WO2018186365A1 - Read-through inducing agent and pharmaceutical application thereof - Google Patents

Read-through inducing agent and pharmaceutical application thereof Download PDF

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Publication number
WO2018186365A1
WO2018186365A1 PCT/JP2018/014162 JP2018014162W WO2018186365A1 WO 2018186365 A1 WO2018186365 A1 WO 2018186365A1 JP 2018014162 W JP2018014162 W JP 2018014162W WO 2018186365 A1 WO2018186365 A1 WO 2018186365A1
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Prior art keywords
group
compound
mmol
added
fluorophenyl
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PCT/JP2018/014162
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French (fr)
Japanese (ja)
Inventor
滋充 武田
弘明 白波瀬
俊輔 高嶋
達哉 北尾
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京都薬品工業株式会社
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Publication of WO2018186365A1 publication Critical patent/WO2018186365A1/en

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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound or a pharmacologically acceptable salt thereof showing a read-through activity for an immature stop codon generated by a nonsense mutation.
  • the present invention is also useful for the prevention or treatment of genetic diseases based on nonsense mutations, such as muscular dystrophy, Duchenne muscular dystrophy, cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc.
  • the present invention relates to a compound or a pharmacologically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof.
  • DNA carrying genetic information is composed of four types of bases, adenine, thymine, guanine, and cytosine, and a three-base sequence of these combinations encodes any of the 20 types of amino acids.
  • TAA, TAG, and TGA are stop codons that do not correspond to any amino acid.
  • the DNA encoding the protein is transcribed into mRNA, moves into the cytoplasm, binds to the ribosome, and translation, that is, protein synthesis occurs. In normal DNA and mRNA, translation or protein synthesis is terminated by a stop codon.
  • Nonsense mutation-type genetic diseases are said to be more than 2,400 types, and typical genetic diseases include Duchenne muscular dystrophy found in boys and mucopolysaccharidosis, which is a type of lysosomal disease.
  • Duchenne muscular dystrophy is a disease caused by a lack of dystrophin protein in the muscle fiber sheath and is characterized by progressive voluntary muscle weakness.
  • a mutation occurs on the muscular dystrophy gene present in the X chromosome, which results in an immature stop codon, and translation is interrupted and terminated at the mutation site, thereby inhibiting normal dystrophin protein expression. .
  • dystrophin protein is lacking and muscular dystrophy occurs.
  • type I mucopolysaccharidosis is caused by a nonsense mutation in the gene encoding mucopolysaccharide-degrading enzyme ⁇ -L-iduronidase (IDUA), resulting in a lack of IDUA, accumulation of mucopolysaccharide in the body, bone joint lesions, skin / bonding It is a disease that causes various systemic disorders such as tissue lesions, central nervous system disorders, respiratory, circulatory, and digestive organs.
  • IDUA mucopolysaccharide-degrading enzyme ⁇ -L-iduronidase
  • Patent Document 1 describes that a negative peptide, which is a dipeptide antibiotic, has a read-through activity, and when negamycin is administered to a muscular dystrophy model mouse. It has been reported that dystrophin protein expression is restored.
  • Patent Document 2 describes that paromomycin-derived aminoglycoside antibiotics exhibit read-through activity and are useful in the treatment of genetic diseases.
  • Non-Patent Document 1 describes that dystrophin protein accumulates when gentamicin, an aminoglycoside antibiotic, is administered to a patient with Duchenne muscular dystrophy.
  • Non-Patent Document 2 describes that typical electrophysiological abnormalities can be normalized by locally administering gentamicin to the respiratory epithelium of a patient with cystic fibrosis.
  • Patent Document 3 describes 1,2,4-oxadiazole benzoic acid derivatives
  • Patent Document 4 discloses pyrimido [4,5-B] quinoline-4,5 (3H, 10H) -dione.
  • Patent Document 5 describes a pyridopyrimidinedione derivative
  • Patent Document 6 describes that a naphthyridinedione derivative has a read-through activity.
  • Non-Patent Documents 3 and 4 include 1,2,4-oxadiazole benzoic acid derivative 3- [5- (2-fluorophenyl)-[1,2,4] -oxadiazol-3-yl] benzoic acid. Acid has been described to increase dystrophin protein in Duchenne muscular dystrophy patients and model mice. However, gentamicin, like other aminoglycoside antibiotics, has remarkable nephrotoxicity and ototoxicity, and negamycin has high antibacterial activity and there is a concern about the generation of resistant bacteria. In view of these side effects, it is desired to provide a therapeutic agent for a nonsense mutant genetic disease that selectively has strong read-through activity and has few side effects.
  • An object of the present invention is to provide a novel compound having read-through activity, high safety and capable of oral administration. Furthermore, it is providing the therapeutic agent of the nonsense variant gene disease containing the said compound.
  • the present inventors have found a superior compound that exhibits a strong read-through promoting action and can be a preventive or therapeutic agent for nonsense mutant genetic diseases, and has completed the present invention.
  • Ring A represents a phenyl group or a 6-membered monocyclic nitrogen-containing heterocyclic group, each of which may be further substituted
  • X represents a single bond, a further divalent 4- to 7-membered monocyclic heterocyclic group which may be further substituted, or a C 2-6 alkynylene group which may be further substituted
  • the aryl group or heterocyclic group which may be further substituted is shown.
  • a pharmaceutically acceptable salt thereof hereinafter sometimes abbreviated as compound (I)).
  • Ring A is a phenyl group or a pyridyl group, each of which may be further substituted
  • X is a single bond or a divalent 5- or 6-membered monocyclic aromatic heterocyclic group which may be further substituted
  • ring B may be further substituted, respectively, C 6-10
  • Ring A is a phenyl group which may be further substituted;
  • X is a single bond or a divalent 5-membered monocyclic aromatic heterocyclic group which may be further substituted, and ring B may be further substituted, respectively, a phenyl group or 8 to 14
  • a pharmaceutical composition comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a lead-through inducer comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a preventive or therapeutic agent for nonsense mutant genetic diseases comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the agent according to [6], wherein the nonsense mutant gene disease is muscular dystrophy, Duchenne muscular dystrophy, cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, or Niemann-Pick disease.
  • the compound (I) of the present invention has a strong read-through activity and is useful as a pharmaceutical product.
  • a pharmaceutical composition containing compound (I) can be provided, and the pharmaceutical composition is particularly suitable for hereditary diseases caused by nonsense mutations (eg, muscular dystrophy, Duchenne muscular dystrophy). , Cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc.).
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl means a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, Xylyl and the like.
  • C 3-8 cycloalkyl means a monovalent group derived from a saturated hydrocarbon ring having 3 to 8 carbon atoms.
  • the C 3-8 cycloalkyl may be bridged.
  • Examples of the “C 3-8 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C 3-8 cycloalkyl C 1-6 alkyl means a monovalent group in which the “C 3-8 cycloalkyl” is substituted on the “C 1-6 alkyl”.
  • Examples of the “C 3-8 cycloalkyl C 1-6 alkyl” include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl and the like.
  • C 2-6 alkenyl refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms. means.
  • Examples of the “C 2-6 alkenyl” include vinyl, 1-propenyl (allyl), 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2 -Buten-2-yl, 3-methyl-2-butenyl, 3-methyl-2-buten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-penten-2-yl 2-penten-3-yl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, butadienyl (eg, buta-1,3-dien-1-yl), pentadienyl (eg, Penta-1,3-dienyl),
  • C 2-6 alkynyl means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms.
  • Examples of the “C 2-6 alkynyl” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl, 1-pentynyl and 2-pentynyl. , 3-pentynyl, 4-pentynyl, 4-methyl-1-pentynyl and the like.
  • C 2-6 alkynylene means a linear or branched divalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms.
  • Examples of the “C 2-6 alkynylene” include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 3-methyl-2-butynylene, 1-pentynylene and 2-pentynylene. , 3-pentynylene, 4-pentynylene, 4-methyl-1-pentynylene and the like.
  • C 1-6 alkoxy means a group in which the above “C 1-6 alkyl” group is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1-ethylpropyloxy And hexyloxy.
  • C 1-6 alkylsulfanyl refers to a group in which the “C 1-6 alkyl” group is bonded to a sulfur atom, that is, a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms. means.
  • C 1-6 alkylsulfanyl examples include, for example, methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neo Examples include pentylsulfanyl, 1-ethylpropylsulfanyl, hexylsulfanyl and the like.
  • C 1-6 alkylsulfinyl refers to a group in which the “C 1-6 alkyl” group is bonded to a sulfinyl group, that is, a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms. means.
  • C 1-6 alkylsulfinyl examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, neo Examples include pentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl and the like.
  • C 1-6 alkylsulfonyl refers to a group in which the “C 1-6 alkyl” group is bonded to a sulfonyl group, that is, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. means.
  • C 1-6 alkylsulfonyl includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neo Examples include pentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl and the like.
  • C 1-6 alkylsulfonyloxy means a monovalent group in which the “C 1-6 alkylsulfonyl” group is bonded to an oxygen atom.
  • Examples of the “C 1-6 alkylsulfonyloxy” include, for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy Pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, 1-ethylpropylsulfonyloxy, hexylsulfonyloxy and the like.
  • “mono- or di -C 1-6 alkylamino” denotes one or two of the "C 1-6 alkyl" monovalent radical group is substituted to an amino group.
  • Examples of the “mono or di-C 1-6 alkylamino” include, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino, neopentylamino, hexylamino, Examples include dimethylamino, diethylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino and the like.
  • the “mono or di-C 1-6 alkyl-carbamoyl group” means a monovalent group in which one or two “C 1-6 alkyl” groups are substituted on the carbamoyl group.
  • Examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl, neopentylcarbamoyl, Examples include xylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl,
  • the “mono or di-C 1-6 alkyl-thiocarbamoyl group” means a monovalent group in which one or two “C 1-6 alkyl” groups are substituted on the thiocarbamoyl group. To do.
  • Examples of the “mono or di-C 1-6 alkyl-thiocarbamoyl group” include, for example, methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl, isopropylthiocarbamoyl, butylthiocarbamoyl, isobutylthiocarbamoyl, pentylthiocarbamoyl, isopentyl Examples include ruthiocarbamoyl, neopentylthiocarbamoyl, hexylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, diisopropylthiocarbamoyl, dibutylthiocarbamoyl, dipentylthiocarbamoyl, dihexylthiocarbamoyl and the like.
  • C 3-8 cycloalkylsulfanyl means a group in which the “C 3-8 cycloalkyl” group is bonded to a sulfur atom.
  • Examples of the “C 3-8 cycloalkylsulfanyl” include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl and the like.
  • C 3-8 cycloalkylsulfinyl means a group in which the “C 3-8 cycloalkyl” group is bonded to a sulfinyl group.
  • Examples of the “C 3-8 cycloalkylsulfinyl” include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclooctylsulfinyl and the like.
  • C 3-8 cycloalkylsulfonyl means a group in which the “C 3-8 cycloalkyl” group is bonded to a sulfonyl group.
  • Examples of the “C 3-8 cycloalkylsulfonyl” include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, cyclooctylsulfonyl and the like.
  • C 3-8 cycloalkylsulfonyloxy means a monovalent group in which the “C 3-8 cycloalkylsulfonyl” group is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkylsulfonyloxy” include cyclopropylsulfonyloxy, cyclobutylsulfonyloxy, cyclopentylsulfonyloxy, cyclohexylsulfonyloxy, cycloheptylsulfonyloxy, cyclooctylsulfonyloxy and the like.
  • mono- or di -C 3-8 cycloalkylamino means one or two of the “C 3-8 cycloalkyl" monovalent radical group is substituted to an amino group.
  • Examples of the “mono or di-C 3-8 cycloalkylamino” include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino and the like.
  • C 1-6 alkoxy-carbonyl means a group in which the above “C 1-6 alkoxy” group is bonded to carbonyl, that is, a linear or branched alkoxy-carbonyl group having 1 to 6 carbon atoms. Means.
  • C 1-6 alkoxy-carbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyl Examples include pentyloxycarbonyl, neopentyloxycarbonyl, 1-ethylpropyloxycarbonyl, hexyloxycarbonyl and the like.
  • aryl means a monovalent aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • examples of the “aryl” include C 6-14 aryl groups such as phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl, phenanthryl and the like.
  • a C 6-10 aryl group is preferable, and phenyl is particularly preferable.
