formula [4a] to produce the compound represented by the formula [5a].
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. For example, alcohol solvents (eg, methanol, ethanol, isopropanol, etc.), amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolide Non-acetate), acetate solvents (eg, ethyl acetate, propyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran) , 1,2-dimethoxyethane, anisole, etc.), nitrile solvents (eg, acetonitrile, propionitrile, etc.), halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.), Select from dimethyl sulfoxide, water, etc. It can be used at least one element. The solvent can be used as a two-layer solvent with water or a water-containing solvent as necessary. Preferred are ether solvents and ketone solvents.
The reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
工程３：
式［５ａ］で示される化合物の脱保護を行い、式［６ａ］で示される化合物を製造する工程である。保護基の脱保護反応は公知であり、例えばProtective Groups in Organic Synthesis, Theodora W Green(John Wiley & Sons)等に記載の方法で実施することができる。反応溶媒としては、工程２記載の溶媒を単独又は混合して用いることができる。好ましくはアルコール系溶媒，水である．
反応温度としては０～１２０℃で、反応時間としては０．５～２４時間で反応させればよい。 Step 3:
In this step, the compound represented by the formula [5a] is deprotected to produce the compound represented by the formula [6a]. The deprotection reaction of the protecting group is known and can be carried out by the method described in, for example, Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like. As the reaction solvent, the solvents described in Step 2 can be used alone or in combination. Alcohol solvents and water are preferred.
The reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
工程４：
式［６ａ］で示される化合物と式［７ａ］で示される化合物を反応させ、式［１］で示される化合物を製造する方法である。
反応溶媒としては、製造Ａの工程２記載の溶媒を単独又は混合して用いることができる。好ましくはアルコール系溶媒である．
反応温度としては０～１２０℃で、反応時間としては０．５～２４時間反応させればよい。 Step 4:
In this method, the compound represented by the formula [6a] and the compound represented by the formula [7a] are reacted to produce the compound represented by the formula [1].
As the reaction solvent, the solvents described in Step 2 of Production A can be used alone or in combination. Alcohol solvents are preferred.
The reaction temperature is 0 to 120 ° C., and the reaction time is 0.5 to 24 hours.
（製法Ｂ）
Figure JPOXMLDOC01-appb-C000063
 （式中、各記号は前記と同意義であり、「Ｈａｌ」はハロゲン、「Ａｌｋ」はアルキル基を意味する。Ａｌｋとしては、メチル基、エチル基等が挙げられる。）
工程１：
式［１ｂ］で示される化合物と二硫化炭素とハロゲン化アルキルを塩基存在下で反応させ、式［２ｂ］で示される化合物を製造する工程である。
ハロゲン化アルキルとしては、ヨウ化メチル，臭化メチル，ヨウ化エチルが挙げられる．
塩基としては、例えば金属水素化物（例、水素化ナトリウムなど）、金属水酸化物（例、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなど）、金属炭酸塩（例、炭酸ナトリウム、炭酸カルシウム、炭酸セシウムなど）、金属アルコキシド（例、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ－ブトキシドなど）、炭酸水素ナトリウム、金属ナトリウム、金属アミド、有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、ＤＢＵ、２，６－ルチジンなど）、ピリジン、アルキルリチウム（ｎ－ＢｕＬｉ、ｓｅｃ－ＢｕＬｉ、ｔｅｒｔ－ＢｕＬｉ）等が挙げられる。特に好ましくは、水素化ナトリウムである。
反応溶媒としては、製法Ａの工程２記載の溶媒を単独又は混合して用いることができる。好ましくはエーテル系溶媒（テトラヒドロフラン）、アミド系溶媒である。
反応温度としては０～１２０℃で、反応時間としては０．５～２４時間で反応させればよい。 (Manufacturing method B)
Figure JPOXMLDOC01-appb-C000063
 (In the formula, each symbol has the same meaning as above, “Hal” means halogen, and “Alk” means an alkyl group. Examples of Alk include a methyl group and an ethyl group.)
Step 1:
In this step, the compound represented by the formula [1b] is reacted with carbon disulfide and an alkyl halide in the presence of a base to produce a compound represented by the formula [2b].
Examples of the alkyl halide include methyl iodide, methyl bromide, and ethyl iodide.
Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium hydrogen carbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like. Particularly preferred is sodium hydride.
As the reaction solvent, the solvents described in Step 2 of Production Method A can be used alone or in combination. Preferred are ether solvents (tetrahydrofuran) and amide solvents.
The reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
工程２：
式［２ｂ］で示される化合物と式［２ａ］で示される化合物を反応させ、式［３ｂ］で示される化合物を製造する工程である。
反応溶媒としては、製法Ａの工程２記載の溶媒を単独又は混合して用いることができる。好ましくはエーテル系溶媒（テトラヒドロフラン）、アミド系溶媒である。
反応温度としては０～１２０℃で、反応時間としては０．５～２４時間で反応させればよい。　 Step 2:
In this step, the compound represented by the formula [2b] is reacted with the compound represented by the formula [2a] to produce a compound represented by the formula [3b].
As the reaction solvent, the solvents described in Step 2 of Production Method A can be used alone or in combination. Preferred are ether solvents (tetrahydrofuran) and amide solvents.
The reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
工程３：
式［３ｂ］で示される化合物と式［４ｂ］で示される化合物をパラジウム触媒下で反応させ、式［１］で示される化合物を製造する工程である。なお、式：［４ｂ］で示される化合物については、ボロン酸エステルを用いてもよい。 Step 3:
In this step, the compound represented by the formula [3b] is reacted with the compound represented by the formula [4b] in the presence of a palladium catalyst to produce a compound represented by the formula [1]. In addition, about the compound shown by Formula: [4b], you may use boronic acid ester.
　溶媒としては、製法Ａの工程２記載の溶媒を用いることができる。好ましくは、Ｎ－ジメチルホルムアミド、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）またはエーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）を用いればよい。 As the solvent, the solvent described in the step 2 of production method A can be used. Preferably, N-dimethylformamide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) or ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
　塩基としては、製法Ｂの第１工程記載の塩基を用いることができる。好ましくは、金属炭酸塩（例、炭酸ナトリウム、炭酸カルシウム、炭酸セシウムなど）または有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、２，６－ルチジンなど）を用いればよい。 As the base, the base described in the first step of production method B can be used. Preferably, a metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.) or an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
　反応は、パラジウム触媒（例：Ｐｄ（ＰＰｈ３）４、ＰｄＣｌ２、Ｐｄ（ＯＡｃ）２、Ｐｄ（ｄｂａ）２等）とホスフィン配位子（例：ＰＰｈ３、ＢＩＮＡＰ等）の存在下、使用する溶媒が還流する温度で０．５～１２時間反応させればよい。 The reaction is used in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.) The reaction may be performed for 0.5 to 12 hours at a temperature at which the solvent to be refluxed.
　マイクロウェーブを用いて反応を行う際は、８０～２００℃で５分～１時間反応させればよい。 When performing the reaction using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
　式：Ｒ３－Ｂ（ＯＨ）２で示される化合物としては、たとえば、フェニルボロン酸などが挙げられる。 Examples of the compound represented by the formula: R 3 —B (OH) 2 include phenylboronic acid.
（製法Ｃ）
Figure JPOXMLDOC01-appb-C000064
（式中、各記号は前記と同意義である。）
工程１：
　式［７ａ］示される化合物とチオウレアを反応させ、式［１ｃ］で示される化合物を製造する工程である。
反応溶媒としては、製造Ａの工程２記載の溶媒を単独又は混合して用いることができる。好ましくはアルコール系溶媒である．
反応温度としては０～１２０℃で、反応時間としては０．５～２４時間で反応させればよい。 (Manufacturing method C)
Figure JPOXMLDOC01-appb-C000064
(In the formula, each symbol is as defined above.)
Step 1:
In this step, the compound represented by the formula [7a] is reacted with thiourea to produce the compound represented by the formula [1c].
As the reaction solvent, the solvents described in Step 2 of Production A can be used alone or in combination. Alcohol solvents are preferred.
The reaction temperature may be 0 to 120 ° C., and the reaction time may be 0.5 to 24 hours.
工程２：
式［１ｃ］示される化合物から式［２ｃ］で示される化合物を製造する工程である。 Step 2:
In this step, the compound represented by the formula [2c] is produced from the compound represented by the formula [1c].
　上記製造Ｂの第１工程と同様に行えばよい。 It may be performed in the same manner as in the first step of the production B.
工程３：
式［２ｃ］示される化合物と式［２ａ］で示される化合物を反応させ，式［１］で示される化合物製造する工程である。 Step 3:
In this step, the compound represented by the formula [2c] is reacted with the compound represented by the formula [2a] to produce a compound represented by the formula [1].
　上記製造Ｂの第２工程と同様に行えばよい。 It may be performed in the same manner as the second step of the production B.
　以下に実施例および参考例、ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。数値（例えば、量、温度など）に関して正確性を保証する努力をしているが、いくらかの誤差および偏差は考慮されるべきである。特に示さなければ、％は成分の重量％および組成物の全重量の重量％であり、当量は成分のモル当量を意味する。圧力は大気圧かまたはそれに近い圧力である。本明細書で使用する他の略語は以下のように定義される。：ｇはグラム、Ｌはリットル、ｍｇはミリグラム、ｍＬはミリリットルを表す。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto. Efforts are being made to ensure accuracy with respect to numbers (eg, amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless otherwise indicated,% is the weight percent of the component and the weight percent of the total weight of the composition, and equivalent means the molar equivalent of the component. The pressure is at or near atmospheric pressure. Other abbreviations used herein are defined as follows: : G represents gram, L represents liter, mg represents milligram, and mL represents milliliter.
　また、本明細書中で用いる略語は以下の意味を表す。
Ａｃ：アセチル
Ｂｎ：ベンジル
Ｂｏｃ：ｔｅｒｔ－ブチルオキシカルボニル
Ｂｏｃ２Ｏ：ジ－ｔｅｒｔ－ブチルジカーボネート
Ｂｕ：ブチル
Ｂｚ：ベンゾイル
ＣＤＩ：カルボニルジイミダゾール
ＤＩＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＤＭＡ：Ｎ，Ｎ－ジメチルアセトアミド
ＤＭＡＰ：４－ジメチルアミノピリジン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＳＯ：ジメチルスルホキシド
ＤＰＰＦ：１，１’－ビス（ジフェニルホスフィノ）フェロセン
Ｅｔ：エチル
Ｆｍｏｃ：９－フルオレニルメチルオキシカルボニル
ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート
Ｈｅｘ：ヘキシル
ｉ－Ｐｒ：イソプロピル
ＬＤＡ：リチウムジイソプロピルアミド
Ｍｅ：メチル
Ｍｓ：メタンスルホニル
ＮＢＳ：Ｎ－ブロモスクシンイミド
ＮＭＰ：Ｎ－メチルピロリドン
ｎ－Ｂｕ：ｎ－ブチル
ｎ－Ｐｒ：ｎ－プロピル
Ｐｄ（ＯＡｃ）２：酢酸パラジウム
Ｐｄ（ＰＰｈ３）４：テトラキス（トリフェニルホスフィン）パラジウム
ＰｄＣｌ２（ｄｐｐｆ）：［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン付加物
ＰｄＣｌ２（ｄｔｂｐｆ）：［１，１’－ビス（ジ‐tert-ブチルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　
Ｐｈ：フェニル
ｔ－Ｂｕ：ｔｅｒｔ－ブチル
Ｘａｎｔｐｈｏｓ：４，５’－ビス（ジフェニルホスフィノ）－９，９’－ジメチルキサンテン
ローソン試薬：２，４－ビス（４－メトキシフェニル）－１，３，２，４－ジチアジホスフェタン－２，４－ジスルフィド Moreover, the abbreviation used in this specification represents the following meaning.
Ac: acetyl Bn: benzyl Boc: tert-butyloxycarbonyl Boc 2 O: di-tert-butyl dicarbonate Bu: butyl Bz: benzoyl CDI: carbonyldiimidazole DIEA: N, N-diisopropylethylamine DMA: N, N-dimethyl Acetamide DMAP: 4-dimethylaminopyridine DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide DPPF: 1,1′-bis (diphenylphosphino) ferrocene Et: ethyl Fmoc: 9-fluorenylmethyloxycarbonyl HATU: O -(7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate Hex: hexyl i-Pr: isopropyl LDA: lithium diisopropylamino Me: methyl Ms: methanesulfonyl NBS: N-bromosuccinimide NMP: N-methylpyrrolidone n-Bu: n-butyl n-Pr: n-propyl Pd (OAc) 2: palladium acetate Pd (PPh 3) 4: tetrakis ( Triphenylphosphine) palladium PdCl 2 (dppf): [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct PdCl 2 (dtbpf): [1,1′-bis (di-tert- Butylphosphino) ferrocene] palladium (II) dichloride
Ph: phenyl t-Bu: tert-butyl Xantphos: 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene Lawson reagent: 2,4-bis (4-methoxyphenyl) -1,3 2,4-dithiadiphosphetane-2,4-disulfide
実施例で得られたＮＭＲ分析は３００ＭＨｚもしくは４００ＭＨｚで行い、ＤＭＳＯ－Ｄ６、ＣＤＣｌ３等を用いて測定した。 The NMR analysis obtained in the examples was performed at 300 MHz or 400 MHz and measured using DMSO-D6, CDCl 3 or the like.
実施例で得られたＬＣＭＳ分析は、以下の条件下で測定した。
（測定条件Ａ）：
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：０．８ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、０．５分間、１００％溶媒［Ｂ］を維持した。
（測定条件Ｂ）：
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：０．８ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は１０ｍＭ炭酸アンモニウム含有水溶液、［Ｂ］はアセトニトリル溶液
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、０．５分間、１００％溶媒［Ｂ］を維持した。
（測定条件Ｃ）：
カラム：Ｌｕｎａ　Ｃ１８（２）（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
流速：３．０ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、１分間、１００％溶媒［Ｂ］を維持した。
（測定条件Ｄ）：
カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）（Ｓｈｉｍａｄｚｕ）
流速：１．５ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０.５分間、１００％溶媒［Ｂ］を維持した。
（測定条件Ｅ）：
カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）（Ｓｈｉｍａｄｚｕ）
流速：１．６ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０.５分間、１００％溶媒［Ｂ］を維持した。 The LCMS analysis obtained in the examples was measured under the following conditions.
(Measurement condition A):
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, [B] was 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes Thereafter, 100% solvent [B] was maintained for 0.5 minutes.
(Measurement condition B):
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is an acetonitrile solution gradient: linear gradient of 5% -100% solvent [B] in 3.5 minutes, then 0.5 minutes, 100 minutes % Solvent [B] was maintained.
(Measurement condition C):
Column: Luna C18 (2) (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3.0 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: After performing a linear gradient of 10% -100% solvent [B] in 3 minutes, 100% solvent [B] was maintained for 1 minute.
(Measurement condition D):
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.5 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 10% -100% solvent [B] is performed for 3 minutes. 100% solvent [B] was maintained for 5 minutes.
(Measurement condition E):
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 10% -100% solvent [B] is performed for 3 minutes. 100% solvent [B] was maintained for 5 minutes.
化合物Ｉ－１の合成　
Figure JPOXMLDOC01-appb-C000065
工程１：　
　化合物１ａ（２ｇ、９．８４ｍｍｏｌ）のトルエン（２０ｍＬ）溶液に、ピリジニウムブロミドペルブロミド（３．１５ｇ、９．８４ｍｍｏｌ）を加えた。１００℃で３時間撹拌した後に、室温まで放冷し、エタノール（３０ｍＬ）、化合物１ｂ（１．５６ｇ、９．８４ｍｍｏｌ）を加えた。６０℃で２時間撹拌した後に、重曹水を加えて中和した。クロロホルムで抽出して、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧濃縮して得られた残渣にクロロホルムと酢酸エチルを加え、析出している固体をろ取することで、化合物Ｉ－１（２．１７ｍｇ、収率６５％）を得た。
1H-NMR (DMSO-D6)δ: 1.87 (m, 2H), 3.37 (m, 4H), 7.24 (s, 1H), 7.49-7.57 (m, 3H), 7.98-8.03 (m, 2H), 8.15 (s, 1H), 8.41 (brs, 2H). Synthesis of Compound I-1
Figure JPOXMLDOC01-appb-C000065
Step 1:
Pyridinium bromide perbromide (3.15 g, 9.84 mmol) was added to a solution of compound 1a (2 g, 9.84 mmol) in toluene (20 mL). After stirring at 100 ° C. for 3 hours, the mixture was allowed to cool to room temperature, and ethanol (30 mL) and compound 1b (1.56 g, 9.84 mmol) were added. After stirring at 60 ° C. for 2 hours, sodium bicarbonate water was added for neutralization. Extraction was performed with chloroform, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Chloroform and ethyl acetate were added to the residue obtained by concentrating the solvent under reduced pressure, and the precipitated solid was collected by filtration to obtain Compound I-1 (2.17 mg, yield 65%).
1 H-NMR (DMSO-D6) δ: 1.87 (m, 2H), 3.37 (m, 4H), 7.24 (s, 1H), 7.49-7.57 (m, 3H), 7.98-8.03 (m, 2H), 8.15 (s, 1H), 8.41 (brs, 2H).
化合物Ｉ－２の合成　
Figure JPOXMLDOC01-appb-C000066
工程１：　化合物２ｂの合成
化合物２ａ（１０．０ｇ、５５．９ｍｍｏｌ）をＤＭＦ（２００ｍＬ）に溶解させ、二硫化炭素（８．４４　ｍＬ、１４０ｍｍｏｌ）、を加えて０℃に冷却、６０％水素化ナトリウム（５．５８ｇ、１４０ｍｍｏｌ）を加え、０℃で４５分間撹拌した。ヨードメタン（８．７３ｍＬ、１４０ｍｍｏｌ）を加えて室温で１８時間撹拌した。残渣を水に加えて、酢酸エチルで抽出した。有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、化合物２ｂ（１６．０ｇ、１００％）を得た。
1H-NMR (CDCl3)δ: 2.62 (s, 6H), 6.98 (s, 1H). Synthesis of Compound I-2
Figure JPOXMLDOC01-appb-C000066
Step 1: Synthesis of Compound 2b Compound 2a (10.0 g, 55.9 mmol) was dissolved in DMF (200 mL), carbon disulfide (8.44 mL, 140 mmol) was added, and the mixture was cooled to 0 ° C., 60% hydrogen Sodium chloride (5.58 g, 140 mmol) was added and stirred at 0 ° C. for 45 minutes. Iodomethane (8.73 mL, 140 mmol) was added and stirred at room temperature for 18 hours. The residue was added to water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 2b (16.0 g, 100%).
1H-NMR (CDCl3) δ: 2.62 (s, 6H), 6.98 (s, 1H).
工程２：　化合物２ｃの合成
化合物２ｂ（１５．９ｇ、５６．１ｍｍｏｌ）をテトラヒドロフラン（２００ｍＬ）に溶解し、１、３－ジアミノプロパン（４．０１ｍＬ、４７．７ｍｍｏｌ）を加え、７０℃で２時間撹拌した。その後溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２ｃ（５．４８ｇ、３７％）を得た。
1H-NMR (CDCl3)δ: 1.92-2.00 (m, 2H), 3.41-3.53 (m, 4H), 6.35 (s, 1H), 7.70 (bs, 1H). Step 2: Synthesis of Compound 2c Compound 2b (15.9 g, 56.1 mmol) was dissolved in tetrahydrofuran (200 mL), 1,3-diaminopropane (4.01 mL, 47.7 mmol) was added, and the mixture was heated at 70 ° C. for 2 hours. Stir. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 2c (5.48 g, 37%).
1H-NMR (CDCl3) δ: 1.92-2.00 (m, 2H), 3.41-3.53 (m, 4H), 6.35 (s, 1H), 7.70 (bs, 1H).
工程３：　化合物Ｉ－２の合成
化合物２ｃ（３０ｍｇ、０．１１５ｍｍｏｌ）をテトラヒドロフラン（０．３ｍＬ）に溶解し、５－クロロチオフェン－２－ボロン酸（９．４ｍｇ、０．１７２　ｍｍｏｌ）、Ｐｄ（ｄｐｐｆ）（９．４　ｍｇ、０．０１１　ｍｍｏｌ）、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０．２３ｍＬ）を加え、１５０℃で１５分間マイクロ波を照射した。残渣にクロロホルム－メタノールの混合溶液（９：１、２ｍｌ）、２ｍｏｌ／Ｌソルビトール水溶液（０．５ｍｌ）、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０．５ｍｌ）を順に加え、１時間撹拌後、有機層を減圧濃縮した。得られた残渣を逆相ＨＰＬＣ（アセトニトリル－水）によって精製し、化合物Ｉ－２（７．８ｍｇ、収率２３％）を得た。
ＬＣＭＳ（測定条件Ｂ）、保持時間：２．２０分、［Ｍ＋Ｈ］＋：２９９
1H-NMR (DMSO-D6)δ: 1.82-1.83 (m, 2H), 3.31-3.33 (m, 4H), 6.95 (s, 1H), 7.07 (d, J = 4.0 Hz, 1H), 7.30 (d, J = 4.0 Hz, 1H), 8.17 (s, 2H). Step 3: Synthesis of Compound I-2 Compound 2c (30 mg, 0.115 mmol) was dissolved in tetrahydrofuran (0.3 mL), and 5-chlorothiophene-2-boronic acid (9.4 mg, 0.172 mmol), Pd (Dppf) (9.4 mg, 0.011 mmol), 2 mol / L sodium carbonate aqueous solution (0.23 mL) was added, and microwave irradiation was performed at 150 ° C. for 15 minutes. Chloroform-methanol mixed solution (9: 1, 2 ml), 2 mol / L sorbitol aqueous solution (0.5 ml), 2 mol / L sodium carbonate aqueous solution (0.5 ml) were sequentially added to the residue, and the mixture was stirred for 1 hour. Concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (acetonitrile-water) to give compound I-2 (7.8 mg, 23% yield).
LCMS (measurement condition B), retention time: 2.20 minutes, [M + H] + : 299
1H-NMR (DMSO-D6) δ: 1.82-1.83 (m, 2H), 3.31-3.33 (m, 4H), 6.95 (s, 1H), 7.07 (d, J = 4.0 Hz, 1H), 7.30 (d , J = 4.0 Hz, 1H), 8.17 (s, 2H).
化合物Ｉ－３の合成　
Figure JPOXMLDOC01-appb-C000067
工程１：化合物３ｂの合成
　１，３－ジブロモプロパン－２－オン（４．５７ｇ，２１．２ｍｏＬ）をアセトン（２０ｍＬ）に溶解させ、室温で化合物３ａ（３．３５ｇ，２１．２ｍｏＬ）を加え、室温で８時間撹拌した。得られた固体をろ取し、粗精製物として化合物３ｂを得て、精製せずに次の反応に用いた。ＬＣＭＳ (測定条件Ａ); 保持時間：０．９４ 分、 ［Ｍ＋Ｈ］＋：３４４  Synthesis of Compound I-3
Figure JPOXMLDOC01-appb-C000067
Step 1: Synthesis of Compound 3b 1,3-Dibromopropan-2-one (4.57 g, 21.2 mol) was dissolved in acetone (20 mL), and Compound 3a (3.35 g, 21.2 mol) was added at room temperature. And stirred at room temperature for 8 hours. The obtained solid was collected by filtration to obtain Compound 3b as a crude product, which was used in the next reaction without purification. LCMS (measurement conditions A); retention time: 0.94 minutes, [M + H] + : 344
工程２：化合物Ｉ－３の合成
　４－クロロフェノール（２７ｍｇ、０．２１ｍｏｌ）をジメチルアセトアミド（１ｍＬ）に溶解し、工程１で得られた化合物３ｂ（５０ｍｇ、０．１４ｍｏｌ）、炭酸カリウム（９７ｍｇ、０．７０ｍｏｌ）を加え、６５℃で３時間撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－３（１１ｍｇ，２７％）を得た。1H-NMR (CDCl3)δ: 1.93-1.99 (m, 2H), 3.37-3.43 (m, 4H), 4.93 (s, 2H), 6.47 (s, 1H), 6.93 (J = 8.8 Hz, d, 2H), 7.23 (J = 8.8 Hz, d, 2H). Step 2: Synthesis of Compound I-3 4-Chlorophenol (27 mg, 0.21 mol) was dissolved in dimethylacetamide (1 mL), and Compound 3b (50 mg, 0.14 mol) obtained in Step 1 and potassium carbonate (97 mg) were dissolved. , 0.70 mol) was added, and the mixture was stirred at 65 ° C. for 3 hours. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-3 (11 mg, 27%). 1H-NMR (CDCl3) δ: 1.93-1.99 (m, 2H), 3.37-3.43 (m, 4H), 4.93 (s, 2H), 6.47 (s, 1H), 6.93 (J = 8.8 Hz, d, 2H ), 7.23 (J = 8.8 Hz, d, 2H).
化合物Ｉ－４の合成　
Figure JPOXMLDOC01-appb-C000068
工程１　化合物４ｃの合成
化合物４ａと化合物４ｂを用いて、実施例５の工程２と同様の手法により合成した。
1H-NMR (CDCl3)δ: 1.47 (s, 9H), 1.52-1.65 (m, 2H), 1.72 (d, J = 9.6Hz, 1H), 1.96 (s, 2H), 2.09 (d, J = 10.0Hz, 1H), 2.68 (s, 1H), 2.81-2.87 (m, 2H), 3.43 (s, 4H), 4.00-4.04 (m, 1H), 4.26 (s, 1H), 6.11 (s, 1H). Synthesis of Compound I-4
Figure JPOXMLDOC01-appb-C000068
Step 1 Synthesis of Compound 4c Synthesis was performed in the same manner as in Step 2 of Example 5 using Compound 4a and Compound 4b.
1 H-NMR (CDCl3) δ: 1.47 (s, 9H), 1.52-1.65 (m, 2H), 1.72 (d, J = 9.6Hz, 1H), 1.96 (s, 2H), 2.09 (d, J = 10.0Hz, 1H), 2.68 (s, 1H), 2.81-2.87 (m, 2H), 3.43 (s, 4H), 4.00-4.04 (m, 1H), 4.26 (s, 1H), 6.11 (s, 1H ).
工程２　化合物４ｄの合成
　化合物４ｃ（１．５ｇ、４．１０ｍｍｏｌ）に２ｍｏｌ／Ｌ塩酸－酢酸エチル溶液（３０ｍＬ、６０ｍｍｏｌ）を加えた。室温で２時間撹拌した後、析出している固体をろ取することにより、化合物４ｄ（１．３５ｇ、収率９７％）を得た。
ＬＣＭＳ（測定条件Ｂ）、保持時間：０．８３分、[Ｍ＋Ｈ]＋：２６６ Step 2 Synthesis of Compound 4d 2 mol / L hydrochloric acid-ethyl acetate solution (30 mL, 60 mmol) was added to Compound 4c (1.5 g, 4.10 mmol). After stirring at room temperature for 2 hours, the precipitated solid was collected by filtration to obtain Compound 4d (1.35 g, yield 97%).
LCMS (measurement condition B), retention time: 0.83 minutes, [M + H] + : 266
工程３　Ｉ－４の合成
　化合物４ｄ（７０ｍｇ、０．２０７ｍｍｏｌ）をＤＭＡ（１．５ｍＬ）に溶解し、化合物４ｅ（３４ｍｇ、０．２０７ｍｍｏｌ）、炭酸セシウム（２７０ｍｇ、０．８２８ｍｍｏｌ）を加えた。１３０℃で４時間撹拌した。水を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製することにより、化合物Ｉ－４（２１ｍｇ、収率２５％）を得た。
1H-NMR (DMSO-D6)δ: 1.59 (m, 1H), 1.66-1.85 (m, 4H), 2.06 (m, 1H), 2.70 (m, 1H), 2.89-3.08 (m, 2H), 3.33 (m, 4H), 4.46 (m, 1H), 4.71 (m, 1H), 6.31 (s, 1H), 7.19 (t, J = 7.2Hz, 1H), 7.27 (d, J = 8.8Hz, 1H), 7.39-7.56 (m, 2H), 7.68 (d, J = 8.0Hz, 1H), 8.01 (d, J = 8.8Hz, 1H), 8.25 (s, 2H). Step 3 Synthesis of I-4 Compound 4d (70 mg, 0.207 mmol) was dissolved in DMA (1.5 mL), and compound 4e (34 mg, 0.207 mmol) and cesium carbonate (270 mg, 0.828 mmol) were added. Stir at 130 ° C. for 4 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-4 (21 mg, yield 25%). .
1 H-NMR (DMSO-D6) δ: 1.59 (m, 1H), 1.66-1.85 (m, 4H), 2.06 (m, 1H), 2.70 (m, 1H), 2.89-3.08 (m, 2H), 3.33 (m, 4H), 4.46 (m, 1H), 4.71 (m, 1H), 6.31 (s, 1H), 7.19 (t, J = 7.2Hz, 1H), 7.27 (d, J = 8.8Hz, 1H ), 7.39-7.56 (m, 2H), 7.68 (d, J = 8.0Hz, 1H), 8.01 (d, J = 8.8Hz, 1H), 8.25 (s, 2H).
化合物Ｉ－５の合成　
Figure JPOXMLDOC01-appb-C000069
工程１：化合物５ｃの合成
化合物５ａ（４００ｍｇ、２．３２６ｍｍｏｌ）と化合物５ｂ（７３０ｍｇ、４．６５ｍｍｏｌ）をジクロロメタン（１２ｍＬ）に溶解し、ピリジン（０．４７ｍＬ、５．８１ｍｍｏｌ）、酢酸銅（４２２ｍｇ、２．３３ｍｍｏｌ）を加えた。室温で激しく５時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物５ｃ（１２２ｍｇ、収率１９％）を得た。
1H-NMR (DMSO-D6)δ: 1.21 (t, J = 7.2Hz, 3H), 1.59-1.72 (m, 2H), 1.78 (m, 1H), 1.93 (m, 1H), 2.69 (m, 1H), 2.93 (m, 1H), 3.12 (dd, J = 12.4, 9.6Hz, 1H), 3.55 (m, 1H), 3.72 (dd, J = 12.4, 3.2Hz, 1H), 4.11 (q, J = 7.2Hz, 2H), 7.18 (s, 1H), 7.25 (m, 1H), 7.30-7.40 (m, 2H), 7.70-7.77 (m, 3H). Synthesis of Compound I-5
Figure JPOXMLDOC01-appb-C000069
Step 1: Synthesis of Compound 5c Compound 5a (400 mg, 2.326 mmol) and Compound 5b (730 mg, 4.65 mmol) were dissolved in dichloromethane (12 mL), pyridine (0.47 mL, 5.81 mmol), copper acetate (422 mg). 2.33 mmol) was added. After vigorously stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 5c (122 mg, yield 19%).
1 H-NMR (DMSO-D6) δ: 1.21 (t, J = 7.2Hz, 3H), 1.59-1.72 (m, 2H), 1.78 (m, 1H), 1.93 (m, 1H), 2.69 (m, 1H), 2.93 (m, 1H), 3.12 (dd, J = 12.4, 9.6Hz, 1H), 3.55 (m, 1H), 3.72 (dd, J = 12.4, 3.2Hz, 1H), 4.11 (q, J = 7.2Hz, 2H), 7.18 (s, 1H), 7.25 (m, 1H), 7.30-7.40 (m, 2H), 7.70-7.77 (m, 3H).
工程２：Ｉ－５の合成
　窒素気流下、化合物５ｃ（３００ｍｇ、１．０６ｍｍｏｌ）のテトラヒドロフラン（３ｍＬ）溶液にクロロヨードメタン（０．３１ｍＬ、４．２３ｍｍｏｌ）を加え、－７８℃に冷却した。０．７５ｍｏｌ／ＬＬＤＡのテトラヒドロフラン溶液（７．１ｍＬ、５．３ｍｍｏｌ）を滴下し、１時間撹拌した。酢酸（０．３ｍＬ、５．２５ｍｍｏｌ）を加え、室温に昇温した。水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Step 2: Synthesis of I-5 Under a nitrogen stream, chloroiodomethane (0.31 mL, 4.23 mmol) was added to a solution of compound 5c (300 mg, 1.06 mmol) in tetrahydrofuran (3 mL), and the mixture was cooled to −78 ° C. A tetrahydrofuran solution (7.1 mL, 5.3 mmol) of 0.75 mol / LLDA was added dropwise and stirred for 1 hour. Acetic acid (0.3 mL, 5.25 mmol) was added and the temperature was raised to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をエタノール（６ｍＬ）に溶解して化合物５ｄ（１４２ｍｇ、０．９０ｍｍｏｌ）を加え、室温にて６時間撹拌した。酢酸エチルを加え、析出している固体をろ取することで、化合物Ｉ－５（１０２ｍｇ、２３％）を得た。
1H-NMR (DMSO-D6)δ: 1.62-1.93 (m, 5H), 2.08 (m, 1H), 2.81-2.95 (m, 2H), 3.05 (m, 1H), 3.43 (m, 4H), 3.82 (m, 1H), 3.99 (m, 1H), 7.04 (brs, 1H), 7.22 (s, 1H), 7.25 (t, J = 7.6Hz, 1H), 7.35-7.44 (m, 2H), 7.69-7.77 (m, 3H), 8.95 (s, 2H), 11.91 (s, 1H). The obtained residue was dissolved in ethanol (6 mL), compound 5d (142 mg, 0.90 mmol) was added, and the mixture was stirred at room temperature for 6 hr. Ethyl acetate was added, and the precipitated solid was collected by filtration to obtain Compound I-5 (102 mg, 23%).
1 H-NMR (DMSO-D6) δ: 1.62-1.93 (m, 5H), 2.08 (m, 1H), 2.81-2.95 (m, 2H), 3.05 (m, 1H), 3.43 (m, 4H), 3.82 (m, 1H), 3.99 (m, 1H), 7.04 (brs, 1H), 7.22 (s, 1H), 7.25 (t, J = 7.6Hz, 1H), 7.35-7.44 (m, 2H), 7.69 -7.77 (m, 3H), 8.95 (s, 2H), 11.91 (s, 1H).
化合物Ｉ－６の合成　
Figure JPOXMLDOC01-appb-C000070
工程１：化合物６ｂの合成
　Ｆｍｏｃイソチオシアネート（１６６ｍｇ、０．５９ｍｍｏｌ）と炭酸水素ナトリウム（２４８ｍｇ、２．９６ｍｍｏｌ）をクロロホルム（３ｍＬ）に懸濁した。この溶液に化合物６ａ（２００ｍｇ、０．５９ｍｍｏｌ）を４回に分けて加えた。室温で２時間撹拌した後に、硫酸マグネシウムを加えた。固体をセライトを用いて除去し、ろ液を減圧濃縮することで化合物６ｂ（３４０ｍｇ）を得た。化合物６ｂは粗精製のまま次工程へ用いた。 Synthesis of Compound I-6
Figure JPOXMLDOC01-appb-C000070
Step 1: Synthesis of Compound 6b Fmoc isothiocyanate (166 mg, 0.59 mmol) and sodium bicarbonate (248 mg, 2.96 mmol) were suspended in chloroform (3 mL). To this solution, compound 6a (200 mg, 0.59 mmol) was added in four portions. After stirring at room temperature for 2 hours, magnesium sulfate was added. The solid was removed using celite, and the filtrate was concentrated under reduced pressure to obtain Compound 6b (340 mg). Compound 6b was used in the next step with crude purification.
工程２：化合物Ｉ－６の合成
　粗精製の化合物６ｂ（３４ｍｇ、０．０６２ｍｍｏｌ）をＤＭＦ（０．７ｍＬ）に溶解し、ピペリジン（０．１４ｍＬ、１．４１ｍｍｏｌ）を加えた。室温で１時間撹拌した後に、化合物６ｃ（１７．７ｍｇ、０．０８９ｍｍｏｌ）を加えて、室温で２時間撹拌した。重曹水を加えてクロロホルムで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物Ｉ－６（１９．９ｍｇ、収率７６％）を得た。
1H-NMR (DMSO-D6)δ: 1.66-1.72 (m, 2H), 1.77-1.86 (m, 3H), 2.04 (m, 1H), 2.79 (m, 1H), 3.15 (m, 2H), 3.29 (m, 4H), 3.88 (m, 1H), 4.19 (m, 1H), 6.32 (s, 1H), 7.25 (s, 1H), 7.28 (t, J = 7.6Hz, 1H), 7.38 (t, J = 7.6Hz, 2H), 7.86 (d, J = 7.6Hz, 2H), 8.25 (s, 2H). Step 2: Synthesis of Compound I-6 Crude compound 6b (34 mg, 0.062 mmol) was dissolved in DMF (0.7 mL) and piperidine (0.14 mL, 1.41 mmol) was added. After stirring at room temperature for 1 hour, compound 6c (17.7 mg, 0.089 mmol) was added and stirred at room temperature for 2 hours. Sodium bicarbonate water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-6 (19.9 mg, yield 76%).
1 H-NMR (DMSO-D6) δ: 1.66-1.72 (m, 2H), 1.77-1.86 (m, 3H), 2.04 (m, 1H), 2.79 (m, 1H), 3.15 (m, 2H), 3.29 (m, 4H), 3.88 (m, 1H), 4.19 (m, 1H), 6.32 (s, 1H), 7.25 (s, 1H), 7.28 (t, J = 7.6Hz, 1H), 7.38 (t , J = 7.6Hz, 2H), 7.86 (d, J = 7.6Hz, 2H), 8.25 (s, 2H).
化合物Ｉ－７の合成　
Figure JPOXMLDOC01-appb-C000071
工程１：化合物７ｂの合成
化合物７ａ（２００ｍｇ、０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、炭酸セシウム（５７８ｍｇ、１．７７ｍｍｏｌ）と２、４－ジクロロピリミジン（１１４ｍｇ、０．７６９ｍｍｏｌ）を加えた。５０℃で４時間撹拌した後、水を加えた。酢酸エチルで抽出して有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物７ｂと化合物７ｃの混合物（１７１ｍｇ）を得た。 Synthesis of Compound I-7
Figure JPOXMLDOC01-appb-C000071
Step 1: Synthesis of Compound 7b To a solution of Compound 7a (200 mg, 0.59 mmol) in DMF (2 mL) was added cesium carbonate (578 mg, 1.77 mmol) and 2,4-dichloropyrimidine (114 mg, 0.769 mmol). . After stirring at 50 ° C. for 4 hours, water was added. Extraction with ethyl acetate was performed, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a mixture (171 mg) of compound 7b and compound 7c.
工程２　化合物Ｉ－７の合成
化合物７ｂと化合物７ｃの混合物（５０ｍｇ、０．１３２ｍｍｏｌ）をエタノール（１ｍＬ）に溶解し、フェニルボロン酸（２２．６ｍｇ、０．１８５ｍｍｏｌ）、ジクロロビストリフェニルホスフィンパラジウム（９．３ｍｇ、０．０１３ｍｍｏｌ）、２．３ｍｏｌ／Ｌ炭酸カリウム水溶液（０．２ｍＬ、０．４６ｍｍｏｌ）を加えた。１２０℃で３時間撹拌した後、重曹水を加えた。クロロホルムで抽出して、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣を逆相ＨＰＬＣ（アセトニトリル－水）により精製して、化合物Ｉ－７（２．６ｍｇ、収率５％）を得た。
1H-NMR (DMSO-D6)δ: 1.55 (m, 1H), 1.68-1.84 (m, 4H), 2.06 (m, 1H), 2.67 (m, 1H), 3.00-3.11 (m, 2H), 3.26 (m, 4H), 4.73 (m, 1H), 4.94 (m, 1H), 6.30 (s, 1H), 7.17 (d, J = 5.2Hz, 1H), 7.48-7.53 (m, 3H), 8.10-8.14 (m, 2H), 8.24 (s, 2H), 8.43 (d, J = 5.2Hz, 1H). Step 2 Synthesis of Compound I-7 A mixture of compound 7b and compound 7c (50 mg, 0.132 mmol) was dissolved in ethanol (1 mL), phenylboronic acid (22.6 mg, 0.185 mmol), dichlorobistriphenylphosphine palladium ( 9.3 mg, 0.013 mmol) and 2.3 mol / L aqueous potassium carbonate (0.2 mL, 0.46 mmol) were added. After stirring at 120 ° C. for 3 hours, sodium bicarbonate water was added. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase HPLC (acetonitrile-water) to give compound I-7 (2.6 mg, yield 5%).
