WO2016098793A1 - Dérivé thiazole ayant un groupe guanidyle cyclique - Google Patents

Dérivé thiazole ayant un groupe guanidyle cyclique Download PDF

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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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Japanese (ja)
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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/ja
Publication of WO2016098793A1 publication Critical patent/WO2016098793A1/fr

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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
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    • 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
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • 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
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    • 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
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    • 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.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne un composé représenté par la formule générale (I) (dans laquelle Z représente -CR1R2- ; R1 et R2 représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe hydroxy ou similaire, ou, forment indépendamment, conjointement avec un atome adjacent à ce dernier, un cycle carbocyclique non aromatique substitué ou non substitué ou un noyau hétérocyclique non aromatique substitué ou non substitué, ou analogue ; G représente un groupe carbocyclique substitué ou non substitué, un groupe hétérocyclique substitué ou non substitué ou analogue ; et n représente un nombre entier de 1 à 5 ou un sel pharmaceutiquement acceptable de ce dernier, utile en tant qu'agent anti-fongique.
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