  • aryloxy means a monovalent group in which the “aryl” group is bonded to an oxygen atom.
  • examples of the “aryloxy” include phenoxy, naphthyloxy (eg, 1-naphthyloxy, 2-naphthyloxy), acenaphthylenyloxy, azulenyloxy, anthryloxy, phenanthryloxy and the like.
  • C 6-14 arylsulfanyl means a group in which the “C 6-14 aryl” group is bonded to a sulfur atom.
  • Examples of the “C 6-14 arylsulfanyl” include phenylsulfanyl, naphthylsulfanyl, acenaphthylenylsulfanyl, azulenylsulfanyl, anthrylsulfanyl, phenanthrylsulfanyl and the like.
  • C 6-14 arylsulfinyl means a group in which the “C 6-14 aryl” group is bonded to a sulfinyl group.
  • Examples of the “C 6-14 arylsulfinyl” include phenylsulfinyl, naphthylsulfinyl, acenaphthylenylsulfinyl, azulenylsulfinyl, anthrylsulfinyl, phenanthrylsulfinyl and the like.
  • C 6-14 arylsulfonyl means a group in which the “C 6-14 aryl” group is bonded to a sulfonyl group.
  • Examples of the “C 6-14 arylsulfonyl” include phenylsulfonyl, naphthylsulfonyl, acenaphthylenylsulfonyl, azulenylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl and the like.
  • C 6-14 arylsulfonyloxy means a monovalent group in which the “C 6-14 arylsulfonyl” group is bonded to an oxygen atom.
  • Examples of the “C 6-14 arylsulfonyloxy” include phenylsulfonyloxy, naphthylsulfonyloxy, acenaphthylenylsulfonyloxy, azulenylsulfonyloxy, anthrylsulfonyloxy, phenanthrylsulfonyloxy and the like.
  • mono- or di -C 6-14 arylamino means one or two of the "C 6-14 aryl" monovalent radical group is substituted to an amino group.
  • Examples of the “mono or di-C 6-14 arylamino” include phenylamino, naphthylamino, acenaphthylenylamino, azulenylamino, anthrylamino, phenanthrylamino, diphenylamino and the like.
  • the “mono or di-C 6-14 aryl-carbamoyl group” means a monovalent group in which one or two of the “C 6-14 aryl” groups are substituted on the carbamoyl group.
  • Examples of the “mono or di-C 6-14 aryl-carbamoyl group” include phenylcarbamoyl, naphthylcarbamoyl, acenaphthylenylcarbamoyl, azulenylcarbamoyl, anthrylcarbamoyl, phenanthrylcarbamoyl, diphenylcarbamoyl and the like.
  • the “mono or di-C 6-14 aryl-thiocarbamoyl group” means a monovalent group in which one or two “C 6-14 aryl” groups are substituted on the thiocarbamoyl group. To do.
  • Examples of the “mono or di-C 6-14 aryl-thiocarbamoyl group” include phenylthiocarbamoyl, naphthylthiocarbamoyl, acenaphthylenylthiocarbamoyl, azulenylthiocarbamoyl, anthrylthiocarbamoyl, phenanthrylthiocarbamoyl, And diphenylthiocarbamoyl.
  • C 6-14 aryl-carbonyl means a monovalent group in which the above “C 6-14 aryl” group is bonded to carbonyl.
  • Examples of the “C 6-14 aryl-carbonyl” include benzoyl, naphthylcarbonyl, acenaphthylenylcarbonyl, azulenylcarbonyl, anthrylcarbonyl, phenanthrylcarbonyl and the like.
  • C 6-14 aryloxy-carbonyl means a monovalent group in which the “C 6-14 aryloxy” group is bonded to carbonyl.
  • Examples of the “C 6-14 aryloxy-carbonyl” include phenoxycarbonyl, naphthyloxycarbonyl, acenaphthylenyloxycarbonyl, azulenyloxycarbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl and the like.
  • C 6-14 aryloxy-carbonyloxy means a monovalent group in which the “C 6-14 aryloxy-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 6-14 aryloxy-carbonyloxy” include phenoxycarbonyloxy, naphthyloxycarbonyloxy, acenaphthylenylcarbonyloxy, azulenyloxycarbonyloxy, anthryloxycarbonyloxy, phenanthryloxy And carbonyloxy.
  • aryl C 1-6 alkyl means a monovalent group in which the “aryl” group is substituted on the “C 1-6 alkyl”.
  • Examples of the “aryl C 1-6 alkyl” include benzyl, naphthylmethyl, 2-phenylethyl, 1-phenylethyl, 1-phenylpropyl and the like.
  • aryl C 1-6 alkoxy means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to an oxygen atom.
  • examples of the “aryl C 1-6 alkoxy” include benzyloxy, naphthylmethyloxy, 2-phenylethyloxy, 1-phenylethyloxy, 1-phenylpropyloxy and the like.
  • aryl C 1-6 alkylsulfanyl means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to a sulfur atom.
  • Examples of the “aryl C 1-6 alkylsulfanyl” include benzylsulfanyl, naphthylmethylsulfanyl, 2-phenylethylsulfanyl, 1-phenylethylsulfanyl, 1-phenylpropylsulfanyl and the like.
  • aryl C 1-6 alkylsulfinyl means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to a sulfinyl group.
  • Examples of the “aryl C 1-6 alkylsulfinyl” include benzylsulfinyl, naphthylmethylsulfinyl, 2-phenylethylsulfinyl, 1-phenylethylsulfinyl, 1-phenylpropylsulfinyl and the like.
  • aryl C 1-6 alkylsulfonyl means the sulfonyl group "aryl C 1-6 alkyl” monovalent radical group is bonded.
  • Examples of the “aryl C 1-6 alkylsulfonyl” include benzylsulfonyl, naphthylmethylsulfonyl, 2-phenylethylsulfonyl, 1-phenylethylsulfonyl, 1-phenylpropylsulfonyl and the like.
  • aryl C 1-6 alkylsulfonyloxy means a monovalent group in which the “aryl C 1-6 alkylsulfonyl” group is bonded to an oxygen atom.
  • Examples of the “aryl C 1-6 alkylsulfonyloxy” include benzylsulfonyloxy, naphthylmethylsulfonyloxy, 2-phenylethylsulfonyloxy, 1-phenylethylsulfonyloxy, 1-phenylpropylsulfonyloxy and the like.
  • “mono or di-aryl C 1-6 alkylamino” means a monovalent group in which one or two “aryl C 1-6 alkyl” groups are substituted on the amino group.
  • Examples of the “mono or di-aryl C 1-6 alkylamino” include benzylamino, naphthylmethylamino, 2-phenylethylamino, 1-phenylethylamino, 1-phenylpropylamino, dibenzylamino and the like. It is done.
  • “mono or di-aryl C 1-6 alkyl-carbamoyl” means a monovalent group in which one or two “aryl C 1-6 alkyl” groups are substituted on the carbamoyl group.
  • Examples of the “mono- or di-aryl C 1-6 alkyl-carbamoyl” include benzylcarbamoyl, naphthylmethylcarbamoyl, 2-phenylethylcarbamoyl, 1-phenylethylcarbamoyl, 1-phenylpropylcarbamoyl, dibenzylcarbamoyl and the like. It is done.
  • “mono or di-aryl C 1-6 alkyl-thiocarbamoyl” is a monovalent group in which one or two “aryl C 1-6 alkyl” groups are substituted on a thiocarbamoyl group.
  • Examples of the “mono- or di-arylC 1-6 alkyl-thiocarbamoyl” include benzylthiocarbamoyl, naphthylmethylthiocarbamoyl, 2-phenylethylthiocarbamoyl, 1-phenylethylthiocarbamoyl, 1-phenylpropylthiocarbamoyl, di Examples thereof include benzylthiocarbamoyl.
  • arylC 1-6 alkoxy-carbonyl means a monovalent group in which the “arylC 1-6 alkoxy” group is bonded to carbonyl.
  • Examples of the “aryl C 1-6 alkoxy-carbonyl” include benzyloxycarbonyl, naphthylmethyloxycarbonyl, 2-phenylethyloxycarbonyl, 1-phenylethyloxycarbonyl, 1-phenylpropyloxycarbonyl and the like.
  • aryl C 1-6 alkoxy-carbonyloxy means a monovalent group in which the “aryl C 1-6 alkoxy-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “aryl C 1-6 alkoxy-carbonyloxy” include benzyloxycarbonyloxy, naphthylmethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 1-phenylpropyloxycarbonyl Examples include oxy.
  • aryl C 1-6 alkyl-carbonyl group means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to carbonyl.
  • Examples of the “aryl C 1-6 alkyl-carbonyl” include benzylcarbonyl, naphthylmethylcarbonyl, 2-phenylethylcarbonyl, 1-phenylethylcarbonyl, 1-phenylpropylcarbonyl and the like.
  • the “aryl C 1-6 alkyl-carbonyloxy group” means a monovalent group in which the “aryl C 1-6 alkyl-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “aryl C 1-6 alkyl-carbonyloxy” include benzylcarbonyloxy, naphthylmethylcarbonyloxy, 2-phenylethylcarbonyloxy, 1-phenylethylcarbonyloxy, 1-phenylpropylcarbonyloxy and the like. .
  • the “heterocyclic group” is a 3 to 14 member (monocyclic, bicyclic or tricyclic system) containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • a heterocyclic group means an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • the “aromatic heterocyclic group” means a monovalent or divalent 5- to 14-membered monocyclic ring containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Means an aromatic heterocyclic group and a fused aromatic heterocyclic group.
  • the condensed aromatic heterocyclic group in the present invention is a 2 or 3 ring system, and a plurality of rings may have heteroatoms.
  • the monocyclic aromatic heterocyclic group includes a 5- or 6-membered ring group, and the condensed aromatic heterocyclic group includes a group in which each ring constituting the group is a 5- or 6-membered ring.
  • aromatic heterocyclic group examples include 5- or 6-membered members such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like.
  • non-aromatic heterocyclic group is a monovalent or divalent 3- to 14-membered single atom containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. It means a cyclic non-aromatic heterocyclic group and a fused non-aromatic heterocyclic group.
  • the fused non-aromatic heterocyclic group in the present invention is a 2 or 3 ring system and may have a hetero atom in both rings.
  • Examples of the monocyclic non-aromatic heterocyclic group include 3- to 9-membered cyclic groups (preferably 4- to 7-membered cyclic groups), and the condensed non-aromatic heterocyclic group includes each ring constituting the group. Group in which is a 5- or 6-membered ring.
  • non-aromatic heterocyclic group examples include oxetanyl (eg, 3-oxetanyl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), Dioxolanyl (eg, 1,3-dioxolan-4-yl), oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl),
  • examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic group”.
  • heterocyclic carbonyl means a monovalent group in which the “heterocyclic group” is bonded to carbonyl.
  • Preferable examples of the “heterocyclic carbonyl” include morpholinocarbonyl, piperidinocarbonyl and the like.
  • heterocyclic carbonyloxy means a monovalent group in which the “heterocyclic carbonyl” group is bonded to an oxygen atom.
  • Suitable examples of the “heterocyclic carbonyloxy” include, for example, tetrahydropyran-4-ylcarbonyloxy, piperidin-4-ylcarbonyloxy, pyrrolidin-2-ylcarbonyloxy, azetidin-3-ylcarbonyloxy Etc.
  • C 1-6 alkyl-carbonyl means a monovalent group in which the “C 1-6 alkyl” group is bonded to carbonyl.
  • Examples of the “C 1-6 alkyl-carbonyl” include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isopentanoyl, 1-methylbutyryl, pivaloyl, hexanoyl, isohexanoyl, 3,3-dimethylbutyryl, 1 -Ethylbutyryl, 4-methylhexanoyl, heptanoyl and the like.
  • C 1-6 alkyl-carbonyloxy means a monovalent group in which the “C 1-6 alkyl-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 1-6 alkyl-carbonyloxy” include acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, isopentanoyloxy, 1-methylbutyryloxy, pivaloyloxy, hexanoyloxy Isohexanoyloxy, 3,3-dimethylbutyryloxy, 1-ethylbutyryloxy, 4-methylhexanoyloxy, heptanoyloxy and the like.
  • aryl-carbonyloxy means a monovalent group in which the “aryl-carbonyl” group is bonded to an oxygen atom.
  • aryl-carbonyloxy include C 6-14 aryl-carbonyloxy such as benzoyloxy.