1 H-NMR (DMSO-D6) δ: 1.55 (m, 1H), 1.68-1.84 (m, 4H), 2.06 (m, 1H), 2.67 (m, 1H), 3.00-3.11 (m, 2H), 3.26 (m, 4H), 4.73 (m, 1H), 4.94 (m, 1H), 6.30 (s, 1H), 7.17 (d, J = 5.2Hz, 1H), 7.48-7.53 (m, 3H), 8.10 -8.14 (m, 2H), 8.24 (s, 2H), 8.43 (d, J = 5.2Hz, 1H).
化合物Ｉ－８の合成　
Figure JPOXMLDOC01-appb-C000072
工程１：化合物８ｂの合成
　化合物８ａ（５ｇ、２３．８ｍｍｏｌ）のエタノール溶液にメチルアミン（４０％メタノール溶液、２８ｍＬ）とシアノ水素化ホウ素ナトリウム（２．２３ｇ、３５．８ｍｍｏｌ）を加えた。次いで酢酸（５．５ｍＬ）を滴下した後に４時間加熱還流した。室温に放冷して水を加え、酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で洗浄した後に無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物８ｂ（２．４ｇ、収率４５％）を得た。
1H-NMR（CDCl3）δ：2.06 (m, 1H), 2.49 (m, 1H), 2.53 (s, 3H), 2.94 (m, 1H), 3.07 (m, 1H), 4.53 (dd, J = 7.6, 5.2Hz, 1H), 5.00 (brs, 1H), 7.13 (t, J = 7.6Hz, 1H), 7.40 (d, J = 7.6Hz, 1H), 7.46 (d, J= 7.6Hz, 1H). Synthesis of Compound I-8
Figure JPOXMLDOC01-appb-C000072
Step 1: Synthesis of Compound 8b To a solution of Compound 8a (5 g, 23.8 mmol) in ethanol was added methylamine (40% methanol solution, 28 mL) and sodium cyanoborohydride (2.23 g, 35.8 mmol). Next, acetic acid (5.5 mL) was added dropwise, and the mixture was heated to reflux for 4 hours. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 8b (2.4 g, yield 45%).
1 H-NMR (CDCl 3 ) δ: 2.06 (m, 1H), 2.49 (m, 1H), 2.53 (s, 3H), 2.94 (m, 1H), 3.07 (m, 1H), 4.53 (dd, J = 7.6, 5.2Hz, 1H), 5.00 (brs, 1H), 7.13 (t, J = 7.6Hz, 1H), 7.40 (d, J = 7.6Hz, 1H), 7.46 (d, J = 7.6Hz, 1H ).
工程２：化合物８ｃ合成
　化合物８ｂ（１．５ｇ、６．６３ｍｍｏｌ）をテトラヒドロフラン（１５ｍＬ）に溶解し、Ｂｏｃ２Ｏ（１．７ｍＬ、７．３ｍｍｏｌ）、ＤＭＡＰ（８１ｍｇ、０．６６３ｍｍｏｌ）を加えた。室温で４時間撹拌した後に、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物８ｃ（１．２６ｇ、収率５８％）を得た。
1H-NMR（CDCl3）δ：1.50 (s, 9H), 1.96 (m, 1H), 2.39 (m, 1H), 2.56 (s, 3H), 2.83 (m, 1H), 3.02 (m, 1H), 5.68 (m, 1H), 5.94 (m, 1H), 7.06-7.10 (m, 2H), 7.38 (m, 1H). Step 2: Compound 8c synthesis Compound 8b (1.5 g, 6.63 mmol) was dissolved in tetrahydrofuran (15 mL), and Boc 2 O (1.7 mL, 7.3 mmol) and DMAP (81 mg, 0.663 mmol) were added. . After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 8c (1.26 g, yield 58%).
1 H-NMR (CDCl 3 ) δ: 1.50 (s, 9H), 1.96 (m, 1H), 2.39 (m, 1H), 2.56 (s, 3H), 2.83 (m, 1H), 3.02 (m, 1H ), 5.68 (m, 1H), 5.94 (m, 1H), 7.06-7.10 (m, 2H), 7.38 (m, 1H).
工程３：化合物８ｅの合成
　化合物８ｃ（１．２５ｇ、３．８３ｍｍｏｌ）をトルエン（１３ｍＬ）に溶解して１－エトキシトリ－ｎ－ブチルスズ（１．４２ｍＬ、４．２１ｍｍｏｌ）、ジクロロビストリフェニルホスフィンパラジウム（０．２７ｇ、０．３８３ｍｍｏｌ）を加えて系内を窒素置換した。１００℃で３時間撹拌した後に水を加えて酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。
得られた残渣をテトラヒドロフラン（２０ｍＬ）、水（２ｍＬ）に溶解した。氷冷下でＮＢＳ（０．６８ｍｇ、０．３８３ｍｍｏｌ）を加えた。１時間撹拌した後に水を加えて酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。
得られた残渣をエタノール（１５ｍＬ）に溶解して化合物８ｄ（０．５５３ｇ、３．４５ｍｍｏｌ）を加えた。室温で３時間撹拌した後に、重曹水を加えて中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。
得られた残渣に４ｍｏｌ／Ｌ塩酸－酢酸エチル溶液（０．９６ｍＬ、３．８３ｍｍｏｌ）を加えた。室温で２時間撹拌した後に、重曹水を加えて中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物８ｅ（９１０ｍｇ、収率７３％）を得た。
ＬＣＭＳ（測定条件Ｂ）、保持時間：１．３８分、［Ｍ＋Ｈ］＋：３２８ Step 3: Synthesis of Compound 8e Compound 8c (1.25 g, 3.83 mmol) was dissolved in toluene (13 mL) and 1-ethoxytri-n-butyltin (1.42 mL, 4.21 mmol), dichlorobistriphenylphosphine palladium ( 0.27 g, 0.383 mmol) was added to replace the system with nitrogen. After stirring at 100 ° C. for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in tetrahydrofuran (20 mL) and water (2 mL). NBS (0.68 mg, 0.383 mmol) was added under ice cooling. After stirring for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in ethanol (15 mL) and compound 8d (0.553 g, 3.45 mmol) was added. The mixture was stirred at room temperature for 3 hours, neutralized with aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
A 4 mol / L hydrochloric acid-ethyl acetate solution (0.96 mL, 3.83 mmol) was added to the resulting residue. The mixture was stirred at room temperature for 2 hours, neutralized with aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 8e (910 mg, yield 73%).
LCMS (measurement condition B), retention time: 1.38 minutes, [M + H] + : 328
工程４：化合物Ｉ－８の合成
　化合物８ｅ（６０ｍｇ、０．１８ｍｍｏｌ）をジクロロメタン（１．５ｍＬ）に溶解し、トリエチルアミン（０．０７６ｍＬ、０．５５ｍｍｏｌ）と塩化ベンゼンスルホニル（０．０２３ｍＬ、０．１８３ｍｍｏｌ）を加えた。室温で１時間撹拌した後、重曹水を加えて中和した。クロロホルムで中和し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－８（４２ｍｇ、収率４９％）を得た。
1H-NMR（DMSO-d6）δ：1.64 (m, 1H), 1.81 (m, 2H), 2.02 (m, 1H), 2.48 (s, 3H), 2,98 (m, 1H), 3.03 (m, 1H), 3.31 (m, 4H), 5.53 (t, J = 8.0Hz, 1H), 6.76 (d, J = 7.2Hz, 1H), 6.81 (s, 1H), 7.22 (t, J = 7.2Hz, 1H), 7.65-7.70 (m, 3H), 7.74 (m, 1H), 7.90-7.94 (m, 2H), 8.26 (brs, 2H). Step 4: Synthesis of Compound I-8 Compound 8e (60 mg, 0.18 mmol) was dissolved in dichloromethane (1.5 mL), and triethylamine (0.076 mL, 0.55 mmol) and benzenesulfonyl chloride (0.023 mL, 0. 183 mmol) was added. After stirring at room temperature for 1 hour, sodium bicarbonate water was added for neutralization. The mixture was neutralized with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-8 (42 mg, yield 49%).
1 H-NMR (DMSO-d 6 ) δ: 1.64 (m, 1H), 1.81 (m, 2H), 2.02 (m, 1H), 2.48 (s, 3H), 2,98 (m, 1H), 3.03 (m, 1H), 3.31 (m, 4H), 5.53 (t, J = 8.0Hz, 1H), 6.76 (d, J = 7.2Hz, 1H), 6.81 (s, 1H), 7.22 (t, J = 7.2Hz, 1H), 7.65-7.70 (m, 3H), 7.74 (m, 1H), 7.90-7.94 (m, 2H), 8.26 (brs, 2H).
化合物Ｉ－９の合成　
Figure JPOXMLDOC01-appb-C000073
 工程１：化合物９ｂの合成　
化合物９ａ（５９０ｍｇ、２．２６ｍｍｏｌ）に、テトラヒドロフラン（８ｍＬ）、（２－（ｔｅｒｔ-ブトキシカルボニル）―１、２、３，４－テトラヒドロイソキノリ－５－イル）ボロン酸（８１４ｍｇ、２．９４ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）ジクロロメタン錯体(１８５ｍｇ、０．２２６ｍｍｏｌ）および２ｍｏｌ/Lの炭酸ナトリウム水溶液（３．３９ｍＬ、６．７８ｍｍｏｌ）を加え、マイクロウエーブ装置を用い１３０℃で３０分反応した。反応液に水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物９ｂ(６６１ｍｇ、７１％)を得た。
1H-NMR(DMSO)δ:1.44(s, 9H), 1.74-1.88(m, 2H), 2.85-2.92(m, 2H), 3.24-3.60(m, 6H), 4.54(s, 2H), 6.66(s, 1H), 7.15(d, J=7.2 Hz, 1H), 7.22(dd, J=7.2Hz,7.2Hz, 1H), 7.37(d, J=7.2Hz, 1H), 8.22-8.24(br, 2H) Synthesis of Compound I-9
Figure JPOXMLDOC01-appb-C000073
 Step 1: Synthesis of Compound 9b
Compound 9a (590 mg, 2.26 mmol) was added to tetrahydrofuran (8 mL), (2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-5-yl) boronic acid (814 mg, 2. 94 mmol), PdCl 2 (dppf) dichloromethane complex (185 mg, 0.226 mmol) and 2 mol / L sodium carbonate aqueous solution (3.39 mL, 6.78 mmol) were added, and the mixture was reacted at 130 ° C. for 30 minutes using a microwave apparatus. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 9b (661 mg, 71%).
1 H-NMR (DMSO) δ: 1.44 (s, 9H), 1.74-1.88 (m, 2H), 2.85-2.92 (m, 2H), 3.24-3.60 (m, 6H), 4.54 (s, 2H), 6.66 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.22 (dd, J = 7.2Hz, 7.2Hz, 1H), 7.37 (d, J = 7.2Hz, 1H), 8.22-8.24 ( br, 2H)
工程２：化合物９ｃの合成
化合物９ｂ（５６３ｍｇ、１．３６ｍｍｏｌ）のメタノール（５ｍＬ）溶液に４ｍｏｌ／Ｌの塩酸－ジオキサン溶液（３．４ｍＬ、１３．６ｍｍｏｌ）を加え室温で３時間半撹拌した。反応液に水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。粗生成物のまま次の反応に用いた。 Step 2: Synthesis of Compound 9c To a solution of Compound 9b (563 mg, 1.36 mmol) in methanol (5 mL) was added 4 mol / L hydrochloric acid-dioxane solution (3.4 mL, 13.6 mmol), and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was used in the next reaction as it was.
工程３：化合物Ｉ－９ の合成　
化合物９ｃ（５０ｍｇ、０．１６０ｍｍｏｌ）のジメチルアセトアミド（１ｍＬ）溶液に水素化ナトリウム（３８．６ｍｇ、０．３１９ｍｍｏｌ）、４－フルオロベンゾニトリル（３８．６ｍｇ、０．３１９ｍｍｏｌ）を加え８０℃で５時間、１２０℃で１時間撹拌した。得られた残渣を分取用ＨＰＬＣ（１０ｍｍｏｌ／Ｌ 炭酸アンンモニウム水溶液－アセトニトリル溶媒）により精製し、化合物Ｉ－９（９ｍｇ、１４％）を得た。
1H-NMR(DMSO)δ:1.76-1.85(m, 2H), 3.08(t, J=5.2Hz, 2H), 3.25-3.40(m, 4H),  3.57(t, J=6.0Hz, 2H), 4.59(s, 2H), 6.68(s,1H), 7.00-7.10(m, 2H), 7.20-7.30(m, 2H), 7.30-7.40(m, 1H), 7.58-7.70(m, 2H), 8.20-8.23(br, 2H) Step 3: Synthesis of Compound I-9
To a solution of compound 9c (50 mg, 0.160 mmol) in dimethylacetamide (1 mL) was added sodium hydride (38.6 mg, 0.319 mmol) and 4-fluorobenzonitrile (38.6 mg, 0.319 mmol). Stir for 1 hour at 120 ° C. The obtained residue was purified by preparative HPLC (10 mmol / L aqueous ammonium carbonate-acetonitrile solvent) to obtain Compound I-9 (9 mg, 14%).
1 H-NMR (DMSO) δ: 1.76-1.85 (m, 2H), 3.08 (t, J = 5.2Hz, 2H), 3.25-3.40 (m, 4H), 3.57 (t, J = 6.0Hz, 2H) , 4.59 (s, 2H), 6.68 (s, 1H), 7.00-7.10 (m, 2H), 7.20-7.30 (m, 2H), 7.30-7.40 (m, 1H), 7.58-7.70 (m, 2H) , 8.20-8.23 (br, 2H)
化合物Ｉ－１０の合成　
Figure JPOXMLDOC01-appb-C000074
工程１：化合物１０ｂの合成
　化合物１０ａ（１８９ｇ，１．４ｍｏＬ）を水（７００ｍＬ）に溶解させ、水酸化ナトリウム（５５．８ｇ，１．４ｍｏＬ）を加えた。室温で３０分撹拌した．反応液を減圧下で濃縮した。エタノール（５００ｍＬ）を加え、不溶物を濾去した。濾液を濃縮し、得られた１０ｂ（１２５ｇ）を粗生成物として次の反応に用いた。 Synthesis of Compound I-10
Figure JPOXMLDOC01-appb-C000074
Step 1: Synthesis of Compound 10b Compound 10a (189 g, 1.4 mol) was dissolved in water (700 mL), and sodium hydroxide (55.8 g, 1.4 mol) was added. Stir at room temperature for 30 minutes. The reaction was concentrated under reduced pressure. Ethanol (500 mL) was added, and the insoluble material was removed by filtration. The filtrate was concentrated and the resulting 10b (125 g) was used in the next reaction as a crude product.
工程２：化合物１０ｃの合成
　工程１で得られた化合物１０ｂ（１０５ｇ、１．０６ｍｏｌ）をテトラヒドロフラン（６００ｍＬ）に溶解し、氷冷下、２－イソチオシアネート－２－メチルプロパン（１１５ｇ、０．９８ｍｏｌ）を加えた。室温に昇温し、１６時間撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（ジクロロメタン－メタノール）によって精製し、化合物１０ｃの粗精製物を得た。粗精製物を石油エーテル：酢酸エチル＝９：１で洗浄して、化合物１０ｃ（１２４ｇ，５９％）を得た。
1H-NMR（DMSO-d6）δ：1.29 (s, 9H), 1.78 (m, 2H), 3.25 (m, 4H), 6.28 (s, 1H), 8.99 (s, 2H). Step 2: Synthesis of Compound 10c Compound 10b (105 g, 1.06 mol) obtained in Step 1 was dissolved in tetrahydrofuran (600 mL), and 2-isothiocyanate-2-methylpropane (115 g, 0.98 mol) was cooled with ice. ) Was added. The mixture was warmed to room temperature and stirred for 16 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (dichloromethane-methanol) to obtain a crude product of compound 10c. The crude product was washed with petroleum ether: ethyl acetate = 9: 1 to obtain Compound 10c (124 g, 59%).
1 H-NMR (DMSO-d 6 ) δ: 1.29 (s, 9H), 1.78 (m, 2H), 3.25 (m, 4H), 6.28 (s, 1H), 8.99 (s, 2H).
工程３：化合物１０ｄの合成
　化合物１０ｃ（１４５ｇ、０．６９ｍｏｌ）を濃塩酸（２２０ｍＬ）に溶解させ、２時間加熱還流した。室温に放冷後、反応液を減圧下で濃縮した。残渣を飽和炭酸水素ナトリウム水溶液でｐＨ＝８とした。得られた固体をろ取し、冷水で洗浄後、減圧乾燥し、化合物１０ｄ（４６ｇ，４３％）を得た。1H-NMR（DMSO-d6）δ：1.79-1.76 (m, 2H), 3.26-3.22 (m, 4H),　6.79 (br, 2H), 8.90 (br, 2H). Step 3: Synthesis of Compound 10d Compound 10c (145 g, 0.69 mol) was dissolved in concentrated hydrochloric acid (220 mL) and heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8 with saturated aqueous sodium hydrogen carbonate solution. The obtained solid was collected by filtration, washed with cold water, and dried under reduced pressure to obtain Compound 10d (46 g, 43%). 1 H-NMR (DMSO-d 6 ) δ: 1.79-1.76 (m, 2H), 3.26-3.22 (m, 4H), 6.79 (br, 2H), 8.90 (br, 2H).
工程４：化合物１０ｅの合成
化合物１０ｄ（３７．５ｇ、０．２３ｍｏｌ）にエタノール(４００ｍＬ)を加え、氷冷下で１－ブロモブタン－２，３－ジオン（３６ｇ，０．２３ｍｏＬ）を加えた。室温に昇温し、６時間撹拌した。反応液を減圧下で濃縮し、飽和炭酸水素ナトリウム水溶液（４００ｍＬ）を加え、塩化メチレン（３００ｍＬx３）で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（ジクロロメタン－メタノール）により精製し、化合物１０ｅを得た。1H-NMR（DMSO-d6）δ：1.79-1.76 (m, 2H), 3.26-3.22 (m, 4H),　6.79 (br, 2H), 8.90 (br, 2H). Step 4: Synthesis of Compound 10e Ethanol (400 mL) was added to Compound 10d (37.5 g, 0.23 mol), and 1-bromobutane-2,3-dione (36 g, 0.23 mol) was added under ice cooling. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (400 mL) was added, and the mixture was extracted with methylene chloride (300 mL × 3). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (dichloromethane-methanol) to obtain compound 10e. 1 H-NMR (DMSO-d 6 ) δ: 1.79-1.76 (m, 2H), 3.26-3.22 (m, 4H), 6.79 (br, 2H), 8.90 (br, 2H).
工程５：化合物１０ｆの合成
化合物１０ｅ（１３．８ｇ、６１．５ｍｍｏＬ）を酢酸(１００ｍＬ)に懸濁させ，３８％臭化水素の酢酸溶液（１００ｍＬ）を室温で加え，１０分間撹拌した．得られた反応溶液に室温で臭素（３．５ｍＬ）を滴下し，室温で終夜撹拌した．アセトン（１００ｍＬ）を反応溶液に加え，１０分間撹拌した．得られた固体をろ過し，アセトンで洗浄して化合物１０ｆ（１６．５ｇ，５８％）を得た． 1H-NMR（DMSO-d6）δ：3.47 (t, 4H), 5.02 (s, 2H), 8.29 (s, 1H), 8.92 (b, 2H). Step 5: Synthesis of Compound 10f Compound 10e (13.8 g, 61.5 mmol) was suspended in acetic acid (100 mL), 38% hydrogen bromide in acetic acid (100 mL) was added at room temperature, and the mixture was stirred for 10 min. Bromine (3.5 mL) was added dropwise to the obtained reaction solution at room temperature, and the mixture was stirred overnight at room temperature. Acetone (100 mL) was added to the reaction solution and stirred for 10 minutes. The resulting solid was filtered and washed with acetone to give compound 10f (16.5 g, 58%). 1 H-NMR (DMSO-d 6 ) δ: 3.47 (t, 4H), 5.02 (s, 2H), 8.29 (s, 1H), 8.92 (b, 2H).
工程６：Ｉ－１０の合成
　化合物１０ｆ（４５ｍｇ，０．１２ｍｍｏＬ）をエタノール（２ｍＬ）に懸濁させ、ピリダジン－３－カルボチオアミド（１８ｍｇ，０．１３ｍｍｏＬ）を加え、３時間加熱還流した。室温まで放冷後、飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－９（１１ｍｇ，２７％）を得た。1H-NMR（DMSO-d6）δ: 1.81-1.87 (m, 2H), 3.32-3.38 (m, 4H), 7.14 (s, 1H), 7.91 (J = 8.5, 5.0 Hz, dd, 1H), 8.24-8.28 (m, 3H), 8.40 (J = 8.5, 1.3 Hz, dd, 1H), 9.33 (J = 4.9, 1.4 Hz, dd, 1H). Step 6: Synthesis of I-10 Compound 10f (45 mg, 0.12 mmol) was suspended in ethanol (2 mL), pyridazine-3-carbothioamide (18 mg, 0.13 mmol) was added, and the mixture was heated to reflux for 3 hours. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform-methanol) to obtain compound I-9 (11 mg, 27%). 1 H-NMR (DMSO-d 6 ) δ: 1.81-1.87 (m, 2H), 3.32-3.38 (m, 4H), 7.14 (s, 1H), 7.91 (J = 8.5, 5.0 Hz, dd, 1H) , 8.24-8.28 (m, 3H), 8.40 (J = 8.5, 1.3 Hz, dd, 1H), 9.33 (J = 4.9, 1.4 Hz, dd, 1H).
化合物Ｉ－１２の合成　
Figure JPOXMLDOC01-appb-C000075
工程１：Ｉ－１２の合成
　２－シクロペンチルエタノール（３０ｍｇ，０．２７ｍｍｏＬ）をジメチルアセトアミド（０．５ｍＬ）に溶解させ、水素化ナトリウム（１１ｍｇ，０．２７ｍｍｏＬ）を加え、１０分間撹拌した。実施例１０と同様の方法で合成した化合物１２ａ（２０ｍｇ，０．０５３ｍｍｏＬ）を加え、１２０℃で終夜撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－１２（１２ｍｇ，５０％）を得た。1H-NMR (DMSO-D6) δ: 1.12-1.99 (m, 11H), 3.14-3.47 (m, 2H), 4.35 (J = 6.8 Hz, t, 2H), 6.94 (J = 8.8 Hz, d, 1H), 7.09 (s, 1H), 8.03 (s, 1H), 8.25 (J = 8.7, 2.4 Hz, dd, 3H), 8.77 (J = 2.3 Hz, d, 1H). Synthesis of Compound I-12
Figure JPOXMLDOC01-appb-C000075
Step 1: Synthesis of I-12 2-Cyclopentylethanol (30 mg, 0.27 mmol) was dissolved in dimethylacetamide (0.5 mL), sodium hydride (11 mg, 0.27 mmol) was added, and the mixture was stirred for 10 minutes. Compound 12a (20 mg, 0.053 mmol) synthesized in the same manner as in Example 10 was added, and the mixture was stirred at 120 ° C. overnight. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-12 (12 mg, 50%). 1H-NMR (DMSO-D6) δ: 1.12-1.99 (m, 11H), 3.14-3.47 (m, 2H), 4.35 (J = 6.8 Hz, t, 2H), 6.94 (J = 8.8 Hz, d, 1H ), 7.09 (s, 1H), 8.03 (s, 1H), 8.25 (J = 8.7, 2.4 Hz, dd, 3H), 8.77 (J = 2.3 Hz, d, 1H).
化合物Ｉ－１５の合成　
Figure JPOXMLDOC01-appb-C000076
工程１：化合物Ｉ－１５の合成
　５－ブロモ－２，４－ジメチルピリミジン（６５ｍｇ，０．３５ｍｍｏＬ）を１，４－ジオキサン（１ｍＬ）に溶解し、ビス（ピナコレート）ジボラン（８８ｍｇ，０．３５ｍｍｏＬ）、ＰｄＣｌ２（ｄｐｐｆ）（２８ｍｇ，０．０３５ｍｍｏｌ）、酢酸カリウム（６８ｍｇ，０．７０ｍｍｏｌ）を加え１００℃で２時間撹拌した。室温まで放冷後、反応液にエタノール（１ｍＬ）、２ｍｏｌ/Ｌ炭酸ナトリム水溶液（０．５ｍＬ）、化合物１５ａ（９９ｍｇ，０．２３ｍｍｏＬ）及びＰｄＣｌ２（ｄｐｐｆ）（３８ｍｇ，０．０４７ｍｍｏｌ）を加え、マイクロウェーブ照射下、１３０℃で４５分間加熱した。室温まで放冷後、反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－１５（６ｍｇ、収率４．６％）を得た。1H-NMR (DMSO-D6) δ: 1.74-1.90 (m, 2H), 2.65 (s, 3H), 2.79 (s, 3H), 3.33-3.37 (m, 4H), 7.12 (s, 1H), 8.23 (s, 1H), 8.26 (s, 2H), 9.04 (s, 1H). Synthesis of Compound I-15
Figure JPOXMLDOC01-appb-C000076
Step 1: Synthesis of Compound I-15 5-Bromo-2,4-dimethylpyrimidine (65 mg, 0.35 mmol) was dissolved in 1,4-dioxane (1 mL) and bis (pinacolato) diborane (88 mg, 0.35 mmol). ), PdCl2 (dppf) (28 mg, 0.035 mmol) and potassium acetate (68 mg, 0.70 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool to room temperature, ethanol (1 mL), 2 mol / L aqueous sodium carbonate solution (0.5 mL), compound 15a (99 mg, 0.23 mmol) and PdCl 2 (dppf) (38 mg, 0.047 mmol) were added to the reaction mixture. The sample was heated at 130 ° C. for 45 minutes under microwave irradiation. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-15 (6 mg, yield 4.6%). 1H-NMR (DMSO-D6) δ: 1.74-1.90 (m, 2H), 2.65 (s, 3H), 2.79 (s, 3H), 3.33-3.37 (m, 4H), 7.12 (s, 1H), 8.23 (s, 1H), 8.26 (s, 2H), 9.04 (s, 1H).
化合物Ｉ－１６の合成　
Figure JPOXMLDOC01-appb-C000077
工程１：化合物Ｉ－１６の合成
　Ｎ－（２－メトキシエチル）メチルアミン（２４ｍｇ，０．２７ｍｍｏＬ）をジメチルアセトアミド（０．５ｍＬ）に溶解させ、実施例15と同様の方法で合成した化合物１６ａ（２０ｍｇ，０．０５３ｍｍｏＬ）、炭酸セシウム（５２ｍｇ，０．１６ｍｍｏＬ）加え、１２０℃で終夜撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－１６（６ｍｇ，２６％）を得た。1H-NMR (CDCl3) δ: 1.84-2.11 (m, 2H), 3.16 (s, 3H), 3.36 (s, 3H), 3.41-3.54 (m, 4H), 3.62 (J = 5.6 Hz, t, 2H), 3.82 (J = 5.6 Hz, t, 2H), 6.57 (J = 9.3 Hz, d, 1H), 7.16 (s, 1H), 7.34 (s, 1H), 8.08 (J = 9.3 Hz, d, 1H), 8.75 (s, 1H). Synthesis of Compound I-16
Figure JPOXMLDOC01-appb-C000077
Step 1: Synthesis of Compound I-16 Compound 16a synthesized in the same manner as in Example 15 by dissolving N- (2-methoxyethyl) methylamine (24 mg, 0.27 mmol) in dimethylacetamide (0.5 mL) (20 mg, 0.053 mmol) and cesium carbonate (52 mg, 0.16 mmol) were added and stirred at 120 ° C. overnight. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-16 (6 mg, 26%). 1 H-NMR (CDCl 3 ) δ: 1.84-2.11 (m, 2H), 3.16 (s, 3H), 3.36 (s, 3H), 3.41-3.54 (m, 4H), 3.62 (J = 5.6 Hz, t , 2H), 3.82 (J = 5.6 Hz, t, 2H), 6.57 (J = 9.3 Hz, d, 1H), 7.16 (s, 1H), 7.34 (s, 1H), 8.08 (J = 9.3 Hz, d , 1H), 8.75 (s, 1H).
化合物Ｉ－１７の合成　
Figure JPOXMLDOC01-appb-C000078
工程１：Ｉ－１７の合成
　実施例15と同様の方法で合成した化合物１７ａ（３０ｍｇ，０．０８１ｍｍｏＬ）をジメチルアセトアミド（１ｍＬ）に溶解し、１－ブロモブタン（１３ｍｇ，０．０９７ｍｍｏＬ）、炭酸カリウム（２７ｍｇ，０．１９ｍｍｏＬ）加え、１２０℃で６時間撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－１７（１４ｍｇ，４１％）を得た。1H-NMR (DMSO-D6) δ: 0.95 (J = 7.4 Hz, t, 3H), 1.42-1.51 (m, 2H), 1.70-1.77 (m, 2H), 1.80-1.87 (m, 2H), 2.72 (s, 3H), 3.28-3.37 (m, 4H), 4.12 (J = 6.4 Hz, t, 2H), 7.11 (s, 1H), 7.72 (J = 2.8 Hz, d, 1H), 8.20 (s, 1H), 8.26 (brs, 2H), 8.29 (J = 2.8 Hz, d, 1H). Synthesis of Compound I-17
Figure JPOXMLDOC01-appb-C000078
Step 1: Synthesis of I-17 Compound 17a (30 mg, 0.081 mmol) synthesized in the same manner as in Example 15 was dissolved in dimethylacetamide (1 mL), 1-bromobutane (13 mg, 0.097 mmol), potassium carbonate (27 mg, 0.19 mmol) was added, and the mixture was stirred at 120 ° C. for 6 hours. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-17 (14 mg, 41%). 1 H-NMR (DMSO-D6) δ: 0.95 (J = 7.4 Hz, t, 3H), 1.42-1.51 (m, 2H), 1.70-1.77 (m, 2H), 1.80-1.87 (m, 2H), 2.72 (s, 3H), 3.28-3.37 (m, 4H), 4.12 (J = 6.4 Hz, t, 2H), 7.11 (s, 1H), 7.72 (J = 2.8 Hz, d, 1H), 8.20 (s , 1H), 8.26 (brs, 2H), 8.29 (J = 2.8 Hz, d, 1H).
化合物Ｉ－１８の合成　
Figure JPOXMLDOC01-appb-C000079
 工程１：化合物１８ｃの合成
化合物１８ａ（５００ｍｇ、１．３２ｍｍｏｌ）に、エタノール（２ｍＬ）、化合物１８ｂ（３１９ｍｇ、１．３２ｍｍｏｌ）を加え室温で４時間撹拌した。反応液に飽和重曹水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた固体をジイソプロピルエーテルで洗浄し化合物１８ｃ（４２８mｇ、収率７３％）を得た。
1H-NMR(CDCl3)δ:1.49(s, 9H), 1.93-2.20(m, 2H),3.41-3.60(m, 12H), 6.80(s, 1H), 6.95(s, 1H)  Synthesis of Compound I-18
Figure JPOXMLDOC01-appb-C000079
 Step 1: Synthesis of Compound 18c To Compound 18a (500 mg, 1.32 mmol) was added ethanol (2 mL) and Compound 18b (319 mg, 1.32 mmol), and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diisopropyl ether to obtain Compound 18c (428 mg, yield 73%).
1 H-NMR (CDCl 3 ) δ: 1.49 (s, 9H), 1.93-2.20 (m, 2H), 3.41-3.60 (m, 12H), 6.80 (s, 1H), 6.95 (s, 1H)
工程２：化合物１８ｄの合成　
化合物１８ｃ（４２０ｍｇ、０．９３ｍｍｏｌ）のメタノール（４ｍＬ）溶解に、４ｍｏｌ／Ｌの塩酸－ジオキサン溶液（１．１７ｍＬ，４．６７ｍｍｏｌ）を加え室温で１時間撹拌した。更に４ｍｏｌ/Lの塩酸（１．１７ｍＬ，４．６７ｍｍｏｌ）ジオキサン溶液を追加し１２時間静置した。溶媒を減圧留去し、得られた固体をジイソプロピルエーテルで洗浄し，粗生成物として化合物１８ｄを得た。 Step 2: Synthesis of Compound 18d
To a solution of compound 18c (420 mg, 0.93 mmol) in methanol (4 mL) was added 4 mol / L hydrochloric acid-dioxane solution (1.17 mL, 4.67 mmol), and the mixture was stirred at room temperature for 1 hour. Further, a 4 mol / L hydrochloric acid (1.17 mL, 4.67 mmol) dioxane solution was added, and the mixture was allowed to stand for 12 hours. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diisopropyl ether to obtain Compound 18d as a crude product.
工程３：Ｉ－１８の合成　
化合物１８ｄ（６２ｍｇ、０．１４ｍｍｏｌ）にジメチルホルムアミド（１ｍＬ）、ベンジルブロミド（０．０２２ｍＬ、０．１８３ｍｍｏｌ）、炭酸カリウム（５８，４ｍｇ、０．４２３ｍｍｏｌ）を加え室温で９０分で撹拌した。更に炭酸カリウム（４０ｍｇ、０．２８２ｍｍｏｌ）を加え１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製した。得られた残渣を酢酸エチルで洗浄し、化合物Ｉ－１８（１６mｇ、収率２６％）を得た。
1H-NMR(DMSO)δ:1.74-1.86(m, 2H), 3.25-3.40(m, 8H), 3.42-3.50(m, 4H), 3.54(s, 2H), 6.77(s, 1H), 7.17(s, 1H), 7.25-7.39(m, 5H), 8.19-8.23(br, 2H) Step 3: Synthesis of I-18
Dimethylformamide (1 mL), benzyl bromide (0.022 mL, 0.183 mmol) and potassium carbonate (58,4 mg, 0.423 mmol) were added to compound 18d (62 mg, 0.14 mmol), and the mixture was stirred at room temperature for 90 minutes. Further, potassium carbonate (40 mg, 0.282 mmol) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained residue was washed with ethyl acetate to obtain Compound I-18 (16 mg, yield 26%).
1 H-NMR (DMSO) δ: 1.74-1.86 (m, 2H), 3.25-3.40 (m, 8H), 3.42-3.50 (m, 4H), 3.54 (s, 2H), 6.77 (s, 1H), 7.17 (s, 1H), 7.25-7.39 (m, 5H), 8.19-8.23 (br, 2H)
化合物Ｉ－１９の合成　
Figure JPOXMLDOC01-appb-C000080
工程１：化合物１９ｂの合成
１－ブロモブタン－２，３－ジオン（４．０１ｇ、２４．３１　ｍｍｏｌ）をエタノール（５０ｍＬ）に溶解させ０℃に冷却し、化合物１９ａを加えて室温で２３時間撹拌した。溶媒を減圧留去した後クロロホルムを加えて、飽和炭酸水素ナトリウム水溶液で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１９ｂ（２．５９ｇ、収率４８％）を得た。
1H-NMR (CDCl3) δ: 1.95-2.03 (m, 2H), 2.51-2.51 (m, 3H), 3.44-3.48 (m, 4H), 7.39 (s, 1H). Synthesis of Compound I-19
Figure JPOXMLDOC01-appb-C000080
Step 1: Synthesis of Compound 19b 1-Bromobutane-2,3-dione (4.01 g, 24.31 mmol) was dissolved in ethanol (50 mL), cooled to 0 ° C., compound 19a was added, and the mixture was stirred at room temperature for 23 hours. did. After distilling off the solvent under reduced pressure, chloroform was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 19b (2.59 g, yield 48%).
1 H-NMR (CDCl 3 ) δ: 1.95-2.03 (m, 2H), 2.51-2.51 (m, 3H), 3.44-3.48 (m, 4H), 7.39 (s, 1H).
工程２：化合物１９ｃの合成
化合物１９ｂ（３．８５ｇ、１７．２ｍｍｏｌ）に臭化水素酸（２５％酢酸溶液、７７ｍＬ、３５４ｍｍｏｌ）、臭素（０．８８４ｍＬ、１７．２ｍｏｌ）を加え、室温で２３時間撹拌した。溶媒を減圧留去した後、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。溶媒を減圧留去した後、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１９ｃ（２．１５ｇ、収率４２％）を得た。
1H-NMR (CDCl3) δ: 1.97-2.04 (m, 2H), 3.45-3.47 (m, 4H), 4.40 (s, 2H), 7.55 (s, 1H). Step 2: Synthesis of Compound 19c To compound 19b (3.85 g, 17.2 mmol) was added hydrobromic acid (25% acetic acid solution, 77 mL, 354 mmol), bromine (0.884 mL, 17.2 mol), and 23 at room temperature. Stir for hours. After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 19c (2.15 g, yield 42%).
1 H-NMR (CDCl 3 ) δ: 1.97-2.04 (m, 2H), 3.45-3.47 (m, 4H), 4.40 (s, 2H), 7.55 (s, 1H).
工程３：化合物１９ｄの合成
化合物１９ｃ（４００ｍｇ、１．３２ｍｍｏｌ）、ｔｅｒｔ－ブチル４－（アミノカルボチオイル）テトラヒドロピリジン－１（２Ｈ）－カルボキシレート（３２２ｍｇ、１．３２ｍｍｏｌ）にエタノール（２ｍＬ）を加え、１２０℃で７分間マイクロ波を照射した。反応液を飽和炭酸水素ナトリウム水溶液に加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄したのち無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１９ｄ（６３６ｍｇ）を粗生成物として得た。
1H-NMR (DMSO-D6) δ: 1.41 (s, 9H), 1.54-1.58 (m, 2H), 1.80-1.84 (m, 2H), 2.01-2.05 (m, 2H), 2.89-2.92 (m, 2H), 3.27-3.40 (m, 5H), 4.01-4.03 (m, 2H), 6.93 (s, 1H), 7.86 (s, 1H), 8.22 (s, 2H). Step 3: Synthesis of Compound 19d Compound 19c (400 mg, 1.32 mmol), tert-butyl 4- (aminocarbothioyl) tetrahydropyridine-1 (2H) -carboxylate (322 mg, 1.32 mmol) in ethanol (2 mL) Then, microwave irradiation was performed at 120 ° C. for 7 minutes. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 19d (636 mg) as a crude product.
1 H-NMR (DMSO-D 6 ) δ: 1.41 (s, 9H), 1.54-1.58 (m, 2H), 1.80-1.84 (m, 2H), 2.01-2.05 (m, 2H), 2.89-2.92 ( m, 2H), 3.27-3.40 (m, 5H), 4.01-4.03 (m, 2H), 6.93 (s, 1H), 7.86 (s, 1H), 8.22 (s, 2H).
工程４：化合物１９ｅの合成
化合物１９ｄ（４１８ｍｇ、０．９３ｍｍｏｌ）をメタノール（４ｍＬ）に溶解させ、４ｍｏｌ／Ｌ塩酸（ジオキサン溶液、４ｍＬ、１６ｍｍｏｌ）を加えて室温で２時間撹拌した。溶媒を減圧留去した後、残渣を水に溶解させ、それを１ｍｏｌ／Ｌ水酸化ナトリウム水溶液に加えて、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し化合物１９ｅ（２４４ｍｇ、収率７５％）を得た。
1H-NMR (CDCl3) δ: 1.69-1.75 (m, 5H), 1.96-2.04 (m, 2H), 2.12-2.16 (m, 2H), 2.75-2.79 (m, 2H), 3.14-3.18 (m, 3H), 3.45-3.47 (m, 4H), 7.03 (s, 1H), 7.34 (s, 1H). Step 4: Synthesis of Compound 19e Compound 19d (418 mg, 0.93 mmol) was dissolved in methanol (4 mL), 4 mol / L hydrochloric acid (dioxane solution, 4 mL, 16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in water, and it was added to a 1 mol / L aqueous sodium hydroxide solution and extracted with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (chloroform-methanol) to obtain Compound 19e (244 mg, yield 75%).
1 H-NMR (CDCl 3 ) δ: 1.69-1.75 (m, 5H), 1.96-2.04 (m, 2H), 2.12-2.16 (m, 2H), 2.75-2.79 (m, 2H), 3.14-3.18 ( m, 3H), 3.45-3.47 (m, 4H), 7.03 (s, 1H), 7.34 (s, 1H).
工程５：化合物Ｉ－１９の合成
化合物１９ｅ（５０ｍｇ、０．１４３ｍｍｏｌ）を塩化メチレン（１ｍＬ）に溶解させ、トリエチルアミン（４０μＬ、０．２８７ｍｍｏｌ）、クロロギ酸イソプロピル（１８μＬ、　０．１５８ｍｍｏｌ）を加えて室温で１８時間撹拌した。トリエチルアミン（４０μＬ、　０．２８７ｍｍｏｌ）、クロロギ酸イソプロピル（３３μＬ、０．２８６ｍｍｏｌ）を加えて室温で３時間撹拌し、水を加えてクロロホルムで抽出した。有機層を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物Ｉ－１９（５６ｍｇ、収率９０％）を得た。.
1H-NMR (DMSO-D6) δ: 1.19 (d, J = 6.3 Hz, 6H), 1.54-1.61 (m, 2H), 1.82-1.83 (m, 2H), 2.03-2.08 (m, 2H), 2.94-3.08 (m, 2H), 3.25-3.35 (m, 5H), 4.00-4.05 (m, 2H), 4.73-4.82 (m, 1H), 6.92 (s, 1H), 7.86 (s, 1H), 8.21 (s, 2H). Step 5: Synthesis of Compound I-19 Compound 19e (50 mg, 0.143 mmol) was dissolved in methylene chloride (1 mL), and triethylamine (40 μL, 0.287 mmol) and isopropyl chloroformate (18 μL, 0.158 mmol) were added. Stir at room temperature for 18 hours. Triethylamine (40 μL, 0.287 mmol) and isopropyl chloroformate (33 μL, 0.286 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with chloroform. The organic layer was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound I-19 (56 mg, yield 90%). .
1 H-NMR (DMSO-D 6 ) δ: 1.19 (d, J = 6.3 Hz, 6H), 1.54-1.61 (m, 2H), 1.82-1.83 (m, 2H), 2.03-2.08 (m, 2H) , 2.94-3.08 (m, 2H), 3.25-3.35 (m, 5H), 4.00-4.05 (m, 2H), 4.73-4.82 (m, 1H), 6.92 (s, 1H), 7.86 (s, 1H) , 8.21 (s, 2H).
化合物Ｉ－２０の合成　
Figure JPOXMLDOC01-appb-C000081
工程１：化合物２０ｂの合成
　化合物２０ａ（１８５ｍｇ，１ｍｍｏＬ）をエタノール（２ｍＬ）に溶解し、イソブチリミダミド塩酸塩（１２３ｍｇ，１ｍｍｏＬ）、２０％ナトリウムエトキシドのエタノール溶液（０．３８６ｍＬ，１ｍｍｏＬ）を加え、４時間加熱還流した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２０ｂ（１４０ｍｇ，６７％）を得た。1H-NMR (CDCl3) δ: 1.35 (J = 7.0 Hz, d, 7H), 1.40 (J = 7.2 Hz, t, 3H), 2.80 (s, 3H), 3.21 (m, 1H), 4.40 (J = 7.1 Hz, q, 2H), 9.08 (s, 1H). Synthesis of Compound I-20
Figure JPOXMLDOC01-appb-C000081
Step 1: Synthesis of Compound 20b Compound 20a (185 mg, 1 mmol) was dissolved in ethanol (2 mL), and isobutyrimidamide hydrochloride (123 mg, 1 mmol), ethanol solution of 20% sodium ethoxide (0.386 mL, 1 mmol). And heated to reflux for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 20b (140 mg, 67%). 1H-NMR (CDCl3) δ: 1.35 (J = 7.0 Hz, d, 7H), 1.40 (J = 7.2 Hz, t, 3H), 2.80 (s, 3H), 3.21 (m, 1H), 4.40 (J = 7.1 Hz, q, 2H), 9.08 (s, 1H).
工程２：化合物２０ｃの合成
　化合物２０ｂ（１４０ｍｇ，０．６７ｍｍｏＬ）をエタノール（２ｍＬ）に溶解させ、２ｍｏＬ/Ｌ水酸化ナトリウム水溶液（１ｍＬ）を加え、室温で２時間撹拌した。エタノールを減圧下留去し、２ｍｏＬ/Ｌ塩酸でｐＨ＝２とした。得られた固体をろ取し、水で洗浄後、減圧乾燥して化合物２０ｃを得た。1H-NMR (CDCl3) δ: 1.37 (J = 7.0 Hz, d, 6H), 2.85 (s, 5H), 3.22-3.29 (m, 1H), 9.21 (s, 1H). Step 2: Synthesis of Compound 20c Compound 20b (140 mg, 0.67 mmol) was dissolved in ethanol (2 mL), 2 mol / L aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 2 hr. Ethanol was distilled off under reduced pressure, and the pH was adjusted to 2 with 2 moL / L hydrochloric acid. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure to obtain compound 20c. 1H-NMR (CDCl3) δ: 1.37 (J = 7.0 Hz, d, 6H), 2.85 (s, 5H), 3.22-3.29 (m, 1H), 9.21 (s, 1H).
工程３：化合物２０ｄの合成
　化合物２０ｃ（８０ｍｇ，０．４４ｍｍｏＬ）をジメチルホルムアミド（１ｍＬ）に溶解させ、ＣＤＩ（２１６ｍｇ，１．３３ｍｍｏＬ）を加え、室温で１時間撹拌した。２８％アンモニア水溶液（１ｍＬ）を加え、室温で３０分撹拌した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２０ｄ（６５ｍｇ，８２％）を得た。1H-NMR (CDCl3) δ: 1.34 (J = 6.8 Hz, d, 6H), 2.70 (s, 3H), 3.17-3.24 (m, 1H), 5.81 (s, 2H), 8.71 (s, 1H). Step 3: Synthesis of Compound 20d Compound 20c (80 mg, 0.44 mmol) was dissolved in dimethylformamide (1 mL), CDI (216 mg, 1.33 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 28% Aqueous ammonia solution (1 mL) was added, and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 20d (65 mg, 82%). 1H-NMR (CDCl3) δ: 1.34 (J = 6.8 Hz, d, 6H), 2.70 (s, 3H), 3.17-3.24 (m, 1H), 5.81 (s, 2H), 8.71 (s, 1H).
工程４：化合物２０ｅの合成
　化合物２０ｄ（６１ｍｇ，０．３４ｍｍｏＬ）をテトラヒドロフラン（１ｍＬ）に溶解させ，ローソン試薬（１３８ｍｇ，０．３４ｍｍｏＬ）を加え、室温で終夜撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２０ｅ（４１ｍｇ，６２％）を得た。1H-NMR (CDCl3) δ: 1.33 (J = 7.0 Hz, d, 6H), 2.65 (s, 3H), 3.14-3.21 (m, 1H), 6.98 (s, 1H), 7.76 (s, 1H), 8.71 (s, 1H). Step 4: Synthesis of Compound 20e Compound 20d (61 mg, 0.34 mmol) was dissolved in tetrahydrofuran (1 mL), Lawesson's reagent (138 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 20e (41 mg, 62%). 1H-NMR (CDCl3) δ: 1.33 (J = 7.0 Hz, d, 6H), 2.65 (s, 3H), 3.14-3.21 (m, 1H), 6.98 (s, 1H), 7.76 (s, 1H), 8.71 (s, 1H).
工程５：化合物Ｉ－２０の合成
　化合物２０ｅを用いて、実施例10と同様の方法でＩ－２０を得た．
1H-NMR (DMSO-D6) δ: 1.31 (J = 7.0 Hz, d, 7H), 1.81-1.87 (m, 2H), 2.81 (s, 3H), 3.14-3.20 (m, 1H), 3.34 (s, 4H), 7.11 (s, 1H), 8.22 (s, 1H), 8.26 (s, 2H), 9.07 (s, 1H). Step 5: Synthesis of Compound I-20 I-20 was obtained in the same manner as in Example 10 using Compound 20e.
1H-NMR (DMSO-D6) δ: 1.31 (J = 7.0 Hz, d, 7H), 1.81-1.87 (m, 2H), 2.81 (s, 3H), 3.14-3.20 (m, 1H), 3.34 (s , 4H), 7.11 (s, 1H), 8.22 (s, 1H), 8.26 (s, 2H), 9.07 (s, 1H).
化合物Ｉ－２１の合成　
Figure JPOXMLDOC01-appb-C000082
工程１：化合物２１ｂの合成
化合物２１ａ（３００ｍｇ、１．５ｍｍｏｌ）を臭化水素酸（２５％酢酸溶液、２２ｍＬ）に溶解し、ピリジニウムトリブロミド（４８６ｍｇ、１．５ｍｍｏｌ）を加え、室温で２３時間撹拌した。反応液を氷水に加えて酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥した。溶媒を留去して、減圧乾燥して化合物２１ｂの粗生成物（３８０ｍｇ）を得た。 Synthesis of Compound I-21
Figure JPOXMLDOC01-appb-C000082
Step 1: Synthesis of Compound 21b Compound 21a (300 mg, 1.5 mmol) was dissolved in hydrobromic acid (25% acetic acid solution, 22 mL), pyridinium tribromide (486 mg, 1.5 mmol) was added, and 23 hours at room temperature. Stir. The reaction mixture was added to ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was dried under reduced pressure to obtain a crude product of compound 21b (380 mg).
工程２：化合物Ｉ－２１の合成
化合物２１ｂ（３８０ｍｇ）、化合物２１ｃ（２０５ｍｇ、０．６ｍｍｏｌ）をエタノール（２０　ｍＬ）に溶解し、室温で２３時間撹拌した。析出した固体を濾取し、エタノールで洗浄後、減圧乾燥して化合物Ｉ－２１（３９３　ｍｇ、収率６１％）を得た。
1H-NMR (DMSO-D6) δ: 1.96 (t, J = 2.5 Hz, 2H), 3.6 (t, J = 2.5 Hz, 4H), 7.45-7.56(m, 3H), 7.94-8.22 (m, 6H), 8.96 (s, 2H), 12.00 (bs, 1H). Step 2: Synthesis of Compound I-21 Compound 21b (380 mg) and compound 21c (205 mg, 0.6 mmol) were dissolved in ethanol (20 mL) and stirred at room temperature for 23 hours. The precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure to obtain Compound I-21 (393 mg, yield 61%).
1 H-NMR (DMSO-D 6 ) δ: 1.96 (t, J = 2.5 Hz, 2H), 3.6 (t, J = 2.5 Hz, 4H), 7.45-7.56 (m, 3H), 7.94-8.22 (m , 6H), 8.96 (s, 2H), 12.00 (bs, 1H).
化合物Ｉ－２２の合成　
Figure JPOXMLDOC01-appb-C000083
工程１：Ｉ－２２の合成
　（３－クロロフェニル）メタノール（４４ｍｇ，０．３１ｍｍｏＬ），実施例２３で合成した化合物２２ａ（３０ｍｇ，０．１０２ｍｍｏＬ）をジメチルスルホキシド（１ｍＬ）に溶解させ、６０％水素化ナトリウム（１３ｍｇ，０．３１ｍｍｏＬ）を加え、室温で４５分間撹拌した。１２０℃に昇温して、１．５時間撹拌した。室温まで放冷後、６０％水素化ナトリウム（４ｍｇ，０．１０ｍｍｏＬ）、（３－クロロフェニル）メタノール（１５ｍｇ，０．１０ｍｍｏＬ）のジメチルスルホキシド（０．３ｍｌ）溶液を加えた後、１２０℃に昇温して１時間撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製した。得られた固体に酢酸エチルを加え、ろ取することで化合物Ｉ－２２（５．６ｍｇ，１４％）を得た。1H-NMR (DMSO-D6) δ: 1.78-1.90 (2H, m), 3.30-3.37 (4H, m),　5.45 (2H, s), 6.77 (1H, d, J = 8.2 Hz), 7.32 (1H, s), 7.36-7.43 (2H, m), 7.47 (1H, d, J = 7.3 Hz), 7.54 (1H, d, J = 7.3 Hz), 7.57 (1H, s), 7.75 (1H, t, J = 7.8 Hz), 8.24 (2H, br s).  Synthesis of Compound I-22
Figure JPOXMLDOC01-appb-C000083
Step 1: Synthesis of I-22 (3-Chlorophenyl) methanol (44 mg, 0.31 mmol), Compound 22a synthesized in Example 23 (30 mg, 0.102 mmol) was dissolved in dimethyl sulfoxide (1 mL), and 60% hydrogen Sodium chloride (13 mg, 0.31 mmol) was added and stirred at room temperature for 45 minutes. It heated up at 120 degreeC and stirred for 1.5 hours. After allowing to cool to room temperature, 60% sodium hydride (4 mg, 0.10 mmol), (3-chlorophenyl) methanol (15 mg, 0.10 mmol) in dimethyl sulfoxide (0.3 ml) were added, and the temperature was raised to 120 ° C. Warmed and stirred for 1 hour. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol). Ethyl acetate was added to the obtained solid and collected by filtration to give compound I-22 (5.6 mg, 14%). 1 H-NMR (DMSO-D6) δ: 1.78-1.90 (2H, m), 3.30-3.37 (4H, m), 5.45 (2H, s), 6.77 (1H, d, J = 8.2 Hz), 7.32 ( 1H, s), 7.36-7.43 (2H, m), 7.47 (1H, d, J = 7.3 Hz), 7.54 (1H, d, J = 7.3 Hz), 7.57 (1H, s), 7.75 (1H, t , J = 7.8 Hz), 8.24 (2H, br s).
化合物Ｉ－２３の合成　
Figure JPOXMLDOC01-appb-C000084
 工程１：化合物２３ｄの合成
　化合物２３ａ（８ｇ，５０．８ｍｍｏＬ）をテトラヒドロフラン（５０ｍＬ）に懸濁させ、０℃に冷却した。塩化オキサリル（５．３３ｍＬ，６０．９ｍｍｏＬ）、Ｎ，Ｎ－ジメチルホルムアミド（０．１９７ｍＬ，２．５４ｍｍｏＬ）を加え、０℃で５分間撹拌した。その後昇温し、室温にて１．５時間撹拌した。テトラヒドロフラン（５０ｍＬ）を加えて希釈し、氷冷下で２ｍｏＬ／Ｌトリメチルシリルジアゾメタンのヘキサン溶液（５５．９ｍＬ，１１２ｍｍｏＬ）を滴下し、０℃で１時間撹拌した。反応液を減圧濃縮し、得られた固体に氷冷下で酢酸（６０ｍＬ）を加えた。続いてこの溶液に４７％臭化水素水溶液 （１４．７ｍＬ，１２７ｍｍｏＬ）を一度に加え、０℃で３０分間攪拌した。反応液を水で希釈し、２ｍｏＬ／Ｌ水酸化ナトリウム水溶液を加えてｐＨ５とした。その後、飽和重曹水を加えて中和し、酢酸エチルで抽出した。有機層を飽和重曹水、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、粗生成物として化合物２３ｂ（７．２１ｇ）を得た。化合物２３ｂの組成物（７．２１ｇ）をエタノール（６０ｍＬ）に溶解し、化合物２３ｃ（４．８７ｇ，３０．７ｍｍｏＬ）を加えた。室温にて１時間撹拌した後、終夜静置した。析出した固体を濾取、エタノール、クロロホルムで洗浄し、化合物２３ｄ（８．１８ｇ，７１％）を得た。1H-NMR (DMSO-D6) δ: 1.91-1.97 (2H, m), 3.44-3.54 (4H, m), 7.49 (1H, d, J = 7.9 Hz), 7.90 (1H, s), 7.97 (1H, t, J = 7.8 Hz), 8.20 (1H, d, J = 7.7 Hz), 8.87 (2H, br s), 12.17 (1H, br s). Synthesis of Compound I-23
Figure JPOXMLDOC01-appb-C000084
 Step 1: Synthesis of Compound 23d Compound 23a (8 g, 50.8 mmol) was suspended in tetrahydrofuran (50 mL) and cooled to 0 ° C. Oxalyl chloride (5.33 mL, 60.9 mmol) and N, N-dimethylformamide (0.197 mL, 2.54 mmol) were added, and the mixture was stirred at 0 ° C. for 5 minutes. The temperature was then raised and the mixture was stirred at room temperature for 1.5 hours. Tetrahydrofuran (50 mL) was added for dilution, and 2 mol / L trimethylsilyldiazomethane in hexane (55.9 mL, 112 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and acetic acid (60 mL) was added to the resulting solid under ice cooling. Subsequently, a 47% aqueous solution of hydrogen bromide (14.7 mL, 127 mmol) was added to the solution all at once, and the mixture was stirred at 0 ° C. for 30 minutes. The reaction solution was diluted with water, and 2 moL / L aqueous sodium hydroxide solution was added to adjust the pH to 5. Then, saturated sodium bicarbonate water was added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 23b (7.21 g) as a crude product. The composition of compound 23b (7.21 g) was dissolved in ethanol (60 mL), and compound 23c (4.87 g, 30.7 mmol) was added. After stirring at room temperature for 1 hour, the mixture was allowed to stand overnight. The precipitated solid was collected by filtration and washed with ethanol and chloroform to obtain Compound 23d (8.18 g, 71%). 1 H-NMR (DMSO-D6) δ: 1.91-1.97 (2H, m), 3.44-3.54 (4H, m), 7.49 (1H, d, J = 7.9 Hz), 7.90 (1H, s), 7.97 ( 1H, t, J = 7.8 Hz), 8.20 (1H, d, J = 7.7 Hz), 8.87 (2H, br s), 12.17 (1H, br s).
工程２：化合物Ｉ－２３の合成
　２－フェニルモルフォリン（２０９ｍｇ，１．２８ｍｍｏＬ）をＮ，Ｎ－ジメチルアセトアミド（２ｍＬ）に溶解させ、化合物２３ｄ（８０ｍｇ，０．２１ｍｍｏＬ）、炭酸セシウム（２７８ｍｇ，０．８５ｍｍｏＬ）を加えた。封管した後、１８０℃に昇温して３日間撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）、逆相ＨＰＬＣ（アセトニトリル－水）により精製して化合物Ｉ－２３（２２ｍｇ，２５％）を得た。1H-NMR (DMSO-D6) δ: 1.73-1.88 (2H, m), 2.76 (1H, dd, J = 12.5, 10.7 Hz), 2.98 (1H, dt, J = 17.4, 6.2 Hz), 3.28-3.33 (4H, m), 3.76 (1H, td, J = 11.8, 2.3 Hz), 4.12 (1H, dd, J = 11.7, 2.5 Hz), 4.24 (1H, d, J = 13.3 Hz), 4.37 (1H, d, J = 12.7 Hz), 4.58 (1H, dd, J = 10.3, 2.3 Hz), 6.83 (1H, d, J = 8.4 Hz), 7.24 (1H, s), 7.27 (1H, d, J = 7.3 Hz), 7.33 (1H, t, J = 7.3 Hz), 7.39 (2H, t, J = 7.5 Hz), 7.48 (2H, d, J = 7.4 Hz), 7.60 (1H, t, J = 8.0 Hz), 8.32 (2H, br s). Step 2: Synthesis of Compound I-23 2-Phenylmorpholine (209 mg, 1.28 mmol) was dissolved in N, N-dimethylacetamide (2 mL), Compound 23d (80 mg, 0.21 mmol), cesium carbonate (278 mg, 0.85 mmol). After sealing, the temperature was raised to 180 ° C. and stirred for 3 days. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) and reverse phase HPLC (acetonitrile-water) to obtain Compound I-23 (22 mg, 25%). 1 H-NMR (DMSO-D6) δ: 1.73-1.88 (2H, m), 2.76 (1H, dd, J = 12.5, 10.7 Hz), 2.98 (1H, dt, J = 17.4, 6.2 Hz), 3.28- 3.33 (4H, m), 3.76 (1H, td, J = 11.8, 2.3 Hz), 4.12 (1H, dd, J = 11.7, 2.5 Hz), 4.24 (1H, d, J = 13.3 Hz), 4.37 (1H , d, J = 12.7 Hz), 4.58 (1H, dd, J = 10.3, 2.3 Hz), 6.83 (1H, d, J = 8.4 Hz), 7.24 (1H, s), 7.27 (1H, d, J = 7.3 Hz), 7.33 (1H, t, J = 7.3 Hz), 7.39 (2H, t, J = 7.5 Hz), 7.48 (2H, d, J = 7.4 Hz), 7.60 (1H, t, J = 8.0 Hz) ), 8.32 (2H, br s).
化合物Ｉ－２４の合成　
Figure JPOXMLDOC01-appb-C000085
工程１：化合物Ｉ－２４の合成
　実施例２３と同様の方法で合成した化合物２４ａ（７０ｍｇ、０．１６７ｍｍｏｌ）のジオキサン（１ｍＬ）溶液に化合物２４ｂ（２４．６ｍｇ、０．１６７ｍｍｏｌ）、Ｐｄ（ＯＡｃ）２（４ｍｇ、０．０１７ｍｍｏｌ）、ｘａｎｔｐｈｏｓ（１４．５ｍｇ、０．０２５ｍｍｏｌ）、炭酸セシウム（１３６ｍｇ、０．４２ｍｍｏｌ）を加えた。系内を窒素置換し、１２０℃の油浴にて３時間撹拌した。重曹水を加えてクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後に無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２４（３４ｍｇ、収率５１ｍｇ）を得た。
1H-NMR（DMSO-d6）δ：1.84 (m, 2H), 3.14 (t, J = 6.4Hz, 2H), 3.35 (m, 4H), 4.31 (t, J = 6.4Hz, 2H), 7.34 (s, 1H), 7.38-7.46 (m, 2H), 7.57 (m, 1H), 7.76 (d, J = 7.2Hz, 1H), 7.81-7.89 (m, 2H), 8.03 (d, J = 7.2Hz, 1H), 8.27 (brs, 2H). Synthesis of Compound I-24
Figure JPOXMLDOC01-appb-C000085
Step 1: Synthesis of Compound I-24 Compound 24b (24.6 mg, 0.167 mmol), Pd (OAc) was added to a solution of compound 24a (70 mg, 0.167 mmol) synthesized in the same manner as in Example 23 in dioxane (1 mL). ) 2 (4 mg, 0.017 mmol), xantphos (14.5 mg, 0.025 mmol), cesium carbonate (136 mg, 0.42 mmol) were added. The system was purged with nitrogen and stirred in an oil bath at 120 ° C. for 3 hours. Sodium bicarbonate water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-24 (34 mg, yield 51 mg).
1 H-NMR (DMSO-d 6 ) δ: 1.84 (m, 2H), 3.14 (t, J = 6.4Hz, 2H), 3.35 (m, 4H), 4.31 (t, J = 6.4Hz, 2H), 7.34 (s, 1H), 7.38-7.46 (m, 2H), 7.57 (m, 1H), 7.76 (d, J = 7.2Hz, 1H), 7.81-7.89 (m, 2H), 8.03 (d, J = 7.2Hz, 1H), 8.27 (brs, 2H).
化合物Ｉ－２５の合成　
Figure JPOXMLDOC01-appb-C000086
 工程１：化合物２５ｂの合成
　化合物２５ａ（５．００ｇ，２１．１ｍｍｏＬ）をジメチルアセトアミド（３０ｍＬ）に溶解し，ピペリジン－３－イルメタノール（２．５５ｇ，２２．２ｍｍｏＬ），炭酸セシウム（１５．１ｇ，４６．４ｍｍｏＬ）を加え、１００℃で５時間加熱した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２５ｂ（４．２８ｇ，７５％）を得た。1H-NMR (CDCl3) δ: 1.33-1.44 (m, 1H), 1.49-1.59 (m, 1H), 1.61-1.75 (m, 1H), 1.81-1.93 (m, 2H), 2.29-2.40 (m, 1H), 3.19-3.27 (m, 1H), 3.32-3.40 (m, 1H), 3.47-3.60 (m, 2H), 3.76-3.86 (m, 2H), 6.53 (J = 8.5 Hz, d, 1H), 6.67 (J = 7.5 Hz, d, 1H), 7.24 (J = 7.8 Hz, t, 1H). Synthesis of Compound I-25
Figure JPOXMLDOC01-appb-C000086
 Step 1: Synthesis of Compound 25b Compound 25a (5.00 g, 21.1 mmol) was dissolved in dimethylacetamide (30 mL), piperidin-3-ylmethanol (2.55 g, 22.2 mmol), cesium carbonate (15.1 g). 46.4 mmol) and heated at 100 ° C. for 5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 25b (4.28 g, 75%). 1 H-NMR (CDCl 3 ) δ: 1.33-1.44 (m, 1H), 1.49-1.59 (m, 1H), 1.61-1.75 (m, 1H), 1.81-1.93 (m, 2H), 2.29-2.40 ( m, 1H), 3.19-3.27 (m, 1H), 3.32-3.40 (m, 1H), 3.47-3.60 (m, 2H), 3.76-3.86 (m, 2H), 6.53 (J = 8.5 Hz, d, 1H), 6.67 (J = 7.5 Hz, d, 1H), 7.24 (J = 7.8 Hz, t, 1H).
工程２：化合物２５ｃの合成
　化合物２５ｂを用いて、実施例26と同様の方法で化合物２５ｃを合成した。1H-NMR (DMSO-D6) δ: 1.15-1.24 (m, 1H), 1.39-1.42 (m, 1H), 1.57-1.89 (m, 5H), 1.80-1.86 (m, 2H), 2.59-2.65 (m, 1H), 2.82-2.89 (m, 1H), 3.25-3.40 (m, 6H),4.22-4.33 (m, 2H), 4.51-4.58 (m, 1H), 6.69 (J = 8.5 Hz, d, 1H), 7.14 (J = 7.3 Hz, d, 1H), 7.19 (s, 1H), 7.53 (J = 7.9 Hz, t, 1H), 8.28 (s, 2H). Step 2: Synthesis of Compound 25c Compound 25c was synthesized in the same manner as in Example 26 using Compound 25b. 1H-NMR (DMSO-D6) δ: 1.15-1.24 (m, 1H), 1.39-1.42 (m, 1H), 1.57-1.89 (m, 5H), 1.80-1.86 (m, 2H), 2.59-2.65 ( m, 1H), 2.82-2.89 (m, 1H), 3.25-3.40 (m, 6H), 4.22-4.33 (m, 2H), 4.51-4.58 (m, 1H), 6.69 (J = 8.5 Hz, d, 1H), 7.14 (J = 7.3 Hz, d, 1H), 7.19 (s, 1H), 7.53 (J = 7.9 Hz, t, 1H), 8.28 (s, 2H).
工程３　化合物２５ｄの合成
　化合物２５ｃ（１．０ｇ，２．６８ｍｍｏＬ）とトリエチルアミン(５９８ｍｇ，２．６８ｍｍｏＬ)をテトラヒドロフラン（１０ｍＬ）に溶解させ、氷冷下でメタンスルホニルクロライド（３６８ｍｇ，３．２２ｍｍｏＬ）を加えた。室温に昇温して、１時間撹拌した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去し化合物２５ｄの粗生成物（１．０９ｇ）を得た。
ＬＣＭＳ（測定条件Ａ）、保持時間：１．４２分、［Ｍ＋Ｈ]＋：４５１ Step 3 Synthesis of Compound 25d Compound 25c (1.0 g, 2.68 mmol) and triethylamine (598 mg, 2.68 mmol) were dissolved in tetrahydrofuran (10 mL), and methanesulfonyl chloride (368 mg, 3.22 mmol) was added under ice cooling. added. The mixture was warmed to room temperature and stirred for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of compound 25d (1.09 g).
LCMS (measurement condition A), retention time: 1.42 minutes, [M + H] + : 451
工程４：化合物Ｉ－２５の合成
　化合物２５ｃ（２０ｍｇ，０．０４４ｍｍｏＬ）をジメチルアセトアミド（１ｍＬ）に溶解させ、３－シアノフェノール（８ｍｇ，０．０６７ｍｍｏＬ）、炭酸カリウム(１８ｍｇ，０．１３ｍｍｏＬ)を加え、１００℃で５時間撹拌した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２５（５ｍｇ，２４％）を得た。
1H-NMR (DMSO-D6) δ: 1.13-1.25 (m, 1H), 1.41-1.50 (m, 1H), 1.60-1.86 (m, 5H), 2.56-2.65 (m, 1H), 2.82-2.89 (m, 1H), 3.25-3.40 (m, 6H), 4.22-4.35 (m, 2H), 4.52-4.56 (m, 1H), 6.69 (J = 8.5 Hz, d, 1H), 7.14 (J = 7.3 Hz, d, 1H), 7.19 (s, 1H), 7.58 (s, 1H), 8.30 (s, 2H). Step 4: Synthesis of Compound I-25 Compound 25c (20 mg, 0.044 mmol) was dissolved in dimethylacetamide (1 mL), and 3-cyanophenol (8 mg, 0.067 mmol) and potassium carbonate (18 mg, 0.13 mmol) were added. Furthermore, it stirred at 100 degreeC for 5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-25 (5 mg, 24%).
1H-NMR (DMSO-D6) δ: 1.13-1.25 (m, 1H), 1.41-1.50 (m, 1H), 1.60-1.86 (m, 5H), 2.56-2.65 (m, 1H), 2.82-2.89 ( m, 1H), 3.25-3.40 (m, 6H), 4.22-4.35 (m, 2H), 4.52-4.56 (m, 1H), 6.69 (J = 8.5 Hz, d, 1H), 7.14 (J = 7.3 Hz , d, 1H), 7.19 (s, 1H), 7.58 (s, 1H), 8.30 (s, 2H).
化合物Ｉ－２６の合成　
Figure JPOXMLDOC01-appb-C000087
 工程1：化合物２６ｂの合成　
化合物２６ａ（３．５ｇ、１４．８ｍｍｏｌ）にジメチルアセトアミド（４０ｍＬ）、３－（メチルアミノ）プロパン－１－オ－ル（１．３８ｇ、１５．５ｍｍｏｌ）、炭酸カリウム（４．４９ｇ、３２．５ｍｍｏｌ）を加え８０℃で７時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物２６ｂ（２．０６ｇ、５７％）を得た。
1H-NMR(DMSO-D6)δ:1.73-1.82(m, 2H), 2.95(s, 3H), 3.53(dd, J=6.0Hz, 11.2Hz, 2H), 3.71(t, J=6.0Hz, 2H), 4.11(dd, J=6.0Hz, 11.2Hz, 1H), 6.39(d, J=8Hz, 1H), 6.68(d, J=7.6Hz, 1H), 7.22-7.31(m, 1H) Synthesis of Compound I-26
Figure JPOXMLDOC01-appb-C000087
 Step 1: Synthesis of Compound 26b
Compound 26a (3.5 g, 14.8 mmol) was added to dimethylacetamide (40 mL), 3- (methylamino) propan-1-ol (1.38 g, 15.5 mmol), potassium carbonate (4.49 g, 32. 5 mmol) was added and stirred at 80 ° C. for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 26b (2.06 g, 57%).
1 H-NMR (DMSO-D6) δ: 1.73-1.82 (m, 2H), 2.95 (s, 3H), 3.53 (dd, J = 6.0Hz, 11.2Hz, 2H), 3.71 (t, J = 6.0Hz , 2H), 4.11 (dd, J = 6.0Hz, 11.2Hz, 1H), 6.39 (d, J = 8Hz, 1H), 6.68 (d, J = 7.6Hz, 1H), 7.22-7.31 (m, 1H)
工程２：化合物２６ｄの合成　
化合物２６ｂ（２．０６ｇ、８．４０ｍｍｏｌ）のトルエン（２０ｍＬ）溶液に、化合物２６ｃ（３．３４ｇ、９．２４ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（０．９７１ｇ、０．８４ｍｍｏｌ）を加え３.５時間加熱還流した。その後１２時間静置し、更に３時間加熱還流した。飽和フッ化カリウム水溶液を加え１時間室温で撹拌しろ過した。水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去し，化合物２６ｄを粗生成物として得た。 Step 2: Synthesis of Compound 26d
To a solution of compound 26b (2.06 g, 8.40 mmol) in toluene (20 mL), compound 26c (3.34 g, 9.24 mmol) and tetrakis (triphenylphosphine) palladium (0.971 g, 0.84 mmol) were added 3 Heated to reflux for 5 hours. Thereafter, the mixture was allowed to stand for 12 hours, and further heated to reflux for 3 hours. A saturated aqueous potassium fluoride solution was added, and the mixture was stirred for 1 hour at room temperature and filtered. Water was added and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 26d as a crude product.
工程３：化合物２６ｇの合成　
化合物２６ｄ（１．９９ｇ、８．４０ｍｍｏｌ）にテトラヒドロフラン（４０ｍＬ）、水（５ｍＬ）を加え０℃に冷却した。Ｎ－ブロモスクシンイミド（１．６５ｇ、９．２４ｍｍｏｌ）を加え０℃で１時間撹拌し、室温で２時間撹拌した。１２時間静置後、Ｎ－ブロモスクシンイミド（１５０ｍｇ、０．８４ｍｍｏｌ）を加え１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。エタノール（４０ｍＬ）に溶解させ化合物２６ｆ（１．０６ｇ、６．７２ｍｍｏｌ）を加え６０℃で２時間加熱した。反応液に飽和重曹水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をアミノシリカカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物２６ｇ（１．３０ｇ、４５％）を得た。
1H-NMR(DMSO-D6)δ:1.62-1.78(m,  2H), 1.80-1.90(m,  2H), 3.02(s, 3H), 3.20-3.50(m, 4H), 3.55-3.65(m, 2H), 4.62(t, J=4Hz, 2H), 6.50-6.55(m, 1H), 7.07-7.12(m, 1H), 7.18(s, 1H), 7.49-7.53(m, 1H), 8.24-8.26(br, 2H) Step 3: Synthesis of Compound 26g
Tetrahydrofuran (40 mL) and water (5 mL) were added to compound 26d (1.99 g, 8.40 mmol) and cooled to 0 ° C. N-bromosuccinimide (1.65 g, 9.24 mmol) was added and stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. After standing for 12 hours, N-bromosuccinimide (150 mg, 0.84 mmol) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Compound 26f (1.06 g, 6.72 mmol) was dissolved in ethanol (40 mL) and heated at 60 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by amino silica column chromatography (chloroform-methanol) to obtain 26 g (1.30 g, 45%) of a compound.
1 H-NMR (DMSO-D6) δ: 1.62-1.78 (m, 2H), 1.80-1.90 (m, 2H), 3.02 (s, 3H), 3.20-3.50 (m, 4H), 3.55-3.65 (m , 2H), 4.62 (t, J = 4Hz, 2H), 6.50-6.55 (m, 1H), 7.07-7.12 (m, 1H), 7.18 (s, 1H), 7.49-7.53 (m, 1H), 8.24 -8.26 (br, 2H)
工程４：化合物Ｉ－２６の合成
化合物２６ｇ（３５ｍｇ、０．１０１ｍｍｏｌ）に、テトラヒドロフラン（０．４ｍＬ）、トリフェニルホスフィン（３９．７ｍｇ、０．１５２ｍｍｏｌ）、４－ヒドロキシベンゾニトリル（１４．４ｍｇ、０．１２１ｍｍｏｌ）を加え０℃に冷却した。アゾジカルボン酸ジイソプロピル（０．０２９ｍＬ、０．１５２ｍｍｏｌ）を加え室温で終夜撹拌した。反応溶液を濃縮後、シリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－２６（４ｍｇ、９％）を得た。
1H-NMR(DMSO-D6)δ:1.78-1.89(m, 2H), 2.00-2.10(m, 2H), 3.03(s, 3H), 3.20-3.55(m, 4H), 3.68-3.80(m, 2H), 4.10-4.20(m, 2H), 6.52(d, J=8.4Hz, 1H), 7.08-7.20(m, 4H), 7.50(dd, J=8.4Hz, 8.8Hz, 1H), 7.74(d, J=8.8Hz, 2H), 8.27-8.31(br, 2H) Step 4: Synthesis of Compound I-26 Compound 26g (35 mg, 0.101 mmol) was added to tetrahydrofuran (0.4 mL), triphenylphosphine (39.7 mg, 0.152 mmol), 4-hydroxybenzonitrile (14.4 mg, 0.121 mmol) was added and cooled to 0 ° C. Diisopropyl azodicarboxylate (0.029 mL, 0.152 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-26 (4 mg, 9%).
1 H-NMR (DMSO-D6) δ: 1.78-1.89 (m, 2H), 2.00-2.10 (m, 2H), 3.03 (s, 3H), 3.20-3.55 (m, 4H), 3.68-3.80 (m , 2H), 4.10-4.20 (m, 2H), 6.52 (d, J = 8.4Hz, 1H), 7.08-7.20 (m, 4H), 7.50 (dd, J = 8.4Hz, 8.8Hz, 1H), 7.74 (d, J = 8.8Hz, 2H), 8.27-8.31 (br, 2H)
化合物Ｉ－２７の合成　
Figure JPOXMLDOC01-appb-C000088
工程１：化合物２７aの合成
　実施例２５と同様の方法で化合物２７ａを合成した。
  1H-NMR (CDCl3) δ: 1.73-1.88 (m, 4H), 2.00-2.05 (m, 2H), 3.41-3.55 (m, 4H), 3.72-3.83 (m, 4H), 4.03 (s, 4H), 6.62 (J = 8.5 Hz, d, 1H), 7.17 (J = 7.5 Hz, d, 1H), 7.31 (s, 1H), 7.53 (J = 7.8 Hz, t, 1H). Synthesis of Compound I-27
Figure JPOXMLDOC01-appb-C000088
Step 1: Synthesis of Compound 27a Compound 27a was synthesized in the same manner as in Example 25.
1H-NMR (CDCl3) δ: 1.73-1.88 (m, 4H), 2.00-2.05 (m, 2H), 3.41-3.55 (m, 4H), 3.72-3.83 (m, 4H), 4.03 (s, 4H) , 6.62 (J = 8.5 Hz, d, 1H), 7.17 (J = 7.5 Hz, d, 1H), 7.31 (s, 1H), 7.53 (J = 7.8 Hz, t, 1H).