  • C 1-6 alkoxy-carbonyloxy means a monovalent group in which the “C 1-6 alkoxy-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 1-6 alkoxy-carbonyloxy” include, for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert- Examples include butoxycarbonyloxy, pentyloxycarbonyloxy, isopentyloxycarbonyloxy, neopentyloxycarbonyloxy, 1-ethylpropyloxycarbonyloxy, hexyloxycarbonyloxy and the like.
  • C 3-8 cycloalkyl-carbonyloxy means a monovalent group in which the “C 3-8 cycloalkyl-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkyl-carbonyloxy” include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, cycloheptylcarbonyloxy and the like.
  • C 3-8 cycloalkyloxy means a monovalent group in which the “C 3-8 cycloalkyl group” is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkyloxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like.
  • C 3-8 cycloalkyloxy-carbonyl means a monovalent group in which the “C 3-8 cycloalkyloxy group” is bonded to carbonyl.
  • Examples of the “C 3-8 cycloalkyloxy-carbonyl” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl and the like.
  • C 3-8 cycloalkyloxy-carbonyloxy means a monovalent group in which the “C 3-8 cycloalkyloxy-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkyloxy-carbonyloxy” include cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy and the like.
  • the “heterocyclic C 1-6 alkyl” means a monovalent group in which the “heterocyclic group” is substituted on the “C 1-6 alkyl”.
  • Suitable examples of the “heterocyclic C 1-6 alkyl” include, for example, azetidin-1-ylmethyl, morpholin-4-ylmethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, tetrahydropyran-4-yl and the like. Is mentioned.
  • heterocyclic oxy means a monovalent group in which the “heterocyclic group” is bonded to an oxygen atom.
  • Preferable examples of the “heterocyclic oxy” include, for example, tetrahydropyran-2-yloxy and the like.
  • heterocyclic sulfanyl means a monovalent group in which the “heterocyclic group” is bonded to a sulfur atom.
  • heterocyclic sulfanyl include, for example, tetrahydropyran-2-ylsulfanyl and the like.
  • heterocyclic sulfinyl means a monovalent group in which the “heterocyclic group” is bonded to a sulfinyl group.
  • Preferable examples of the “heterocyclic sulfinyl” include, for example, tetrahydropyran-2-ylsulfinyl and the like.
  • heterocyclic sulfonyl means a monovalent group in which the “heterocyclic group” is bonded to a sulfonyl group.
  • Preferable examples of the “heterocyclic sulfonyl” include, for example, tetrahydropyran-2-ylsulfonyl and the like.
  • heterocyclic sulfonyloxy means a monovalent group in which the “heterocyclic sulfonyl” group is bonded to an oxygen atom.
  • heterocyclic sulfonyloxy examples include tetrahydropyran-2-ylsulfonyloxy and the like.
  • heterocyclic oxycarbonyl means a monovalent group in which the “heterocyclic oxy group” is bonded to carbonyl.
  • examples of the “heterocyclic oxycarbonyl” include tetrahydropyran-4-yloxycarbonyl and the like.
  • “mono or di-heterocyclic amino” means a monovalent group in which one or two “heterocyclic groups” are substituted on the amino group.
  • Examples of the “mono or di-heterocyclic amino” include pyrrolidinylamino, piperidylamino and the like.
  • “mono or di-heterocyclic carbamoyl” means a monovalent group in which one or two “heterocyclic groups” are substituted on a carbamoyl group.
  • Examples of the “mono or di-heterocyclic carbamoyl” include pyrrolidinylcarbamoyl, piperidylcarbamoyl and the like.
  • “mono or di-heterocyclic thiocarbamoyl” means a monovalent group in which one or two “heterocyclic groups” are substituted on a thiocarbamoyl group.
  • Examples of the “mono or di-heterocyclic thiocarbamoyl” include pyrrolidinylthiocarbamoyl, piperidylthiocarbamoyl and the like.
  • heterocyclic oxycarbonyloxy means “heterocyclic oxycarbonyloxy” in which the heterocyclic moiety is the “heterocyclic group”.
  • heterocyclic oxycarbonyloxy include, for example, tetrahydropyran-4-yloxycarbonyloxy and the like.
  • substituents of each group of “which may be further substituted” in the definition of ring A, X and ring B in formula (I) include substituents selected from the following substituent group ⁇ .
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • the above substituent may be further substituted with the above substituent.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • the substituent may further include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 6-14 aryl group, a complex Ring group, halogen atom, hydroxy group, carboxy group, formyl group, amino group, carbamoyl group, cyano group, nitro group, oxo group, C 1-6 alkylsulfonyl group, C 6-14 arylsulfonyl group, C 1-6 Alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group and the like (preferably C 1-6 alkyl group, C 1-6 alkoxy group, halogen atom, hydroxy group, carboxy group, formyl group, amino group, di-C 1-6 alkylamino group, a carbamoyl group, a cyano group, a nitro group, an ox
  • Ring A represents a phenyl group or a 6-membered monocyclic nitrogen-containing heterocyclic group (eg, pyridyl group, piperidyl group, piperazinyl group, etc.) which may be further substituted.
  • a 6-membered monocyclic nitrogen-containing heterocyclic group eg, pyridyl group, piperidyl group, piperazinyl group, etc.
  • Ring A is preferably a phenyl group or a pyridyl group, each of which may be further substituted, and more preferably a phenyl group that may be further substituted.
  • a preferred example of ring A is: (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a carboxy group, (c) a hydroxy group, (d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group, (e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl) A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
  • a more preferred specific example of ring A is (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy), (4) a C 1-6 alkyl-carbonyl group (preferably acetyl), (5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl
  • ring A are: (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group, A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted with 1 to 3 substituents selected from (3) A phenyl group which may be further substituted with 1 to 3 substituents selected from a cyano group.
  • a halogen atom preferably a fluorine atom or a chlorine atom
  • a halogen atom preferably a fluorine atom
  • a hydroxy group preferably methyl, ethyl, propyl, isopropyl
  • X represents a single bond, a divalent 4- to 7-membered monocyclic heterocyclic group which may be further substituted (eg, oxadiazolyl group, furyl group, thienyl group, triazolyl group, oxazolyl group, pyrazolyl group, imidazolyl group) , A divalent group derived from a thiazolyl group, a pyridyl group, a pyrimidyl group, a piperidyl group, a piperazinyl group, etc.) or a C 2-6 alkynylene group (eg, an ethynylene group) which may be further substituted.
  • a divalent 4- to 7-membered monocyclic heterocyclic group which may be further substituted
  • X is preferably a single bond or an optionally substituted divalent 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxadiazolyl group, furyl group, thienyl group, triazolyl group, oxazolyl group)
  • a cyclic aromatic heterocyclic group eg, a divalent group derived from an oxadiazolyl group, a furyl group, a thienyl group, a triazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, and the like).
  • Suitable examples of X are a single bond, or (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a carboxy group, (c) a hydroxy group, (d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group, (e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl) A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents
  • a more preferred specific example of X is a single bond, or (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy), (4) a C 1-6 alkoxy-carbonyl group, (5) a carbamoyl group optionally mono- or di-substituted with a
  • a particularly preferred example of X is a single bond, or (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group, A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from: (3) a C 1-6 alkoxy-carbonyl group, (4) a carbamoyl group, (5) a cyano group, and (6) A divalent 5-membered monocyclic aromatic heterocyclic group (preferably an oxadiazolyl group, an oxazolyl group, a thiazolyl group) which may be further substituted with 1 to 3 substituents selected from a carboxy group A divalent group derived from a group, a triazolyl group and a pyrazolyl group).
  • a halogen atom preferably
  • Ring B represents an aryl group (eg, phenyl group, naphthyl group, anthranyl group, etc.) or heterocyclic group, each of which may be further substituted.
  • aryl group eg, phenyl group, naphthyl group, anthranyl group, etc.
  • heterocyclic group each of which may be further substituted.
  • Ring B is preferably a C 6-10 aryl group (eg, phenyl group, naphthyl group), 5- or 6-membered monocyclic heterocyclic group (eg, pyridyl group, pyrazinyl group), each of which may be further substituted.
  • aryl group eg, phenyl group, naphthyl group
  • 5- or 6-membered monocyclic heterocyclic group eg, pyridyl group, pyrazinyl group
  • an 8- to 14-membered condensed heterocyclic group eg, pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzooxazolyl group, pyridopyrazinyl group, etc.
  • a further substituted phenyl group or 8- to 14-membered condensed aromatic heterocyclic group eg, pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzoxazolyl group, pyridopyrazinyl group
  • Suitable examples of ring B are: (1) a halogen atom (preferably a fluorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a carboxy group, (c) a hydroxy group, (d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group, (e) an oxo group, (f) a cyano group, and (g) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-) optionally substituted with 1 to 3 substituents selected from a heterocyclic group Butyl, tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl) A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substitu
  • a more preferred specific example of ring B is (1) a halogen atom (preferably a fluorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) a dimethylamino group, (d) an oxo group, (e) a cyano group, and (f) a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from 4- to 7-membered monocyclic nitrogen-containing heterocyclic groups (preferably Methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy), (4) a C 1-6 alkyl-carbonyl group (
  • a particularly preferred embodiment of ring B is (1) a halogen atom (preferably a fluorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a dimethylamino group, (c) a hydroxy group, and (d) a 4- to 7-membered monocyclic nitrogen-containing heterocyclic group (preferably an azetidinyl group, a morpholinyl group, a pyrrolidinyl group)
  • a C 1-4 alkyl group preferably methyl, ethyl, propyl, isopropyl
  • substituents selected from: (3) a C 1-6 alkyl-carbonyl group (preferably acetyl), (4) hydroxy group, (5) an oxo group, (6) a cyano group, (7) a nitro group, and (8) a 4- to 7-membered monocyclic nitrogen-containing heterocyclic group (preferably a 4-methylpiperazin-1-
  • Ring A is (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a carboxy group, (c) a hydroxy group, (d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group, (e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl) A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by
  • Ring A is (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl), (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy), (4) a C 1-6 alkyl-carbonyl group (preferably acetyl), (5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
  • Ring A is (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group, A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted with 1 to 3 substituents selected from (3) a phenyl group which may be further substituted with 1 to 3 substituents selected from a cyano group;
  • X is a single bond, or (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group, A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from: (3) a C 1-6 alkoxy-carbony
  • compound (I) include, for example, the following examples and the compounds of Examples 1 to 59 described in Table 1-1 to Table 1-5 (hereinafter also referred to as compounds 1 to 59).
  • compounds 1 to 59 include, for example, the following examples and the compounds of Examples 1 to 59 described in Table 1-1 to Table 1-5 (hereinafter also referred to as compounds 1 to 59).
  • N- (4- ⁇ 5- (2-fluorophenyl) [1,2,4] oxadiazol-3-yl ⁇ phenyl) sulfamide compound 1
  • compound 2 N- ⁇ 4- [1- (2-fluorophenyl) -1H-pyrazol-4-yl] phenyl ⁇ sulfamide
  • Compound 3 N- [4- ⁇ 2- (2-fluorophenyl) -4-methyloxazol-5-yl ⁇ phenyl] sulfamide
  • Compound 5 N- ⁇ 4- [4- (2-fluorophenyl) imida
  • the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I).
  • Compound (I) of the present invention can be converted to a pharmaceutically acceptable salt thereof by a method known per se.
  • the compound (I) of the present invention has an acidic group or basic group, it can be converted into a basic salt or acidic salt by reacting with a base or acid.
  • the pharmaceutically acceptable “basic salt” of the compound (I) of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; alkaline earth salt such as magnesium salt or calcium salt.
  • Metal salts N-methylmorpholine salt, ethanolamine salt, piperazine salt, diethylamine salt, triethylamine salt, tributylamine salt, tert-butylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, meglumine salt, tromethamine Salt, choline salt, benzathine salt, 4-phenylcyclohexylamine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salt such as picoline salt or glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, asparagine Like salt
  • a Bruno acid salt preferably an alkali metal salt.
  • the pharmaceutically acceptable “acid salt” of the compound (I) of the present invention is preferably a hydrogen halide such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide.
  • Inorganic acid salts such as acid salts, nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate
  • Aryl sulfonates such as p-toluenesulfonate, acetate, trifluoroacetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate,
  • Organic acid salts such as maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate
  • the compound of the present invention can be produced by applying various known production methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
  • it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group.
  • Examples of such a functional group include an amino group, a hydroxyl group, and a carboxy group.
  • protective groups for these functional groups include Protective Groups in Organic Synthesis (3rd edition, 1999) by TW Greene and PG Wuts. May be appropriately selected depending on these reaction conditions. According to such a method, after carrying out the reaction by introducing the substituent, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
  • the prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can.
  • the reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
  • the manufacturing method is not limited to the following method.
  • the raw material compound in each reaction can obtain and use a commercially available thing easily, or can also manufacture it according to a method known per se, or a method according to it. .
  • Production Method 1 is a method for producing Compound (I) of the present invention by converting —NH 2 of Compound (1) into —NHSO 2 NH 2 .
  • compound (1) and compound (2) are reacted in an inert solvent by a method known per se to obtain compound (3), and then the t-butoxycarbonyl group of compound (3) is itself
  • compound (I) is produced by desorption by a known method.
  • reaction of compound (1) and compound (2) is carried out by using triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene
  • Organic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate and other alkali metal carbonates may be used in the presence of a base.
  • Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Halogenated hydrocarbons, or mixtures
  • the amount of compound (2) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • the compound (2) used in this production method can be produced according to a method known per se in which chlorosulfonyl isocyanate and t-butyl alcohol are reacted or a method analogous thereto.
  • the manufacturing method of the compound (1) used in the manufacturing method 1 is shown below.
  • Production Method 2 is a method for producing Compound (1a) of the present invention in which X in Compound (1) is 1,2,4-oxadiazole.
  • Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
  • reaction between the compound (4) and the compound (5) is carried out in an inert solvent by a method known per se.
  • inert solvent examples include those described above.
  • the amount of compound (5) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (4).
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • the reaction between the compound (6) and the compound (7) is a method known per se, for example, a method in which the compound (6) and the compound (7) are directly condensed, or the reactivity between the compound (6) and the compound (7). This is performed using a method of reacting with a derivative.
  • the method of directly condensing the compound (6) and the compound (7) is performed in an inert solvent in the presence of a condensing agent.
  • a condensing agent examples include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4 Carbodiimide compounds such as -diethylaminocyclohexyl) carbodiimide; azolide compounds such as N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole; condensing agents such as phosphorus compounds such as diethyl cyanophosphate and diphenylphosphoryl azide It is done.
  • Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Halogenated hydrocarbons, or mixtures
  • the amount of compound (7) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (6).
  • the amount of the condensing agent to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (7).
  • a condensation accelerator for example, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • the reaction yield can be improved.
  • the reaction yield can be improved by adding an organic base such as triethylamine or N, N-diisopropylethylamine as necessary.
  • azolide compound when used as a condensing agent, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, etc. It is desirable to carry out the reaction in the presence of a base such as an alkali metal carbonate such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, or cesium carbonate.
  • a base such as an alkali metal carbonate such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, or cesium carbonate.
  • the amount of the above condensation accelerator, organic base and alkali metal carbonate to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (7).
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • examples of the reactive derivative of the compound (7) include acid halides such as acid chloride and acid bromide; acid anhydrides; dialkyl phosphoric acid Such as substituted phosphoric acid, mixed acid anhydride with chlorocarbonate such as methyl chlorocarbonate, ethyl chlorocarbonate or isobutyl chlorocarbonate; active amide with imidazole; ester such as cyanomethyl ester, 4-nitrophenyl ester, etc. Can be mentioned.
  • the acid halide When the acid halide is used as the reactive derivative of compound (7), it is usually carried out in an inert solvent in the presence of a base.
  • the base used in the reaction is not particularly limited, and is an organic base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine; sodium carbonate, sodium hydrogen carbonate, potassium carbonate, hydrogen carbonate Examples include alkali metal carbonates such as potassium and cesium carbonate.
  • Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Halogenated hydrocarbons, or mixtures
  • the amount of compound (7) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (6).
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • the compound (7) and the substituted phosphoric acid or chlorocarbonate are converted into a base (for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N , N-dimethylaniline; an organic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) to make a reactive derivative, and further react with compound (6).
  • a base for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N , N-dimethylaniline; an organic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.
  • the amount of compound (7) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (6).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually ⁇ 30 to 150 ° C. and the reaction time is 30 minutes to 20 hours.
  • Production method 3 is a method for producing compound (1b) in which X in compound (1) is 1,2,3-triazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
  • compound (9) is reacted with sodium azide in an inert solvent by a method known per se to obtain compound (10), and the obtained compound (10) is compounded with compound (11) as described above.
  • compound (12) is obtained by reacting in an inert solvent by a method known per se, and then reducing the nitro group of compound (12) by a method known per se. .
  • the reaction between compound (9) and sodium azide may be performed in the presence of ascorbic acid and copper sulfate.
  • the amount of sodium azide to be used is generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound (9).
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • Production method 4 is a method for producing compound (1c) in which X in compound (1) is 1,2,3-triazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
  • Production method 4 is a method for producing compound (1c) by reacting compound (13) and compound (14) in an inert solvent by a method known per se. This production method is carried out by subjecting the reaction to the same reaction as described in Production Method 3.
  • Production Method 5 is a method for producing Compound IV (1d) in which X in Compound (1) is oxazole.
  • Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
  • This production method was obtained by reacting compound (15) and compound (16) in the presence of silver trifluoromethanesulfonate to obtain compound (17) or amination of compound (15) with hexamethylenetetramine or the like.
  • Compound (18) and compound (7) are reacted to obtain compound (19), and the obtained compound (19) is cyclized with phosphorus oxychloride to obtain compound (17), and then nitro of compound (17)
  • Each step of the production method can be carried out by a method known per se in an inert solvent.
  • the inert solvent used include those described above.
  • reaction of a compound (18) and a compound (7) can be performed on the conditions similar to reaction with the compound (6) and the compound (7) of the manufacturing method 2.
  • the compound (1d * ) and the compound (1d ** ) in which X in the compound (1) is oxazole can be produced according to production method 5.
  • Production method 6 is a method for producing compound (1e) in which X in compound (1) is imidazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
  • the compound (20) is reacted with formamide, the obtained compound (21) is reacted with the compound (22) to obtain a compound (23), and then the nitro group of the compound (23) is known per se.
  • This is a method for producing a compound (1e) by reduction by a method.
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 7 is a method for producing compound (1f) in which X in compound (1) is imidazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
  • compound (15) and compound (24) are reacted to obtain compound (25), and then the nitro group of compound (25) is reduced by a method known per se to produce compound (1f). It is.
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • Production Method 8 is a method for producing Compound (1g) in which X in Compound (1) is 1,3,4-oxadiazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
  • the compound (26) and the compound (27) are reacted, and then the obtained compound (28) is cyclized with thionyl chloride to obtain a compound (29), and then the nitro group of the compound (29) is removed.
  • This is a method for producing a compound (1 g) by reduction by a method known per se.
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • Production Method 9 is a method for producing Compound IV (1h) in which X in Compound (1) is isoxazole.
  • Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
  • the compound (30) is reacted with hydroxylamine, the obtained compound (31) is chlorinated with N-chlorosuccinimide, the obtained compound (32) and the compound (33) are reacted, and the compound (34 Then, the nitro group of compound (34) is reduced by a method known per se to produce compound (1h).
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 10 is a method for producing compound (1i) in which X in compound (1) is isoxazol-3-one.
  • the compound (35) is reacted with triethyl phosphonoacetate, the obtained compound (36) is brominated with bromine, the obtained compound (37) is reacted with hydroxylamine, and the obtained compound (38 ) And compound (22) are obtained to obtain compound (39), and then the nitro group of compound (39) is reduced by a method known per se to produce compound (1i).
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 11 is a method for producing compound (1j) in which X in compound (1) is pyrazole.
  • the compound (40) is reacted with pyrazole, the obtained compound (41) is brominated with bromine, and then the obtained compound (42) and the compound (43) are coupled using an organometallic catalyst.
  • This is a method for producing a compound (1j) by subjecting to a reaction.
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • reaction of the compound (42) and the compound (43) is carried out in an inert solvent, if necessary, in the presence of a base. Moreover, you may perform reaction of a compound (42) and a compound (43) in presence of a phosphine ligand as needed. Examples of the inert solvent used include those described above.
  • organometallic catalyst examples include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
  • Examples of the base include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate; metal hydrides such as potassium hydride and sodium hydride.
  • phosphine ligand examples include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl and the like.
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • Production method 12 is a method for producing compound (1k) in which X in compound (1) is a single bond and B is imidazo [1,2-a] pyridine.
  • compound (15) and compound (44) are reacted to obtain compound (45), and then the nitro group of compound (45) is reduced by a method known per se to produce compound (1k). It is.
  • Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 13 is a method for producing compound (1 l) in which X in compound (1) is a single bond and B is quinazoline.
  • compound (30) and compound (46) are reacted to obtain compound (47), and then the nitro group of compound (47) is reduced by a method known per se to produce compound (1l). It is.
  • This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 14 is a method for producing compound (1 m) in which X in compound (1) is a single bond and B is chromen-4-one.
  • compound (48) and compound (49) are reacted to obtain compound (50), and then the nitro group of compound (50) is reduced by a method known per se to produce compound (1m). It is.
  • This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 15 is a method for producing compound (1n) in which X in compound (1) is ethynylene.
  • compound (9) and compound (40) are subjected to a coupling reaction using an organometallic catalyst to obtain compound (51), and then the nitro group of compound (51) is obtained by a method known per se.
  • Reduction is a method for producing a compound (1n).
  • This production method is carried out in an inert solvent, if necessary, in the presence of a base. Moreover, you may perform this manufacturing method in presence of a phosphine ligand as needed. Examples of the inert solvent used include those described above.
  • organometallic catalyst examples include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
  • Examples of the base include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate; metal hydrides such as potassium hydride and sodium hydride.
  • phosphine ligand examples include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl and the like.
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from ⁇ 30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
  • Production method 16 is a method for producing compound (1o) of the present invention in which X in compound (1) is a single bond and B is naphthalene.
  • compound (52) and compound (53) are subjected to a coupling reaction using an organometallic catalyst to obtain compound (54), and then the nitro group of compound (54) is obtained by a method known per se.
  • compound (43) and compound (55) are subjected to a coupling reaction using an organometallic catalyst to produce compound (1o).
  • This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
  • Production method 17 is a method for producing compound (1p) in which X in compound (1) is a single bond and B is quinoline.
  • This production method is a method for producing the compound (1p) by subjecting the compound (43) and the compound (56) to a coupling reaction using an organometallic catalyst. This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
  • Production method 18 is a method for producing compound (1q) in which X in compound (1) is pyrimidine.
  • the compound (57) and the compound (58) are subjected to a coupling reaction using an organometallic catalyst, and the resulting compound (59) and the compound (43) are coupled using an organometallic catalyst.
  • Each process of this manufacturing method is performed by attaching
  • Production method 19 is a method for producing compound (1r) in which X in compound (1) is a single bond and B is quinoxaline.
  • This production method is a method for producing compound (1r) by subjecting compound (43) and compound (60) to a coupling reaction using an organometallic catalyst. This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
  • Production method 20 is a method for producing compound (1s) in which X in compound (1) is pyrazine.
  • the compound (61) and the compound (58) are subjected to a coupling reaction using an organometallic catalyst, and the obtained compound (62) and the compound (43) are further combined with a cup using an organometallic catalyst.
  • This is a method for producing a compound (1s) by subjecting it to a ring reaction. Each process of this manufacturing method is performed by attaching
  • Production method 21 is a method for producing compound (1t) in which X in compound (1) is a single bond and B is benzoxazole.
  • This production method is a method for producing compound (1t) by subjecting compound (43) and compound (63) to a coupling reaction using an organometallic catalyst. This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
  • Production method 22 is a method for producing compound (1u) in which X in compound (1) is a single bond and B is 4-oxo-1,4-dihydroquinoline.
  • compound (9) and compound (64) are reacted to obtain compound (65), and then the nitro group of compound (65) is reduced by a method known per se to produce compound (1u). It is.
  • This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
  • Production Method 23 is a method for producing Compound IV (1v) in which X in Compound (1) is thiazole.
  • the compound (66) and the compound (58) are subjected to a coupling reaction using an organometallic catalyst, the obtained compound (67) is brominated with N-bromosuccinimide, and then the obtained compound (68) and compound (43) are subjected to a coupling reaction using an organometallic catalyst to produce compound (1v).