工程２：化合物２７ｂの合成
　化合物２７ａ（１０００ｍｇ，２．５ｍｍｏＬ）をテトラヒドロフラン（２５ｍL）－２ｍｏＬ塩酸水溶液の混合液に溶解させ、６５℃で６時間撹拌した。減圧下濃縮し、飽和重曹水を加え塩基性として、５％メタノール/クロロホルムで３回抽出した。有機層を合わせ、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物２７ｂ（８１０ｍｇ，９１％）を得た。1H-NMR (CDCl3)δ: 1.98-2.04 (m, 2H), 2.45-2.61 (m, 4H), 3.38-3.57 (m, 4H), 3.90-4.08 (m, 4H), 6.68 (J = 8.3 Hz, d, 1H), 7.24 (J = 7.5 Hz, d, 1H), 7.30 (s, 1H), 7.58 (J = 7.8 Hz, t, 1H). Step 2: Synthesis of Compound 27b Compound 27a (1000 mg, 2.5 mmol) was dissolved in a mixed solution of tetrahydrofuran (25 mL) -2 mol aqueous hydrochloric acid and stirred at 65 ° C. for 6 hours. The mixture was concentrated under reduced pressure, made basic by adding saturated aqueous sodium hydrogen carbonate, and extracted three times with 5% methanol / chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 27b (810 mg, 91%). 1 H-NMR (CDCl 3 ) δ: 1.98-2.04 (m, 2H), 2.45-2.61 (m, 4H), 3.38-3.57 (m, 4H), 3.90-4.08 (m, 4H), 6.68 (J = 8.3 Hz, d, 1H), 7.24 (J = 7.5 Hz, d, 1H), 7.30 (s, 1H), 7.58 (J = 7.8 Hz, t, 1H).
工程３：化合物Ｉ－２７の合成
　化合物２７ｂ（３０ｍｇ，０．０８４ｍｍｏＬ）をエタノール（１ｍＬ）に溶解させ、トリエチルアミン(１３ｍｇ，０．１３ｍｍｏＬ)とＯ－メチルヒドロキシルアミン(１１ｍｇ，０．１３ｍｍｏＬ)を加え、室温で３時間撹拌した。水を加え、得られた固体をろ取し、水で洗浄後減圧乾燥し、化合物Ｉ－２７（１５ｍｇ，４６％）を得た。
1H-NMR (CDCl3)δ: 1.98-2.03 (m, 2H), 2.42-2.50 (m, 2H), 2.63-2.73 (m, 2H), 3.37-3.53 (m, 4H), 3.73-3.83 (m, 4H), 3.86 (s, 3H), 6.58 (J = 8.5 Hz, d, 1H), 7.17 (J = 7.3 Hz, d, 1H), 7.29 (s, 1H), 7.53 (J = 7.9 Hz, t, 1H). Step 3: Synthesis of Compound I-27 Compound 27b (30 mg, 0.084 mmol) was dissolved in ethanol (1 mL), and triethylamine (13 mg, 0.13 mmol) and O-methylhydroxylamine (11 mg, 0.13 mmol) were added. And stirred at room temperature for 3 hours. Water was added, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain Compound I-27 (15 mg, 46%).
1H-NMR (CDCl3) δ: 1.98-2.03 (m, 2H), 2.42-2.50 (m, 2H), 2.63-2.73 (m, 2H), 3.37-3.53 (m, 4H), 3.73-3.83 (m, 4H), 3.86 (s, 3H), 6.58 (J = 8.5 Hz, d, 1H), 7.17 (J = 7.3 Hz, d, 1H), 7.29 (s, 1H), 7.53 (J = 7.9 Hz, t, 1H).
化合物Ｉ－２８の合成　
Figure JPOXMLDOC01-appb-C000089
工程１：Ｉ－２８の合成　
化合物２８ａ（５０ｍｇ，０．１４ｍｍｏＬ）をＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）に溶解させ、Ｎ，Ｎ－ジメチルホルムアミドジメチルアセタール（０．０３８ｍＬ，０．２８ｍｍｏＬ）を加え、１３０℃で２時間撹拌した。この溶液にエタノール（０．５ｍＬ）、２－フェニル－アセトアミジン塩酸塩（２９ｍｇ，０．１７ｍｍｏＬ）を加え、８０℃で終夜撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２８（２ｍｇ，３％）を得た．1H-NMR (DMSO-D6)δ: 1.77-1.87 (2H, m), 2.94 (2H, t, J = 5.9 Hz), 3.25-3.35 (4H, m), 3.98 (2H, t, J = 5.9 Hz), 4.14 (2H, s), 4.77 (2H, s), 6.86 (1H, d, J = 8.4 Hz), 7.18-7.31 (7H, m), 7.61 (1H, t, J = 7.7 Hz), 8.26 (2H, br s), 8.62 (1H, s). Synthesis of Compound I-28
Figure JPOXMLDOC01-appb-C000089
Step 1: Synthesis of I-28
Compound 28a (50 mg, 0.14 mmol) was dissolved in N, N-dimethylformamide (0.5 mL), N, N-dimethylformamide dimethyl acetal (0.038 mL, 0.28 mmol) was added, and 130 ° C. for 2 hours. Stir. Ethanol (0.5 mL) and 2-phenyl-acetamidine hydrochloride (29 mg, 0.17 mmol) were added to this solution, and the mixture was stirred at 80 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-28 (2 mg, 3%). 1H-NMR (DMSO-D6) δ: 1.77-1.87 (2H, m), 2.94 (2H, t, J = 5.9 Hz), 3.25-3.35 (4H, m), 3.98 (2H, t, J = 5.9 Hz) ), 4.14 (2H, s), 4.77 (2H, s), 6.86 (1H, d, J = 8.4 Hz), 7.18-7.31 (7H, m), 7.61 (1H, t, J = 7.7 Hz), 8.26 (2H, br s), 8.62 (1H, s).
化合物Ｉ－３０の合成　
Figure JPOXMLDOC01-appb-C000090
工程１：化合物３０ｃの合成
　化合物３０ａ（１．８９ｇ、８．７５ｍｍｏｌ）と１－エトキシビニルトリ－ｎ－ブチルスズ（３．５５ｍｌ、１０．５ｍｍｏｌ）をトルエン（２０ｍＬ）に溶解した。Ｐｄ（ＰＰｈ３）４（１．０１ｇ、０．８７５ｍｍｏｌ）を加えて窒素置換し、１１０℃で３時間撹拌した。水を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Synthesis of Compound I-30
Figure JPOXMLDOC01-appb-C000090
Step 1: Synthesis of Compound 30c Compound 30a (1.89 g, 8.75 mmol) and 1-ethoxyvinyltri-n-butyltin (3.55 ml, 10.5 mmol) were dissolved in toluene (20 mL). Pd (PPh 3 ) 4 (1.01 g, 0.875 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at 110 ° C. for 3 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をテトラヒドロフラン（２０ｍＬ）と水（２ｍＬ）に溶解し、氷冷下でＮＢＳ（１．５６ｇ、８．７５ｍｍｏｌ）を加えた。３０分後に水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 The obtained residue was dissolved in tetrahydrofuran (20 mL) and water (2 mL), and NBS (1.56 g, 8.75 mmol) was added under ice cooling. After 30 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をエタノール（２０ｍＬ）に溶解して化合物３０ｂ（１．０４ｇ、６．５６ｍｍｏｌ）を加えた。室温で１時間撹拌した後に、重曹水を加えて中和した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣に酢酸エチルを加えて固化し、固体をろ取することで、化合物３０ｃ（１．６５ｇ、収率５９％）を得た。
1H-NMR（DMSO-d6）δ：1.84 (m, 2H), 3.34 (m, 2H), 3.91 (s, 3H), 7.36 (s, 1H), 7.91 (d, J = 8.0Hz, 1H), 8.02 (t, J = 8.0Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 8.22 (brs, 2H). The resulting residue was dissolved in ethanol (20 mL) and compound 30b (1.04 g, 6.56 mmol) was added. After stirring at room temperature for 1 hour, sodium bicarbonate water was added for neutralization. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue to solidify, and the solid was collected by filtration to obtain Compound 30c (1.65 g, yield 59%).
1 H-NMR (DMSO-d 6 ) δ: 1.84 (m, 2H), 3.34 (m, 2H), 3.91 (s, 3H), 7.36 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H ), 8.02 (t, J = 8.0Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 8.22 (brs, 2H).
工程２：化合物３０ｄの合成
　化合物３０ｃ（２００ｍｇ、０．６３０ｍｍｏｌ）をメタノール（４ｍＬ）に懸濁し、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．９ｍＬ、１．９ｍｍｏｌ）を加えた。室温で１３時間撹拌した後に、１０％クエン酸水溶液を加えた。析出した固体をろ取することで、化合物３０ｄ（１８３ｍｇ、収率９６％）を得た。
1H-NMR（DMSO-d6）δ：1.84 (m, 2H), 3.34 (m, 2H), 7.58 (s, 1H), 7.91 (d, J = 8.0Hz, 1H), 8.01 (t, J = 8.0Hz, 1H), 8.18 (d, J = 8.0Hz, 1H), 8.23 (brs, 2H). Step 2: Synthesis of Compound 30d Compound 30c (200 mg, 0.630 mmol) was suspended in methanol (4 mL), and 1 mol / L aqueous sodium hydroxide solution (1.9 mL, 1.9 mmol) was added. After stirring at room temperature for 13 hours, a 10% aqueous citric acid solution was added. The precipitated solid was collected by filtration to obtain compound 30d (183 mg, yield 96%).
1 H-NMR (DMSO-d 6 ) δ: 1.84 (m, 2H), 3.34 (m, 2H), 7.58 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.01 (t, J = 8.0Hz, 1H), 8.18 (d, J = 8.0Hz, 1H), 8.23 (brs, 2H).
工程３：化合物Ｉ－３０の合成
　化合物３０ｄ（４０ｍｇ、０．１３２ｍｍｏｌ）のＤＭＦ（１ｍＬ）溶液にＮ－メチルベンジルアミン（２４ｍｇ、０．１９８ｍｍｏｌ）、ＨＡＴＵ（７５ｍｇ、０．１９８ｍｍｏｌ）、トリエチルアミン（０．０５５ｍＬ、０．３９６ｍｍｏｌ）を加えた。室温で２時間撹拌した後に、水を加えた。クロロホルムで抽出して無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣を逆相ＨＰＬＣ（１０ｍＭ炭酸アンモニウム含有水―アセトニトリル）により精製して、化合物Ｉ－３０（２０．２ｍｇ、収率３８％）を得た。
1H-NMR（DMSO-d6）δ：1.83 (m, 2H), 2.95 (s, 1.8H), 2.97 (s, 1.2H), 3.32 (m, 4H), 4.65 (s, 1.2H), 4.72 (s, 0.8H), 7.24-7.44 (m, 5H), 7.51 (m, 1H), 7.89-8.05 (m, 2H), 8.19 (brs, 1.2H), 8.24 (brs, 0.8H). Step 3: Synthesis of Compound I-30 To a solution of compound 30d (40 mg, 0.132 mmol) in DMF (1 mL) was added N-methylbenzylamine (24 mg, 0.198 mmol), HATU (75 mg, 0.198 mmol), triethylamine (0 0.055 mL, 0.396 mmol) was added. After stirring for 2 hours at room temperature, water was added. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to obtain Compound I-30 (20.2 mg, 38% yield).
1 H-NMR (DMSO-d 6 ) δ: 1.83 (m, 2H), 2.95 (s, 1.8H), 2.97 (s, 1.2H), 3.32 (m, 4H), 4.65 (s, 1.2H), 4.72 (s, 0.8H), 7.24-7.44 (m, 5H), 7.51 (m, 1H), 7.89-8.05 (m, 2H), 8.19 (brs, 1.2H), 8.24 (brs, 0.8H).
化合物Ｉ－３２の合成　
Figure JPOXMLDOC01-appb-C000091
工程１：化合物Ｉ－３２の合成
　化合物３２ａ（５０ｍｇ、０．１７ｍｍｏｌ）をＤＭＡ（１ｍＬ）に溶解し、ピペリジン（１７μL、０．１７ｍｍｏｌ）を加え、マイクロウエーブ照射下１００℃で３０分撹拌した後、ピペリジン（８５μL、０．８５ｍｍｏｌ）を追加して、マイクロウエーブ照射下１５０℃で３時間撹拌した。水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣を分取用ＨＰＬＣ（０．１％ギ酸含有アセトニトリル－０．１％ギ酸含有水）より精製して化合物Ｉ－３２（３７ｍｇ、収率６４％）を得た。
ＬＣＭＳ（測定条件Ｂ）：保持時間＝１．４１分、[Ｍ＋Ｈ]＋ = ３４３ Synthesis of Compound I-32
Figure JPOXMLDOC01-appb-C000091
Step 1: Synthesis of Compound I-32 Compound 32a (50 mg, 0.17 mmol) was dissolved in DMA (1 mL), piperidine (17 μL, 0.17 mmol) was added, and the mixture was stirred at 100 ° C. for 30 minutes under microwave irradiation. Piperidine (85 μL, 0.85 mmol) was added, and the mixture was stirred at 150 ° C. for 3 hours under microwave irradiation. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC (0.1% formic acid-containing acetonitrile-0.1% formic acid-containing water) to give compound I-32 (37 mg, 64% yield). Obtained.
LCMS (measurement condition B): retention time = 1.41 minutes, [M + H] + = 343
化合物Ｉ－３３の合成　
Figure JPOXMLDOC01-appb-C000092
工程１：化合物３３ｂの合成
　化合物３１ａ（１５０ｍｇ、０．９６４ｍｍｏｌ）のジオキサン（２．５ｍＬ）溶液に４－クロロアニリン（１６０ｍｇ、１．２５ｍｍｏｌ）とＰｄ（ＯＡｃ）２（４３ｍｇ、０．１９３ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（２２３ｍｇ、０．３８６ｍｍｏｌ）、炭酸カリウム（２００ｍｇ、１．４４６ｍｍｏｌ）を加えた。系内を窒素置換し、マイクロ波照射下、１２０℃で１５分反応させた。水を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して、化合物３３ｂ（１５０ｍｇ、収率６３％）を得た。
1H-NMR (CDCl3)δ: 2.64 (s, 3H), 6.76 (dd, J = 4.4, 7.6Hz, 1H), 7.29 (d, J = 8.0Hz, 2H), 7.67 (d, J = 8.0Hz, 2H), 8.11 (d, J = 7.6Hz, 1H), 8.38 (d, J = 4.4Hz, 1H), 11.10 (s, 1H). Synthesis of Compound I-33
Figure JPOXMLDOC01-appb-C000092
Step 1: Synthesis of Compound 33b To a solution of Compound 31a (150 mg, 0.964 mmol) in dioxane (2.5 mL), 4-chloroaniline (160 mg, 1.25 mmol) and Pd (OAc) 2 (43 mg, 0.193 mmol), Xantphos (223 mg, 0.386 mmol) and potassium carbonate (200 mg, 1.446 mmol) were added. The system was purged with nitrogen and reacted at 120 ° C. for 15 minutes under microwave irradiation. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 33b (150 mg, yield 63%).
1 H-NMR (CDCl3) δ: 2.64 (s, 3H), 6.76 (dd, J = 4.4, 7.6Hz, 1H), 7.29 (d, J = 8.0Hz, 2H), 7.67 (d, J = 8.0Hz , 2H), 8.11 (d, J = 7.6Hz, 1H), 8.38 (d, J = 4.4Hz, 1H), 11.10 (s, 1H).
工程：化合物Ｉ－３３の合成
　窒素気流下、化合物３３ｂ（１５０ｍｇ、０．６０８ｍｍｏｌ）をテトラヒドロフラン（２ｍＬ）に溶解して－７８℃に冷却した。０．５ｍｏｌ／ＬＬＤＡ（２．６８ｍＬ、１．３３８ｍｍｏｌ）を滴下した。２０分後にクロロトリメチルシラン（０．２２ｍＬ、１．７０ｍｍｏｌ）を加えた。３０分後にＮＢＳ（１１９ｍｇ、０．６６９ｍｍｏｌ）、炭酸水素ナトリウム（２０４ｍｇ、２．４３ｍｍｏｌ）を加えた。室温に昇温して３時間撹拌した後に、水を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Step: Synthesis of Compound I-33 Under a stream of nitrogen, Compound 33b (150 mg, 0.608 mmol) was dissolved in tetrahydrofuran (2 mL) and cooled to −78 ° C. 0.5 mol / LLDA (2.68 mL, 1.338 mmol) was added dropwise. After 20 minutes, chlorotrimethylsilane (0.22 mL, 1.70 mmol) was added. After 30 minutes, NBS (119 mg, 0.669 mmol) and sodium bicarbonate (204 mg, 2.43 mmol) were added. After warming to room temperature and stirring for 3 hours, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をエタノール（３ｍＬ）に溶解して化合物３１ｃ（９６ｍｇ、０．６０８ｍｍｏｌ）を加え、室温で撹拌した。３時間後に重曹水を加えて中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物Ｉ－３３（４１ｍｇ、収率１８％）を得た。
1H-NMR (DMSO-D6)δ: 1.85 (m, 2H), 3.28 (m, 1H), 6.87 (dd, J = 7.2, 4.8Hz, 1H), 7.07 (s, 1H), 7.33 (d, J = 8.4Hz, 2H), 7.72 (d, J = 8.4Hz, 2H), 7.86-7.97 (m, 3H), 8.16 (d, J = 4.8Hz, 1H), 10.09 (s, 1H). The obtained residue was dissolved in ethanol (3 mL), compound 31c (96 mg, 0.608 mmol) was added, and the mixture was stirred at room temperature. Three hours later, sodium bicarbonate water was added to neutralize, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-33 (41 mg, yield 18%).
1 H-NMR (DMSO-D6) δ: 1.85 (m, 2H), 3.28 (m, 1H), 6.87 (dd, J = 7.2, 4.8Hz, 1H), 7.07 (s, 1H), 7.33 (d, J = 8.4Hz, 2H), 7.72 (d, J = 8.4Hz, 2H), 7.86-7.97 (m, 3H), 8.16 (d, J = 4.8Hz, 1H), 10.09 (s, 1H).
化合物Ｉ－３４の合成　
Figure JPOXMLDOC01-appb-C000093
工程１：化合物３４ｂの合成
　２ｍｏｌ／Ｌトリメチルシリルジアゾメタンのヘキサン溶液（１２．５ｍＬ、２５ｍｍｏｌ）をテトラヒドロフラン（４０ｍＬ）に溶解し、氷冷下で化合物３４ａ（２ｇ、１１．３６ｍｍｏｌ）を加えた。１時間撹拌した後に反応液を減圧濃縮した。得られた残渣を酢酸（１６ｍＬ）に溶解し、氷冷下で４７％臭化水素酸（３．２８ｍＬ、２８．４ｍｍｏｌ）を加えた。１時間撹拌した後に水酸化ナトリウムを加えてｐＨ５とし、次いで重曹水を加えて中和した。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去することで、化合物３４ｂ（２．２０ｇ、収率８３％）を得た。
1H-NMR (CDCl3)δ: 4.56 (s, 2H), 7.39 (dd, J = 7.2, 4.4Hz, 1H), 7.94 (dd, J = 7.2, 1.6Hz, 1H), 8.55 (dd, J = 4.4, 1.6Hz, 1H). Synthesis of Compound I-34
Figure JPOXMLDOC01-appb-C000093
Step 1: Synthesis of Compound 34b A hexane solution (12.5 mL, 25 mmol) of 2 mol / L trimethylsilyldiazomethane was dissolved in tetrahydrofuran (40 mL), and Compound 34a (2 g, 11.36 mmol) was added under ice cooling. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (16 mL), and 47% hydrobromic acid (3.28 mL, 28.4 mmol) was added under ice cooling. After stirring for 1 hour, sodium hydroxide was added to adjust the pH to 5, and then sodium bicarbonate water was added to neutralize. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, Compound 34b (2.20 g, yield 83%) was obtained.
1 H-NMR (CDCl3) δ: 4.56 (s, 2H), 7.39 (dd, J = 7.2, 4.4Hz, 1H), 7.94 (dd, J = 7.2, 1.6Hz, 1H), 8.55 (dd, J = 4.4, 1.6Hz, 1H).
工程２：化合物３４ｄの合成
　化合物３４ｂ（１．９６ｇ、８．３４ｍｍｏｌ）と化合物３４ｃ（１．１ｇ、６．９５ｍｍｏｌ）をエタノール（２５ｍＬ）に懸濁した。１００℃で１時間撹拌した後、室温まで放冷して重曹水を加えて中和した。クロロホルムで抽出して有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物３４ｄ（６０９ｍｇ、収率３０％）を得た。
1H-NMR (CDCl3)δ: 2.02 (m, 2H), 3.46 (m, 4H), 7.08 (s, 1H), 7.29 (dd, J = 7.6, 4.8Hz, 1H), 8.08 (dd, J = 7.6, 1.6Hz, 1H), 8.32 (dd, J = 4.8, 1.6Hz, 1H). Step 2: Synthesis of Compound 34d Compound 34b (1.96 g, 8.34 mmol) and compound 34c (1.1 g, 6.95 mmol) were suspended in ethanol (25 mL). After stirring at 100 ° C. for 1 hour, the mixture was allowed to cool to room temperature and neutralized by adding sodium bicarbonate water. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 34d (609 mg, yield 30%).
1 H-NMR (CDCl3) δ: 2.02 (m, 2H), 3.46 (m, 4H), 7.08 (s, 1H), 7.29 (dd, J = 7.6, 4.8Hz, 1H), 8.08 (dd, J = 7.6, 1.6Hz, 1H), 8.32 (dd, J = 4.8, 1.6Hz, 1H).
工程３：化合物Ｉ－３４の合成
　化合物３４ｄ（３０ｍｇ、０．１０２ｍｍｏｌ）とフェノール（１９ｍｇ、０．２０４ｍｍｏｌ）をＤＭＳＯ（０．６ｍＬ）に溶解した。炭酸セシウム（６６．５ｍｇ、０．２０４ｍｍｏｌ）を加え、１２０℃で１０時間撹拌した。水を加えてクロロホルムで抽出し、有機層を減圧濃縮した。得られた残渣を逆相ＨＰＬＣ（１０ｍＭ炭酸アンモニウム含有水－アセトニトリル）により精製し、化合物Ｉ－３４（９ｍｇ、収率２５％）を得た。
1H-NMR (DMSO-D6)δ: 1.82 (m, 2H), 3.31 (m, 4H), 7.15 (m, 2H), 7.18-7.24 (m, 2H), 7.30 (s, 1H), 7.42 (m, 2H), 8.01 (d, J = 4.8Hz, 1H), 8.23 (s, 2H), 8.45 (d, J = 7.2Hz, 1H). Step 3: Synthesis of Compound I-34 Compound 34d (30 mg, 0.102 mmol) and phenol (19 mg, 0.204 mmol) were dissolved in DMSO (0.6 mL). Cesium carbonate (66.5 mg, 0.204 mmol) was added and stirred at 120 ° C. for 10 hours. Water was added and extracted with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to obtain Compound I-34 (9 mg, yield 25%).
1 H-NMR (DMSO-D6) δ: 1.82 (m, 2H), 3.31 (m, 4H), 7.15 (m, 2H), 7.18-7.24 (m, 2H), 7.30 (s, 1H), 7.42 ( m, 2H), 8.01 (d, J = 4.8Hz, 1H), 8.23 (s, 2H), 8.45 (d, J = 7.2Hz, 1H).
化合物Ｉ－３５の合成　
Figure JPOXMLDOC01-appb-C000094
工程１：化合物Ｉ－３５の合成
　化合物３５ｂ（３８ｍｇ、０．９５３ｍｍｏｌ）をＤＭＦ（１．５ｍＬ）に溶解し、氷冷下で６０％水素化ナトリウム（３８．１ｍｇ、０．９５３ｍｍｏｌ）を加え、撹拌した。１０分後に化合物３５ａ（７０ｍｇ、０．２３８ｍｍｏｌ）を加えて１２０℃で３時間撹拌した。氷冷して塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した。溶媒を減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－３５（５６ｍｇ、収率６６％）を得た。
1H-NMR (DMSO-D6)δ: 1.37 (m, 2H), 1.49-1.68 (m, 4H), 1.77-1.87 (m, 4H), 2.42 (m, 1H), 3.33 (m, 4H), 4.28 (d, J = 7.2Hz, 2H), 7.04 (m, 1H), 7.26 (s, 1H), 8.04 (m, 1H), 8.19 (brs, 2H), 8.34 (m, 1H). Synthesis of Compound I-35
Figure JPOXMLDOC01-appb-C000094
Step 1: Synthesis of Compound I-35 Compound 35b (38 mg, 0.953 mmol) was dissolved in DMF (1.5 mL), and 60% sodium hydride (38.1 mg, 0.953 mmol) was added under ice cooling. Stir. After 10 minutes, compound 35a (70 mg, 0.238 mmol) was added and stirred at 120 ° C. for 3 hours. The mixture was ice-cooled, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-35 (56 mg, 66% yield).
1 H-NMR (DMSO-D6) δ: 1.37 (m, 2H), 1.49-1.68 (m, 4H), 1.77-1.87 (m, 4H), 2.42 (m, 1H), 3.33 (m, 4H), 4.28 (d, J = 7.2Hz, 2H), 7.04 (m, 1H), 7.26 (s, 1H), 8.04 (m, 1H), 8.19 (brs, 2H), 8.34 (m, 1H).
化合物Ｉ－３６の合成　
Figure JPOXMLDOC01-appb-C000095
工程１：化合物３６ｂの合成
　化合物３６ａ（１ｇ、５．７ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）溶液に、氷冷下で塩化オキサリル（０．５５ｍＬ、６．２７ｍｍｏｌ）、ＤＭＦ（０．０２ｍＬ、０．２８５ｍｍｏｌ）を加えた。１０分後に室温に昇温して１時間撹拌した。テトラヒドロフラン（１０ｍＬ）を加えて希釈し、氷冷下で２ｍｏｌ／Ｌトリメチルシリルジアゾメタンのヘキサン溶液（６．２７ｍＬ、１２．５ｍｍｏｌ）を滴下した。氷冷下で１時間撹拌した後、４７％臭化水素酸を加えた。３０分後に水酸化ナトリウム水溶液を加えてｐＨ５とし、さらに重曹水で中和した。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去することで、化合物３６ｂ（９９０ｍｇ、収率６８％）を得た。
1H-NMR (CDCl3)δ: 4.54 (s, 2H), 7.69 (m, 1H), 8.41 (m, 1H). Synthesis of Compound I-36
Figure JPOXMLDOC01-appb-C000095
Step 1: Synthesis of Compound 36b To a solution of Compound 36a (1 g, 5.7 mmol) in tetrahydrofuran (10 mL) under cooling with ice, oxalyl chloride (0.55 mL, 6.27 mmol), DMF (0.02 mL, 0.285 mmol) Was added. After 10 minutes, the mixture was warmed to room temperature and stirred for 1 hour. Tetrahydrofuran (10 mL) was added for dilution, and a 2 mol / L trimethylsilyldiazomethane hexane solution (6.27 mL, 12.5 mmol) was added dropwise under ice cooling. After stirring for 1 hour under ice cooling, 47% hydrobromic acid was added. After 30 minutes, an aqueous sodium hydroxide solution was added to adjust the pH to 5, followed by neutralization with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, Compound 36b (990 mg, yield 68%) was obtained.
1 H-NMR (CDCl3) δ: 4.54 (s, 2H), 7.69 (m, 1H), 8.41 (m, 1H).
工程２：化合物３６ｄの合成
　化合物３６ｂ（９９０ｍｇ、３．９２ｍｍｏｌ）をエタノール（１０ｍＬ）に溶解して、化合物３６ｃ（５４１ｍｇ、３．４２ｍｍｏｌ）を加えた。室温で２時間撹拌した後に、重曹水で中和した。クロロホルムで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物３６ｄ（３６８ｍｇ、収率３０％）を得た。
1H-NMR (DMSO-D6)δ: 1.80 (m, 2H), 3.28-3.31 (m, 4H), 7.36 (s, 1H), 8.13 (s, 2H), 8.26 (m, 1H), 8.39 (m, 1H). Step 2: Synthesis of Compound 36d Compound 36b (990 mg, 3.92 mmol) was dissolved in ethanol (10 mL), and Compound 36c (541 mg, 3.42 mmol) was added. After stirring at room temperature for 2 hours, the mixture was neutralized with an aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 36d (368 mg, yield 30%).
1 H-NMR (DMSO-D6) δ: 1.80 (m, 2H), 3.28-3.31 (m, 4H), 7.36 (s, 1H), 8.13 (s, 2H), 8.26 (m, 1H), 8.39 ( m, 1H).
工程３：化合物Ｉ－３６の合成
　化合物３６ｄ（７０ｍｇ、０．２３ｍｍｏｌ）のＤＭＡ（１．５ｍＬ）溶液に、４－クロロフェノール（５７．７ｍｇ、０．４４９ｍｍｏｌ）、ヨウ化銅（８．６ｍｇ、０．０４５ｍｍｏｌ）、Ｎ，Ｎ－ジメチルグリシン（９．３ｍｇ、０．０９ｍｍｏｌ）、炭酸カリウム（９３ｍｇ、０．６７４ｍｍｏｌ）を加えた。２００℃で２時間撹拌した後に、酢酸エチルと水を加えた。不溶物をセライトでろ去した。有機層と水層を分離し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）に付し、次いでアミノカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物Ｉ－３６（１６ｍｇ、収率１８％）を得た。
1H-NMR (DMSO-D6)δ: 1.82 (m, 2H), 3.31 (m, 4H), 7.20 (d, J = 8.4Hz, 2H), 7.39 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 8.01 (m, 1H), 8.11 (s, 2H), 8.39 (m, 1H). Step 3: Synthesis of Compound I-36 To a solution of Compound 36d (70 mg, 0.23 mmol) in DMA (1.5 mL), 4-chlorophenol (57.7 mg, 0.449 mmol), copper iodide (8.6 mg, 0.045 mmol), N, N-dimethylglycine (9.3 mg, 0.09 mmol) and potassium carbonate (93 mg, 0.674 mmol) were added. After stirring at 200 ° C. for 2 hours, ethyl acetate and water were added. The insoluble material was filtered off through celite. The organic layer and the aqueous layer were separated, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (chloroform-methanol) and then purified by amino column chromatography (hexane-ethyl acetate) to give a compound. I-36 (16 mg, 18% yield) was obtained.
1 H-NMR (DMSO-D6) δ: 1.82 (m, 2H), 3.31 (m, 4H), 7.20 (d, J = 8.4Hz, 2H), 7.39 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 8.01 (m, 1H), 8.11 (s, 2H), 8.39 (m, 1H).
化合物Ｉ－３７の合成　
Figure JPOXMLDOC01-appb-C000096
工程１：Ｉ－３７の合成　　
実施例34と同様の方法で合成した化合物３７ａ（６０ｍｇ、０．２１６ｍｍｏｌ）のＤＭＳＯ（１．２ｍＬ）溶液に、４－クロロフェノール（７０ｍｇ、０．５４ｍｍｏｌ）、炭酸セシウム（２８２ｍｇ、０．８６５ｍｍｏｌ）を加えた。１５０℃で４時間撹拌した後に、水を加えた。酢酸エチルで抽出して、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をアミノカラムクロマトグラフィー（ヘキサン－酢酸エチル）に付し、次いでシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物Ｉ－３７（２９ｍｇ、３５％）を得た。
1H-NMR (DMSO-D6)δ: 1.81 (m, 2H), 3,32 (m, 4H), 7.01 (d, J = 8.8Hz, 2H), 7.27 (s, 1H), 7.42 (d, J = 8.8Hz, 2H), 8.02 (d, J = 4.8Hz, 1H), 8.15 (s, 2H), 8.29 (s, 1H), 8.46 (d, J = 4.8Hz, 1H). Synthesis of Compound I-37
Figure JPOXMLDOC01-appb-C000096
Step 1: Synthesis of I-37
To a solution of compound 37a (60 mg, 0.216 mmol) synthesized in the same manner as in Example 34 in DMSO (1.2 mL), 4-chlorophenol (70 mg, 0.54 mmol), cesium carbonate (282 mg, 0.865 mmol) Was added. After stirring at 150 ° C. for 4 hours, water was added. Extraction with ethyl acetate was performed, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to amino column chromatography (hexane-ethyl acetate) and then purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-37 (29 mg, 35%).
1 H-NMR (DMSO-D6) δ: 1.81 (m, 2H), 3,32 (m, 4H), 7.01 (d, J = 8.8Hz, 2H), 7.27 (s, 1H), 7.42 (d, J = 8.8Hz, 2H), 8.02 (d, J = 4.8Hz, 1H), 8.15 (s, 2H), 8.29 (s, 1H), 8.46 (d, J = 4.8Hz, 1H).
化合物Ｉ－３８の合成　
Figure JPOXMLDOC01-appb-C000097
工程１：化合物３８ｂの合成
　実施例３４と同様の方法で合成した化合物３８ａ（１ｇ、２．６８ｍｍｏｌ）のＤＭＡ（１５ｍＬ）溶液に、４－クロロフェノール（０．３１８ｍＬ、３．２２ｍｍｏｌ）と炭酸セシウム（２．１９ｇ、６．７１ｍｍｏｌ）を加えた。１２０℃で４時間撹拌した後に、重曹水を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物３８ｂ（４７７ｍｇ、収率３８％）を得た。
1H-NMR (DMSO-D6)δ: 2.06 (m, 2H), 3.31 (m, 4H), 7.23 (d, J = 7.2Hz, 2H), 7.38 (s, 1H), 7.48 (d, J = 7.2Hz, 2H), 8.09-8.13 (m, 3H), 8.54 (s, 1H). Synthesis of Compound I-38
Figure JPOXMLDOC01-appb-C000097
Step 1: Synthesis of Compound 38b To a solution of Compound 38a (1 g, 2.68 mmol) synthesized in the same manner as in Example 34 in DMA (15 mL), 4-chlorophenol (0.318 mL, 3.22 mmol) and cesium carbonate were added. (2.19 g, 6.71 mmol) was added. After stirring at 120 ° C. for 4 hours, an aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 38b (477 mg, yield 38%).
1 H-NMR (DMSO-D6) δ: 2.06 (m, 2H), 3.31 (m, 4H), 7.23 (d, J = 7.2Hz, 2H), 7.38 (s, 1H), 7.48 (d, J = 7.2Hz, 2H), 8.09-8.13 (m, 3H), 8.54 (s, 1H).
工程２：化合物Ｉ－３８の合成
　１ｍｏｌ／Ｌジエチル亜鉛ヘキサン溶液（０．６４５ｍＬ、０．６４５ｍｍｏｌ）をテトラヒドロフラン（０．７５ｍＬ）、ＮＭＰ（０．５ｍＬ）に溶解した。氷冷して化合物３８ｂ（７５ｍｇ、０．１６ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（３７ｍｇ、０．０３ｍｍｏｌ）を同時に加えた。１０分撹拌した後に、８０℃に昇温した。３時間後に、重曹水を加えてクロロホルムで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）に付し、次いでアミノカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物Ｉ－３８（２９ｍｇ、収率４５％）を得た。
1H-NMR (DMSO-D6)δ: 1.82 (m, 2H), 2.32 (s, 3H), 3.30 (m, 4H), 7.15 (m, 2H), 7.23 (s, 1H), 7.44 (m, 2H), 7.85 (d, J = 2.0Hz, 1H), 8.20 (s, 2H), 8.23 (d, J = 2.0Hz, 1H). Step 2: Synthesis of Compound I-38 A 1 mol / L diethyl zinc hexane solution (0.645 mL, 0.645 mmol) was dissolved in tetrahydrofuran (0.75 mL) and NMP (0.5 mL). Compound 38b (75 mg, 0.16 mmol) and Pd (PPh 3 ) 4 (37 mg, 0.03 mmol) were added simultaneously with ice cooling. After stirring for 10 minutes, the temperature was raised to 80 ° C. After 3 hours, sodium bicarbonate water was added and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform-methanol), and then purified by amino column chromatography (chloroform-methanol) to give compound I-38 (29 mg, yield 45%).
1 H-NMR (DMSO-D6) δ: 1.82 (m, 2H), 2.32 (s, 3H), 3.30 (m, 4H), 7.15 (m, 2H), 7.23 (s, 1H), 7.44 (m, 2H), 7.85 (d, J = 2.0Hz, 1H), 8.20 (s, 2H), 8.23 (d, J = 2.0Hz, 1H).
化合物Ｉ－３９の合成　
Figure JPOXMLDOC01-appb-C000098
工程１：化合物Ｉ－３９の合成
　実施例１と同様の方法で合成した化合物３９ａ（７０ｍｇ、０．２４ｍｍｏｌ）のエタノール（１．５ｍＬ）溶液に４－フルオロベンゼンボロン酸（５０ｍｇ、０．３６ｍｍｏｌ）とジクロロビストリフェニルホスフィンパラジウム（１７ｍｇ、０．０２４ｍｍｏｌ）、２ｍｏｌ／Ｌ炭酸カリウム水溶液（０．３６ｍＬ、０．７２ｍｍｏｌ）を加えた。系内を窒素置換し、１００℃で４時間撹拌した後、水を加えてクロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物Ｉ－３９（２９ｍｇ、収率３５％）を得た。
1H-NMR (DMSO-D6)δ: 1.85 (m, 2H), 3.35 (m, 4H), 7.33 (m, 2H), 7.65 (s, 1H), 7.78 (dd, J = 5.2, 1.6Hz, 1H), 8.20-8.26 (m, 4H), 8.29 (s, 1H), 8.64 (d, J = 5.2Hz, 1H). Synthesis of Compound I-39
Figure JPOXMLDOC01-appb-C000098
Step 1: Synthesis of Compound I-39 4-fluorobenzeneboronic acid (50 mg, 0.36 mmol) was added to a solution of Compound 39a (70 mg, 0.24 mmol) synthesized in the same manner as in Example 1 in ethanol (1.5 mL). And dichlorobistriphenylphosphine palladium (17 mg, 0.024 mmol), 2 mol / L aqueous potassium carbonate solution (0.36 mL, 0.72 mmol) were added. The system was purged with nitrogen, stirred at 100 ° C. for 4 hours, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-39 (29 mg, yield 35%).
1 H-NMR (DMSO-D6) δ: 1.85 (m, 2H), 3.35 (m, 4H), 7.33 (m, 2H), 7.65 (s, 1H), 7.78 (dd, J = 5.2, 1.6Hz, 1H), 8.20-8.26 (m, 4H), 8.29 (s, 1H), 8.64 (d, J = 5.2Hz, 1H).
化合物Ｉ－４０の合成　
Figure JPOXMLDOC01-appb-C000099
工程１　化合物Ｉ－４０の合成
　化合物４０ａ（５０ｍｇ、０．１３３ｍｍｏｌ）をＤＭＡ（０．７ｍＬ）に溶解した。４－シアノフェノール（２０．７ｍｇ、０．１７３ｍｍｏｌ）、Ｎ，Ｎ－ジメチルグリシン（４．１ｍｇ、０．０４ｍｍｏｌ）、ヨウ化銅（３．８ｍｇ、０．０２ｍｍｏｌ）、炭酸カリウム（５５ｍｇ、０．４０ｍｍｏｌ）を加えた。２００℃で３時間撹拌した後、水を加えた。酢酸エチルで抽出して、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物Ｉ－４０（１５ｍｇ、収率３０％）を得た。
1H-NMR (DMSO-D6)δ: 1.82 (m, 2H), 3.31 (m, 4H), 7.34 (d, J = 8.8Hz, 2H), 7.53-7.58 (m, 2H), 7.65 (m, 1H), 7.89 (d, J = 8.8Hz, 2H), 8.14-8.19 (m, 3H). Synthesis of Compound I-40
Figure JPOXMLDOC01-appb-C000099
Step 1 Synthesis of Compound I-40 Compound 40a (50 mg, 0.133 mmol) was dissolved in DMA (0.7 mL). 4-cyanophenol (20.7 mg, 0.173 mmol), N, N-dimethylglycine (4.1 mg, 0.04 mmol), copper iodide (3.8 mg, 0.02 mmol), potassium carbonate (55 mg, 0. 40 mmol) was added. After stirring at 200 ° C. for 3 hours, water was added. Extraction with ethyl acetate was performed, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-40 (15 mg, yield 30%).
1 H-NMR (DMSO-D6) δ: 1.82 (m, 2H), 3.31 (m, 4H), 7.34 (d, J = 8.8Hz, 2H), 7.53-7.58 (m, 2H), 7.65 (m, 1H), 7.89 (d, J = 8.8Hz, 2H), 8.14-8.19 (m, 3H).
化合物Ｉ－４１の合成　
Figure JPOXMLDOC01-appb-C000100
工程１：　化合物Ｉ－４１の合成
　化合物４１ａ（７０ｍｇ、０．１８７ｍｍｏｌ）のジオキサン（１．０ｍＬ）溶解に、４－クロロアニリン（３１ｍｇ、０．２４３ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（４３ｍｇ、０．０７５ｍｍｏｌ）、Ｐｄ（ＯＡｃ）２（８，４ｍｇ、０．０３７ｍｍｏｌ）、炭酸カリウム（６４．５ｍｇ、０．４７ｍｍｏｌ）を加えた。マイクロ波照射化、１２０℃で１５分反応させた。水を加えてクロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物Ｉ－４１（２６ｍｇ、収率３６％）を得た。
1H-NMR (DMSO-D6)δ: 1.85 (m, 2H), 3.35 (m, 4H), 7.18 (d, J = 4.8Hz, 1H), 7.21-7.32 (m, 4H), 7.74 (d, J = 7.2Hz, 2H), 8.13 (d, J = 4.8Hz, 1H), 8.27 (s, 2H), 9.14 (s, 1H). Synthesis of Compound I-41
Figure JPOXMLDOC01-appb-C000100
Step 1: Synthesis of Compound I-41 Compound 41a (70 mg, 0.187 mmol) dissolved in dioxane (1.0 mL) was dissolved in 4-chloroaniline (31 mg, 0.243 mmol), Xantphos (43 mg, 0.075 mmol), Pd (OAc) 2 (8.4 mg, 0.037 mmol), potassium carbonate (64.5 mg, 0.47 mmol) were added. Microwave irradiation was carried out at 120 ° C. for 15 minutes. Water was added and the mixture was extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-41 (26 mg, yield 36%).
1 H-NMR (DMSO-D6) δ: 1.85 (m, 2H), 3.35 (m, 4H), 7.18 (d, J = 4.8Hz, 1H), 7.21-7.32 (m, 4H), 7.74 (d, J = 7.2Hz, 2H), 8.13 (d, J = 4.8Hz, 1H), 8.27 (s, 2H), 9.14 (s, 1H).
化合物Ｉ－４３の合成　
Figure JPOXMLDOC01-appb-C000101
工程１：化合I－４３の合成
　実施例３４と同様の方法で合成した化合物４３ａ（２５０ｍｇ、０．５３８ｍｍｏｌ）のエタノール（５ｍＬ）溶液に、トランス－２－シクロプロピルボロン酸ピナコールエステル（１５７ｍｇ、０．８０７ｍｍｏｌ）、ジクロロビストリフェニルホスフィンパラジウム（３７．８ｍｇ、０．０５４ｍｍｏｌ）、２ｍｏｌ／Ｌ炭酸カリウム水溶液を加えた。１１０℃で３時間撹拌した後に、水を加えた。クロロホルムで抽出して、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物I－４３（１７１ｍｇ、収率７０％）を得た。
1H-NMR (DMSO-D6)δ: 0.54 (m, 2H), 0.82 (m, 2H), 1.66 (m, 1H), 1.83 (m, 2H), 3.33 (m, 4H), 5.92 (dd, J = 15.6, 9.2Hz, 1H), 6.74 (d, J = 15.6Hz, 1H), 7.00 (dd, J = 8.8, 2.8Hz, 1H), 7.21 (dd, J = 7.2, 4.8Hz, 1H), 7.31 (s, 1H), 7.41-7.45 (m, 2H), 8.00 (dd, J = 4.8, 1.6Hz, 1H), 8.23 (s, 2H), 8.45 (dd, J = 7.2, 1.6Hz, 1H). Synthesis of Compound I-43
Figure JPOXMLDOC01-appb-C000101
Step 1: Synthesis of Compound I-43 To a solution of compound 43a (250 mg, 0.538 mmol) synthesized in the same manner as in Example 34 in ethanol (5 mL), trans-2-cyclopropylboronic acid pinacol ester (157 mg, 0 .807 mmol), dichlorobistriphenylphosphine palladium (37.8 mg, 0.054 mmol), 2 mol / L aqueous potassium carbonate solution was added. After stirring at 110 ° C. for 3 hours, water was added. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate and concentrating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-43 (171 mg, yield 70%).
1 H-NMR (DMSO-D6) δ: 0.54 (m, 2H), 0.82 (m, 2H), 1.66 (m, 1H), 1.83 (m, 2H), 3.33 (m, 4H), 5.92 (dd, J = 15.6, 9.2Hz, 1H), 6.74 (d, J = 15.6Hz, 1H), 7.00 (dd, J = 8.8, 2.8Hz, 1H), 7.21 (dd, J = 7.2, 4.8Hz, 1H), 7.31 (s, 1H), 7.41-7.45 (m, 2H), 8.00 (dd, J = 4.8, 1.6Hz, 1H), 8.23 (s, 2H), 8.45 (dd, J = 7.2, 1.6Hz, 1H) .
化合物Ｉ－４４の合成　
Figure JPOXMLDOC01-appb-C000102
工程１：化合物４４ｂの合成
　化合物４４ａ（６００ｍｇ、２．８５ｍｍｏｌ）のＤＭＡ（３ｍＬ）溶液に、４－クロロフェノール（３６７ｍｇ、２．８５ｍｍｏｌ）と炭酸セシウム（１．１２ｇ、３．４２ｍｍｏｌ）を加えた。６０℃で２時間撹拌した後、水を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去することで、化合物４４ｂ（９１６ｍｇ）を粗生成物として得た。得られた化合物４４ｂは精製せずそのまま次の工程に用いた。
1H-NMR (CDCl3)δ: 6.94 (d, J = 8.0Hz, 1H), 7.11 (d, J = 8.8Hz, 2H), 7.37 (d, J = 8.8Hz, 2H), 7.85 (d, J = 8.0Hz, 1H). Synthesis of Compound I-44
Figure JPOXMLDOC01-appb-C000102
Step 1: Synthesis of Compound 44b To a solution of Compound 44a (600 mg, 2.85 mmol) in DMA (3 mL) was added 4-chlorophenol (367 mg, 2.85 mmol) and cesium carbonate (1.12 g, 3.42 mmol). . After stirring at 60 ° C. for 2 hours, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain Compound 44b (916 mg) as a crude product. The obtained compound 44b was used in the next step without purification.
1 H-NMR (CDCl3) δ: 6.94 (d, J = 8.0Hz, 1H), 7.11 (d, J = 8.8Hz, 2H), 7.37 (d, J = 8.8Hz, 2H), 7.85 (d, J = 8.0Hz, 1H).
工程２：化合物４４ｄの合成
　化合物４４ｂ（９５０ｍｇ、２．９８ｍｍｏｌ）をトルエン（１５ｍＬ）に溶解し、１－エトキシビニルトリ－ｎ－ブチルスズ（１．１ｍＬ、３．２８ｍｍｏｌ）、Ｐｄ（ＰＰｈ３）４（２０９ｍｇ、０．２９８ｍｍｏｌ）を加えた。９０℃で２時間撹拌した後に、水を加えた。酢酸エチルで抽出して有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Step 2: Synthesis of Compound 44d Compound 44b (950 mg, 2.98 mmol) was dissolved in toluene (15 mL), and 1-ethoxyvinyltri-n-butyltin (1.1 mL, 3.28 mmol), Pd (PPh 3 ) 4 (209 mg, 0.298 mmol) was added. After stirring at 90 ° C. for 2 hours, water was added. Extraction with ethyl acetate was performed, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をテトラヒドロフラン（９ｍＬ）と水（１ｍＬ）に溶解して氷冷した。ＮＢＳ（５３０ｍｇ、２．９８ｍｍｏｌ）を加え、室温にて１時間撹拌した。水を加えて酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 The resulting residue was dissolved in tetrahydrofuran (9 mL) and water (1 mL) and ice-cooled. NBS (530 mg, 2.98 mmol) was added and stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
　得られた残渣をエタノール（１０ｍＬ）に溶解して化合４４ｃ（４２４ｍｇ、２．６８ｍｍｏｌ）を加えた。室温にて４時間撹拌した後、析出している固体をろ取することで、化合物４４ｄ（８８５ｍｇ、収率６５％）を得た。
1H-NMR (DMSO-D6)δ: 1.93 (m, 2H), 3.46 (m,, 4H), 7.31 (d, J = 8.8Hz, 2H), 7.37 (d, J = 8.0Hz, 1H), 7.54 (d, J = 8.8Hz, 2H), 7.88 (s, 1H), 8.70 (d, J = 8.0Hz, 1H), 8.89 (s, 2H), 12.12 (s, 1H). The resulting residue was dissolved in ethanol (10 mL) and compound 44c (424 mg, 2.68 mmol) was added. After stirring at room temperature for 4 hours, the precipitated solid was collected by filtration to obtain Compound 44d (885 mg, yield 65%).
1 H-NMR (DMSO-D6) δ: 1.93 (m, 2H), 3.46 (m ,, 4H), 7.31 (d, J = 8.8Hz, 2H), 7.37 (d, J = 8.0Hz, 1H), 7.54 (d, J = 8.8Hz, 2H), 7.88 (s, 1H), 8.70 (d, J = 8.0Hz, 1H), 8.89 (s, 2H), 12.12 (s, 1H).
工程３　化合物Ｉ－４４の合成
　化合物４４ｄ（６３ｍｇ、０．１４ｍｍｏｌ）のＤＭＦ（１．２ｍＬ）溶液に２８％ナトリウムメトキシド（８０ｍｇ、０．４１ｍｍｏｌ）を加えた。６０℃で２時間撹拌した後、塩化アンモニウム水溶液を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣を逆相ＨＰＬＣ（１０ｍＭ炭酸アンモニウム含有水－アセトニトリル）により精製して、化合物Ｉ－４４（７．７ｍｇ、収率１３％）を得た。
1H-NMR (DMSO-D6)δ: 1.82 (m, 2H), 3.30 (m, 4H), 3.61 (s, 3H), 6.65 (d, J = 8.4Hz, 1H), 7.06 (s, 1H), 7.25 (m, 2H), 7.47 (m, 2H), 8.20 (s, 2H), 8.39 (d, J = 8.4Hz, 1H). Step 3 Synthesis of Compound I-44 To a solution of compound 44d (63 mg, 0.14 mmol) in DMF (1.2 mL) was added 28% sodium methoxide (80 mg, 0.41 mmol). After stirring at 60 ° C. for 2 hours, an aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to give compound I-44 (7.7 mg, yield 13%).
1 H-NMR (DMSO-D6) δ: 1.82 (m, 2H), 3.30 (m, 4H), 3.61 (s, 3H), 6.65 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H) , 7.25 (m, 2H), 7.47 (m, 2H), 8.20 (s, 2H), 8.39 (d, J = 8.4Hz, 1H).
化合物Ｉ－４５の合成　
Figure JPOXMLDOC01-appb-C000103
工程１：化合物４５ｂの合成
　水素化ナトリウム（１０７２ｍｇ，２６．８ｍｍｏＬ）をジメチルホルムアミド（３０ｍＬ）に懸濁させ、４－クロロフェノール（３４４５ｍｇ，２６．８ｍｍｏＬ）を氷冷下で加えた。室温に昇温し、１５分撹拌した。氷冷下でエチル ４－クロロピリミジン－５－カルボキシレート（２５００ｍｇ，１４．８４ｍｍｏＬ）を加え、室温に昇温し、終夜で撹拌した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物４５ｂ（２３７ｍｇ，６％）を得た。1H-NMR (CDCl3)δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H). Synthesis of Compound I-45
Figure JPOXMLDOC01-appb-C000103
Step 1: Synthesis of Compound 45b Sodium hydride (1072 mg, 26.8 mmol) was suspended in dimethylformamide (30 mL), and 4-chlorophenol (3445 mg, 26.8 mmol) was added under ice cooling. The mixture was warmed to room temperature and stirred for 15 minutes. Ethyl 4-chloropyrimidine-5-carboxylate (2500 mg, 14.84 mmol) was added under ice cooling, the temperature was raised to room temperature, and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 45b (237 mg, 6%). 1 H-NMR (CDCl 3 ) δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H).
工程２：化合物Ｉ－４５の合成
　化合物４５ｂ（１００ｍｇ，０．３６ｍｍｏＬ）をテトラヒドロフラン（５ｍL）に溶解させ，ドライアイス－アセトンでー７８℃に冷却した。これにクロロヨードメタン（２５３ｍｇ，１．４４ｍｍｏＬ）、ＬＤＡの２ｍｏＬ/Ｌのテトラヒドロフラン/ヘプタン/エチルベンゼン溶液（Ａｌｄｒｉｃｈ社製）を加え、‐７８℃で３０分撹拌した。酢酸（０．５ｍＬ）を加えた後、水を加え、室温まで昇温した。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣にエタノール（２ｍＬ）に溶解させ、化合物４５ｃ（２８ｍｇ，０．１８ｍｍｏＬ）を加え６０℃で２時間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノールにより精製して化合物Ｉ－４５（１３ｍｇ，９％）を得た．1H-NMR (CDCl3)δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H). Step 2: Synthesis of Compound I-45 Compound 45b (100 mg, 0.36 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to −78 ° C. with dry ice-acetone. To this were added chloroiodomethane (253 mg, 1.44 mmol) and 2 mol / L tetrahydrofuran / heptane / ethylbenzene solution (manufactured by Aldrich) of LDA, and the mixture was stirred at -78 ° C for 30 minutes. Acetic acid (0.5 mL) was added, water was added, and the temperature was raised to room temperature. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (2 mL), compound 45c (28 mg, 0.18 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel chromatography (purified with chloroform-methanol to obtain compound I-45 (13 mg, 9%). 1 H-NMR (CDCl 3 ) δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H) , 9.13 (s, 1H).
化合物Ｉ－４６の合成　
Figure JPOXMLDOC01-appb-C000104
工程１：化合物４６ｂの合成
　エチル　３－クロロピラジン－２－カルボキシレート（２．０２ｇ，１０．８３ｍｍｏＬ）をジメチルアセトアミド（２０ｍＬ）に溶解させ，４－クロロフェノール（１．５３ｇ，１１．９１ｍｍｏＬ）と炭酸セシウム（７．７６ｇ，２３．８２ｍｍｏＬ）を加え、１００℃で８時間撹拌した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物４６ｂ（６２４ｍｇ，２１％）を得た。1H-NMR (CDCl3)δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H). Synthesis of Compound I-46
Figure JPOXMLDOC01-appb-C000104
Step 1: Synthesis of Compound 46b Ethyl 3-chloropyrazine-2-carboxylate (2.02 g, 10.83 mmol) was dissolved in dimethylacetamide (20 mL) and 4-chlorophenol (1.53 g, 11.91 mmol) was dissolved. Cesium carbonate (7.76 g, 23.82 mmol) was added and stirred at 100 ° C. for 8 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 46b (624 mg, 21%). 1 H-NMR (CDCl 3 ) δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H).
工程２：化合物Ｉ－４６の合成
　化合物４６ｂを用いて実施例４５と同様の方法で，化合物Ｉ－４６を合成した．1H-NMR (CDCl3)δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H). Step 2: Synthesis of Compound I-46 Compound I-46 was synthesized in the same manner as in Example 45 using Compound 46b. 1 H-NMR (CDCl 3 ) δ: 1.42 (J = 7.0 Hz, t, 3H), 4.45 (J = 7.0 Hz, q, 2H), 7.13 (J = 9.0 Hz, d, 2H), 7.41 (J = 8.8 Hz, d, 2H), 8.80 (s, 1H), 9.13 (s, 1H).
化合物Ｉ－４７の合成　
Figure JPOXMLDOC01-appb-C000105
工程１　化合物４７ｃの合成
化合物４７ａ（４００ｍｇ、２．５３ｍｍｏｌ）と化合物４７ｂ（６２５ｍｇ、２．６５ｍｍｏｌ）をエタノール（４ｍｌ）に懸濁させ、封管１１０℃で１０分間撹拌した。反応液を０℃まで冷却後、濾過しエタノールで洗浄した後、化合物４７ｃ（５７０ｍｇ、収率６０％）を得た。
1H-NMR（DMSO-d6）δ：1.88-1.98 (m, 2H), 3.43-3.52 (m, 4H), 8.23 (s, 1H), 8.31 (d, J = 8.0Hz, 1H), 8.80-8.90 (m, 3H) Synthesis of Compound I-47
Figure JPOXMLDOC01-appb-C000105
Step 1 Synthesis of Compound 47c Compound 47a (400 mg, 2.53 mmol) and compound 47b (625 mg, 2.65 mmol) were suspended in ethanol (4 ml) and stirred at 110 ° C. for 10 minutes in a sealed tube. The reaction solution was cooled to 0 ° C., filtered and washed with ethanol to obtain Compound 47c (570 mg, yield 60%).
1 H-NMR (DMSO-d 6 ) δ: 1.88-1.98 (m, 2H), 3.43-3.52 (m, 4H), 8.23 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.80 -8.90 (m, 3H)
工程２：化合物Ｉ－４７の合成
化合物４７ｃ（５０ｍｇ、０．１３３ｍｍｏｌ）、フェニルボロン酸（２４．３ｍｇ、０．２ｍｍｏｌ）、ＰｄＣｌ２（ｄｔｂｐｆ）（８．６７ｍｇ、０．０１３ｍｍｏｌ）をテトラヒドロフラン（１ｍｌ）に懸濁させ、２モル／Ｌ炭酸ナトリウム水溶液（０．２６６ｍｌ、０．５３２ｍｍｏｌ）を加えて、封管１３０℃で３０分間撹拌した。反応溶液に水を加え、クロロホルム―メタノール（９：１）で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣を逆相分取ＬＣＭＳ（水―アセトニトリル）により精製し、化合物Ｉ－４７（３．８ｍｇ、収率８．５％）を得た。
1H-NMR（CDCl3）δ：1.99-2.08 (m, 2H), 3.46-3.54 (m, 4H), 7.48-7.52 (m, 3H), 7.58-7.64 (m, 2H), 7.72 (s, 1H), 7.81 (s, 1H), 8.50-8.56 (m, 1H), 8.59 (d, J = 8.0Hz, 1H), 8.82 (d, J = 8.0Hz, 1H) Step 2: Synthesis of Compound I-47 Compound 47c (50 mg, 0.133 mmol), phenylboronic acid (24.3 mg, 0.2 mmol), PdCl2 (dtbpf) (8.67 mg, 0.013 mmol) in tetrahydrofuran (1 ml) 2 mol / L aqueous sodium carbonate solution (0.266 ml, 0.532 mmol) was added, and the mixture was stirred at 130 ° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with chloroform-methanol (9: 1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by reverse phase preparative LCMS (water-acetonitrile) to obtain Compound I-47 (3.8 mg, yield 8.5%).
1 H-NMR (CDCl 3 ) δ: 1.99-2.08 (m, 2H), 3.46-3.54 (m, 4H), 7.48-7.52 (m, 3H), 7.58-7.64 (m, 2H), 7.72 (s, 1H), 7.81 (s, 1H), 8.50-8.56 (m, 1H), 8.59 (d, J = 8.0Hz, 1H), 8.82 (d, J = 8.0Hz, 1H)
化合物Ｉ－４８の合成　
Figure JPOXMLDOC01-appb-C000106
工程１：化合物Ｉ－４８の合成
　化合物４８ａ（５０ｍｇ、０．１３ｍｍｏｌ）のＤＭＡ（０．５ｍＬ）溶液に、化合物４８ｂ（５５ｍｇ、０．２６６ｍｍｏｌ）、炭酸セシウム（２１７ｍｇ、０．６６５ｍｍｏｌ）を加えた。１５０℃で５時間撹拌した後に、重曹水を加えた。クロロホルムで抽出し、有機層を硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－４８（１５．６ｍｇ、収率３０％）を得た。
1H-NMR (DMSO-D6)δ: 1.83 (m, 2H), 2.90 (t, J = 6.0Hz, 2H), 3.33 (m, 4H), 4.08 (t, J = 6.0Hz, 2H), 4.97 (s, 2H), 7.18-7.22 (m, 2H), 7.65 (s, 1H), 8.23 (s, 2H), 8.33 (d, J = 4.8Hz, 1H), 8.46 (d, J = 4.8Hz, 1H), 8.49 (s, 1H). Synthesis of Compound I-48
Figure JPOXMLDOC01-appb-C000106
Step 1: Synthesis of Compound I-48 Compound 48b (55 mg, 0.266 mmol) and cesium carbonate (217 mg, 0.665 mmol) were added to a solution of compound 48a (50 mg, 0.13 mmol) in DMA (0.5 mL). . After stirring at 150 ° C. for 5 hours, sodium bicarbonate water was added. Extraction was performed with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-48 (15.6 mg, yield 30%).
1 H-NMR (DMSO-D6) δ: 1.83 (m, 2H), 2.90 (t, J = 6.0Hz, 2H), 3.33 (m, 4H), 4.08 (t, J = 6.0Hz, 2H), 4.97 (s, 2H), 7.18-7.22 (m, 2H), 7.65 (s, 1H), 8.23 (s, 2H), 8.33 (d, J = 4.8Hz, 1H), 8.46 (d, J = 4.8Hz, 1H), 8.49 (s, 1H).
化合物Ｉ－５０の合成　
Figure JPOXMLDOC01-appb-C000107
工程１：化合物Ｉ－５０の合成
　２，４－ジメチルフェノール（６６ｍｇ，０．５４ｍｍｏＬ），化合物５０ａ（８０ｍｇ，０．２７ｍｍｏＬ）をＮ，Ｎ－ジメチルアセトアミド（２．６ｍＬ）に溶解させ、炭酸セシウム（３５４ｍｇ，１．０９ｍｍｏＬ）を加えた。封管した後、マイクロウエーブで２００℃に昇温して、１５分間撹拌した。室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－５０（１０ｍｇ，１０％）を得た。1H-NMR (DMSO-D6)δ: 1.78-1.87 (2H, m), 2.05 (3H, s), 2.30 (3H, s), 3.30-3.35 (4H, m), 7.00 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 8.3 Hz), 7.12 (1H, s), 7.47 (1H, s), 7.71 (1H, d, J = 5.1 Hz), 8.19 (2H, br s), 8.56 (1H, d, J = 5.1 Hz). Synthesis of Compound I-50
Figure JPOXMLDOC01-appb-C000107
Step 1: Synthesis of Compound I-50 2,4-Dimethylphenol (66 mg, 0.54 mmol) and Compound 50a (80 mg, 0.27 mmol) were dissolved in N, N-dimethylacetamide (2.6 mL) to obtain cesium carbonate. (354 mg, 1.09 mmol) was added. After sealing, the temperature was raised to 200 ° C. with a microwave and stirred for 15 minutes. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-50 (10 mg, 10%). 1 H-NMR (DMSO-D6) δ: 1.78-1.87 (2H, m), 2.05 (3H, s), 2.30 (3H, s), 3.30-3.35 (4H, m), 7.00 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 8.3 Hz), 7.12 (1H, s), 7.47 (1H, s), 7.71 (1H, d, J = 5.1 Hz), 8.19 (2H, br s) , 8.56 (1H, d, J = 5.1 Hz).
化合物Ｉ－５１の合成　
Figure JPOXMLDOC01-appb-C000108
工程１：化合物５１ｂの合成
　化合物５１ａ（１．５６ｇ、１０．４７ｍｍｏｌ）を２－プロパノール（１６ｍＬ）に溶解した。ＤＩＥＡ（３．６６ｍＬ、２０．９４ｍｍｏｌ）、テトラヒドロイソキノリン（１。４０ｍＬ、１１．０ｍｍｏｌ）を加え室温で８時間撹拌した。水を加え、酢酸エチルで抽出して無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をカラムクロマトグラフィー（ヘキサン‐酢酸エチル）により精製して、化合物５１ｂ（２．０９ｇ、収率８１％）を得た。
1H-NMR (CDCl3)δ: 8.07 (1H, d, J = 6.1 Hz), 7.26-7.19 (4H, m), 6.44 (1H, d, J = 6.1 Hz), 4.74 (2H, s), 3.84 (2H, s), 2.97 (2H, t, J = 5.8 Hz). Synthesis of Compound I-51
Figure JPOXMLDOC01-appb-C000108
Step 1: Synthesis of Compound 51b Compound 51a (1.56 g, 10.47 mmol) was dissolved in 2-propanol (16 mL). DIEA (3.66 mL, 20.94 mmol) and tetrahydroisoquinoline (1.40 mL, 11.0 mmol) were added, and the mixture was stirred at room temperature for 8 hours. Water was added, extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 51b (2.09 g, yield 81%).
1 H-NMR (CDCl 3 ) δ: 8.07 (1H, d, J = 6.1 Hz), 7.26-7.19 (4H, m), 6.44 (1H, d, J = 6.1 Hz), 4.74 (2H, s), 3.84 (2H, s), 2.97 (2H, t, J = 5.8 Hz).
工程２：化合物Ｉ－５１の合成
　化合物５１ｂ（３６０．３ｍｇ、１．４６６ｍｍｏｌ）と１－エトキシビニルトリ－ｎ－ブチルスズ（５４５μｌ、１．６１３ｍｍｏｌ）をトルエン（４ｍＬ）に溶解した。Ｐｄ（ＰＰｈ３）４（１６９ｍｇ、０．１４７ｍｍｏｌ）を加えて窒素置換し、１６０℃で４時間撹拌した。水を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Step 2: Synthesis of Compound I-51 Compound 51b (360.3 mg, 1.466 mmol) and 1-ethoxyvinyltri-n-butyltin (545 μl, 1.613 mmol) were dissolved in toluene (4 mL). Pd (PPh 3 ) 4 (169 mg, 0.147 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at 160 ° C. for 4 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をテトラヒドロフラン（４ｍＬ）と水（０．４ｍＬ）に溶解し、氷冷下でＮＢＳ（２８７ｍｇ、１．６１５ｍｍｏｌ）を加えた。１時間後に水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 The obtained residue was dissolved in tetrahydrofuran (4 mL) and water (0.4 mL), and NBS (287 mg, 1.615 mmol) was added under ice cooling. After 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をエタノール（５ｍＬ）に溶解して化合物５１ｃ（２０９ｍｇ、１．３２２ｍｍｏｌ）を加えた。室温で１時間撹拌した後に、重曹水を加えて中和した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣に酢酸エチルを加えて固化し、固体をろ取することで、化合物Ｉ－５１（２６．７ｍｇ、収率５％）を得た。
1H-NMR (DMSO-D6)δ: 8.60 (2H, br s), 8.26 (1H, d, J = 6.0 Hz), 7.48 (1H, s), 7.28-7.19 (4H, m), 6.74 (1H, d, J = 6.1 Hz), 4.83 (2H, br s), 3.91 (2H, br s), 3.38-3.30 (4H, m), 2.93 (2H, t, J = 5.7 Hz), 1.86 (2H, t, J = 5.3 Hz). The resulting residue was dissolved in ethanol (5 mL) and compound 51c (209 mg, 1.322 mmol) was added. After stirring at room temperature for 1 hour, sodium bicarbonate water was added for neutralization. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue to solidify, and the solid was collected by filtration to obtain Compound I-51 (26.7 mg, yield 5%).
1 H-NMR (DMSO-D6) δ: 8.60 (2H, br s), 8.26 (1H, d, J = 6.0 Hz), 7.48 (1H, s), 7.28-7.19 (4H, m), 6.74 (1H , d, J = 6.1 Hz), 4.83 (2H, br s), 3.91 (2H, br s), 3.38-3.30 (4H, m), 2.93 (2H, t, J = 5.7 Hz), 1.86 (2H, t, J = 5.3 Hz).
化合物Ｉ－５３の合成　
Figure JPOXMLDOC01-appb-C000109
工程１：化合物５３ｄの合成
窒素雰囲気下、化合物５３ａ（５．０ｇ、２４．４ｍｍｏｌ）のジエチルエーテル溶液（５０ｍｌ）を氷水で５℃に冷却し、塩化アルミニウム（０．１６３ｇ、１．２２ｍｍｏｌ）を加えた。さらに臭素（３．９０ｇ、２４．４ｍｍｏｌ）を５～１０℃で滴下し、１０℃で３時間撹拌した。反応液に飽和重曹水を加えて、酢酸エチルで抽出した後、飽和食塩水で洗浄した。溶媒を硫酸マグネシウムで乾燥後、減圧留去し、粗生成物として化合物５３ｂ（４．７ｇ、６８％）を得た。粗生成物５３ｂ（４．８７ｇ、１７．２ｍｍｏｌ）と化合物５３ｃ（１．１ｇ、６．８６ｍｍｏｌ）をエタノール（１８ｍｌ）に懸濁させ、封管１１０℃で１０分間撹拌した。反応液に飽和重曹水と酢酸エチルを加えて撹拌後、不溶物を濾過した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残渣をシルカゲルカラムクロマトグラフィー（ヘキサン―酢酸エチル）で精製し、化合物５３ｄ（６００ｍｇ、２６％）を得た。
1H-NMR（DMSO-d6）δ：1.74-1.86 (m, 2H), 3.30-3.38 (m, 4H), 6.94 (s, 1H), 7.66 (d, J = 4.0Hz, 1H), 7.85 (d, J = 4.0Hz, 1H), 8.15-8.23 (br, 2H) Synthesis of Compound I-53
Figure JPOXMLDOC01-appb-C000109
Step 1: Synthesis of Compound 53d In a nitrogen atmosphere, a diethyl ether solution (50 ml) of compound 53a (5.0 g, 24.4 mmol) was cooled to 5 ° C. with ice water, and aluminum chloride (0.163 g, 1.22 mmol) was added. added. Further bromine (3.90 g, 24.4 mmol) was added dropwise at 5 to 10 ° C., and the mixture was stirred at 10 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was dried over magnesium sulfate and then distilled off under reduced pressure to obtain Compound 53b (4.7 g, 68%) as a crude product. Crude product 53b (4.87 g, 17.2 mmol) and compound 53c (1.1 g, 6.86 mmol) were suspended in ethanol (18 ml), and the mixture was stirred at 110 ° C. for 10 minutes. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture and stirred, and the insoluble material was filtered off. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 53d (600 mg, 26%).
1 H-NMR (DMSO-d 6 ) δ: 1.74-1.86 (m, 2H), 3.30-3.38 (m, 4H), 6.94 (s, 1H), 7.66 (d, J = 4.0Hz, 1H), 7.85 (d, J = 4.0Hz, 1H), 8.15-8.23 (br, 2H)
工程２：化合物Ｉ－５３の合成
化合物５３ｄ（３０ｍｇ、０．０８７ｍｍｏｌ）、フェニルボロン酸（１６ｍｇ、０．１３ｍｍｏｌ）、ＰｄＣｌ２（ｄｔｂｐｆ）（５．７ｍｇ、８．７４μｍｏｌ）をテトラヒドロフラン（０．６ｍｌ）に懸濁させ、２モル／Ｌ炭酸ナトリウム水溶液（０．１３１ｍｌ、０．２６２ｍｍｏｌ）を加えて、封管１３０℃で３０分間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシルカゲルカラムクロマトグラフィー（ヘキサン―酢酸エチル）で精製し、化合物Ｉ－５３（５．０ｍｇ、１７％）を得た。
1H-NMR（DMSO-d6）δ：1.78-1.88 (m, 2H), 3.32-3.36 (m, 4H), 6.97 (s, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.44 (t, J = 8.0Hz, 2H), 7.70 (d, J = 8.0Hz, 2H), 7.84 (s, 1H), 7.93 (s, 1H), 8.10-8.30 (br, 2H) Step 2: Synthesis of Compound I-53 Compound 53d (30 mg, 0.087 mmol), phenylboronic acid (16 mg, 0.13 mmol), PdCl 2 (dtbpf) (5.7 mg, 8.74 μmol) was added to tetrahydrofuran (0.6 ml). 2 mol / L aqueous sodium carbonate solution (0.131 ml, 0.262 mmol) was added, and the mixture was stirred at 130 ° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound I-53 (5.0 mg, 17%).
1 H-NMR (DMSO-d 6 ) δ: 1.78-1.88 (m, 2H), 3.32-3.36 (m, 4H), 6.97 (s, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.44 (t, J = 8.0Hz, 2H), 7.70 (d, J = 8.0Hz, 2H), 7.84 (s, 1H), 7.93 (s, 1H), 8.10-8.30 (br, 2H)
化合物Ｉ－５４の合成　
Figure JPOXMLDOC01-appb-C000110
 工程１　化合物５４ｄの合成
化合物５４ａ（５１４ｍｇ，２．０９ｍｍｏＬ）をクロロホルム（１０ｍＬ）に溶解させ、０℃に冷却した。臭素（０．１１８ｍＬ，２．３０ｍｍｏＬ）を滴下し、昇温して室温で７時間撹拌した。飽和重曹水で中和した後、クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、粗生成物として化合物５４ｂ（６９７ｍｇ）を得た。粗生成物５４ｂ（６９７ｍｇ）をエタノール（８ｍＬ）に溶解し、化合物５４ｃ（３０５ｍｇ，１．９３ｍｍｏＬ）を加えた。室温で１．５時間撹拌した後、飽和重曹水、クロロホルムを加えた。沈殿物を濾取し、化合物５４ｄ（２７８ｍｇ，３４％）を得た。1H-NMR (DMSO-D6)δ: 1.77-1.89 (2H, m), 3.30-3.36 (4H, m), 7.14-7.21 (2H, m), 7.61 (1H, d, J = 7.6 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.14 (1H, s), 8.20 (2H, br s). Synthesis of Compound I-54
Figure JPOXMLDOC01-appb-C000110
 Step 1 Synthesis of Compound 54d Compound 54a (514 mg, 2.09 mmol) was dissolved in chloroform (10 mL) and cooled to 0 ° C. Bromine (0.118 mL, 2.30 mmol) was added dropwise, the temperature was raised, and the mixture was stirred at room temperature for 7 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with chloroform, and the organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 54b (697 mg) as a crude product. The crude product 54b (697 mg) was dissolved in ethanol (8 mL) and compound 54c (305 mg, 1.93 mmol) was added. After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate and chloroform were added. The precipitate was collected by filtration to give compound 54d (278 mg, 34%). 1 H-NMR (DMSO-D6) δ: 1.77-1.89 (2H, m), 3.30-3.36 (4H, m), 7.14-7.21 (2H, m), 7.61 (1H, d, J = 7.6 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.14 (1H, s), 8.20 (2H, br s).
工程３：化合物Ｉ－５４の合成
　化合物５４ｄ（１００ｍｇ，０．２６ｍｍｏＬ），フェニルボロン酸（３８ｍｇ，０．３１ｍｍｏＬ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（１８ｍｇ，０．０２６ｍｍｏＬ）をエタノール（１．５ｍＬ）に溶解させ、２ｍｏＬ／Ｌ炭酸カリウム水溶液（０．２６ｍＬ，０．５２ｍｍｏＬ）を加えた。封管した後、１００℃に昇温して２時間撹拌した。室温まで放冷後、水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をアミノシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製した。得られた残渣に酢酸エチルを加え、ろ取することによって化合物Ｉ－５４（２１ｍｇ，２４％）を得た。1H-NMR (DMSO-D6)δ: 1.76-1.91 (2H, m), 3.31-3.37 (4H, m), 7.22 (1H, s), 7.39 (1H, t, J = 7.3 Hz), 7.45-7.52 (3H, m), 7.56 (1H, d, J = 7.8 Hz), 7.73 (2H, d, J = 7.4 Hz), 7.84 (1H, d, J = 7.7 Hz), 8.05 (1H, s), 8.30 (2H, br s). Step 3: Synthesis of Compound I-54 Compound 54d (100 mg, 0.26 mmol), phenylboronic acid (38 mg, 0.31 mmol), bis (triphenylphosphine) palladium (II) dichloride (18 mg, 0.026 mmol) were ethanol. (1.5 mL) was dissolved, and 2 moL / L potassium carbonate aqueous solution (0.26 mL, 0.52 mmol) was added. After sealing, the temperature was raised to 100 ° C. and stirred for 2 hours. After allowing to cool to room temperature, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by amino silica gel chromatography (hexane-ethyl acetate). Ethyl acetate was added to the obtained residue, and the mixture was collected by filtration to give compound I-54 (21 mg, 24%). 1 H-NMR (DMSO-D6) δ: 1.76-1.91 (2H, m), 3.31-3.37 (4H, m), 7.22 (1H, s), 7.39 (1H, t, J = 7.3 Hz), 7.45- 7.52 (3H, m), 7.56 (1H, d, J = 7.8 Hz), 7.73 (2H, d, J = 7.4 Hz), 7.84 (1H, d, J = 7.7 Hz), 8.05 (1H, s), 8.30 (2H, br s).
化合物Ｉ－５５の合成　
Figure JPOXMLDOC01-appb-C000111
工程１：化合物５５ｃの合成
　化合物５５ａ（３００ｍｇ、１．２２ｍｍｏｌ）、化合物５５ｂ（２１２ｍｇ、１．２２ｍｍｏｌ）のエタノール（４ｍＬ）溶液にジクロロビストリフェニルホスフィンパラジウム（８６ｍｇ、０．１２ｍｍｏｌ）、２ｍｏｌ／Ｌ炭酸カリウム水溶液（０．９ｍＬ、１．８ｍｍｏｌ）を加えた。１１０℃で４時間撹拌した後に、クロロホルムで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物５５ｃ（２９４ｍｇ、収率９７％）を得た。
1H-NMR (CDCl3)δ: 2.65 (s, 3H), 2.79 (t, J = 8.0Hz, 2H), 2.98 (t, J = 8.0Hz, 2H), 6.92 (s, 1H), 7.12-7.24 (m, 4H), 7.47 (t, J = 8.0Hz, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.86 (d, J = 8.0Hz, 1H), 8.13 (s, 1H). Synthesis of Compound I-55
Figure JPOXMLDOC01-appb-C000111
Step 1: Synthesis of Compound 55c Dichlorobistriphenylphosphine palladium (86 mg, 0.12 mmol), 2 mol / L carbonic acid in a solution of Compound 55a (300 mg, 1.22 mmol) and Compound 55b (212 mg, 1.22 mmol) in ethanol (4 mL) Aqueous potassium solution (0.9 mL, 1.8 mmol) was added. After stirring at 110 ° C. for 4 hours, the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 55c (294 mg, yield 97%).