  • the reaction between compound (66) and compound (58) and the reaction between compound (68) and compound (43) are the same as the reaction between compound (42) and compound (43) described in production method 11. It is done by attaching to.
  • Production method 24 is a method for producing compound (1w) in which X in compound (1) is 1,2,4-triazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
  • compound (69) and compound (35) are reacted to obtain compound (70), and then the nitro group of compound (70) is reduced by a method known per se to produce compound (1w). It is.
  • This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
  • Production method 25 is a method for producing the present compound (1x) in which X in compound (1) is a single bond and B is pyrido [3,4-b] pyrazine. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
  • the compound (71) is oxidized with selenium dioxide, the resulting compound (72) and the compound (73) are reacted to obtain a compound (74), and then the nitro group of the compound (74) is known per se.
  • This is a method for producing a compound (1x) by reduction by a method.
  • This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
  • inorganic acid hydrogen chloric acid, sulfuric acid, hydrobromic acid, etc.
  • organic acid methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid
  • Oxalic acid fumaric acid, maleic acid, tartaric acid, etc.
  • inorganic bases alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium
  • organic bases trimethylamine, triethylamine, pyridine, A salt with picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine, etc.
  • the compound when the raw material compound can form a salt, the compound may be used as a salt.
  • a salt for example, those exemplified as the salt of compound (I) (pharmaceutically acceptable salt) are used.
  • the compound (I) of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like. Further, when the compound (I) of the present invention or the intermediate of production has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography. The isomer can also be produced by asymmetric synthesis. As a reference for a method for resolving an optical isomer from a racemate, there can be mentioned “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
  • the compound (I) of the present invention has low toxicity, and can be used alone or in admixture with a pharmaceutically acceptable carrier to make a pharmaceutical composition so that mammals (eg, mice, rats, hamsters, rabbits, cats) , Dogs, cows, sheep, monkeys, humans, etc.).
  • mammals eg, mice, rats, hamsters, rabbits, cats
  • the compound of the present invention is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
  • Examples of the pharmaceutically acceptable carrier to be blended in the pharmaceutical composition of the present invention include, for example, excipients (for example, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (for example, starch, gum arabic, Carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.), disintegrating agents (eg, carboxymethyl cellulose, talc, etc.) and the like.
  • excipients for example, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.
  • binders for example, starch, gum arabic, Carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • disintegrating agents eg, carboxymethyl cellulose, talc, etc.
  • the mixture After mixing Compound (I) and, if necessary, a pharmaceutically acceptable carrier, the mixture is used for oral administration such as capsules, tablets, fine granules, granules, dry syrup, etc., according to a method known per se, or It can be set as the formulation for parenteral administration, such as an injection and a suppository.
  • the content of compound (I) in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 100% by weight, preferably about 0.1 to the total preparation. The range is from about 50 to 50% by weight, and more preferably about 0.5 to 20% by weight.
  • the pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
  • the preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives.
  • parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like.
  • the preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives.
  • Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
  • the dose of the compound (I) of the present invention varies depending on the symptoms, age, body weight, type of drug to be administered in combination and the dose, etc., but is usually an equivalent amount of the compound (I) and one adult (body weight of about 60 kg).
  • it in the range of 0.001-1000 mg at a time, systemically or locally, month: once to several times, week: once to several times, day: once to several times, oral or parenteral
  • it is administered or administered intravenously in the range of 1-24 hours per day.
  • the solvent was distilled off under reduced pressure to obtain 0.40 g of a fine brown powder.
  • 0.40 g of the obtained fine brown powder was suspended in 5 mL of methylene chloride, 1 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5.5 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried (Na 2 SO 4 ).
  • Formamide 11.0 mL and water 1.00 mL were added and suspended in 4.67 g of the obtained light brown oily substance, and the mixture was stirred at 140 ° C. for 2.5 hours. After cooling to room temperature, the insoluble material was filtered off, and 30 mL of 1 M aqueous sodium hydroxide was added to adjust to pH 10. The aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 9: 1, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain a light brown powder.
  • 8 mL of t-butyl methyl ether was added, the insoluble material was collected by filtration, and further washed twice with 5 mL of n-hexane to give N- ⁇ 4- [4- (2-fluorophenyl) 208 mg (25% yield) of a light brown powder of imidazol-1-yl] phenyl ⁇ sulfamide was obtained.
  • the solvent was distilled off under reduced pressure to obtain 2.87 g of a pale red powder.
  • the obtained pale red powder (2.75 g) was suspended in a mixture of tetrahydrofuran (58 mL) and water (14 mL), and 2-bromo-1- (4-nitrophenyl) ethanone 3.49 g (13.2 mmol), sodium hydrogen carbonate 4.81 g (48.0 mmol) was added and heated to reflux for 2.5 hours. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure to obtain 0.19 g of a light brown powder.
  • 0.19 g of the obtained light brown powder was suspended in 3 mL of methylene chloride, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1.5 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction solution for neutralization, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 ⁇ 9: 1 ⁇ 1: 1, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure, 5 mL of methylene chloride was added to the residue, the insoluble material was collected by filtration, and washed with 10 mL of methylene chloride. Further, it was washed with 10 mL of t-butyl methyl ether, and 70 mg (yield 46%) of 4- [2- (2-fluorophenyl) -3H-imidazol-4-yl] phenylsulfamide as a gray powder was obtained. Obtained.
  • 2-amino-1- (4-nitrophenyl) ethanone hydrochloride prepared in (11-1) 3.96 g (18.3 mmol) and 2-fluorobenzoic acid 2.56 g (18.3 mmol) were suspended in 50 mL of methylene chloride, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 4.21 g (21.9 mmol), 1-hydroxybenzotriazole 2.96 g (21.9 mmol) and triethylamine 3.8 mL (27 mmol) were added. Stir. Water and chloroform were added to the reaction solution, the insoluble material was filtered off, and the two layers were separated.
  • the organic layer was washed successively with 5% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting residue, and the insoluble material was collected by filtration to obtain 1.31 g of a yellow powder.
  • 300 mg of the obtained yellow powder was suspended in 13 mL of phosphorus oxychloride and heated to reflux for 2 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure to obtain 0.20 g of a light brown powder.
  • 0.20 g of the obtained light brown powder was suspended in 5 mL of methylene chloride, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 2 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 95: 5, V / V).
  • the solvent was distilled off under reduced pressure to obtain 0.70 g of a fine brown powder.
  • 0.70 g of the obtained fine brown powder was suspended in 5 mL of methylene chloride, 1 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5.5 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure to obtain 310 mg of a yellow powder.
  • 310 mg of the obtained yellow powder was suspended in 2 mL of methylene chloride, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 0.5 hour.
  • the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate.
  • the organic layers were combined, washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure.
  • the residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 2 ⁇ 1: 4, V / V), and the solvent of the target fraction was evaporated under reduced pressure.
  • the organic layer was washed with saturated brine and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure to obtain 547 mg of orange powder.
  • the resulting orange powder (547 mg) was suspended in methylene chloride (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 0.5 hr.
  • the solvent was distilled off under reduced pressure, 10 mL of chloroform was added to the residue, and insolubles were collected by filtration.
  • Example 16 673 mg (1.66 mmol) of ethyl 2- (2-fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4-carboxylate prepared in (16-3) was suspended in 7 mL of methanol. The mixture became cloudy, 7 mL of tetrahydrofuran and 1.0 mL (5.0 mmol) of 5.0 M aqueous sodium hydroxide were added, and the mixture was stirred at room temperature for 20 minutes, and further stirred at 40 ° C. for 1.5 hours.
  • Insoluble material was collected by filtration.
  • the obtained powder was washed successively with 10 mL of water and 10 mL of chloroform-n-hexane (1: 1) to obtain 339 mg of a light brown powder.
  • 339 mg of the obtained fine brown powder was suspended in 2 mL of methylene chloride, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 18 hours.
  • Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the precipitate was collected by filtration.
  • the obtained powder was dissolved in 2.0 M aqueous sodium hydroxide and washed 3 times with chloroform.
  • 1-azido-2-fluorobenzene prepared in (19-1) 1.08 g (7.89 mmol) was dissolved in 10 mL of t-butanol, 10 mL of water, 924 mg (7.89 mmol) of 4-ethynylaniline, L-ascorbine Sodium 156 mg (0.789 mmol) and copper sulfate pentahydrate 20 mg (0.079 mmol) were added, and the mixture was stirred at 60 ° C. for 27 hours.
  • reaction solution was washed with saturated aqueous ammonium chloride and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure to obtain 970 mg of a light brown powder.
  • 970 mg of the obtained light brown powder was suspended in 3 mL of methylene chloride, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour.
  • Examples 22 to 59 shown in Table 1-1 to Table 1-5 below were synthesized according to Examples 1 to 21.
  • Test Example 1 Luciferase assay A gene having a Kozak sequence (gccacc) and an initiation codon (ATG) at the 5 'end of 38 bp around the Q70X mutation of IDUA (NM_000203.4) was synthesized. After cutting with EcoRV of pNLF1-C [CMV / Hygro] Vector (Promega, Madison, WI) and ligating the synthesized gene, the plasmid vector (IDUA-Q70X-Luc ) HeLa cells were cultured in MEM medium (Nacalai Tesque Cat. No. 21443-15) containing 10% fetal calf serum under conditions of 37 ° C. and 5% CO 2 .
  • MEM medium Nacalai Tesque Cat. No. 21443-15
  • the cells were transfected with a plasmid vector (IDUA-Q70X-Luc) using FuGENE HD Transfection Reagent (Promega, Madison, Wis.). From the next day, Hygromycin B (Nacalai Tesque Cat. No. 09287-84) was added and cultured under conditions of 37 ° C. and 5% CO 2 for about 2 weeks to select stably expressing cells. Prepared stably expressing cells in 96-well white half area plate (Greiner) in MEM medium (Nacalai Tesque Cat. No. 21443-15) containing 10% fetal calf serum 1 ⁇ 10 4 cells / 50 ⁇ L / well Seeded at a cell density of.
  • MEM medium Nacalai Tesque Cat. No. 21443-15
  • each test compound was added to a final concentration of 0.001 to 100 ⁇ M.
  • DMSO at a final concentration of 0.1% (v / v) was added to the control.
  • the cells were cultured for 48 hours at 37 ° C. under 5% CO 2 , and luciferase activity was measured with a multi-plate reader (BioTek) by Nano-Glo Luciferase Assay (Promega, Madison, Wis.).
  • the activity value of the Example compound is expressed as a relative value where the activity of the control (that is, the residual activity without addition of the compound (activity of the protein produced by spontaneous read-through)) is 100%, and the activity is increased to 200%.
  • the concentration was determined as the EC 200 value.
  • the activity ratio of the example compound to the control compound was calculated from the following formula and shown in Table 2.
  • Example 1 Manufacture of capsules
  • Example compound 10 mg 2) Fine powder cellulose 10 mg 3) Lactose 19 mg
  • Magnesium stearate 1 mg 40 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has excellent read-through activity, is a compound that can be administered orally and is highly safe, and is nonsense mutant gene disease (for example, muscular dystrophy, Duchenne muscular dystrophy, cyst) Sexual fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc.).
  • nonsense mutant gene disease for example, muscular dystrophy, Duchenne muscular dystrophy, cyst
  • Sexual fibrosis for example, muscular dystrophy, Duchenne muscular dystrophy, cyst
  • mucopolysaccharidosis for example, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc.

Abstract

The present invention relates to a novel read-through inducing agent, and also relates to a compound represented by general formula (I) (symbols in the formula are as described in the specification) or a pharmaceutically accepted salt thereof, and a pharmaceutical composition containing the compound as an effective component. Because the compound has the read-through activity, the present invention can provide a drug useful as an agent to prevent or treat nonsense-mediated genetic diseases such as muscular dystrophy, Duchenne muscular dystrophy, cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, and Niemann-Pick disease.