1 H-NMR (CDCl3) δ: 2.65 (s, 3H), 2.79 (t, J = 8.0Hz, 2H), 2.98 (t, J = 8.0Hz, 2H), 6.92 (s, 1H), 7.12-7.24 (m, 4H), 7.47 (t, J = 8.0Hz, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.86 (d, J = 8.0Hz, 1H), 8.13 (s, 1H).
工程２：化合物Ｉ－５５の合成
　化合物５５ｃ（１７１ｍｇ、０．６９ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液を－７８℃に冷却し、２．０ｍｏｌ／ＬＬＤＡ（０．３８ｍＬ、０．７６ｍｍｏｌ）を滴下した。３０分後に塩化トリメチルシラン（０．１１ｍＬ、０．９０ｍｍｏｌ）を加えた。３０分撹拌した後に、ＮＢＳ（１２３ｍｇ、０．７０ｍｍｏｌ）と炭酸水素ナトリウム（１１６ｍｇ、１．３８ｍｍｏｌ）を同時に加えた。室温に昇温して１時間撹拌した後に、塩化アンモニウム水溶液を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Step 2: Synthesis of Compound I-55 A solution of compound 55c (171 mg, 0.69 mmol) in tetrahydrofuran (1 mL) was cooled to −78 ° C., and 2.0 mol / LLDA (0.38 mL, 0.76 mmol) was added dropwise. After 30 minutes, trimethylsilane chloride (0.11 mL, 0.90 mmol) was added. After stirring for 30 minutes, NBS (123 mg, 0.70 mmol) and sodium bicarbonate (116 mg, 1.38 mmol) were added simultaneously. After warming to room temperature and stirring for 1 hour, an aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をエタノール（３ｍＬ）に溶解し、化合物５５ｄ（８７ｍｇ、０．５５ｍｍｏｌ）を加えた。室温で２時間撹拌した後に、重曹水を加えて中和した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣を逆相ＨＰＬＣ（１０ｍＭ炭酸アンモニウム含有水－アセトニトリル）により精製し、化合物Ｉ－５５（５４ｍｇ、収率２０％）を得た。1H-NMR (DMSO-D6)δ: 1.84 (m, 2H), 2.75 (t, J = 8.0Hz, 2H), 2.92 (t, J = 8.0Hz, 2H), 3.34 (m, 4H), 7.06 (s, 1H), 7.12-7.24 (m, 5H), 7.41 (t, J = 7.6Hz, 1H), 7.51 (d, J = 7.6Hz, 1H), 7.77 (d, J = 7.6Hz, 1H), 8.01 (s, 1H), 8.31 (s, 2H). The resulting residue was dissolved in ethanol (3 mL) and compound 55d (87 mg, 0.55 mmol) was added. After stirring at room temperature for 2 hours, sodium bicarbonate water was added for neutralization. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC (10 mM ammonium carbonate-containing water-acetonitrile) to obtain Compound I-55 (54 mg, yield 20%). . 1 H-NMR (DMSO-D6) δ: 1.84 (m, 2H), 2.75 (t, J = 8.0Hz, 2H), 2.92 (t, J = 8.0Hz, 2H), 3.34 (m, 4H), 7.06 (s, 1H), 7.12-7.24 (m, 5H), 7.41 (t, J = 7.6Hz, 1H), 7.51 (d, J = 7.6Hz, 1H), 7.77 (d, J = 7.6Hz, 1H) , 8.01 (s, 1H), 8.31 (s, 2H).
化合物Ｉ－５６の合成　
Figure JPOXMLDOC01-appb-C000112
工程１：化合物５６ｂの合成
　化合物５６ａ（１ｇ、８．２９ｍｍｏｌ）のジクロロメタン（７ｍＬ）溶液を氷冷し、臭素（０．４３ｍＬ、８．２９ｍｍｏｌ）を滴下した。室温にて昇温して１時間撹拌した後、水を加えた。酢酸エチルで抽出し、有機層を重曹水、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。 Synthesis of Compound I-56
Figure JPOXMLDOC01-appb-C000112
Step 1: Synthesis of Compound 56b A solution of compound 56a (1 g, 8.29 mmol) in dichloromethane (7 mL) was ice-cooled, and bromine (0.43 mL, 8.29 mmol) was added dropwise. After raising the temperature at room temperature and stirring for 1 hour, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をＤＭＦ（７ｍＬ）に溶解し、炭酸カリウム（３．４４ｇ、２４．９ｍｍｏｌ）と４－クロロフェノール（１．０７ｇ、８．２９ｍｍｏｌ）を加えた。６０℃で３時間撹拌し、その後９０℃に昇温して３時間撹拌した。水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物５６ｂ（８９７ｍｇ、収率５１％）を得た。1H-NMR (CDCl3)δ: 1.26-1.32 (m, 2H), 1.60-1.66 (m, 2H), 2.24 (s, 3H), 6.84 (d, J = 8.8Hz, 2H), 7.25 (d, J = 8.8Hz, 2H). The obtained residue was dissolved in DMF (7 mL), and potassium carbonate (3.44 g, 24.9 mmol) and 4-chlorophenol (1.07 g, 8.29 mmol) were added. The mixture was stirred at 60 ° C. for 3 hours, then heated to 90 ° C. and stirred for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 56b (897 mg, 51% yield). 1 H-NMR (CDCl3) δ: 1.26-1.32 (m, 2H), 1.60-1.66 (m, 2H), 2.24 (s, 3H), 6.84 (d, J = 8.8Hz, 2H), 7.25 (d, J = 8.8Hz, 2H).
工程２：化合物５６ｃの合成
　化合物５６ｂ（１１０ｍｇ、０．５２ｍｍｏｌ）のエタノール（１ｍＬ）溶液を氷冷し、臭素（０．０２７ｍＬ、０．５２ｍｍｏｌ）のエタノール（１ｍＬ）溶液を滴下した。室温で１時間撹拌した後に、水を加えた。酢酸エチルで抽出し、有機層を重曹水、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去することで、化合物５６ｃ（１４０ｍｇ）を得た。得られた化合物５６ｃは精製せず、そのまま次工程に用いた。1H-NMR (CDCl3)δ: 1.38-1.43 (m, 2H), 1.71-1.77 (m, 2H), 4.18 (s, 2H), 6.85 (m, 2H), 7.27 (m, 2H). Step 2: Synthesis of Compound 56c A solution of compound 56b (110 mg, 0.52 mmol) in ethanol (1 mL) was ice-cooled, and a solution of bromine (0.027 mL, 0.52 mmol) in ethanol (1 mL) was added dropwise. After stirring at room temperature for 1 hour, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate, water and saturated brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, Compound 56c (140 mg) was obtained. The obtained compound 56c was used in the next step without purification. 1 H-NMR (CDCl3) δ: 1.38-1.43 (m, 2H), 1.71-1.77 (m, 2H), 4.18 (s, 2H), 6.85 (m, 2H), 7.27 (m, 2H).
工程３：化合物Ｉ－５６の合成
　化合物５６ｃ（１４０ｍｇ、０．４８ｍｍｏｌ）のエタノール（１．５ｍＬ）溶液に化合物５６ｄ（７０ｍｇ、０．４４ｍｍｏｌ）を加えた。室温で６時間撹拌した後に、重曹水を加えて中和した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－５６（１１０ｍｇ、収率６１％）を得た。1H-NMR (DMSO-D6)δ: 1.17-1.23 (m, 2H), 1.39-1.45 (m, 2H), 1.77 (m, 2H), 3.23 (m, 4H), 6.15 (s, 1H), 6.97 (d, J = 8.8Hz, 2H), 7.30 (d, J = 8.8z, 2H), 8.03 (s, 2H). Step 3: Synthesis of Compound I-56 Compound 56d (70 mg, 0.44 mmol) was added to a solution of compound 56c (140 mg, 0.48 mmol) in ethanol (1.5 mL). After stirring at room temperature for 6 hours, sodium bicarbonate water was added for neutralization. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-56 (110 mg, yield 61%). 1 H-NMR (DMSO-D6) δ: 1.17-1.23 (m, 2H), 1.39-1.45 (m, 2H), 1.77 (m, 2H), 3.23 (m, 4H), 6.15 (s, 1H), 6.97 (d, J = 8.8Hz, 2H), 7.30 (d, J = 8.8z, 2H), 8.03 (s, 2H).
化合物Ｉ－５７の合成　
Figure JPOXMLDOC01-appb-C000113
工程１：化合物５７ｂの合成
　化合物５７ａ（４．５ｇ、８．２２．８ｍｍｏｌ）のＤＭＦ（４０ｍＬ）溶液に、４－クロロフェノール（２．９４ｇ、２２．８ｍｍｏｌ）、炭酸カリウム（９．４７ｇ、６８．５ｍｍｏｌ）を順次加えた。８０℃で３時間撹拌した後、水を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して、化合物５７ｂ（３．８１ｇ、収率７８％）を得た。
1H-NMR (CDCl3)δ: 3.83 (s, 3H), 4.95 (m, 1H), 5.75 (m, 1H), 6.97 (d, J = 6.8Hz, 2H), 7.31 (d, J = 6.8Hz, 2H). Synthesis of Compound I-57
Figure JPOXMLDOC01-appb-C000113
Step 1: Synthesis of Compound 57b To a solution of Compound 57a (4.5 g, 8.22.8 mmol) in DMF (40 mL) was added 4-chlorophenol (2.94 g, 22.8 mmol), potassium carbonate (9.47 g, 68). .5 mmol) was added sequentially. After stirring at 80 ° C. for 3 hours, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 57b (3.81 g, yield 78%).
1 H-NMR (CDCl3) δ: 3.83 (s, 3H), 4.95 (m, 1H), 5.75 (m, 1H), 6.97 (d, J = 6.8Hz, 2H), 7.31 (d, J = 6.8Hz , 2H).
工程２：化合物Ｉ－５７の合成
　化合物５７ｂ（１ｇ、４．７ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液にクロロヨードメタン（１．７ｍＬ、２３．５ｍｍｏｌ）を加えて－７８℃に冷却した。０．５ｍｏｌ／ＬＬＤＡ（５６．４ｍＬ、２８．２ｍｍｏｌ）を３０分かけて滴下した後、さらに１時間撹拌した。酢酸（１．７ｍＬ、２９．７ｍｍｏｌ）を加え、室温に昇温した。室温で３０分撹拌した後、水を加えた。酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。 Step 2: Synthesis of Compound I-57 To a solution of Compound 57b (1 g, 4.7 mmol) in tetrahydrofuran (30 mL) was added chloroiodomethane (1.7 mL, 23.5 mmol) and cooled to -78 ° C. 0.5 mol / LLDA (56.4 mL, 28.2 mmol) was added dropwise over 30 minutes, and the mixture was further stirred for 1 hour. Acetic acid (1.7 mL, 29.7 mmol) was added and the temperature was raised to room temperature. After stirring at room temperature for 30 minutes, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
　得られた残渣をエタノール（２０ｍＬ）に溶解して化合物５７ｃ（７４４ｍｇ、４．７ｍｍｏｌ）を加えた。４５℃で２時間撹拌した後に、重曹水を加えた。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－５７（７９７ｍｇ、収率５０％）を得た。
1H-NMR (DMSO-D6)δ: 1.92 (m, 2H), 3.45 (m, 4H), 4.66 (s, 1H), 5.73 (s, 1H), 7.13 (d, J = 7.2 Hz, 2H), 7.33 (s, 1H), 7.46 (d, J = 7.1 Hz, 2H), 8.85 (s, 2H). The obtained residue was dissolved in ethanol (20 mL), and compound 57c (744 mg, 4.7 mmol) was added. After stirring at 45 ° C. for 2 hours, an aqueous sodium bicarbonate solution was added. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-57 (797 mg, yield 50%).
1 H-NMR (DMSO-D6) δ: 1.92 (m, 2H), 3.45 (m, 4H), 4.66 (s, 1H), 5.73 (s, 1H), 7.13 (d, J = 7.2 Hz, 2H) , 7.33 (s, 1H), 7.46 (d, J = 7.1 Hz, 2H), 8.85 (s, 2H).
化合物Ｉ－５８の合成　
Figure JPOXMLDOC01-appb-C000114
 工程１：化合物５８ｂの合成
　化合物５８ａ（５００ｍｇ、１．９３ｍｍｏＬ）のＤＭＦ（１０ｍＬ）溶液に、氷冷下で二硫化炭素（０．２９１ｍＬ，４．８２ｍｍｏＬ）と水素化ナトリウム（１９３ｍｇ，４．８２ｍｍｏＬ）を加え，氷冷下で10分間撹拌した。反応液に氷冷下でヨードメタン（０．６０ｍＬ、９．６４ｍｍｏｌ）を加え、氷冷下で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥して溶媒を減圧留去し、粗生成物として化合物５８ｂ（３５５ｍｇ）を得た。 Synthesis of Compound I-58
Figure JPOXMLDOC01-appb-C000114
 Step 1: Synthesis of Compound 58b To a solution of Compound 58a (500 mg, 1.93 mmol) in DMF (10 mL), carbon disulfide (0.291 mL, 4.82 mmol) and sodium hydride (193 mg, 4.82 mmol) under ice-cooling. ) And stirred for 10 minutes under ice cooling. To the reaction solution was added iodomethane (0.60 mL, 9.64 mmol) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 58b (355 mg) as a crude product.
工程２：化合物Ｉ－５８の合成
　粗生成物５８ｂ（１００ｍｇ、０．２８ｍｍｏｌ）のＤＭＦ（３０ｍＬ）溶液にシクロヘキサン－１，３－ジアミン（１５７ｍｇ、１．３８ｍｍｏｌ）を加え85℃で１２時間撹拌した。室温に放冷後，水を加え，酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物Ｉ－５８（４８ｍｇ、収率４６％）を得た。
ＬＣＭＳ（測定条件Ａ）：保持時間：１．６１分、［Ｍ＋Ｈ］＋：３８２ Step 2: Synthesis of Compound I-58 Cyclohexane-1,3-diamine (157 mg, 1.38 mmol) was added to a solution of the crude product 58b (100 mg, 0.28 mmol) in DMF (30 mL) and stirred at 85 ° C. for 12 hours. . After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. It dried with the anhydrous sodium sulfate and the solvent was depressurizingly distilled. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-58 (48 mg, yield 46%).
LCMS (measurement condition A): retention time: 1.61 minutes, [M + H] + : 382
化合物Ｉ－８２９の合成　
Figure JPOXMLDOC01-appb-C000115
工程１　化合物８２９ｂの合成
化合物８２９ａ（４.１８ｇ、３０．５ｍｍｏｌ）をテトラヒドロフラン（８５ｍＬ）に溶解させ、窒素気流下氷冷し、水素化ナトリウム（１．４２ｇ、３６．６ｍｍｏｌ）を加え室温にて１０分攪拌後、２，４－ジブロモチアゾールを加え室温にて一時間攪拌した。反応液を飽和塩化アンモニウム水溶液中に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８２９ｂ(８．３８ｇ、９２％)を得た。
1H-NMR (CDCl3) δ: 2.54 (s, 3H), 2.59 (s, 3H), 5.44 (s, 2H), 6.62 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H). Synthesis of Compound I-829
Figure JPOXMLDOC01-appb-C000115
Step 1 Synthesis of Compound 829b Compound 829a (4.18 g, 30.5 mmol) was dissolved in tetrahydrofuran (85 mL), ice-cooled under a nitrogen stream, and sodium hydride (1.42 g, 36.6 mmol) was added at room temperature. After stirring for 10 minutes, 2,4-dibromothiazole was added and stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 829b (8.38 g, 92%).
1H-NMR (CDCl3) δ: 2.54 (s, 3H), 2.59 (s, 3H), 5.44 (s, 2H), 6.62 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 7.59 ( d, J = 7.8 Hz, 1H).
工程２　化合物８２９ｃの合成
　化合物８２９ｂを用いて実施例２３の工程２および３と同じ方法で化合物８２９ｃ(７．１３ｇ、７５％)を得た。
1H-NMR (CDCl3) δ: 2.54 (s, 3H), 2.63 (s, 3H), 4.51 (s, 2H), 5.50 (s, 2H), 7.03 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H). Step 2 Synthesis of Compound 829c Compound 829c (7.13 g, 75%) was obtained in the same manner as in Steps 2 and 3 of Example 23 using Compound 829b.
1H-NMR (CDCl3) δ: 2.54 (s, 3H), 2.63 (s, 3H), 4.51 (s, 2H), 5.50 (s, 2H), 7.03 (d, J = 7.8 Hz, 1H), 7.63 ( d, J = 7.8 Hz, 1H), 7.72 (s, 1H).
工程３　化合物Ｉ－８２９の合成
　化合物８２９ｃを用いて実施例２３の工程４と同じ方法で化合物１－８２９(７．２７ｇ、８７％)を得た。
1H-NMR (DMSO-D6) δ: 1.79-1.84 (m, 2H), 2.43 (s, 3H), 3.32-3.40 (m, 4H), 5.50 (s, 2H), 6.87 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 8.22 (s, 2H). Step 3 Synthesis of Compound I-829 Compound 1-829 (7.27 g, 87%) was obtained in the same manner as in Step 4 of Example 23 using Compound 829c.
1H-NMR (DMSO-D6) δ: 1.79-1.84 (m, 2H), 2.43 (s, 3H), 3.32-3.40 (m, 4H), 5.50 (s, 2H), 6.87 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 8.22 (s, 2H).
化合物Ｉ－８３０の合成　
Figure JPOXMLDOC01-appb-C000116
化合物Ｉ－８３０の合成
化合物８３０ａ（１００ｍｇ、０．２３５ｍｍｏｌ）をＤＭＡ（３ｍＬ）に懸濁させ、３－ヒドロキシ－２－メチルピリジン（３８．５ｍｇ、０．３５３ｍｍｏｌ）、炭酸セシウム(２３０ｍｇ、０．７０６ｍｍｏｌ）を加え、１２０℃にて７時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物Ｉ－８３０(５５．３ｍｇ、６３％)を得た。
1H-NMR (DMSO-D6) δ: 1.79-1.84 (m, 2H), 2.44 (s, 3H), 3.32-3.35 (m, 4H), 6.75 (s, 1H), 7.39 (dd, J = 7.8, 4.0 Hz, 1H), 7.54 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 8.21 (s, 2H), 8.44 (d, J = 4.0 Hz, 1H). Synthesis of Compound I-830
Figure JPOXMLDOC01-appb-C000116
Synthesis of Compound I-830 Compound 830a (100 mg, 0.235 mmol) was suspended in DMA (3 mL), 3-hydroxy-2-methylpyridine (38.5 mg, 0.353 mmol), cesium carbonate (230 mg, 0.25 mmol). 706 mmol) was added and the mixture was stirred at 120 ° C. for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-830 (55.3 mg, 63%).
1H-NMR (DMSO-D6) δ: 1.79-1.84 (m, 2H), 2.44 (s, 3H), 3.32-3.35 (m, 4H), 6.75 (s, 1H), 7.39 (dd, J = 7.8, 4.0 Hz, 1H), 7.54 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 8.21 (s, 2H), 8.44 (d, J = 4.0 Hz, 1H).
化合物Ｉ－８３１の合成　
Figure JPOXMLDOC01-appb-C000117
化合物Ｉ－８３１の合成
化合物８３１ａ（１００ｍｇ、０．２３５ｍｍｏｌ）をＤＭＡ（３ｍＬ）に懸濁させ、１，２，３，４－テトラヒドロイソキノリン－７－カルボニトリル（５５．８ｍｇ、０．３５３ｍｍｏｌ）、炭酸セシウム(２３０ｍｇ、０．７０６ｍｍｏｌ）を加え、１２０℃にて１２時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物Ｉ－８３１(４．６ｍｇ、４．６％)を得た。
1H-NMR (DMSO-D6) δ: 1.79-1.84 (m, 2H), 3.05 (t, J = 5.8 Hz, 2H), 3.34-3.36 (m, 4H), 3.78 (t, J = 5.8 Hz, 2H), 4.70 (s, 2H), 6.83 (s, 1H), 7.22 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 7.8, 1.6 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 8.23 (s, 2H). Synthesis of Compound I-831
Figure JPOXMLDOC01-appb-C000117
Synthesis of Compound I-831 Compound 831a (100 mg, 0.235 mmol) was suspended in DMA (3 mL), 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (55.8 mg, 0.353 mmol), Cesium carbonate (230 mg, 0.706 mmol) was added and stirred at 120 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-831 (4.6 mg, 4.6%).
1H-NMR (DMSO-D6) δ: 1.79-1.84 (m, 2H), 3.05 (t, J = 5.8 Hz, 2H), 3.34-3.36 (m, 4H), 3.78 (t, J = 5.8 Hz, 2H ), 4.70 (s, 2H), 6.83 (s, 1H), 7.22 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 7.8, 1.6 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 8.23 (s, 2H).
化合物Ｉ－８３２の合成
Figure JPOXMLDOC01-appb-C000118
工程１　化合物８３２ｂの合成
化合物８３２ａ（３ｇ、１４．８５ｍｍｏｌ）に、ＤＭＦ（３０ｍＬ）、Ｎ，Ｏ－ジメチルヒドロキシアミン塩酸塩（１．５９ｇ、１６．３４ｍｍｏｌ）、ＨＡＴＵ（６．７８ｇ、１７．８２ｍｍｏｌ）、トリエチルアミン（５．１５ｍＬ、３７．１ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８３２ｂ(３．３５ｇ、９２％)を得た。
1H-NMR（CDCl3）δ：3.37 (s, 3H), 3.81 (s, 3H), 7.55-7.67 (m, 3H). Synthesis of Compound I-832
Figure JPOXMLDOC01-appb-C000118
Step 1 Synthesis of Compound 832b Compound 832a (3 g, 14.85 mmol) was added to DMF (30 mL), N, O-dimethylhydroxyamine hydrochloride (1.59 g, 16.34 mmol), HATU (6.78 g, 17.82 mmol). ), Triethylamine (5.15 mL, 37.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 832b (3.35 g, 92%).
1 H-NMR (CDCl 3 ) δ: 3.37 (s, 3H), 3.81 (s, 3H), 7.55-7.67 (m, 3H).
工程２　化合物８３２ｃの合成
　３－ブロモ－２－メチルピリジン（４９１ｍｇ、２．８６ｍｍｏｌ）をトルエン（５ｍＬ）に溶解して－７０℃に冷却し、１．６ｍｏｌ／Ｌのｎ－ブチルリチウム－ヘキサン溶液（１．５３ｍＬ、２．４５ｍｍｏｌ）を加えて２０分撹拌した。続いて化合物２（５００ｍｇ、２．０４ｍｍｏｌ）をトルエン（５ｍＬ）に溶解して滴下した、１時間撹拌した。反応液に塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８３２ｃ(３２８ｍｇ、５８％)を得た。
1H-NMR（CDCl3）δ: 2.60 (s, 3H), 7.24 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.84 (dd, 8.0, 1.2 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 8.64 (t, J = 4.8, 1.2 Hz, 1H). Step 2 Synthesis of Compound 832c 3-Bromo-2-methylpyridine (491 mg, 2.86 mmol) was dissolved in toluene (5 mL), cooled to −70 ° C., and 1.6 mol / L n-butyllithium-hexane solution. (1.53 mL, 2.45 mmol) was added and stirred for 20 minutes. Subsequently, Compound 2 (500 mg, 2.04 mmol) was dissolved in toluene (5 mL) and added dropwise, followed by stirring for 1 hour. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 832c (328 mg, 58%).
1 H-NMR (CDCl 3 ) δ: 2.60 (s, 3H), 7.24 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.84 ( dd, 8.0, 1.2 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 8.64 (t, J = 4.8, 1.2 Hz, 1H).
工程３　化合物Ｉ－８３２の合成
　化合物８３２ｃおよび化合物８ｄを用いて実施例８の工程３と同じ方法で化合物１－８３２(１２６ｍｇ、４４％)を得た。
1H-NMR (DMSO-D6) δ: 1.83 (m, 2H), 2.45 (s, 3H), 3.32 (m, 4H), 6.95 (s, 1H), 7.39 (dd, J = 7.6, 4.8 Hz, 1H), 7.95 (dd, J = 7.6, 2.0 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.18-8.25 (m, 3H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H). Step 3 Synthesis of Compound I-832 Compound 1-832 (126 mg, 44%) was obtained in the same manner as in Step 3 of Example 8 using Compound 832c and Compound 8d.
1 H-NMR (DMSO-D6) δ: 1.83 (m, 2H), 2.45 (s, 3H), 3.32 (m, 4H), 6.95 (s, 1H), 7.39 (dd, J = 7.6, 4.8 Hz, 1H), 7.95 (dd, J = 7.6, 2.0 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.18-8.25 (m, 3H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H).
化合物Ｉ－８３３の合成　
Figure JPOXMLDOC01-appb-C000119
工程１　化合物Ｉ－８３３の合成
化合物８３３ａ（３０ｍｇ、０．０７９ｍｍｏｌ）をテトラヒドロフラン（１ｍＬ）に懸濁して、ＴＦＡ（０．５ｍＬ）、亜鉛（２６ｍｇ、０．３９６ｍｍｏｌ）を加え、室温で３時間撹拌した。炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物１－８３３(２１ｍｇ、７１％)を得た。
1H- NMR (DMSO-D6) δ: 1.91 (m, 2H), 2.62 (s, 3H), 3.44 (m, 4H), 5.97 (d, J = 4.0 Hz, 1H), 6.27 (d, J = 4.0 Hz, 1H), 7.25 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.81-7.92 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.77 (s, 2H).
(m, 3H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H). Synthesis of Compound I-833
Figure JPOXMLDOC01-appb-C000119
Step 1 Synthesis of Compound I-833 Compound 833a (30 mg, 0.079 mmol) was suspended in tetrahydrofuran (1 mL), TFA (0.5 mL) and zinc (26 mg, 0.396 mmol) were added, and the mixture was stirred at room temperature for 3 hours. did. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 1-833 (21 mg, 71%).
1 H-NMR (DMSO-D6) δ: 1.91 (m, 2H), 2.62 (s, 3H), 3.44 (m, 4H), 5.97 (d, J = 4.0 Hz, 1H), 6.27 (d, J = 4.0 Hz, 1H), 7.25 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.81-7.92 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.77 (s, 2H).
(m, 3H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H).
化合物Ｉ－８３４の合成　
Figure JPOXMLDOC01-appb-C000120
工程１　化合物Ｉ－８３４の合成
３－ブロモ－２－メチルピリジン（４５ｍｇ、０．２６ｍｍｏｌ）、ビスピナコラートジボラン（７３ｍｇ、０．２８６ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）（１９ｍｇ、０．０２４ｍｍｏｌ）、酢酸カリウム（４７ｍｇ、０．４７７ｍｍｏｌ）、ジオキサン（１ｍＬ）を１３０℃で１時間撹拌した。室温まで放冷して、テトラヒドロフラン（１．５ｍＬ）、化合物８３４ａ（１００ｍｇ、０．２３９ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）（１９ｍｇ、０．０２４ｍｍｏｌ）、２ｍｏｌ／Ｌ炭酸カリウム水溶液（０．５ｍＬ、１．０ｍｍｏｌ）を加え、１３０℃で１時間撹拌した。水を加えてクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物１－８３４(２８ｍｇ、３４％)を得た。
1H-NMR (DMSO-D6) δ: 1.86 (s, 2H), 2.60 (s, 3H), 3.36 (m, 4H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.39 (s, 1H), 7.49 (m, 1H), 7.87 (dd, J = 8.0, 1.2 Hz, 1H), 7.92-7.99 (m, 2H), 8.31 (s, 2H), 8.52 (d, J = 4.0 Hz, 1H). Synthesis of Compound I-834
Figure JPOXMLDOC01-appb-C000120
Step 1 Synthesis of Compound I-834 3-Bromo-2-methylpyridine (45 mg, 0.26 mmol), bispinacolato diborane (73 mg, 0.286 mmol), PdCl 2 (dppf) (19 mg, 0.024 mmol), acetic acid Potassium (47 mg, 0.477 mmol) and dioxane (1 mL) were stirred at 130 ° C. for 1 hour. After cooling to room temperature, tetrahydrofuran (1.5 mL), compound 834a (100 mg, 0.239 mmol), PdCl 2 (dppf) (19 mg, 0.024 mmol), 2 mol / L potassium carbonate aqueous solution (0.5 mL, 1. 0 mmol) was added and the mixture was stirred at 130 ° C. for 1 hour. Water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 1-834 (28 mg, 34%).
1 H-NMR (DMSO-D6) δ: 1.86 (s, 2H), 2.60 (s, 3H), 3.36 (m, 4H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.39 (s, 1H), 7.49 (m, 1H), 7.87 (dd, J = 8.0, 1.2 Hz, 1H), 7.92-7.99 (m, 2H), 8.31 (s, 2H), 8.52 (d, J = 4.0 Hz, 1H ).
化合物Ｉ－８３５の合成
Figure JPOXMLDOC01-appb-C000121
工程１　化合物８３５ｃの合成
　化合物８３５ａ（５００ｍｇ、４．１３ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）溶液に、亜鉛（３５１ｍｇ、５．３７ｍｍｏｌ）を加えた。次いで化合物８３５ｂ（１ｇ、４．９５ｍｍｏｌ）を滴下した後に３時間加熱還流した。室温に放冷して酢酸エチルと塩化アンモニウム水溶液を加えた。不要物をセライトで除去し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物８３５ｃ（６５２．１ｍｇ、収率６４％）を得た。
1H-NMR (CDCl3) δ: 1.34 (3H, t, J = 7.2 Hz), 4.36 (2H, q, J = 7.2 Hz), 5.48 (1H, dd, J = 17.3, 5.2 Hz), 7.21 (1H, dd, J = 7.9, 4.9 Hz), 7.95 (1H, d, J = 7.9 Hz), 8.41 (1H, d, J = 4.5 Hz). Synthesis of Compound I-835
Figure JPOXMLDOC01-appb-C000121
Step 1 Synthesis of Compound 835c To a solution of Compound 835a (500 mg, 4.13 mmol) in tetrahydrofuran (10 mL) was added zinc (351 mg, 5.37 mmol). Next, Compound 835b (1 g, 4.95 mmol) was added dropwise, and the mixture was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature, and ethyl acetate and an aqueous ammonium chloride solution were added. Unnecessary substances were removed with celite, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 835c (652.1 mg, yield 64%). .
1H-NMR (CDCl3) δ: 1.34 (3H, t, J = 7.2 Hz), 4.36 (2H, q, J = 7.2 Hz), 5.48 (1H, dd, J = 17.3, 5.2 Hz), 7.21 (1H, dd, J = 7.9, 4.9 Hz), 7.95 (1H, d, J = 7.9 Hz), 8.41 (1H, d, J = 4.5 Hz).
工程２　化合物８３５ｅの合成
　化合物８３５ｃ（１００ｍｇ、０．４１ｍｍｏｌ）を１，２－ジクロロエタン（１ｍＬ）に溶解し、ＤＭＡＰ（５．０ｍｇ、０．０４１ｍｍｏｌ）、化合物８３５ｄ（１４５ｍｇ、０．８２ｍｍｏｌ）を加えた。室温で１時間撹拌した後に溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物８３５ｅ（１０８．０ｍｇ、収率７５％）を得た。
1H-NMR (CDCl3) δ: 1.29 (3H, t, J = 7.2 Hz), 2.80 (3H, s), 4.36 (2H, t, J = 7.8 Hz), 6.99 (1H, dd, J = 16.9, 5.3 Hz), 7.09 (1H, s), 7.21 (1H, dd, J = 7.6, 4.8 Hz), 7.64 (1H, s), 7.70 (1H, d, J = 7.8 Hz), 8.36 (1H, s), 8.57 (1H, d, J = 4.5 Hz). Step 2 Synthesis of Compound 835e Compound 835c (100 mg, 0.41 mmol) was dissolved in 1,2-dichloroethane (1 mL), and DMAP (5.0 mg, 0.041 mmol) and Compound 835d (145 mg, 0.82 mmol) were added. It was. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 835e (108.0 mg, 75% yield). .
1H-NMR (CDCl3) δ: 1.29 (3H, t, J = 7.2 Hz), 2.80 (3H, s), 4.36 (2H, t, J = 7.8 Hz), 6.99 (1H, dd, J = 16.9, 5.3 Hz), 7.09 (1H, s), 7.21 (1H, dd, J = 7.6, 4.8 Hz), 7.64 (1H, s), 7.70 (1H, d, J = 7.8 Hz), 8.36 (1H, s), 8.57 (1H, d, J = 4.5 Hz).
工程３　化合物８３５ｆの合成
　トリｎ－ブチルスズ（１７７ｍｇ、０．６０８ｍｍｏｌ）のトルエン溶液（２ｍＬ）を８０℃に加熱し、化合物８３５ｅ（１０８ｍｇ、０．３０４ｍｍｏｌ）のトルエン溶液（１ｍＬ）を滴下した後に３時間加熱還流した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物８３５ｆ（１５．８ｍｇ、収率２３％）を得た。
1H-NMR (CDCl3) δ: 1.30 (3H, t, J = 7.1 Hz), 2.60 (3H, s), 3.42 (2H, t, J = 16.8 Hz), 4.30 (2H, q, J = 7.2 Hz), 7.10-7.12 (1H, m), 7.53 (1H, d, J = 7.6 Hz), 8.45 (1H, d, J = 4.8 Hz). Step 3 Synthesis of Compound 835f A toluene solution (2 mL) of tri-n-butyltin (177 mg, 0.608 mmol) was heated to 80 ° C., and a toluene solution (1 mL) of Compound 835e (108 mg, 0.304 mmol) was added dropwise. Heated to reflux for hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 835f (15.8 mg, yield 23%).
1H-NMR (CDCl3) δ: 1.30 (3H, t, J = 7.1 Hz), 2.60 (3H, s), 3.42 (2H, t, J = 16.8 Hz), 4.30 (2H, q, J = 7.2 Hz) , 7.10-7.12 (1H, m), 7.53 (1H, d, J = 7.6 Hz), 8.45 (1H, d, J = 4.8 Hz).
工程４　化合物８３５ｇの合成
　化合物８３５ｆ（１５．８ｍｇ、０．０６９ｍｍｏｌ）を７ｍｏｌ／Ｌのアンモニア－メタノール溶液（２ｍＬ）に溶解した。室温で２時間撹拌した後に溶媒を減圧留去し、化合物８３５ｇ（１４．０ｍｇ）を粗生成物として得た。 Step 4 Synthesis of Compound 835g Compound 835f (15.8 mg, 0.069 mmol) was dissolved in a 7 mol / L ammonia-methanol solution (2 mL). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure to obtain 835 g (14.0 mg) of a compound as a crude product.
工程５　化合物８３５ｈの合成
　化合物８３５ｇ（１４．０ｍｇ）のトルエン（２ｍＬ）溶液にローソン試薬（３３．５ｍｇ、０．０８３ｍｍｏｌ）を加え、８０℃で終夜撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物８３５ｈ（９．９ｍｇ，収率６６％）を得た。
1H-NMR (CDCl3) δ: 2.63 (3H, s), 3.67 (2H, t, J = 16.6 Hz), 7.11 (1H, dd, J = 7.7, 4.7 Hz), 7.43 (2H, br), 7.61 (1H, d, J = 7.7 Hz), 8.46 (1H, d, J = 4.8 Hz). Step 5 Synthesis of Compound 835h Lawesson's reagent (33.5 mg, 0.083 mmol) was added to a solution of compound 835 g (14.0 mg) in toluene (2 mL), and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 835h (9.9 mg, 66% yield).
1H-NMR (CDCl3) δ: 2.63 (3H, s), 3.67 (2H, t, J = 16.6 Hz), 7.11 (1H, dd, J = 7.7, 4.7 Hz), 7.43 (2H, br), 7.61 ( 1H, d, J = 7.7 Hz), 8.46 (1H, d, J = 4.8 Hz).
工程６　化合物Ｉ－８３５の合成
　化合物８３５ｈ（９．９ｍｇ、０．０４６ｍｍｏｌ）と化合物８３５ｉ（１９．３ｍｇ、０．０５ｍｍｏｌ）をエタノール（０．２ｍＬ）に懸濁させた。５時間加熱還流した後に室温に放冷した。重曹水を加えてクロロホルムで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物Ｉ－８３５（６．１ｍｇ、収率３２％）を得た。
1H-NMR (CDCl3) δ: 2.00-2.03 (2H, m), 2.61 (3H, s), 3.46-3.49 (4H, m), 3.82 (2H, t, J = 16.3 Hz), 7.06 (1H, dd, J = 6.3, 3.1 Hz), 7.15 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 7.56 (1H, s), 8.42 (1H, dd, J = 4.8, 2.4 Hz). Step 6 Synthesis of Compound I-835 Compound 835h (9.9 mg, 0.046 mmol) and compound 835i (19.3 mg, 0.05 mmol) were suspended in ethanol (0.2 mL). The mixture was heated to reflux for 5 hours and then allowed to cool to room temperature. Sodium bicarbonate water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-835 (6.1 mg, yield 32%).
1H-NMR (CDCl3) δ: 2.00-2.03 (2H, m), 2.61 (3H, s), 3.46-3.49 (4H, m), 3.82 (2H, t, J = 16.3 Hz), 7.06 (1H, dd , J = 6.3, 3.1 Hz), 7.15 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 7.56 (1H, s), 8.42 (1H, dd, J = 4.8, 2.4 Hz).
化合物Ｉ－８３６の合成
Figure JPOXMLDOC01-appb-C000122
工程１　化合物８３６ｂの合成
　化合物８３６ａ（２００ｍｇ、１．６２ｍｍｏｌ）のＤＭＦ（３ｍＬ）溶液に、氷冷下、水素化ナトリウム（１９５ｍｇ、４．８７ｍｍｏｌ）を加えた。１０分撹拌した後、ブロモ酢酸エチル（３２５ｍｇ、１．９５ｍｍｏｌ）を滴下した。室温に昇温し、終夜撹拌した。水を加えて酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して、化合物８３６ｂ（１４５．５ｍｇ、収率４３％）を得た。
1H-NMR (CDCl3) δ: 1.30 (3H, t, J = 7.2 Hz), 2.58 (3H, s), 4.16 (2H, s), 4.25 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 7.14 (1H, dd, J = 7.5, 4.9 Hz), 7.68 (1H, dd, J = 7.8, 1.6 Hz), 8.44 (1H, dd, J = 4.9, 1.6 Hz). Synthesis of Compound I-836
Figure JPOXMLDOC01-appb-C000122
Step 1 Synthesis of Compound 836b To a solution of compound 836a (200 mg, 1.62 mmol) in DMF (3 mL) was added sodium hydride (195 mg, 4.87 mmol) under ice cooling. After stirring for 10 minutes, ethyl bromoacetate (325 mg, 1.95 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. Water was added and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 836b (145.5 mg, 43% yield).
1H-NMR (CDCl3) δ: 1.30 (3H, t, J = 7.2 Hz), 2.58 (3H, s), 4.16 (2H, s), 4.25 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 7.14 (1H, dd, J = 7.5, 4.9 Hz), 7.68 (1H, dd, J = 7.8, 1.6 Hz), 8.44 (1H, dd, J = 4.9, 1.6 Hz).
工程２　化合物８３６ｃの合成
　化合物８３６ｂを用いて、実施例５７の工程４と同様の方法で化合物３を粗生成物として得た。 Step 2 Synthesis of Compound 836c Compound 3 was obtained as a crude product in the same manner as in Step 4 of Example 57 using Compound 836b.