Description

リードスルー誘導剤およびその医薬用途Lead-through inducer and its pharmaceutical use
　本発明は、ナンセンス変異により生じる未熟終止コドンに対してリードスルー活性を示す新規化合物またはその薬理上許容される塩に関する。また、本発明は、ナンセンス変異に基づく遺伝性疾患、例えば、筋ジストロフィー、デュシェンヌ型筋ジストロフィー、嚢胞性線維症、ムコ多糖症、セロイドリポフスチン症、ニーマンピック病などの予防または治療のために有用な当該化合物またはその薬理上許容される塩に関する。さらに、本発明は、当該化合物またはその薬理上許容される塩を含有してなる医薬組成物に関する。 The present invention relates to a novel compound or a pharmacologically acceptable salt thereof showing a read-through activity for an immature stop codon generated by a nonsense mutation. The present invention is also useful for the prevention or treatment of genetic diseases based on nonsense mutations, such as muscular dystrophy, Duchenne muscular dystrophy, cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc. The present invention relates to a compound or a pharmacologically acceptable salt thereof. Furthermore, the present invention relates to a pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof.
　遺伝情報を担うＤＮＡは、４種の塩基、アデニン、チミン、グアニン、シトシンより構成され、これらの組み合わせによる３塩基配列が、２０種アミノ酸のいずれかをコードしている。しかし、３塩基配列の内、ＴＡＡ、ＴＡＧ、ＴＧＡはいずれのアミノ酸にも対応しない終止コドンとなっている。蛋白質をコードしたＤＮＡはｍＲＮＡに転写され、細胞質に移行して、リボゾームに結合し、翻訳すなわちタンパク合成が生じる。正常のＤＮＡおよびｍＲＮＡでは、終止コドンにより、翻訳すなわちタンパク合成が終了する。ナンセンス変異型遺伝子疾患では、ＤＮＡ上の本来アミノ酸をコードしている３塩基配列が変異により未熟終止コドンとなり、翻訳すなわちタンパク合成が中断され、本来の機能を有する完全長タンパク質が合成されず、種々の生理機能が障害され発病する。ナンセンス変異型遺伝子疾患は、２４００種類以上とも言われ、代表的な遺伝子疾患としては、男児に見られるデュシェンヌ型筋ジストロフィーやライソゾーム病の一種であるムコ多糖症などが挙げられる。デュシェンヌ型筋ジストロフィーは、筋線維鞘におけるジストロフィンタンパク質の欠如に起因する疾患で、進行性の随意筋力低下を特徴とする。当該疾患では、Ｘ染色体中に存在する筋ジストロフィー遺伝子上に変異が生じ、該変異により未熟終止コドンとなり、翻訳がその変異部位で中断・終了してしまうことにより正常なジストロフィンタンパク質の発現が阻害される。その結果、ジストロフィンタンパク質が欠如し、筋ジストロフィーが起こる。また、Ｉ型ムコ多糖症は、ムコ多糖分解酵素α－L－イズロニダーゼ（ＩＤＵＡ）をコードする遺伝子のナンセンス変異により、ＩＤＵＡが欠損し、体内にムコ多糖が蓄積し、骨関節病変、皮膚・結合組織病変、中枢神経障害、呼吸器・循環器・消化器など、全身性の多様な障害を引き起こす疾患である。 DNA carrying genetic information is composed of four types of bases, adenine, thymine, guanine, and cytosine, and a three-base sequence of these combinations encodes any of the 20 types of amino acids. However, among the three nucleotide sequences, TAA, TAG, and TGA are stop codons that do not correspond to any amino acid. The DNA encoding the protein is transcribed into mRNA, moves into the cytoplasm, binds to the ribosome, and translation, that is, protein synthesis occurs. In normal DNA and mRNA, translation or protein synthesis is terminated by a stop codon. In nonsense mutation-type genetic diseases, the three-base sequence encoding the original amino acid on DNA becomes an immature stop codon due to mutation, translation, that is, protein synthesis is interrupted, and a full-length protein having the original function is not synthesized. Physiological function is impaired and the disease develops. Nonsense mutation-type genetic diseases are said to be more than 2,400 types, and typical genetic diseases include Duchenne muscular dystrophy found in boys and mucopolysaccharidosis, which is a type of lysosomal disease. Duchenne muscular dystrophy is a disease caused by a lack of dystrophin protein in the muscle fiber sheath and is characterized by progressive voluntary muscle weakness. In this disease, a mutation occurs on the muscular dystrophy gene present in the X chromosome, which results in an immature stop codon, and translation is interrupted and terminated at the mutation site, thereby inhibiting normal dystrophin protein expression. . As a result, dystrophin protein is lacking and muscular dystrophy occurs. In addition, type I mucopolysaccharidosis is caused by a nonsense mutation in the gene encoding mucopolysaccharide-degrading enzyme α-L-iduronidase (IDUA), resulting in a lack of IDUA, accumulation of mucopolysaccharide in the body, bone joint lesions, skin / bonding It is a disease that causes various systemic disorders such as tissue lesions, central nervous system disorders, respiratory, circulatory, and digestive organs.
　ナンセンス変異により未熟終止コドンが生じ特定のタンパク質が欠如している患者に特定の化合物を投与した際に、当該化合物がリボソームに作用し、リボソームが終止コドンを読み越えて翻訳を行う現象が見られる。このとき、終止コドンはアミノ酸コドンとして読み取られるが、必ずしも正常蛋白質と同一のアミノ酸が挿入されるわけではない。しかし、一種のアミノ酸が異なっても蛋白質の機能が大きく損なわれることはないので、機能が正常化することになる。この現象を、リードスルーという。ナンセンス変異型遺伝子疾患の治療におけるリードスルー活性を有する化合物の有用性が報告されている。このようなリードスルー活性を有する化合物としては、例えば、特許文献１には、ジペプチド系抗生物質であるネガマイシンがリードスルー活性を有することが記載されており、ネガマイシンを筋ジストロフィーモデルマウスに投与した場合にジストロフィンタンパク質の発現が回復することが報告されている。特許文献２には、パロモマイシン由来アミノグリコシド系抗生物質類が、リードスルー活性を示し、遺伝子疾患の治療において有用であると記載されている。非特許文献１には、アミノグリコシド系抗生物質であるゲンタマイシンをデュシェンヌ型筋ジストロフィー患者に投与した場合に、ジストロフィンタンパク質が蓄積することが記載されている。また、非特許文献２には、嚢胞性線維症患者の気道上皮にゲンタマイシンを局所投与することにより、典型的な電気生理学的異常を正常化できることが記載されている。さらに、特許文献３には、１，２，４－オキサジアゾール安息香酸誘導体が記載され、特許文献４には、ピリミド[４，５－Ｂ]キノリン－４，５（３Ｈ，１０Ｈ）－ジオン誘導体が、特許文献５には、ピリドピリミジンジオン誘導体が記載され、また、特許文献６には、ナフチリジンジオン誘導体がリードスルー活性を有することが記載されている。非特許文献３、４には、１，２，４－オキサジアゾール安息香酸誘導体３-［５-（２-フルオロフェニル）-［１，２，４］-オキサジアゾール-３-イル］安息香酸がデュシェンヌ型筋ジストロフィー患者およびモデルマウスにおいて、ジストロフィンタンパク質を増加させることが記載されている。しかし、ゲンタマイシンは、他のアミノグリコシド系抗生物質と同様に、腎毒性および耳毒性が顕著であり、また、ネガマイシンは抗菌活性も高く耐性菌の発生が懸念される。これらの副作用を考慮すると、強力なリードスルー活性を選択的に有し、副作用の少ないナンセンス変異型遺伝子疾患の治療薬を提供することが望まれている。 When a specific compound is administered to a patient who lacks a specific protein due to a nonsense mutation due to a nonsense mutation, the compound acts on the ribosome, and the ribosome reads the stop codon and translates . At this time, the stop codon is read as an amino acid codon, but the same amino acid as the normal protein is not necessarily inserted. However, even if one kind of amino acid is different, the function of the protein is not greatly impaired, so that the function is normalized. This phenomenon is called lead-through. The usefulness of compounds having read-through activity in the treatment of nonsense mutant genetic diseases has been reported. As such a compound having a read-through activity, for example, Patent Document 1 describes that a negative peptide, which is a dipeptide antibiotic, has a read-through activity, and when negamycin is administered to a muscular dystrophy model mouse. It has been reported that dystrophin protein expression is restored. Patent Document 2 describes that paromomycin-derived aminoglycoside antibiotics exhibit read-through activity and are useful in the treatment of genetic diseases. Non-Patent Document 1 describes that dystrophin protein accumulates when gentamicin, an aminoglycoside antibiotic, is administered to a patient with Duchenne muscular dystrophy. Non-Patent Document 2 describes that typical electrophysiological abnormalities can be normalized by locally administering gentamicin to the respiratory epithelium of a patient with cystic fibrosis. Further, Patent Document 3 describes 1,2,4-oxadiazole benzoic acid derivatives, and Patent Document 4 discloses pyrimido [4,5-B] quinoline-4,5 (3H, 10H) -dione. As for the derivative, Patent Document 5 describes a pyridopyrimidinedione derivative, and Patent Document 6 describes that a naphthyridinedione derivative has a read-through activity. Non-Patent Documents 3 and 4 include 1,2,4-oxadiazole benzoic acid derivative 3- [5- (2-fluorophenyl)-[1,2,4] -oxadiazol-3-yl] benzoic acid. Acid has been described to increase dystrophin protein in Duchenne muscular dystrophy patients and model mice. However, gentamicin, like other aminoglycoside antibiotics, has remarkable nephrotoxicity and ototoxicity, and negamycin has high antibacterial activity and there is a concern about the generation of resistant bacteria. In view of these side effects, it is desired to provide a therapeutic agent for a nonsense mutant genetic disease that selectively has strong read-through activity and has few side effects.
国際公開第２００２／１０２３６１号International Publication No. 2002/102361 国際公開第２００７／１１３８４１号International Publication No. 2007/113841 国際公開第２００４／０９１５０２号International Publication No. 2004/095022 国際公開第２０１４／０９１４４６号International Publication No. 2014/091446 国際公開第２０１５／１８６０６１号International Publication No. 2015/186061 国際公開第２０１５／１８６０６３号International Publication No. 2015/186063
　本発明の課題は、リードスルー活性を有し、かつ安全性が高く経口投与が可能な新規化合物を提供することである。さらには、当該化合物を含むナンセンス変異型遺伝子疾患の治療薬を提供することである。 An object of the present invention is to provide a novel compound having read-through activity, high safety and capable of oral administration. Furthermore, it is providing the therapeutic agent of the nonsense variant gene disease containing the said compound.
　本発明者らは、かかる状況下、鋭意検討を重ねた結果、強いリードスルー促進作用を示し、ナンセンス変異型遺伝子疾患の予防若しくは治療薬になり得る優れた化合物を見出し、本発明を完成した。 As a result of intensive studies under these circumstances, the present inventors have found a superior compound that exhibits a strong read-through promoting action and can be a preventive or therapeutic agent for nonsense mutant genetic diseases, and has completed the present invention.
　すなわち、本発明は、以下を提供する。
［１］一般式（Ｉ）： That is, the present invention provides the following.
[1] General formula (I):
Figure JPOXMLDOC01-appb-C000002
 　　　
Figure JPOXMLDOC01-appb-C000002
 　　　
［式中、
環Ａは、それぞれさらに置換されていてもよい、フェニル基または６員の単環式含窒素複素環基を示し；
Ｘは、単結合、さらに置換されていてもよい二価の４ないし７員の単環式複素環基またはさらに置換されていてもよいＣ２－６アルキニレン基を示し；および
環Ｂは、それぞれさらに置換されていてもよい、アリール基または複素環基を示す。］で表される化合物またはその医薬上許容される塩（以下、化合物（Ｉ）と略記することがある。）。
［２］環Ａが、それぞれさらに置換されていてもよい、フェニル基またはピリジル基であり、
Ｘが、単結合またはさらに置換されていてもよい二価の５または６員の単環式芳香族複素環基であり、ならびに
環Ｂが、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基、５または６員の単環式複素環基あるいは８ないし１４員の縮合複素環基である、上記［１］に記載の化合物またはその医薬上許容される塩。
［３］環Ａが、さらに置換されていてもよいフェニル基であり、
Ｘが、単結合またはさらに置換されていてもよい二価の５員の単環式芳香族複素環基であり、ならびに
環Ｂが、それぞれさらに置換されていてもよい、フェニル基または８ないし１４員の縮合芳香族複素環基である、上記［１］に記載の化合物またはその医薬上許容される塩。
［４］上記［１］～［３］のいずれかに記載の化合物またはその医薬上許容される塩を有効成分として含有する医薬組成物。 
［５］上記［１］～［３］のいずれかに記載の化合物またはその医薬上許容される塩を有効成分として含有するリードスルー誘導剤。
［６］上記［１］～［３］のいずれかに記載の化合物またはその医薬上許容される塩を有効成分として含有するナンセンス変異型遺伝子疾患の予防または治療剤。
［７］ナンセンス変異型遺伝子疾患が、筋ジストロフィー、デュシェンヌ型筋ジストロフィー、嚢胞性線維症、ムコ多糖症、セロイドリポフスチン症またはニーマンピック病である、［６］に記載の剤。 [Where:
Ring A represents a phenyl group or a 6-membered monocyclic nitrogen-containing heterocyclic group, each of which may be further substituted;
X represents a single bond, a further divalent 4- to 7-membered monocyclic heterocyclic group which may be further substituted, or a C 2-6 alkynylene group which may be further substituted; Furthermore, the aryl group or heterocyclic group which may be further substituted is shown. Or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as compound (I)).
[2] Ring A is a phenyl group or a pyridyl group, each of which may be further substituted,
X is a single bond or a divalent 5- or 6-membered monocyclic aromatic heterocyclic group which may be further substituted, and ring B may be further substituted, respectively, C 6-10 The compound or a pharmaceutically acceptable salt thereof according to the above [1], which is an aryl group, a 5- or 6-membered monocyclic heterocyclic group or an 8- to 14-membered condensed heterocyclic group.
[3] Ring A is a phenyl group which may be further substituted;
X is a single bond or a divalent 5-membered monocyclic aromatic heterocyclic group which may be further substituted, and ring B may be further substituted, respectively, a phenyl group or 8 to 14 The compound or a pharmaceutically acceptable salt thereof according to the above [1], which is a membered condensed aromatic heterocyclic group.
[4] A pharmaceutical composition comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[5] A lead-through inducer comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[6] A preventive or therapeutic agent for nonsense mutant genetic diseases comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[7] The agent according to [6], wherein the nonsense mutant gene disease is muscular dystrophy, Duchenne muscular dystrophy, cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, or Niemann-Pick disease.
　本発明の化合物（Ｉ）は、強力なリードスルー活性を有し、医薬品として有用である。また、本発明によれば、化合物（Ｉ）を含有する医薬組成物を提供することができ、該医薬組成物は、特に、ナンセンス変異に起因する遺伝性の疾患（例えば、筋ジストロフィー、デュシェンヌ型筋ジストロフィー、嚢胞性線維症、ムコ多糖症、セロイドリポフスチン症、ニーマンピック病等）の治療および／または予防に極めて有用である。 The compound (I) of the present invention has a strong read-through activity and is useful as a pharmaceutical product. In addition, according to the present invention, a pharmaceutical composition containing compound (I) can be provided, and the pharmaceutical composition is particularly suitable for hereditary diseases caused by nonsense mutations (eg, muscular dystrophy, Duchenne muscular dystrophy). , Cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc.).
　以下に本発明ついて詳細に説明する。
　本明細書中、化合物の標記に用いられる置換基等の用語の意味は以下の通りである。 The present invention is described in detail below.
In this specification, the meanings of terms such as substituents used for the title of compounds are as follows.
　本明細書において、「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子をいう。 In this specification, “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　本明細書において、「Ｃ１－６アルキル」は、炭素数が１～６の直鎖状または分岐鎖状の一価の飽和炭化水素基を意味する。該「Ｃ１－６アルキル」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、４－メチルペンチル、へキシル等が挙げられる。 In the present specification, “C 1-6 alkyl” means a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the “C 1-6 alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, Xylyl and the like.
　本明細書において、「Ｃ３－８シクロアルキル」は、炭素数が３～８の飽和炭化水素環から誘導される一価の基を意味する。また、該Ｃ３－８シクロアルキルは、架橋していてもよい。該「Ｃ３－８シクロアルキル」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。 In the present specification, “C 3-8 cycloalkyl” means a monovalent group derived from a saturated hydrocarbon ring having 3 to 8 carbon atoms. The C 3-8 cycloalkyl may be bridged. Examples of the “C 3-8 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
　本明細書において、「Ｃ３－８シクロアルキルＣ１－６アルキル」は、前記「Ｃ１－６アルキル」に前記「Ｃ３－８シクロアルキル」が置換した一価の基を意味する。該「Ｃ３－８シクロアルキルＣ１－６アルキル」としては、例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、シクロヘプチルメチル、シクロオクチルメチル等が挙げられる。 In the present specification, “C 3-8 cycloalkyl C 1-6 alkyl” means a monovalent group in which the “C 3-8 cycloalkyl” is substituted on the “C 1-6 alkyl”. Examples of the “C 3-8 cycloalkyl C 1-6 alkyl” include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl and the like.
　本明細書において、「Ｃ２－６アルケニル」は、１個以上の炭素－炭素二重結合を有し、炭素数が２～６の直鎖状または分岐鎖状の一価の炭化水素基を意味する。該「Ｃ２－６アルケニル」としては、例えば、ビニル、１－プロペニル（アリル）、２－プロペニル、イソプロペニル、２－メチル－１－プロペニル、１－ブテニル、２－ブテニル、３－ブテニル、２－ブテン－２－イル、３－メチル－２－ブテニル、３－メチル－２－ブテン－２－イル、１－ペンテニル、２－ペンテニル、３－ペンテニル、４－ペンテニル、２－ペンテン－２－イル、２－ペンテン－３－イル、４－メチル－１－ペンテニル、１－ヘキセニル、２－ヘキセニル、３－ヘキセニル、ブタジエニル（例、ブタ－１，３－ジエン－１－イル）、ペンタジエニル（例、ペンタ－１，３－ジエン－１－イル）等が挙げられる。 In the present specification, “C 2-6 alkenyl” refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms. means. Examples of the “C 2-6 alkenyl” include vinyl, 1-propenyl (allyl), 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2 -Buten-2-yl, 3-methyl-2-butenyl, 3-methyl-2-buten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-penten-2-yl 2-penten-3-yl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, butadienyl (eg, buta-1,3-dien-1-yl), pentadienyl (eg, Penta-1,3-dien-1-yl) and the like.
　本明細書において、「Ｃ２－６アルキニル」は、１個以上の炭素－炭素三重結合を有し、炭素数が２～６の直鎖状または分岐鎖状の一価の炭化水素基を意味する。該「Ｃ２－６アルキニル」としては、例えば、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、３－ブチニル、３－メチル－２－ブチニル、１－ペンチニル、２－ペンチニル、３－ペンチニル、４－ペンチニル、４－メチル－１－ペンチニル等が挙げられる。 In the present specification, “C 2-6 alkynyl” means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms. To do. Examples of the “C 2-6 alkynyl” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl, 1-pentynyl and 2-pentynyl. , 3-pentynyl, 4-pentynyl, 4-methyl-1-pentynyl and the like.
　本明細書において、「Ｃ２－６アルキニレン」は、１個以上の炭素－炭素三重結合を有し、炭素数が２～６の直鎖状または分岐鎖状の二価の炭化水素基を意味する。該「Ｃ２－６アルキニレン」としては、例えば、エチニレン、１－プロピニレン、２－プロピニレン、１－ブチニレン、２－ブチニレン、３－ブチニレン、３－メチル－２－ブチニレン、１－ペンチニレン、２－ペンチニレン、３－ペンチニレン、４－ペンチニレン、４－メチル－１－ペンチニレン等が挙げられる。 In the present specification, “C 2-6 alkynylene” means a linear or branched divalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms. To do. Examples of the “C 2-6 alkynylene” include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 3-methyl-2-butynylene, 1-pentynylene and 2-pentynylene. , 3-pentynylene, 4-pentynylene, 4-methyl-1-pentynylene and the like.
　本明細書において、「Ｃ１－６アルコキシ」は、酸素原子に前記「Ｃ１－６アルキル」基が結合した基、すなわち、炭素数が１～６の直鎖または分岐鎖アルコキシ基を意味する。該「Ｃ１－６アルコキシ」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、１－エチルプロピルオキシ、へキシルオキシ等が挙げられる。 In the present specification, “C 1-6 alkoxy” means a group in which the above “C 1-6 alkyl” group is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms. . Examples of the “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1-ethylpropyloxy And hexyloxy.
　本明細書において、「Ｃ１－６アルキルスルファニル」は、硫黄原子に前記「Ｃ１－６アルキル」基が結合した基、すなわち、炭素数が１～６の直鎖または分岐鎖アルキルスルファニル基を意味する。該「Ｃ１－６アルキルスルファニル」としては、例えば、メチルスルファニル、エチルスルファニル、プロピルスルファニル、イソプロピルスルファニル、ブチルスルファニル、イソブチルスルファニル、ｓｅｃ－ブチルスルファニル、ｔｅｒｔ－ブチルスルファニル、ペンチルスルファニル、イソペンチルスルファニル、ネオペンチルスルファニル、１－エチルプロピルスルファニル、へキシルスルファニル等が挙げられる。 In the present specification, “C 1-6 alkylsulfanyl” refers to a group in which the “C 1-6 alkyl” group is bonded to a sulfur atom, that is, a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms. means. Examples of the “C 1-6 alkylsulfanyl” include, for example, methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neo Examples include pentylsulfanyl, 1-ethylpropylsulfanyl, hexylsulfanyl and the like.
　本明細書において、「Ｃ１－６アルキルスルフィニル」は、スルフィニル基に前記「Ｃ１－６アルキル」基が結合した基、すなわち、炭素数が１～６の直鎖または分岐鎖アルキルスルフィニル基を意味する。該「Ｃ１－６アルキルスルフィニル」としては、例えば、メチルスルフィニル、エチルスルフィニル、プロピルスルフィニル、イソプロピルスルフィニル、ブチルスルフィニル、イソブチルスルフィニル、ｓｅｃ－ブチルスルフィニル、ｔｅｒｔ－ブチルスルフィニル、ペンチルスルフィニル、イソペンチルスルフィニル、ネオペンチルスルフィニル、１－エチルプロピルスルフィニル、へキシルスルフィニル等が挙げられる。 In the present specification, “C 1-6 alkylsulfinyl” refers to a group in which the “C 1-6 alkyl” group is bonded to a sulfinyl group, that is, a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms. means. Examples of the “C 1-6 alkylsulfinyl” include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, neo Examples include pentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl and the like.
　本明細書において、「Ｃ１－６アルキルスルホニル」は、スルホニル基に前記「Ｃ１－６アルキル」基が結合した基、すなわち、炭素数が１～６の直鎖または分岐鎖アルキルスルホニル基を意味する。該「Ｃ１－６アルキルスルホニル」としては、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル、ｔｅｒｔ－ブチルスルホニル、ペンチルスルホニル、イソペンチルスルホニル、ネオペンチルスルホニル、１－エチルプロピルスルホニル、へキシルスルホニル等が挙げられる。 In the present specification, “C 1-6 alkylsulfonyl” refers to a group in which the “C 1-6 alkyl” group is bonded to a sulfonyl group, that is, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. means. The “C 1-6 alkylsulfonyl” includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neo Examples include pentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl and the like.
　本明細書において、「Ｃ１－６アルキルスルホニルオキシ」は、酸素原子に前記「Ｃ１－６アルキルスルホニル」基が結合した一価の基を意味する。該「Ｃ１－６アルキルスルホニルオキシ」としては、例えば、メチルスルホニルオキシ、エチルスルホニルオキシ、プロピルスルホニルオキシ、イソプロピルスルホニルオキシ、ブチルスルホニルオキシ、イソブチルスルホニルオキシ、ｓｅｃ－ブチルスルホニルオキシ、ｔｅｒｔ－ブチルスルホニルオキシ、ペンチルスルホニルオキシ、イソペンチルスルホニルオキシ、ネオペンチルスルホニルオキシ、１－エチルプロピルスルホニルオキシ、へキシルスルホニルオキシ等が挙げられる。 In the present specification, “C 1-6 alkylsulfonyloxy” means a monovalent group in which the “C 1-6 alkylsulfonyl” group is bonded to an oxygen atom. Examples of the “C 1-6 alkylsulfonyloxy” include, for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy Pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, 1-ethylpropylsulfonyloxy, hexylsulfonyloxy and the like.