工程３　化合物８３６ｄの合成
　化合物８３６ｃ（１２６．０ｍｇ、０．６９５ｍｍｏｌ）のテトラヒドロフラン（４ｍＬ）溶液にローソン試薬（３０９ｍｇ、０．７６５ｍｍｏｌ）を加えた。室温で５時間撹拌した後に重曹水を加えて酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物８３６ｄ（５８．２ｍｇ，収率４３％）を得た。
1H-NMR (CDCl3) δ: 2.57 (3H, s), 4.40 (2H, s), 4.62 (2H, s), 7.16 (1H, dd, J = 7.7, 4.9 Hz), 7.58-7.60 (2H, m), 7.94 (1H, brs), 8.49 (1H, d, J = 3.4 Hz). Step 3 Synthesis of Compound 836d To a solution of Compound 836c (126.0 mg, 0.695 mmol) in tetrahydrofuran (4 mL) was added Lawesson's reagent (309 mg, 0.765 mmol). After stirring at room temperature for 5 hours, aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 836d (58.2 mg, 43% yield).
1H-NMR (CDCl3) δ: 2.57 (3H, s), 4.40 (2H, s), 4.62 (2H, s), 7.16 (1H, dd, J = 7.7, 4.9 Hz), 7.58-7.60 (2H, m ), 7.94 (1H, brs), 8.49 (1H, d, J = 3.4 Hz).
工程４　化合物Ｉ－８３６の合成
 化合物４を用いて、実施例５７の工程６と同様の方法で化合物Ｉ－８３６（２５．１ｍｇ、収率６２％）を得た。
1H-NMR (CDCl3) δ: 2.01-2.02 (2H, m), 2.57 (3H, s), 3.46-3.48 (4H, m), 4.69 (2H, s), 4.91 (2H, s), 7.05 (1H, s), 7.15 (1H, dd, J = 7.5, 4.9 Hz), 7.48 (1H, s), 7.69 (1H, dd, J = 7.7, 1.4 Hz), 8.45 (1H, dd, J = 5.0, 1.8 Hz). Step 4 Synthesis of Compound I-836 Compound I-836 (25.1 mg, yield 62%) was obtained using Compound 4 in the same manner as in Step 6 of Example 57.
1H-NMR (CDCl3) δ: 2.01-2.02 (2H, m), 2.57 (3H, s), 3.46-3.48 (4H, m), 4.69 (2H, s), 4.91 (2H, s), 7.05 (1H , s), 7.15 (1H, dd, J = 7.5, 4.9 Hz), 7.48 (1H, s), 7.69 (1H, dd, J = 7.7, 1.4 Hz), 8.45 (1H, dd, J = 5.0, 1.8 Hz).
化合物Ｉ－８３７の合成
Figure JPOXMLDOC01-appb-C000123
工程１　化合物８３７ｃの合成
化合物８３７ａおよび化合物８３７ｂを用いて、実施例５７の工程１と同様の方法で化合物８３７ｃ（８９２．３ｍｇ、収率７０％）を得た。
1H-NMR (CDCl3) δ: 1.46 (3H, t, J = 7.2 Hz), 2.00-2.01 (2H, m), 3.46-3.49 (4H, m), 4.50 (2H, q, J = 7.1 Hz), 7.26 (1H, s), 7.73 (1H, s). Synthesis of Compound I-837
Figure JPOXMLDOC01-appb-C000123
Step 1 Synthesis of Compound 837c Compound 837c (892.3 mg, yield 70%) was obtained in the same manner as in Step 1 of Example 57 using Compound 837a and Compound 837b.
1H-NMR (CDCl3) δ: 1.46 (3H, t, J = 7.2 Hz), 2.00-2.01 (2H, m), 3.46-3.49 (4H, m), 4.50 (2H, q, J = 7.1 Hz), 7.26 (1H, s), 7.73 (1H, s).
工程２　化合物８３７ｄの合成
　水素化アルミニウムリチウム（１２４ｍｇ、３．２６ｍｍｏｌ）をテトラヒドロフラン（１０ｍＬ）に懸濁した。氷冷下、化合物８３７ｃ（５００ｍｇ、１．４８ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液を滴下した。室温に昇温し、１時間撹拌した。氷冷下、硫酸ナトリウム十水和物（５ｇ）を加え、２０分撹拌した。不溶物をセライトで除去した後、無水硫酸マグネシウムで乾燥して溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物８３７ｄ（１６４．１ｍｇ、収率３８％）を得た。
1H-NMR (CDCl3) δ: 1.99-2.01 (2H, m), 3.45-3.47 (4H, m), 4.98 (2H, s), 7.04 (1H, s), 7.45 (1H, s). Step 2 Synthesis of Compound 837d Lithium aluminum hydride (124 mg, 3.26 mmol) was suspended in tetrahydrofuran (10 mL). A solution of compound 837c (500 mg, 1.48 mmol) in tetrahydrofuran (15 mL) was added dropwise under ice cooling. The mixture was warmed to room temperature and stirred for 1 hour. Under ice-cooling, sodium sulfate decahydrate (5 g) was added and stirred for 20 minutes. The insoluble material was removed with celite, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 837d (164.1 mg, yield). The rate was 38%).
1H-NMR (CDCl3) δ: 1.99-2.01 (2H, m), 3.45-3.47 (4H, m), 4.98 (2H, s), 7.04 (1H, s), 7.45 (1H, s).
工程３　化合物８３７ｅの合成
　化合物８３７ｄ（５０ｍｇ、０．１６９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下でトリエチルアミン（５１．４ｍｇ、０．５０８ｍｍｏｌ）とメタンスルホニルクロライド（２９．１ｍｇ、０．２５４ｍｍｏｌ）を加えた。室温で２時間撹拌した後に水を加えて酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去することで化合物８３７ｅ（３８ｍｇ）を得た。化合物８３７ｅは精製することなく次工程へ用いた。 Step 3 Synthesis of Compound 837e To a solution of Compound 837d (50 mg, 0.169 mmol) in DMF (2 mL) under ice-cooling, triethylamine (51.4 mg, 0.508 mmol) and methanesulfonyl chloride (29.1 mg, 0.254 mmol) Was added. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 837e (38 mg). Compound 837e was used in the next step without purification.
工程４　化合物Ｉ－８３７の合成
　化合物８３７ｅ（３８ｍｇ）のＤＭＦ（２ｍＬ）溶液に、炭酸カリウム（２３．３ｍｇ、０．１６８ｍｍｏｌ）と２－メチルピリジン－３－オール（１１．０ｍｇ、０．１０１ｍｍｏｌ）を加えた。１００℃で３時間加熱した後に室温に放冷した。重曹水を加えてクロロホルムで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物Ｉ－８３７（８．０ｍｇ、収率２５％）を得た。
1H-NMR (CDCl3) δ: 2.00-2.02 (2H, m), 2.58 (3H, s), 3.46-3.48 (4H, m), 5.41 (2H, s), 7.09-7.10 (2H, m), 7.19 (1H, d, J = 7.9 Hz), 7.50 (1H, s), 8.14 (1H, d, J = 4.9 Hz). Step 4 Synthesis of Compound I-837 To a solution of Compound 837e (38 mg) in DMF (2 mL) was added potassium carbonate (23.3 mg, 0.168 mmol) and 2-methylpyridin-3-ol (11.0 mg, 0.101 mmol). Was added. After heating at 100 ° C. for 3 hours, the mixture was allowed to cool to room temperature. Sodium bicarbonate water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-837 (8.0 mg, yield 25%).
1H-NMR (CDCl3) δ: 2.00-2.02 (2H, m), 2.58 (3H, s), 3.46-3.48 (4H, m), 5.41 (2H, s), 7.09-7.10 (2H, m), 7.19 (1H, d, J = 7.9 Hz), 7.50 (1H, s), 8.14 (1H, d, J = 4.9 Hz).
化合物Ｉ－８３８の合成
Figure JPOXMLDOC01-appb-C000124
工程１　化合物８３８ｃの合成
化合物８３８ａおよび化合物８３８ｂを用いて、実施例５７の工程６と同様の方法で化合物８３８ｃ（８９２．３ｍｇ、収率７０％）を得た。
1H-NMR (CDCl3) δ: 1.46 (3H, t, J = 7.2 Hz), 2.00-2.01 (2H, m), 3.46-3.49 (4H, m), 4.50 (2H, q, J = 7.1 Hz), 7.26 (1H, s), 7.73 (1H, s). Synthesis of Compound I-838
Figure JPOXMLDOC01-appb-C000124
Step 1 Synthesis of Compound 838c Compound 838c (892.3 mg, yield 70%) was obtained in the same manner as in Step 6 of Example 57 using Compound 838a and Compound 838b.
1H-NMR (CDCl3) δ: 1.46 (3H, t, J = 7.2 Hz), 2.00-2.01 (2H, m), 3.46-3.49 (4H, m), 4.50 (2H, q, J = 7.1 Hz), 7.26 (1H, s), 7.73 (1H, s).
工程２　化合物８３８ｄの合成
　化合物８３８ｃ（１００ｍｇ、０．２９６ｍｍｏｌ）をテトラヒドロフラン（３ｍＬ）、エタノール（３ｍL）に溶解した後、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（５ｍＬ，１０．０ｍｍｏｌ）を加えた。室温で３時間撹拌した後、有機溶媒を減圧留去した。残渣に２ｍｏｌ／Ｌ塩酸を加え、ｐＨ＝２とした。得られた固体をろ取し、冷水で洗浄後、減圧乾燥し、化合物８３８ｄ（８０ｍｇ、収率８７％）を得た。
1H-NMR (DMSO-D6) δ: 1.92-1.95 (2H, m), 3.45-3.48 (4H, m), 7.62 (1H, s), 8.68 (1H, s), 8.89 (2H, s). Step 2 Synthesis of Compound 838d Compound 838c (100 mg, 0.296 mmol) was dissolved in tetrahydrofuran (3 mL) and ethanol (3 mL), and then a 2 mol / L aqueous sodium hydroxide solution (5 mL, 10.0 mmol) was added. After stirring at room temperature for 3 hours, the organic solvent was distilled off under reduced pressure. 2 mol / L hydrochloric acid was added to the residue to adjust to pH = 2. The obtained solid was collected by filtration, washed with cold water, and dried under reduced pressure to obtain Compound 838d (80 mg, yield 87%).
1H-NMR (DMSO-D6) δ: 1.92-1.95 (2H, m), 3.45-3.48 (4H, m), 7.62 (1H, s), 8.68 (1H, s), 8.89 (2H, s).
工程３　化合物Ｉ－８３８の合成
　化合物８３８ｄ（８．３ｍｇ、０．０２７ｍｍｏｌ）のＤＭＦ（１ｍＬ）溶液に、トリエチルアミン（２．７ｍｇ、０．０２７ｍｍｏｌ）とＨＡＴＵ（１０．２ｍｇ，０．０２７ｍｍｏｌ）を加えた。室温で２時間撹拌した後に水を加えてクロロホルムで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－８３８（７．７ｍｇ、収率６７％）を得た。
ＬＣＭＳ (測定条件Ａ); 保持時間：０．８０ 分、 ［Ｍ＋Ｈ］＋：４２８ Step 3 Synthesis of Compound I-838 To a solution of Compound 838d (8.3 mg, 0.027 mmol) in DMF (1 mL) was added triethylamine (2.7 mg, 0.027 mmol) and HATU (10.2 mg, 0.027 mmol). It was. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-838 (7.7 mg, 67% yield).
LCMS (measurement condition A); retention time: 0.80 min, [M + H] +: 428
化合物Ｉ－８３９の合成
Figure JPOXMLDOC01-appb-C000125
工程１　化合物８３９ｂの合成
　化合物８３９ａ（１ｇ、８．１２ｍｍｏｌ）のテトラヒドロフラン（２５ｍＬ）溶液に、氷冷下でトリエチルアミン（２．４７ｇ、２４．４ｍｍｏｌ）とメタンスルホニルクロライド（１．４０ｍｇ、１２．２ｍｍｏｌ）を加えた。室温で１時間撹拌した後に水を加えて酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去することで化合物８３９ｂ（１．６ｇ）を得た。化合物８３９ｂは精製することなく次工程へ用いた。 Synthesis of Compound I-839
Figure JPOXMLDOC01-appb-C000125
Step 1 Synthesis of Compound 839b To a solution of Compound 839a (1 g, 8.12 mmol) in tetrahydrofuran (25 mL) was added triethylamine (2.47 g, 24.4 mmol) and methanesulfonyl chloride (1.40 mg, 12.2 mmol) under ice cooling. Was added. After stirring at room temperature for 1 hour, water was added and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 839b (1.6 g). Compound 839b was used in the next step without purification.
工程２　化合物８３９ｃの合成
　化合物８３９ｂ（１．６ｇ）のエタノール（１０ｍＬ）溶液に、メチルアミン（３３％エタノール溶液、１０ｍＬ）を加え、室温で終夜撹拌した。溶媒を減圧留去して得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製することで、化合物８３９ｃ（７３５．８ｍｇ、収率６７％）を得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 2.57 (3H, s), 3.74 (2H, s), 7.10-7.11 (1H, m), 7.60 (1H, d, J = 7.6 Hz), 8.39 (1H, d, J = 4.8 Hz). Step 2 Synthesis of Compound 839c To a solution of Compound 839b (1.6 g) in ethanol (10 mL) was added methylamine (33% ethanol solution, 10 mL), and the mixture was stirred overnight at room temperature. The residue obtained by evaporating the solvent under reduced pressure was purified by amino silica gel column chromatography (chloroform-methanol) to obtain Compound 839c (735.8 mg, yield 67%).
1H-NMR (CDCl3) δ: 2.50 (3H, s), 2.57 (3H, s), 3.74 (2H, s), 7.10-7.11 (1H, m), 7.60 (1H, d, J = 7.6 Hz), 8.39 (1H, d, J = 4.8 Hz).
工程３　化合物８３９ｄの合成
　化合物８３９ｃ（１００ｍｇ、０．７３４ｍｍｏｌ）のＤＭＦ（５ｍＬ）溶液に、トリエチルアミン（２６０ｍｇ、２．５７ｍｍｏｌ）とブロモアセトアミド（１１１ｍｇ、０．８０８ｍｍｏｌ）を加えた。室温で２時間撹拌した後に溶媒を減圧留去し、得られた残渣を酢酸エチル（３ｍＬ）に懸濁した。不要物をろ去し、ろ液を減圧濃縮することで化合物８３９ｄ（９８．１ｍｇ）を得た。化合物８３９ｄは精製することなく次工程へ用いた。 Step 3 Synthesis of Compound 839d To a solution of Compound 839c (100 mg, 0.734 mmol) in DMF (5 mL) was added triethylamine (260 mg, 2.57 mmol) and bromoacetamide (111 mg, 0.808 mmol). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was suspended in ethyl acetate (3 mL). Unnecessary substances were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Compound 839d (98.1 mg). Compound 839d was used in the next step without purification.
工程４　化合物８３９ｅの合成
化合物８３９ｄおよび化合物８３９ｆを用いて、実施例５８の工程３と同様の方法で化合物８３９ｅ（１９ｍｇ、収率１８％）を得た。
1H-NMR (CDCl3) δ: 2.31 (3H, s), 2.60 (3H, s), 3.50 (2H, s), 3.60 (2H, s), 7.13 (1H, dd, J = 7.4, 4.5 Hz), 7.53 (1H, d, J = 7.5 Hz), 7.63 (1H, brs), 7.83 (1H, brs), 8.44-8.46 (2H, m). Step 4 Synthesis of Compound 839e Compound 839e (19 mg, 18% yield) was obtained in the same manner as in Step 3 of Example 58, using Compound 839d and Compound 839f.
1H-NMR (CDCl3) δ: 2.31 (3H, s), 2.60 (3H, s), 3.50 (2H, s), 3.60 (2H, s), 7.13 (1H, dd, J = 7.4, 4.5 Hz), 7.53 (1H, d, J = 7.5 Hz), 7.63 (1H, brs), 7.83 (1H, brs), 8.44-8.46 (2H, m).
工程５　化合物Ｉ－８３９の合成
化合物８３９ｅおよび化合物８３９ｆを用いて、実施例５７の工程６と同様の方法で化合物Ｉ－８３９（１２．２ｍｇ、収率３３％）を得た。
1H-NMR (CDCl3) δ: 1.99-2.01 (2H, m), 2.35 (3H, s), 2.62 (3H, s), 3.44-3.47 (4H, m), 3.66 (2H, s), 3.93 (2H, s), 7.04 (1H, s), 7.12 (1H, dd, J = 7.3, 5.1 Hz), 7.42 (1H, s), 7.69 (1H, d, J = 7.6 Hz), 8.41 (1H, d, J = 4.5 Hz). Step 5 Synthesis of Compound I-839 Compound I-839 (12.2 mg, 33% yield) was obtained in the same manner as in Step 6 of Example 57 using Compound 839e and Compound 839f.
1H-NMR (CDCl3) δ: 1.99-2.01 (2H, m), 2.35 (3H, s), 2.62 (3H, s), 3.44-3.47 (4H, m), 3.66 (2H, s), 3.93 (2H , s), 7.04 (1H, s), 7.12 (1H, dd, J = 7.3, 5.1 Hz), 7.42 (1H, s), 7.69 (1H, d, J = 7.6 Hz), 8.41 (1H, d, J = 4.5 Hz).
化合物Ｉ－８４０の合成
Figure JPOXMLDOC01-appb-C000126
工程１　化合物８４０ｂの合成
化合物８４０ａ（１８ｇ、１１４ｍｍｏｌ）に、ジメチルアセタミド（１８０ｍＬ）、フェノール（１２．９ｇ、１３７ｍｍｏｌ）、炭酸カリウム(３１．６ｇ、２２８ｍｍｏｌ）およびヨウ化銅（Ｉ）（１．７４ｇ、９．１４ｍｍｏｌ）を加え、１７０度で３時間加熱撹拌した。室温に冷却後、反応液に水（９０ｍｌ）、４ｍｏｌ／Ｌ塩酸水溶液（９０ｍｌ）を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４０ｂ(１７ｇ、６９％)を得た。
1H-NMR (CDCl3) δ: 7.15-7.22 (m, 3H), 7.31 (t, J = 7.3 Hz, 1H), 7.44-7.50 (m, 2H), 8.32 (dd, J = 4.8, 1.9 Hz, 1H), 8.53 (d, J = 7.5 Hz, 1H). Synthesis of Compound I-840
Figure JPOXMLDOC01-appb-C000126
Step 1 Synthesis of Compound 840b Compound 840a (18 g, 114 mmol) was added to dimethylacetamide (180 mL), phenol (12.9 g, 137 mmol), potassium carbonate (31.6 g, 228 mmol) and copper (I) iodide (1 .74 g, 9.14 mmol) was added, and the mixture was heated and stirred at 170 degrees for 3 hours. After cooling to room temperature, water (90 ml) and 4 mol / L hydrochloric acid aqueous solution (90 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 840b (17 g, 69%).
1H-NMR (CDCl3) δ: 7.15-7.22 (m, 3H), 7.31 (t, J = 7.3 Hz, 1H), 7.44-7.50 (m, 2H), 8.32 (dd, J = 4.8, 1.9 Hz, 1H ), 8.53 (d, J = 7.5 Hz, 1H).
工程２　化合物８４０ｃの合成
　化合物８４０ｂ（２７ｇ、１２５ｍｍｏｌ）に、塩化チオニル（２９．８ｇ、２５１ｍｍｏｌ）およびＮ、Ｎ－ジメチルホルムアミド（０．５ｍｌ）を加え９０度で２時間撹拌した。室温に放冷後、溶媒を減圧留去した。得られた残渣をテトラヒドロフラン（２００ｍｌ）に溶解させ、氷冷下で２ｍｏｌ／Ｌトリメチルシリルジアゾメタンのヘキサン溶液（１３８ｍｌ、２７６ｍｍｏｌ）を滴下し、０度で５０分撹拌した。４７％臭化水素水溶液（３６．２ｍｌ）を０度で滴下し、０度でさらに５０分撹拌した。水（３００ｍｌ）を加えた後、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液によってｐＨを７に調整した。酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をエタノール（２００ｍｌ）に溶解させ、チオウレア（９．５５ｇ、１２５ｍｍｏｌ）加え、室温で３時間撹拌した。重曹水を加えてクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物８４０ｃ(１９．３ｇ、５７％)を得た。
1H-NMR (CDCl3) δ: 4.95 (s, 2H), 7.07 (dd, J = 7.5, 4.9 Hz, 1H), 7.16-7.23 (m, 3H), 7.39-45 (m, 3H), 8.04 (dd, J = 4.7, 1.7 Hz, 1H), 8.49 (dd, J = 7.6, 1.6 Hz, 1H). Step 2 Synthesis of Compound 840c To Compound 840b (27 g, 125 mmol) was added thionyl chloride (29.8 g, 251 mmol) and N, N-dimethylformamide (0.5 ml), and the mixture was stirred at 90 degrees for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (200 ml), and a 2 mol / L trimethylsilyldiazomethane hexane solution (138 ml, 276 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 50 minutes. A 47% aqueous solution of hydrogen bromide (36.2 ml) was added dropwise at 0 degree, and the mixture was further stirred at 0 degree for 50 minutes. After adding water (300 ml), the pH was adjusted to 7 with a 2 mol / L aqueous sodium hydroxide solution. Extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (200 ml), thiourea (9.55 g, 125 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Sodium bicarbonate water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 840c (19.3 g, 57%).
1H-NMR (CDCl3) δ: 4.95 (s, 2H), 7.07 (dd, J = 7.5, 4.9 Hz, 1H), 7.16-7.23 (m, 3H), 7.39-45 (m, 3H), 8.04 (dd , J = 4.7, 1.7 Hz, 1H), 8.49 (dd, J = 7.6, 1.6 Hz, 1H).
工程３　化合物８４０ｄの合成
　化合物８４０ｃ（５００ｍｇ、１．８６ｍｍｏｌ）をＮ、Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶解させ、窒素雰囲気下、二硫化炭素（０．２８ｍｌ、４．６５ｍｍｏｌ）および水素化ナトリウム（１９０ｍｇ、４．６５ｍｍｏｌ）を０度で加え、０度で２０分間撹拌した。ヨウ化メチル（０．５８ｍｌ、９．３ｍｍｏｌ）を０度で加え、さらに０度で１時間撹拌した。水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４０ｄ(３００ｍｇ、４３％)を得た。
1H NMR (DMSO-d6): δ2.63 (s, 6H), 7.21－7.28 (m, 4H), 7.45(t, 2 H, J=7.8 Hz), 8.06－8.08(m, 2H), 8.53－8.55(m, 1H). Step 3 Synthesis of Compound 840d Compound 840c (500 mg, 1.86 mmol) was dissolved in N, N-dimethylformamide (10 ml), and under a nitrogen atmosphere, carbon disulfide (0.28 ml, 4.65 mmol) and sodium hydride ( 190 mg, 4.65 mmol) was added at 0 degrees and stirred at 0 degrees for 20 minutes. Methyl iodide (0.58 ml, 9.3 mmol) was added at 0 degree, and the mixture was further stirred at 0 degree for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 840d (300 mg, 43%).
1H NMR (DMSO-d6): δ2.63 (s, 6H), 7.21-7.28 (m, 4H), 7.45 (t, 2 H, J = 7.8 Hz), 8.06-8.08 (m, 2H), 8.53- 8.55 (m, 1H).
工程４　化合物Ｉ－８４０の合成
化合物８４０ｄ（１０１ｍｇ、０．２７ｍｍｏｌ）をＮ、Ｎ－ジメチルアセトアミド（１ｍｌ）に溶解させ、１－（アミノメチル）シクロブタンアミン二塩酸塩（２３０ｍｇ、１．３３ｍｍｏｌ）およびトリエチルアミン（０．７５ｍｌ、５．４２ｍｍｏｌ）を加え１００度で６時間撹拌した。室温に放冷後、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物Ｉ－８４０(７４ｍｇ、７３％)を得た。
1H-NMR (DMSO-D6) δ: 1.62-1.68 (m, 2H), 2.07-2.16 (m, 2H), 2.20-2.31 (m, 2H), 3.68 (s, 2H), 7.24-7.45 (m, 4H), 7.39-7.46 (m, 3H), 7.82 (s, 1H), 7.93 (s, 1H), 8.00-8.04 (m, 1H), 8.61 (d, J = 7.5 Hz, 1H). Step 4 Synthesis of Compound I-840 Compound 840d (101 mg, 0.27 mmol) was dissolved in N, N-dimethylacetamide (1 ml) and 1- (aminomethyl) cyclobutanamine dihydrochloride (230 mg, 1.33 mmol) and Triethylamine (0.75 ml, 5.42 mmol) was added and stirred at 100 degrees for 6 hours. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-840 (74 mg, 73%).
1H-NMR (DMSO-D6) δ: 1.62-1.68 (m, 2H), 2.07-2.16 (m, 2H), 2.20-2.31 (m, 2H), 3.68 (s, 2H), 7.24-7.45 (m, 4H), 7.39-7.46 (m, 3H), 7.82 (s, 1H), 7.93 (s, 1H), 8.00-8.04 (m, 1H), 8.61 (d, J = 7.5 Hz, 1H).
化合物Ｉ－８４１の合成
Figure JPOXMLDOC01-appb-C000127
工程１：　
　化合物８４１ａ（１ｇ、２．３５ｍｍｏｌ）にテトラヒドロフラン（１０ｍＬ）、Ｂｏｃ２Ｏ（２．０５ｇ、９．４１ｍｍｏｌ）、トリエチルアミン（９５２ｍｇ、９．４１ｍｍｏｌ）およびＤＭＡＰ（２８７ｍｇ、２．３５ｍｍｏｌ）を加え、室温で終夜撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４１ｂ(１１９３ｍｇ、９３％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：２．７９ 分、 ［Ｍ＋Ｈ］＋：５４４ Synthesis of Compound I-841
Figure JPOXMLDOC01-appb-C000127
Step 1:
To compound 841a (1 g, 2.35 mmol) was added tetrahydrofuran (10 mL), Boc 2 O (2.05 g, 9.41 mmol), triethylamine (952 mg, 9.41 mmol) and DMAP (287 mg, 2.35 mmol) at room temperature. Stir overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 841b (1193 mg, 93%). LCMS (measurement conditions A); retention time: 2.79 minutes, [M + H] +: 544
工程２：　
　化合物８４１ｂ（３２７ｍｇ、０．６ｍｍｏｌ）をテトラヒドロフラン（１０ｍＬ）に溶解させ、イソプロピルマグネシウムクロリド－塩化リチウム錯体のテトラヒドロフラン溶液（０．６９ｍｌ、０．９ｍｍｏｌ）を－３０度で加え、－３０度で１時間撹拌した。２－メチル－３－ホルミルピリジン（１６０ｍｇ、１．３２ｍｍｏｌ）を－３０度で加え、室温まで昇温し、１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４１ｃ(９５ｍｇ、２７％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：１．７１ 分、 ［Ｍ＋Ｈ］＋：５８７ Step 2:
Compound 841b (327 mg, 0.6 mmol) was dissolved in tetrahydrofuran (10 mL), a solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (0.69 ml, 0.9 mmol) was added at −30 degrees, and −30 degrees for 1 hour. Stir. 2-Methyl-3-formylpyridine (160 mg, 1.32 mmol) was added at −30 degrees, and the mixture was warmed to room temperature and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 841c (95 mg, 27%). LCMS (measurement conditions A); retention time: 1.71 minutes, [M + H] +: 587
工程３：　
　化合物８４１ｃ（９０ｍｇ、０．１５ｍｍｏｌ）をトリフルオロ酢酸（５ｍＬ）に溶解させ、室温で２時間撹拌した。溶媒を減圧留去し、重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物８４１ｄ(４８ｍｇ、８１％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：０．６５ 分、 ［Ｍ＋Ｈ］＋：３８７ Step 3:
Compound 841c (90 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 841d (48 mg, 81%). LCMS (measurement conditions A); retention time: 0.65 minutes, [M + H] +: 387
工程４：　
化合物８４１ｄ（３６ｍｇ、０．０９３ｍｍｏｌ）をテトラヒドロフラン（５ｍＬ）に溶解させ、二酸化マンガン（８１ｍｇ、０．９３ｍｍｏｌ）を加え、６５度で６時間撹拌した。不溶物をセライトろ過によって除去し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物Ｉ－８４１(１２ｍｇ、３４％)を得た。
1H-NMR (DMSO-D6) δ: 1.76-1.78 (m, 2H), 2.58 (s, 3H), 3.28-3.35 (m, 4H), 6.95 (s, 1H), 7.44 (dd, J = 7.7, 4.9 Hz, 1H), 8.23 (s, 2H), 8.31-8.36 (m, 1H), 8.60 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H). Step 4:
Compound 841d (36 mg, 0.093 mmol) was dissolved in tetrahydrofuran (5 mL), manganese dioxide (81 mg, 0.93 mmol) was added, and the mixture was stirred at 65 degrees for 6 hours. Insoluble matter was removed by Celite filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-841 (12 mg, 34%).
1H-NMR (DMSO-D6) δ: 1.76-1.78 (m, 2H), 2.58 (s, 3H), 3.28-3.35 (m, 4H), 6.95 (s, 1H), 7.44 (dd, J = 7.7, 4.9 Hz, 1H), 8.23 (s, 2H), 8.31-8.36 (m, 1H), 8.60 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H).
化合物Ｉ－８４２の合成
Figure JPOXMLDOC01-appb-C000128
工程１：化合物８４２ｂの合成　
　化合物８４２ａ（１００ｍｇ、０．６４ｍｍｏｌ）のＤＭＦ（１ｍＬ）溶液に、１－ブロモ－２－メトキシエタン（１０７ｍｇ、０．７７ｍｍｏｌ）および炭酸カリウム（２１２ｍｇ、１．５４ｍｍｏｌ）を加え、６５℃で６時間撹拌した。室温まで放冷し、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４２ｂ(１１６ｍｇ、８５％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：１．３０ 分、 ［Ｍ＋Ｈ］＋：２１５  Synthesis of Compound I-842
Figure JPOXMLDOC01-appb-C000128
Step 1: Synthesis of Compound 842b
To a solution of compound 842a (100 mg, 0.64 mmol) in DMF (1 mL), 1-bromo-2-methoxyethane (107 mg, 0.77 mmol) and potassium carbonate (212 mg, 1.54 mmol) were added, and the mixture was stirred at 65 ° C. for 6 hours. Stir. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 842b (116 mg, 85%). LCMS (measurement conditions A); retention time: 1.30 minutes, [M + H] + : 215
工程２：化合物８４２ｃの合成　
　化合物８４２ｂ（１１６ｍｇ、０．５４ｍｍｏｌ）のエタノール（３ｍＬ）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（３ｍＬ）を加え、６時間加熱還流した。水を加え、２ｍｏｌ／Ｌ塩酸水溶液でｐＨを２に調整し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をＤＭＦ（１ｍＬ）に溶解させ、ＣＤＩ（１３８ｍｇ、０．３８ｍｍｏｌ）を加え、室温で３０分撹拌した。２８％アンモニア水溶液（１ｍｌ）加え、さらに室温で３０分撹拌した。水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物８４２ｃ(７５ｍｇ、８８％)を得た。
1H-NMR (CDCl3) δ: 3.43 (s, 3H), 3.71-3.73 (m, 2H), 4.02 (s, 3H), 4.30-4.33 (m, 2H), 5.93 (s, 1H). Step 2: Synthesis of Compound 842c
To a solution of compound 842b (116 mg, 0.54 mmol) in ethanol (3 mL) was added 2 mol / L aqueous sodium hydroxide solution (3 mL), and the mixture was heated to reflux for 6 hours. Water was added, the pH was adjusted to 2 with a 2 mol / L hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (1 mL), CDI (138 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature for 30 min. A 28% aqueous ammonia solution (1 ml) was added, and the mixture was further stirred at room temperature for 30 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 842c (75 mg, 88%).
1H-NMR (CDCl3) δ: 3.43 (s, 3H), 3.71-3.73 (m, 2H), 4.02 (s, 3H), 4.30-4.33 (m, 2H), 5.93 (s, 1H).
工程３：化合物８４２ｄの合成　
　化合物８４２ｃ（７４ｍｇ、０．３７ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、ローソン試薬（１８０ｍｇ、０．４５ｍｍｏｌ）を加え、室温で終夜撹拌した。水（５ｍｌ）および重曹水（５ｍｌ）を加え、室温で３０分撹拌した。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４２ｄ(４０ｍｇ、５０％)を得た。
1H-NMR (DMSO-D6) δ: 3.28 (s, 3H), 3.59-3.61 (m, 2H), 3.89 (s, 3H), 4.14-4.17 (m, 2H), 5.99 (s, 1H), 9.43 (s, 1H), 9.93 (s, 1H). Step 3: Synthesis of Compound 842d
To a solution of compound 842c (74 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added Lawesson's reagent (180 mg, 0.45 mmol), and the mixture was stirred at room temperature overnight. Water (5 ml) and sodium bicarbonate water (5 ml) were added, and the mixture was stirred at room temperature for 30 minutes. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 842d (40 mg, 50%).
1H-NMR (DMSO-D6) δ: 3.28 (s, 3H), 3.59-3.61 (m, 2H), 3.89 (s, 3H), 4.14-4.17 (m, 2H), 5.99 (s, 1H), 9.43 (s, 1H), 9.93 (s, 1H).
工程４：化合物Ｉ－８４２の合成　
　化合物８４２ｄおよび化合物１０ｆを用いて、実施例１０の工程６と同様の方法で化合物Ｉ－８４２(３５ｍｇ、４５％)を得た。
1H-NMR (DMSO-D6) δ: 1.80-1.87 (m, 2H), 3.29-3.42 (m, 7H), 3.62-3.65 (m, 2H), 4.09 (s, 3H), 4.20-4.22 (m, 2H), 6.31 (s, 1H), 7.10 (s, 1H), 8.13 (s, 1H), 8.25 (s, 2H). Step 4: Synthesis of Compound I-842
Compound I-842 (35 mg, 45%) was obtained in the same manner as in Step 6 of Example 10 using Compound 842d and Compound 10f.
1H-NMR (DMSO-D6) δ: 1.80-1.87 (m, 2H), 3.29-3.42 (m, 7H), 3.62-3.65 (m, 2H), 4.09 (s, 3H), 4.20-4.22 (m, 2H), 6.31 (s, 1H), 7.10 (s, 1H), 8.13 (s, 1H), 8.25 (s, 2H).
化合物Ｉ－８４３の合成
Figure JPOXMLDOC01-appb-C000129
工程１：　
　実施例１０と同様の方法で合成した化合物８４３ａ（２０ｍｇ、０．０５６ｍｍｏｌ）をＤＭＦ（０．５ｍＬ）に懸濁させ、水素化ナトリウム（４．９ｍｇ、０．１２２ｍｍｏｌ）を加え８０度で１０分間撹拌した。１－クロロ－２－メトキシエタン（６．８ｍｇ、０．０７２ｍｍｏｌ）を加え１００度で２時間撹拌した。放冷後、重曹水を加え、１０％メタノール／クロロホルム溶液で抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物Ｉ－８４３(１４ｍｇ、６２％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：１．７９ 分、 ［Ｍ＋Ｈ］＋：４１８ Synthesis of Compound I-843
Figure JPOXMLDOC01-appb-C000129
Step 1:
Compound 843a (20 mg, 0.056 mmol) synthesized in the same manner as in Example 10 was suspended in DMF (0.5 mL), sodium hydride (4.9 mg, 0.122 mmol) was added, and 80 ° C. for 10 minutes. Stir. 1-Chloro-2-methoxyethane (6.8 mg, 0.072 mmol) was added and stirred at 100 degrees for 2 hours. After allowing to cool, sodium bicarbonate water was added, and the mixture was extracted with a 10% methanol / chloroform solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-843 (14 mg, 62%). LCMS (measurement condition A); retention time: 1.79 minutes, [M + H] +: 418
化合物Ｉ－８４４の合成
Figure JPOXMLDOC01-appb-C000130
工程１　化合物８４４ｂの合成
化合物８４４ａ（３００ｍｇ、１．３７ｍｍｏｌ）に、エタノール（８ｍＬ）、（２、４－ジメチルフェニルボロン酸（２４７ｍｇ、１．６４ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）ジクロロメタン錯体(５６ｍｇ、０．０６８ｍｍｏｌ）および２ｍｏｌ/Lの炭酸ナトリウム水溶液（２．７４ｍＬ、５．４８ｍｍｏｌ）を加え、１２時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４４ｂ(６８ｍｇ、１９％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：２．１２ 分、 ［Ｍ＋Ｈ］＋：２５９ Synthesis of Compound I-844
Figure JPOXMLDOC01-appb-C000130
Step 1 Synthesis of Compound 844b Compound 844a (300 mg, 1.37 mmol) was added to ethanol (8 mL), (2,4-dimethylphenylboronic acid (247 mg, 1.64 mmol), PdCl 2 (dppf) dichloromethane complex (56 mg, 0. 068 mmol) and a 2 mol / L aqueous sodium carbonate solution (2.74 mL, 5.48 mmol) were added, and the mixture was heated to reflux for 12 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 844b (68 mg, 19%) LCMS (Measurement Condition A ); Retention time: 2.12 minutes, [M + H] +: 259
工程２　化合物Ｉ－８４４の合成
　化合物８４４ｂおよび化合物４５ｃを用いて、実施例３９の工程２と同じ方法で化合物Ｉ－８４４(５１ｍｇ、５３％)を得た。
1H-NMR (DMSO-D6) δ: 1.76-1.84 (m, 2H), 2.16 (s, 3H), 2.34 (s, 3H), 3.27-3.35 (m, 4H), 3.53 (s, 3H), 6.77 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 8.21 (s, 2H). Step 2 Synthesis of Compound I-844 Compound I-844 (51 mg, 53%) was obtained in the same manner as in Step 2 of Example 39, using Compound 844b and Compound 45c.
1H-NMR (DMSO-D6) δ: 1.76-1.84 (m, 2H), 2.16 (s, 3H), 2.34 (s, 3H), 3.27-3.35 (m, 4H), 3.53 (s, 3H), 6.77 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 8.21 (s, 2H) .
化合物Ｉ－８４５の合成
Figure JPOXMLDOC01-appb-C000131
工程１：　
　実施例５６の工程１と同様の方法で合成した化合物８４５ａ（２９ｍｇ、０．１１ｍｍｏｌ）と化合物４５ｃから実施例３９の工程２と同じ方法によって化合物Ｉ－８４５（１６ｍｇ、４０％）を得た。
1H-NMR (CDCl3) δ: 1.93-1.99 (m, 2H), 2.11 (s, 3H), 2.31 (s, 3H), 2.59 (s, 3H), 3.38-3.44 (m, 4H), 6.49 (s, 1H), 7.06 (t, J = 8.6 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 6.5 Hz, 1H). Synthesis of Compound I-845
Figure JPOXMLDOC01-appb-C000131
Step 1:
Compound I-845 (16 mg, 40%) was obtained from Compound 845a (29 mg, 0.11 mmol) synthesized in the same manner as in Step 1 of Example 56 and Compound 45c by the same method as in Step 2 of Example 39.
1H-NMR (CDCl3) δ: 1.93-1.99 (m, 2H), 2.11 (s, 3H), 2.31 (s, 3H), 2.59 (s, 3H), 3.38-3.44 (m, 4H), 6.49 (s , 1H), 7.06 (t, J = 8.6 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 6.5 Hz, 1H).
化合物Ｉ－８４６の合成
Figure JPOXMLDOC01-appb-C000132
工程１　化合物８４６ｂの合成
化合物８４６ａ（４６５ｍｇ、１．８５ｍｍｏｌ）に、エタノール（１０ｍＬ）、３－ブロモ－２、６－ジメチルピリジン（３７９ｍｇ、２．０４ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）ジクロロメタン錯体(７６ｍｇ、０．０９３ｍｍｏｌ）および２ｍｏｌ/Lの炭酸ナトリウム水溶液（２ｍＬ）を加え、６時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物８４６ｂ(１５０ｍｇ、３５％)を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：２．６１ 分、 ［Ｍ＋Ｈ］＋：２３０ Synthesis of Compound I-846
Figure JPOXMLDOC01-appb-C000132
Step 1 Synthesis of Compound 846b Compound 846a (465 mg, 1.85 mmol) was added to ethanol (10 mL), 3-bromo-2,6-dimethylpyridine (379 mg, 2.04 mmol), PdCl 2 (dppf) dichloromethane complex (76 mg, 0 0.093 mmol) and 2 mol / L sodium carbonate aqueous solution (2 mL) were added, and the mixture was heated to reflux for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 846b (150 mg, 35%). LCMS (measurement conditions A); retention time: 2.61 minutes, [M + H] +: 230
工程２　化合物８４６ｃの合成
　化合物８４６ｂ（１０４ｍｇ、０．４５ｍｍｏｌ）をテトラヒドロフラン（３ｍＬ）に溶解し、水素化ナトリウム（２２ｍｇ、０．５４ｍｍｏｌ）およびヨウ化メチル（０．０３４ｍＬ、０．５４ｍｍｏｌ）を加え、１００度で５時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン―酢酸エチル）により精製し、化合物８４６ｃ(３１ｍｇ、２８％)を得た。
1H-NMR (CDCl3) δ: 2.11 (s, 3H), 2.37 (s, 3H), 3.65 (s, 3H), 3.84 (s, 3H), 6.05 (d, J = 3.0 Hz, 1H), 7.02-7.14 (m, 3H), 7.28 (s, 1H). Step 2 Synthesis of Compound 846c Compound 846b (104 mg, 0.45 mmol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (22 mg, 0.54 mmol) and methyl iodide (0.034 mL, 0.54 mmol) were added, Stir at 100 degrees for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 846c (31 mg, 28%).
1H-NMR (CDCl3) δ: 2.11 (s, 3H), 2.37 (s, 3H), 3.65 (s, 3H), 3.84 (s, 3H), 6.05 (d, J = 3.0 Hz, 1H), 7.02- 7.14 (m, 3H), 7.28 (s, 1H).
工程３　化合物Ｉ－８４６の合成
　化合物８４６ｃおよび化合物４５ｃを用いて実施例３９の工程２と同じ方法で化合物Ｉ－８４６(１８ｍｇ、３９％)を得た。
1H-NMR (CDCl3) δ：1.94-2.02 (m, 2H), 2.21 (s, 3H), 2.37 (s, 3H), 3.40-3.46 (m, 4H), 3.49 (s, 3H), 6.07 (d, J = 3.8 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 6.50 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H). Step 3 Synthesis of Compound I-846 Compound I-846 (18 mg, 39%) was obtained in the same manner as in Step 2 of Example 39 using Compound 846c and Compound 45c.
1H-NMR (CDCl3) δ: 1.94-2.02 (m, 2H), 2.21 (s, 3H), 2.37 (s, 3H), 3.40-3.46 (m, 4H), 3.49 (s, 3H), 6.07 (d , J = 3.8 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 6.50 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.17 (d , J = 7.6 Hz, 1H).
化合物Ｉ－８４７の合成
Figure JPOXMLDOC01-appb-C000133
工程１：　
　化合物８４７ａ（８４２ｍｇ、２．５９ｍｍｏｌ）をテトラヒドロフラン（１０ｍＬ）に懸濁させ、０度でトリエチルアミン（１．０８ｍｌ、７．７６ｍｍｏｌ）およびメタンスルホニルクロライド（３５６ｍｇ、０．２４ｍｍｏｌ）を加えた。室温まで昇温し、２時間撹拌した。反応液に水を加え、得られた沈殿物をろ取し、粗精製物として化合物８４７ｂ（９２０ｍｇ、８８％）を得た。ＬＣＭＳ (測定条件Ａ); 保持時間：１．２５ 分、 ［Ｍ＋Ｈ］＋：４０４ Synthesis of Compound I-847
Figure JPOXMLDOC01-appb-C000133
Step 1:
Compound 847a (842 mg, 2.59 mmol) was suspended in tetrahydrofuran (10 mL) and triethylamine (1.08 ml, 7.76 mmol) and methanesulfonyl chloride (356 mg, 0.24 mmol) were added at 0 degrees. The mixture was warmed to room temperature and stirred for 2 hours. Water was added to the reaction solution, and the resulting precipitate was collected by filtration to obtain Compound 847b (920 mg, 88%) as a crude product. LCMS (measurement conditions A); retention time: 1.25 minutes, [M + H] +: 404
工程２：　
　化合物８４７ｂ（３１ｍｇ、０．０７７ｍｍｏｌ）をＤＭＡ（１ｍＬ）に溶解させ、２、６－ジメチルピリジン（１９ｍｇ、０．１５４ｍｍｏｌ）および炭酸カリウム（５３ｍｇ、０．３９ｍｍｏｌ）を加え、１００度で２時間撹拌した。放冷後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム―メタノール）により精製し、化合物Ｉ－８４７(８ｍｇ、２４％)を得た。
1H-NMR (CDCl3) δ: 1.96-2.04 (m, 2H), 2.45 (s, 3H), 2.46 (s, 3H), 3.43-3.49 (m, 4H), 4.33 (t, J = 4.7 Hz, 2H), 4.84 (t, J = 4.7 Hz, 2H), 6.88-6.94 (m, 3H), 7.05 (d, J = 8.3 Hz, 1H). Step 2:
Compound 847b (31 mg, 0.077 mmol) was dissolved in DMA (1 mL), 2,6-dimethylpyridine (19 mg, 0.154 mmol) and potassium carbonate (53 mg, 0.39 mmol) were added, and the mixture was stirred at 100 degrees for 2 hours. did. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-847 (8 mg, 24%).
1H-NMR (CDCl3) δ: 1.96-2.04 (m, 2H), 2.45 (s, 3H), 2.46 (s, 3H), 3.43-3.49 (m, 4H), 4.33 (t, J = 4.7 Hz, 2H ), 4.84 (t, J = 4.7 Hz, 2H), 6.88-6.94 (m, 3H), 7.05 (d, J = 8.3 Hz, 1H).
　上記実施例に従い、以下の化合物を合成した。
Figure JPOXMLDOC01-appb-T000134
 According to the above Example, the following compounds were synthesized.
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000260
Figure JPOXMLDOC01-appb-T000260
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000305
上記実施例に従い、下記の参考例を合成した。
Figure JPOXMLDOC01-appb-T000306
 The following reference examples were synthesized according to the above examples.
Figure JPOXMLDOC01-appb-T000306
　以下に各化合物の１Ｈ－ＮＭＲ分析結果を示す。
化合物Ｉ－９３：1H-NMR（DMSO-D6）δ：1.79-1.84 (2H, m), 3.26-3.40 (4H, m), 6.94 (1H, s), 7.66 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 8.19 (br, 2H).
化合物Ｉ－７０６：1H-NMR（DMSO-D6）δ 1.08-1.19(m, 4H), 1.84(s, 2H), 2.93-2.95(m, 1H), 3.34(s, 4H), 7.15(s, 1H), 8.04(d, 2H, J=8.0Hz) 8.24(d, 2H, J=7.2Hz), 8.27(br, 3H).
化合物Ｉ－７４０：1H-NMR（DMSO-D6）δ：1.84(s, 2H), 3.34(s, 4H), 3.40(s, 3H), 7.18(s, 1H), 8.00(t, 1H, J=7.8Hz), 8.07(d, 1H, J=8.4Hz), 8.13(d, 1H, J=11.2 Hz), 8.28(br, 3H).
化合物Ｉ－７６３：1H-NMR（DMSO-D6）δ：1.84(s, 2H), 3.34(s, 4H), 3.44(s, 3H), 7.20(s, 1H), 8.20(q, 2H, J=8.4Hz), 8.26(br, 2H), 8.28(s, 1H), 8.31(s,1H). The results of 1 H-NMR analysis of each compound are shown below.
Compound I-93: 1 H-NMR (DMSO-D6) δ: 1.79-1.84 (2H, m), 3.26-3.40 (4H, m), 6.94 (1H, s), 7.66 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 8.19 (br, 2H).
Compound I-706: 1 H-NMR (DMSO-D6) δ 1.08-1.19 (m, 4H), 1.84 (s, 2H), 2.93-2.95 (m, 1H), 3.34 (s, 4H), 7.15 (s , 1H), 8.04 (d, 2H, J = 8.0Hz) 8.24 (d, 2H, J = 7.2Hz), 8.27 (br, 3H).
Compound I-740: 1 H-NMR (DMSO-D6) δ: 1.84 (s, 2H), 3.34 (s, 4H), 3.40 (s, 3H), 7.18 (s, 1H), 8.00 (t, 1H, J = 7.8Hz), 8.07 (d, 1H, J = 8.4Hz), 8.13 (d, 1H, J = 11.2 Hz), 8.28 (br, 3H).
Compound I-763: 1 H-NMR (DMSO-D6) δ: 1.84 (s, 2H), 3.34 (s, 4H), 3.44 (s, 3H), 7.20 (s, 1H), 8.20 (q, 2H, J = 8.4Hz), 8.26 (br, 2H), 8.28 (s, 1H), 8.31 (s, 1H).
　次に、本発明の代表的化合物の有用性を以下の試験例で説明する。
試験例１：ＭＩＣ試験方法
被験物質の抗真菌活性評価は、Ｃｌｉｎｉｃａｌ ａｎｄ Ｌａｂｏｒａｔｏｒｙ Ｓｔａｎｄａｒｄｓ Ｉｎｓｔｉｔｕｔｅ（ＣＬＳＩ）が推奨する微量液体希釈法を用いて測定した。測定用培地は酵母培養用の最小合成培地（２％グルコース、０．６７ ％ yeast nitrogen base w/o amino acid、０．２ ％アミノ酸・ヌクレオチドミックス）にモルホリンプロパンスルホン酸（ＭＯＰＳ，終濃度５０ ｍＭ）を加えて緩衝液とし、１ Ｍ水酸化ナトリウムを添加してｐＨ ７．０ に調整したものを用いた（ＹＮＢ／ＭＯＰＳ）。被験薬剤はＤＭＳＯを用いて２倍段階希釈し、９６ウェルマイクロプレートの各ウェルに２μＬ分注した。サブロ一寒天培地にて３５℃で一晩培養したCandida albicans ATCC MYA-574（ｆｌｕｃｏｎａｚｏｌｅ耐性株）を滅菌生理食塩液に懸濁後、分光光度計で濁度を測定し、菌懸濁液をＹＮＢ／ＭＯＰＳで希釈して接種菌液（約２．５ × １０３ ＣＦＵ／ｍＬ）を調製した。－８０℃に保存されているAspergillus fumigatus ATCC204305、Aspergillus flavus IFM50915およびAspergillus terreus IFM46871をＹＮＢ／ＭＯＰＳで希釈し、接種菌液（１×１０４ ＣＦＵ／ｍＬ）を調製した。接種菌液１９８μＬを各ウェルに分注し、所定濃度の被験物質、培地および菌体が含まれるマイクロプレー卜を作製した。Candida albicans は３５℃ で１日間培養、Aspergillus fumigatus、Aspergillus flavusおよびAspergillus terreus は３５℃ で２日間培養した後、ＭＩＣ判定を行った。Candida albicansのＭＩＣは被験物質無添加の対照にくらべ、濁度で５０％以上発育阻害する最小濃度とした。Aspergillus fumigatus とAspergillus terreusのＭＩＣは目視で１００％、Aspergillus flavusのＭＩＣは目視で５０％発育阻害する最小濃度とした。Aspergillus　fumigatusについては、ＹＮＢ／ＭＯＰＳ培地に５０％ ｂｏｖｉｎｅ ｓｅｒｕｍ（ＢＳ）を添加した条件でのＭＩＣ測定も行った。
用いた菌株および条件を表１７４に示す。
Figure JPOXMLDOC01-appb-T000307
 Next, the usefulness of the representative compounds of the present invention will be described in the following test examples.
Test Example 1: MIC Test Method The antifungal activity of the test substance was evaluated using a micro liquid dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI). The medium for measurement is minimal synthetic medium for yeast culture (2% glucose, 0.67% yeast nitrogen base w / o amino acid, 0.2% amino acid / nucleotide mix) and morpholine propane sulfonic acid (MOPS, final concentration 50 mM). ) Was added to obtain a buffer solution, and 1M sodium hydroxide was added to adjust the pH to 7.0 (YNB / MOPS). The test drug was serially diluted 2-fold with DMSO, and 2 μL was dispensed into each well of a 96-well microplate. Candida albicans ATCC MYA-574 (fluconazole resistant strain) cultured overnight at 35 ° C on a Sabro-Agar medium was suspended in sterile physiological saline, then the turbidity was measured with a spectrophotometer, and the bacterial suspension was treated with YNB. An inoculum (about 2.5 × 10 3 CFU / mL) was prepared by dilution with / MOPS. Aspergillus fumigatus ATCC204305, Aspergillus flavus IFM50915 and Aspergillus terreus IFM46871 stored at −80 ° C. were diluted with YNB / MOPS to prepare an inoculum solution (1 × 10 4 CFU / mL). 198 μL of the inoculum solution was dispensed into each well to prepare a microplate containing a test substance, a medium, and bacterial cells of a predetermined concentration. Candida albicans was cultured at 35 ° C. for 1 day, and Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus were cultured at 35 ° C. for 2 days, and MIC determination was performed. The MIC of Candida albicans was set to the minimum concentration that inhibits growth by 50% or more in turbidity compared to the control without addition of the test substance. The MIC of Aspergillus fumigatus and Aspergillus terreus was 100% visually, and the MIC of Aspergillus flavus was the minimum concentration that visually inhibited 50%. Aspergillus fumigatus was also subjected to MIC measurement under the condition that 50% bovine serum (BS) was added to the YNB / MOPS medium.
The strains and conditions used are shown in Table 174.
Figure JPOXMLDOC01-appb-T000307
比較化合物は、下式の化合物を用いた。
Figure JPOXMLDOC01-appb-C000308
菌・株番号１のＭＩＣ測定結果を表１７５～１８２に示す。
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000316
 The compound of the following formula was used as a comparative compound.
Figure JPOXMLDOC01-appb-C000308
Tables 175 to 182 show the results of MIC measurement of the bacteria / strain number 1.
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000316
菌・株番号２のＭＩＣ測定結果を表１８３～１８９に示す。
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000323
 Tables 183 to 189 show the results of MIC measurement of the bacteria / strain number 2.
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000323
菌・株番号３のＭＩＣ測定結果を表１９０～１９４に示す。
Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000325
Figure JPOXMLDOC01-appb-T000326
Figure JPOXMLDOC01-appb-T000327
Figure JPOXMLDOC01-appb-T000328
 Tables 190 to 194 show the results of MIC measurement of the bacteria / strain number 3.
Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000325
Figure JPOXMLDOC01-appb-T000326
Figure JPOXMLDOC01-appb-T000327
Figure JPOXMLDOC01-appb-T000328
菌・株番号４のＭＩＣ測定結果を表１９５および表１９６に示す。
Figure JPOXMLDOC01-appb-T000329
Figure JPOXMLDOC01-appb-T000330
 Table 195 and Table 196 show the MIC measurement results of the bacteria / strain number 4.
Figure JPOXMLDOC01-appb-T000329
Figure JPOXMLDOC01-appb-T000330
菌・株番号５のＭＩＣ測定結果を表１９７および表１９８に示す。
Figure JPOXMLDOC01-appb-T000331
Figure JPOXMLDOC01-appb-T000332
 Table 197 and Table 198 show the MIC measurement results of the bacteria / strain number 5.
Figure JPOXMLDOC01-appb-T000331
Figure JPOXMLDOC01-appb-T000332
試験例２：ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価した。 Test Example 2: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始した。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止した。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量した。 As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction. Started. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、溶媒に加えた本発明化合物の各濃度における残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。 The residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated. The IC 50 was calculated by inverse estimation using a logistic model.
試験例３：ＢＡ試験
経口吸収性の検討実験材料と方法
（１）使用動物：マウスあるいはＳＤラットを使用した。
（２）飼育条件：マウスあるいはＳＤラットは、固形飼料および滅菌水道水を自由摂取させた。
（３）投与量、群分けの設定：経口投与、静脈内投与を所定の投与量により投与した。以下のように群を設定した。（化合物ごとで投与量は変更有）
　経口投与　１～３０ｍｇ／ｋｇ（ｎ＝２～３）
　静脈内投与　０．５～１０ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：経口投与は溶液または懸濁液として投与した。静脈内投与は可溶化して投与した。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与した。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与した。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定した。
（７）統計解析：血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群のＡＵＣから本発明化合物のバイオアベイラビリティ（ＢＡ）を算出した。 Test Example 3: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats were used.
(2) Breeding conditions: Mice or SD rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dose and grouping: Oral administration and intravenous administration were administered at a predetermined dose. Groups were set up as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group.
試験例４：代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価した。 Test Example 4: Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させた（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心した。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の本発明化合物の残存量を０分反応時の化合物量を１００％として計算した。なお、加水分解反応はＮＡＤＰＨ非存在下で、グルクロン酸抱合反応はＮＡＤＰＨに換えて５ｍｍｏｌ／Ｌ　ＵＤＰ－グルクロン酸の存在下で反応を行い、以後同じ操作を実施することができる。 In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.
試験例５：ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による本発明化合物のＣＹＰ３Ａ４阻害の増強を調べる試験である。ＣＹＰ３Ａ４酵素（大腸菌発現酵素）により７－ベンジルオキシトリフルオロメチルクマリン（７－ＢＦＣ）が脱ベンジル化されて、蛍光を発する代謝物７－ハイドロキシトリフルオロメチルクマリン（７－ＨＦＣ）が生じる。７－ＨＦＣ生成反応を指標としてＣＹＰ３Ａ４阻害を評価した。 Test Example 5: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
　反応条件は以下のとおり：基質、５．６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ、反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；本発明化合物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止した。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始した。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止した。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定した。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ） The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in the K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition. A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction was stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed. (Ex = 420nm, Em = 535nm)
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。ＩＣ５０値の差が５μｍｏｌ／Ｌ以上の場合を（＋）とし、３μｍｏｌ／Ｌ以下の場合を（－）とした。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. The IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 μmol / L or more was designated as (+), and the case where it was 3 μmol / L or less was designated as (−).
試験例６：Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価した。 Test Example 6: Fluctuation Ames Test
The mutagenicity of the compounds of the present invention was evaluated.
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養した。ＴＡ９８株は９ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去した。９ｍＬのＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１１０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加した。ＴＡ１００株は３．１６ｍＬ菌液に対しＥｘｐｏｓｕｒｅ培地１２０ｍＬに添加し試験菌液を調製した。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養した。本発明化合物を暴露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養した。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価した。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。 Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L) Buffer). The TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). (mixture of 90 μL of mix) was mixed and incubated at 37 ° C. for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer solution containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each, and dispensed into 48 wells / dose of the microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation was made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).
試験例７：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャンネルを発現させたＨＥＫ２９３細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討した。 Test Example 7: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role, was investigated.
　全自動パッチクランプシステム（ＰａｔｃｈＸｐｒｅｓｓ　７０００Ａ、ＡｘｏｎＩｎｓｔｒｕｍｅｎｔｓ　Ｉｎｃ．）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持した後、＋４０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録した。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１３５　ｍｍｏｌ／Ｌ、ＫＣｌ：５．４　ｍｍｏｌ／Ｌ、ＮａＨ２ＰＯ４：０．３ｍｍｏｌ／Ｌ、ＣａＣｌ２・２Ｈ２Ｏ：１．８ｍｍｏｌ／Ｌ、ＭｇＣｌ２・６Ｈ２Ｏ：１ｍｍｏｌ／Ｌ、グルコース：１０ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温で、１０分間細胞に適用させた。得られたＩＫｒから、解析ソフト（ＤａｔａＸｐｒｅｓｓ　ｖｅｒ．１、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ　Ｃｏｒｐｏｒａｔｉｏｎ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測した。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価した。 Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of −80 mV by whole cell patch clamp, a +40 mV depolarization stimulus was applied for 2 seconds, followed by a −50 mV repolarization. The I Kr elicited when the stimulus was applied for 2 seconds was recorded. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH 2 PO 4 : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl 2 · 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
試験例８：溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定した。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液６　μＬをｐＨ６．８人工腸液（０．２ｍｏｌ／Ｌ　リン酸二水素カリウム試液　２５０ｍＬに０．２ｍｏｌ／Ｌ　ＮａＯＨ試液１１８ｍＬ、水を加えて１０００ｍＬとした）５９４μＬに添加した。２５℃で１６時間静置させた後、混液を吸引濾過した。濾液をメタノール／水＝１／１（Ｖ／Ｖ）にて２倍希釈し、絶対検量線法によりＨＰＬＣまたはＬＣ／ＭＳ／ＭＳを用いて濾液中濃度を測定した。 Test Example 8: Solubility test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) Was added to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate was measured by HPLC or LC / MS / MS using the absolute calibration curve method.
試験例９：粉末溶解度試験
　適当な容器に本発明化合物を適量入れ、各容器にＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとする）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加える）、２０ｍｍｏｌ／Ｌ　タウロコール酸ナトリウム（ＴＣＡ）／ＪＰ－２液（ＴＣＡ１．０８ｇにＪＰ－２液を加え１００ｍＬとする）を２００μＬずつ添加する。試験液添加後に全量溶解した場合には、適宜、本発明化合物を追加する。密閉して３７℃で１時間振とう後に濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないことを確認し、密閉して振とうする。絶対検量線法によりＨＰＬＣを用いて本発明化合物を定量する。 Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Make sure there are no bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
試験例１０：目視溶解性試験
化合物約5mg微量試験管3本に秤量し、各媒体(注射用水、生食注、0.5%ブドウ糖液)を化合物濃度20%になるように添加する。ボルテックスにて撹拌後、目視にて溶解の有無を確認する。溶解していればその媒体での溶解度を>20%とする。それら試験液に各媒体(注射用水、生食注、ブドウ糖液)を更に加えて化合物濃度10%の試験液を調製し、ボルテックスにて撹拌後、目視にて溶解の有無を確認する。溶解していればその媒体での溶解度を20%～10%とする。同様に5%濃度、2.5%濃度、1%濃度まで試験をし、1%濃度で溶解しない場合はその媒体での溶解度を<1%とする。1%濃度の試験液でのpHを測定し、記録する。　 Test Example 10: Visual Solubility Test Compound Weigh out to about 3 mg test tube of about 5 mg, and add each medium (water for injection, saline feed, 0.5% glucose solution) to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be <1%. Measure and record the pH with 1% test solution.
試験例１１：ｐＫａ測定（キャピラリー電気泳動法 (capillary electrophoresis法，CE法)の測定方法）
キャピラリーゾーン電気泳動技術を用いた手法で，電解質を含む緩衝液中での各試料成分の自由泳動を利用した分離方法である。
pH2.5～11.5に調製した緩衝液が充填されたフューズドシリカキャピラリーに、化合物溶液を注入した後、キャピラリーに高電圧 (Inlet側＋，Outlet側－) をかけると、化合物は緩衝液ｐＨにおけるイオン化状態を反映した速度 (＋チャージした化合物は速く、－チャージした化合物は遅く) で移動する。この化合物の移動時間と中性分子 (DMSO) の移動時間との差をpHに対してプロットし、フィッティングをかけてpKaを算出した。測定条件を以下に示す。
使用装置：Beckman P/ACEシステムMDQ　PDA
泳動液：pH2.5～11.5　Buffer (10vol%　MeOH含有)
サンプル溶液：　　　　Blank DMSO 10μL+注用水90μL混合
　　　　　　　　　　　Sample　10mM DMSO stock solution 4uL + DMSO 6uL + 注用水 90uL
（メソッド）
キャピラリー　　　　：Fused silica capillary (BECKMAN COULTER，内径50 μm，全長30.2 cm，有効長20.0 cm)
印加電圧　　　　　：10kV　(331 V/cm)
印加空気圧　　　　：0.7 psi
キャピラリー温度　　　：25°C
電気浸透流マーカー　　：DMSO
検出　　　　　　：紫外部多波長吸光検出 (測定波長；215 nm，238 nm)
試料注入　　　　　：加圧法 (0.5 psi，5 sec) Test Example 11: pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method)
This is a separation method using capillary zone electrophoresis technology and free migration of each sample component in a buffer solution containing an electrolyte.
After injecting a compound solution into a fused silica capillary filled with a buffer solution adjusted to pH 2.5 to 11.5 and then applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow). The difference between the migration time of this compound and the migration time of neutral molecule (DMSO) was plotted against pH, and pKa was calculated by fitting. The measurement conditions are shown below.
Equipment used: Beckman P / ACE system MDQ PDA
Electrophoresis: pH2.5 to 11.5 Buffer (containing 10vol% MeOH)
Sample solution: Blank DMSO 10 μL + Injection water 90 μL Sample 10 mM DMSO stock solution 4 uL + DMSO 6 uL + Injection water 90 uL
(Method)
Capillary: Fused silica capillary (BECKMAN COULTER, inner diameter 50 μm, total length 30.2 cm, effective length 20.0 cm)
Applied voltage: 10 kV (331 V / cm)
Applied air pressure: 0.7 psi
Capillary temperature: 25 ° C
Electroosmotic flow marker: DMSO
Detection: UV multi-wavelength absorption detection (measurement wavelength: 215 nm, 238 nm)
Sample injection: pressurized method (0.5 psi, 5 sec)
製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１：　錠剤
　本発明化合物、乳糖およびステアリン酸カルシウムを混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1: Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例２：　カプセル剤
　本発明化合物、乳糖およびステアリン酸カルシウムを均一に混合して粉末または細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2: Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
製剤例３：　顆粒剤
　本発明化合物、乳糖およびステアリン酸カルシウムを均一に混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3: Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
製剤例４：　口腔内崩壊錠
　本発明化合物および結晶セルロースを混合し、造粒後打錠して口腔内崩壊錠とする。 Formulation Example 4: Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
製剤例５：　ドライシロップ
　本発明化合物および乳糖を混合し、粉砕、整粒、篩別して適当な大きさのドライシロップとする。 Formulation Example 5: Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
製剤例６：　注射剤
　本発明化合物およびリン酸緩衝液を混合し、注射剤とする。 Formulation Example 6: Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
製剤例７：　点滴剤
　本発明化合物およびリン酸緩衝液を混合し、点滴剤とする。 Formulation Example 7: Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
製剤例８：　吸入剤
　本発明化合物および乳糖を混合し細かく粉砕することにより、吸入剤とする。 Formulation Example 8: Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
製剤例９：　軟膏剤
　本発明化合物およびワセリンを混合し、軟膏剤とする。 Formulation Example 9: Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
製剤例１０： 貼付剤
　本発明化合物および粘着プラスターなどの基剤を混合し、貼付剤とする。 Formulation Example 10: Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
式（Ｉ）で示される化合物またはその製薬上許容される塩は、優れた抗真菌活性を有し、抗真菌剤として有用である。また、別の態様では、式（Ｉ）で示される化合物またはその製薬上許容される塩は、安全性にも優れ、カンジダ属菌およびアルペルギルス属菌に対する抗真菌剤として有用である。 The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has excellent antifungal activity and is useful as an antifungal agent. In another embodiment, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is excellent in safety and useful as an antifungal agent against Candida and Alpergillus.

Claims (16)

  1. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、Ｚは－ＣＲ１Ｒ２－であり、
    Ｒ１はそれぞれ独立して、
    水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、ペンタハロゲノチオ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルであり、
    隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレン、置換もしくは非置換のアルケニレン、または置換もしくは非置換のアルキニレンを形成するか、
    Ｒ２はそれぞれ独立して、
    水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、ペンタハロゲノチオ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルであるか、
    同一炭素原子に結合するＲ１およびＲ２が、該炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成するか、
    または、
    同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソ、置換もしくは非置換のアルキルイミノ、置換もしくは非置換のアルケニルイミノ、置換もしくは非置換のアルキニルイミノ、置換もしくは非置換のアルキルカルボニルイミノ、置換もしくは非置換のアルケニルカルボニルイミノ、置換もしくは非置換のアルキニルカルボニルイミノ、置換もしくは非置換のアルキルオキシイミノ、置換もしくは非置換のアルケニルオキシイミノ、置換もしくは非置換のアルキニルオキシイミノ、または置換もしくは非置換のメチリデンを形成し、
    Ｇは置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、または式（Ｉ－Ｇ１）：
    Figure JPOXMLDOC01-appb-C000002
    （式中、
    Ｒ３およびＲ４については、
    ａ）Ｒ３およびＲ４が隣接する原子と一緒になって、置換もしくは非置換の非芳香族炭素環、または置換もしくは非置換の非芳香族複素環を形成するか、または、
    ｂ）Ｒ３およびＲ４が一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し、
    Ｘ’はハロゲン、ヒドロキシ、カルボキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである。）
    で示される基であり、
    ｎは２～５の整数である。
    ただし、
    Ｇの炭素環式基がフェニルの場合、
    ｉ）該フェニル基は少なくとも１つ以上の置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキルまたは置換もしくは非置換の複素環アルキルで置換されており、該フェニルはさらに置換されていてもよく、および／または
    ｉｉ）該フェニル基の少なくとも１つのメタ位が置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシで置換されており、該フェニル基はさらに置換されていてもよく、かつ、
    以下の化合物（Ａ－１）～（Ａ－３４）を除く。
    Figure JPOXMLDOC01-appb-C000003

    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
    ）で示される化合物またはその製薬上許容される塩。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    Wherein Z is —CR 1 R 2 —,
    Each R 1 is independently
    Hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, pentahalogenothio, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted Substituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Rubonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl Substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic compound Ring oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or substituted or unsubstituted non-aromatic heterocyclic A ring sulfonyl,
    Neighboring two R 1 attached to a carbon atom which is not together form a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene or,
    Each R 2 is independently
    Hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, pentahalogenothio, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted Substituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Rubonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl Substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic compound Ring oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or substituted or unsubstituted non-aromatic heterocyclic A ring sulfonyl,
    R 1 and R 2 bonded to the same carbon atom, together with the carbon atom, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
    Or
    R 1 and R 2 bonded to the same carbon atom are combined to form oxo, substituted or unsubstituted alkylimino, substituted or unsubstituted alkenylimino, substituted or unsubstituted alkynylimino, substituted or unsubstituted alkylcarbonyl Imino, substituted or unsubstituted alkenylcarbonylimino, substituted or unsubstituted alkynylcarbonylimino, substituted or unsubstituted alkyloxyimino, substituted or unsubstituted alkenyloxyimino, substituted or unsubstituted alkynyloxyimino, or substituted or Forming unsubstituted methylidene,
    G is a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or formula (I-G1):
    Figure JPOXMLDOC01-appb-C000002
    (Where
    For R 3 and R 4 ,
    a) R 3 and R 4 together with adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, or
    b) R 3 and R 4 together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
    X ′ is halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy, substituted or Unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynyl Sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted Alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic A group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, Replacement or non- Substituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic Heterocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, Or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl. )
    A group represented by
    n is an integer of 2 to 5.
    However,
    When the carbocyclic group of G is phenyl,
    i) The phenyl group is substituted with at least one or more substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl, or substituted or unsubstituted heterocyclic alkyl The phenyl may be further substituted, and / or ii) an aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic ring in which at least one meta position of the phenyl group is substituted or unsubstituted. Substituted with oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, or substituted or unsubstituted aromatic heterocyclic alkyloxy, the phenyl group may be further substituted, and
    The following compounds (A-1) to (A-34) are excluded.
    Figure JPOXMLDOC01-appb-C000003

    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
    Or a pharmaceutically acceptable salt thereof.
  2. Ｇが式（Ｉ－Ｇ１）：
    Figure JPOXMLDOC01-appb-C000006
    （式中、各記号は前記と同意義である。）で示される基
    または式（Ｉ－Ｇ２）：
    Figure JPOXMLDOC01-appb-C000007
    （式中、
    Ｙは炭素環または複素環であり、ｍは０～５であり、
    Ｘはそれぞれ独立してハロゲン、ヒドロキシ、カルボキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、ペンタハロゲノチオ、シアノ、ニトロ、ニトロソ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、置換もしくは非置換の非芳香族複素環アルキルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである。）で示される基である、請求項１記載の化合物またはその製薬上許容される塩。
    G is the formula (I-G1):
    Figure JPOXMLDOC01-appb-C000006
    Wherein each symbol is as defined above, or a group represented by formula (IG2):
    Figure JPOXMLDOC01-appb-C000007
    (Where
    Y is a carbocyclic or heterocyclic ring, m is 0-5,
    X is independently halogen, hydroxy, carboxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, pentahalogenothio, cyano, nitro, nitroso, hydrazino, ureido, amidino, guanidino, acyl, acyloxy Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylamino Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Lucenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted Substituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic group, substituted Or an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic alkyl, Or unsubstituted non-aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted Non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic Carbocyclic alkyloxy, substituted or unsubstituted aromatic heterocyclic alkyloxy, substituted or unsubstituted nonaromatic heterocyclic alkyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted nonaromatic Carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic Heterocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, or substituted or unsubstituted non-aromatic heterocyclic sulfonyl. The compound or its pharmaceutically acceptable salt of Claim 1 which is group shown by this.
  3. Ｇが式（Ｉ－Ｇ２）で示される基である、請求項１記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein G is a group represented by the formula (I-G2).
  4. Ｙが複素環である、請求項３記載の化合物またはその製薬上許容される塩。
    The compound according to claim 3, wherein Y is a heterocyclic ring, or a pharmaceutically acceptable salt thereof.
  5. ｎが２または３である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein n is 2 or 3.
  6. ｎが３である、請求項５記載の化合物またはその製薬上許容される塩。
    6. The compound according to claim 5, wherein n is 3, or a pharmaceutically acceptable salt thereof.
  7. 式：
    Figure JPOXMLDOC01-appb-C000008
    が、式：
    Figure JPOXMLDOC01-appb-C000009
    （式中、各定義は前記と同意義である。）
    である、請求項５記載の化合物またはその製薬上許容される塩。
    formula:
    Figure JPOXMLDOC01-appb-C000008
    But the formula:
    Figure JPOXMLDOC01-appb-C000009
    (In the formula, each definition is as defined above.)
    The compound according to claim 5 or a pharmaceutically acceptable salt thereof.
  8. Ｒ１がそれぞれ独立して、水素原子、ハロゲン、シアノ、置換もしくは非置換のアルキルであるか、隣接しない炭素原子に結合する２つのＲ１が一緒になって、置換もしくは非置換のアルキレンを形成するか、Ｒ２がそれぞれ独立して、水素原子、ハロゲン、シアノ、置換もしくは非置換のアルキルであるか、同一炭素原子に結合するＲ１およびＲ２が隣接する原子と一緒になって置換もしくは非置換のシクロアルカンを形成するか、
    または、同一炭素原子に結合するＲ１およびＲ２が一緒になって、オキソまたは置換もしくは非置換のメチリデンである、請求項１～７のいずれかに記載の化合物またはその製薬上許容される塩。
    Each R 1 is independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or two R 1 bonded to non-adjacent carbon atoms together form a substituted or unsubstituted alkylene Each of R 2 is independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or R 1 and R 2 bonded to the same carbon atom are substituted with adjacent atoms or Form an unsubstituted cycloalkane, or
    Or a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 and R 2 bonded to the same carbon atom are together oxo or substituted or unsubstituted methylidene. .
  9. Ｘがそれぞれ独立して、ハロゲン、シアノ、アシル、アシルオキシ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換のもしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の非芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の非芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、置換もしくは非置換の非芳香族炭素環アルキルオキシ、置換もしくは非置換の芳香族複素環アルキルオキシ、または置換もしくは非置換の非芳香族複素環アルキルオキシである、請求項２～８のいずれかに記載の化合物またはその製薬上許容される塩。
    Each X is independently halogen, cyano, acyl, acyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkylamino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic carbocycle Group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbon Ring alkyl, substituted or unsubstituted non-aromatic carbocyclic alkyl, substituted Or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted non-aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted Aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted non-aromatic carbocyclic alkyloxy, substituted or unsubstituted fragrance The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 8, which is an aromatic heterocyclic alkyloxy, or a substituted or unsubstituted non-aromatic heterocyclic alkyloxy.
  10. Ｘがそれぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルアミノ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換のもしくは非置換の芳香族炭素環アルキル、置換もしくは非置換の芳香族複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシであり、ｍが１または２である、請求項２～８のいずれかに記載の化合物またはその製薬上許容される塩。
    Each X is independently halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted alkenyloxy, Substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted An aromatic carbocyclic alkyloxy or a substituted or unsubstituted aromatic heterocyclic alkyloxy, wherein m is 1 or 2 Compound or a pharmaceutically acceptable salt thereof according to any one of claims 2-8.
  11. Ｙが芳香族炭素環であり、ｍが２であり、Ｘがそれぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基、置換もしくは非置換の炭素環アルキル、置換もしくは非置換の複素環アルキル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環アルキルオキシ、または置換もしくは非置換の芳香族複素環アルキルオキシである、請求項２、３、および５～１０のいずれかに記載の化合物またはその製薬上許容される塩。
    Y is an aromatic carbocycle, m is 2, and each X is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted carbocyclic group Substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy The compound according to any one of claims 2, 3, and 5 to 10, or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted aromatic carbocyclic alkyloxy, or a substituted or unsubstituted aromatic heterocyclic alkyloxy Salt.
  12. 化合物Ｉ－０００４、Ｉ－００３４、Ｉ－００８４、Ｉ－０１５９、Ｉ－０１８３、Ｉ－０２５１、Ｉ－０３３２、Ｉ－０３５５、Ｉ－０３７６、Ｉ－０３８２、Ｉ－０４７４、Ｉ－０４７８、Ｉ－０６０９、Ｉ－０６１６、Ｉ－０６５０、Ｉ－０８２９、Ｉ－０８３０、Ｉ－０８４２、Ｉ－０８４５、Ｉ－０８５６、Ｉ－０８７４、Ｉ－０８９４、Ｉ－０９１１、Ｉ－０９３２、Ｉ－０９３７、Ｉ－０９５８、およびＩ－１０５２から選択される、請求項１記載の化合物、またはその製薬上許容される塩。
    Compounds I-0004, I-0034, I-0084, I-0159, I-0183, I-0251, I-0332, I-0355, I-0376, I-0382, I-0474, I-0478, I -0609, I-0616, I-0650, I-0929, I-0830, I-0842, I-0845, I-0856, I-0874, I-0894, I-0911, I-0932, I-0937 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: I-0958, I-0958, and I-1052.
  13. 請求項１～１２のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
    A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
  14. 抗真菌作用を有する、請求項１３記載の医薬組成物。
    The pharmaceutical composition according to claim 13, which has an antifungal action.
  15. 請求項１～１２のいずれかに記載の化合物、またはその製薬上許容される塩を投与することを特徴とする、真菌感染に関連する疾患の治療またはその予防方法。
    A method for treating or preventing a disease associated with a fungal infection, which comprises administering the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
  16. 真菌感染に関連する疾患を治療または予防するための、請求項１～１２のいずれかに記載の化合物、またはその製薬上許容される塩。 The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease associated with a fungal infection.
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