　本明細書において、「モノまたはジ－Ｃ１－６アルキルアミノ」は、アミノ基に１個または２個の前記「Ｃ１－６アルキル」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ１－６アルキルアミノ」としては、例えば、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ブチルアミノ、イソブチルアミノ、ペンチルアミノ、イソペンチルアミノ、ネオペンチルアミノ、へキシルアミノ、ジメチルアミノ、ジエチルアミノ、ジイソプロピルアミノ、ジブチルアミノ、ジペンチルアミノ、ジヘキシルアミノ等が挙げられる。 As used herein, "mono- or di -C 1-6 alkylamino" denotes one or two of the "C 1-6 alkyl" monovalent radical group is substituted to an amino group. Examples of the “mono or di-C 1-6 alkylamino” include, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino, neopentylamino, hexylamino, Examples include dimethylamino, diethylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino and the like.
　本明細書において、「モノまたはジ－Ｃ１－６アルキル－カルバモイル基」は、カルバモイル基に１個または２個の前記「Ｃ１－６アルキル」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ１－６アルキル－カルバモイル基」としては、例えば、メチルカルバモイル、エチルカルバモイル、プロピルカルバモイル、イソプロピルカルバモイル、ブチルカルバモイル、イソブチルカルバモイル、ペンチルカルバモイル、イソペンチルカルバモイル、ネオペンチルカルバモイル、へキシルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジイソプロピルカルバモイル、ジブチルカルバモイル、ジペンチルカルバモイル、ジヘキシルカルバモイル等が挙げられる。 In the present specification, the “mono or di-C 1-6 alkyl-carbamoyl group” means a monovalent group in which one or two “C 1-6 alkyl” groups are substituted on the carbamoyl group. Examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl, neopentylcarbamoyl, Examples include xylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl and the like.
　本明細書において、「モノまたはジ－Ｃ１－６アルキル－チオカルバモイル基」は、チオカルバモイル基に１個または２個の前記「Ｃ１－６アルキル」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ１－６アルキル－チオカルバモイル基」としては、例えば、メチルチオカルバモイル、エチルチオカルバモイル、プロピルチオカルバモイル、イソプロピルチオカルバモイル、ブチルチオカルバモイル、イソブチルチオカルバモイル、ペンチルチオカルバモイル、イソペンチルチオカルバモイル、ネオペンチルチオカルバモイル、へキシルチオカルバモイル、ジメチルチオカルバモイル、ジエチルチオカルバモイル、ジイソプロピルチオカルバモイル、ジブチルチオカルバモイル、ジペンチルチオカルバモイル、ジヘキシルチオカルバモイル等が挙げられる。 In the present specification, the “mono or di-C 1-6 alkyl-thiocarbamoyl group” means a monovalent group in which one or two “C 1-6 alkyl” groups are substituted on the thiocarbamoyl group. To do. Examples of the “mono or di-C 1-6 alkyl-thiocarbamoyl group” include, for example, methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl, isopropylthiocarbamoyl, butylthiocarbamoyl, isobutylthiocarbamoyl, pentylthiocarbamoyl, isopentyl Examples include ruthiocarbamoyl, neopentylthiocarbamoyl, hexylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, diisopropylthiocarbamoyl, dibutylthiocarbamoyl, dipentylthiocarbamoyl, dihexylthiocarbamoyl and the like.
　本明細書において、「Ｃ３－８シクロアルキルスルファニル」は、硫黄原子に前記「Ｃ３－８シクロアルキル」基が結合した基を意味する。該「Ｃ３－８シクロアルキルスルファニル」としては、例えば、シクロプロピルスルファニル、シクロブチルスルファニル、シクロペンチルスルファニル、シクロヘキシルスルファニル、シクロヘプチルスルファニル、シクロオクチルスルファニル等が挙げられる。 In the present specification, “C 3-8 cycloalkylsulfanyl” means a group in which the “C 3-8 cycloalkyl” group is bonded to a sulfur atom. Examples of the “C 3-8 cycloalkylsulfanyl” include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl and the like.
　本明細書において、「Ｃ３－８シクロアルキルスルフィニル」は、スルフィニル基に前記「Ｃ３－８シクロアルキル」基が結合した基を意味する。該「Ｃ３－８シクロアルキルスルフィニル」としては、例えば、シクロプロピルスルフィニル、シクロブチルスルフィニル、シクロペンチルスルフィニル、シクロヘキシルスルフィニル、シクロヘプチルスルフィニル、シクロオクチルスルフィニル等が挙げられる。 In the present specification, “C 3-8 cycloalkylsulfinyl” means a group in which the “C 3-8 cycloalkyl” group is bonded to a sulfinyl group. Examples of the “C 3-8 cycloalkylsulfinyl” include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclooctylsulfinyl and the like.
　本明細書において、「Ｃ３－８シクロアルキルスルホニル」は、スルホニル基に前記「Ｃ３－８シクロアルキル」基が結合した基を意味する。該「Ｃ３－８シクロアルキルスルホニル」としては、例えば、シクロプロピルスルホニル、シクロブチルスルホニル、シクロペンチルスルホニル、シクロヘキシルスルホニル、シクロヘプチルスルホニル、シクロオクチルスルホニル等が挙げられる。 In the present specification, “C 3-8 cycloalkylsulfonyl” means a group in which the “C 3-8 cycloalkyl” group is bonded to a sulfonyl group. Examples of the “C 3-8 cycloalkylsulfonyl” include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, cyclooctylsulfonyl and the like.
　本明細書において、「Ｃ３－８シクロアルキルスルホニルオキシ」は、酸素原子に前記「Ｃ３－８シクロアルキルスルホニル」基が結合した一価の基を意味する。該「Ｃ３－８シクロアルキルスルホニルオキシ」としては、例えば、シクロプロピルスルホニルオキシ、シクロブチルスルホニルオキシ、シクロペンチルスルホニルオキシ、シクロヘキシルスルホニルオキシ、シクロヘプチルスルホニルオキシ、シクロオクチルスルホニルオキシ等が挙げられる。 In the present specification, “C 3-8 cycloalkylsulfonyloxy” means a monovalent group in which the “C 3-8 cycloalkylsulfonyl” group is bonded to an oxygen atom. Examples of the “C 3-8 cycloalkylsulfonyloxy” include cyclopropylsulfonyloxy, cyclobutylsulfonyloxy, cyclopentylsulfonyloxy, cyclohexylsulfonyloxy, cycloheptylsulfonyloxy, cyclooctylsulfonyloxy and the like.
　本明細書において、「モノまたはジ－Ｃ３－８シクロアルキルアミノ」は、アミノ基に１個または２個の前記「Ｃ３－８シクロアルキル」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ３－８シクロアルキルアミノ」としては、例えば、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ、シクロヘプチルアミノ、シクロオクチルアミノ等が挙げられる。 As used herein, "mono- or di -C 3-8 cycloalkylamino" means one or two of the "C 3-8 cycloalkyl" monovalent radical group is substituted to an amino group. Examples of the “mono or di-C 3-8 cycloalkylamino” include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino and the like.
　本明細書において、「Ｃ１－６アルコキシ－カルボニル」は、カルボニルに前記「Ｃ１－６アルコキシ」基が結合した基、すなわち、炭素数が１～６の直鎖または分岐鎖アルコキシ－カルボニル基を意味する。該「Ｃ１－６アルコキシ－カルボニル」としては、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、ネオペンチルオキシカルボニル、１－エチルプロピルオキシカルボニル、へキシルオキシカルボニル等が挙げられる。 In the present specification, “C 1-6 alkoxy-carbonyl” means a group in which the above “C 1-6 alkoxy” group is bonded to carbonyl, that is, a linear or branched alkoxy-carbonyl group having 1 to 6 carbon atoms. Means. Examples of the “C 1-6 alkoxy-carbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyl Examples include pentyloxycarbonyl, neopentyloxycarbonyl, 1-ethylpropyloxycarbonyl, hexyloxycarbonyl and the like.
　本明細書において、「アリール」は、炭素数が６～１４の一価の芳香族炭化水素基を意味する。該「アリール」としては、例えば、フェニル、ナフチル（例、１－ナフチル、２－ナフチル）、アセナフチレニル、アズレニル、アントリル、フェナントリル等のＣ６－１４アリール基が挙げられる。中でも、Ｃ６－１０アリール基が好ましく、フェニルが特に好ましい。 In the present specification, “aryl” means a monovalent aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples of the “aryl” include C 6-14 aryl groups such as phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl, phenanthryl and the like. Among them, a C 6-10 aryl group is preferable, and phenyl is particularly preferable.
　本明細書において、「アリールオキシ」は、酸素原子に前記「アリール」基が結合した一価の基を意味する。該「アリールオキシ」としては、例えば、フェノキシ、ナフチルオキシ（例、１－ナフチルオキシ、２－ナフチルオキシ）、アセナフチレニルオキシ、アズレニルオキシ、アントリルオキシ、フェナントリルオキシ等が挙げられる。 In the present specification, “aryloxy” means a monovalent group in which the “aryl” group is bonded to an oxygen atom. Examples of the “aryloxy” include phenoxy, naphthyloxy (eg, 1-naphthyloxy, 2-naphthyloxy), acenaphthylenyloxy, azulenyloxy, anthryloxy, phenanthryloxy and the like.
　本明細書において、「Ｃ６－１４アリールスルファニル」は、硫黄原子に前記「Ｃ６－１４アリール」基が結合した基を意味する。該「Ｃ６－１４アリールスルファニル」としては、例えば、フェニルスルファニル、ナフチルスルファニル、アセナフチレニルスルファニル、アズレニルスルファニル、アントリルスルファニル、フェナントリルスルファニル等が挙げられる。 In the present specification, “C 6-14 arylsulfanyl” means a group in which the “C 6-14 aryl” group is bonded to a sulfur atom. Examples of the “C 6-14 arylsulfanyl” include phenylsulfanyl, naphthylsulfanyl, acenaphthylenylsulfanyl, azulenylsulfanyl, anthrylsulfanyl, phenanthrylsulfanyl and the like.
　本明細書において、「Ｃ６－１４アリールスルフィニル」は、スルフィニル基に前記「Ｃ６－１４アリール」基が結合した基を意味する。該「Ｃ６－１４アリールスルフィニル」としては、例えば、フェニルスルフィニル、ナフチルスルフィニル、アセナフチレニルスルフィニル、アズレニルスルフィニル、アントリルスルフィニル、フェナントリルスルフィニル等が挙げられる。 In the present specification, “C 6-14 arylsulfinyl” means a group in which the “C 6-14 aryl” group is bonded to a sulfinyl group. Examples of the “C 6-14 arylsulfinyl” include phenylsulfinyl, naphthylsulfinyl, acenaphthylenylsulfinyl, azulenylsulfinyl, anthrylsulfinyl, phenanthrylsulfinyl and the like.
　本明細書において、「Ｃ６－１４アリールスルホニル」は、スルホニル基に前記「Ｃ６－１４アリール」基が結合した基を意味する。該「Ｃ６－１４アリールスルホニル」としては、例えば、フェニルスルホニル、ナフチルスルホニル、アセナフチレニルスルホニル、アズレニルスルホニル、アントリルスルホニル、フェナントリルスルホニル等が挙げられる。 In the present specification, “C 6-14 arylsulfonyl” means a group in which the “C 6-14 aryl” group is bonded to a sulfonyl group. Examples of the “C 6-14 arylsulfonyl” include phenylsulfonyl, naphthylsulfonyl, acenaphthylenylsulfonyl, azulenylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl and the like.
　本明細書において、「Ｃ６－１４アリールスルホニルオキシ」は、酸素原子に前記「Ｃ６－１４アリールスルホニル」基が結合した一価の基を意味する。該「Ｃ６－１４アリールスルホニルオキシ」としては、例えば、フェニルスルホニルオキシ、ナフチルスルホニルオキシ、アセナフチレニルスルホニルオキシ、アズレニルスルホニルオキシ、アントリルスルホニルオキシ、フェナントリルスルホニルオキシ等が挙げられる。 In the present specification, “C 6-14 arylsulfonyloxy” means a monovalent group in which the “C 6-14 arylsulfonyl” group is bonded to an oxygen atom. Examples of the “C 6-14 arylsulfonyloxy” include phenylsulfonyloxy, naphthylsulfonyloxy, acenaphthylenylsulfonyloxy, azulenylsulfonyloxy, anthrylsulfonyloxy, phenanthrylsulfonyloxy and the like.
　本明細書において、「モノまたはジ－Ｃ６－１４アリールアミノ」は、アミノ基に１個または２個の前記「Ｃ６－１４アリール」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ６－１４アリールアミノ」としては、例えば、フェニルアミノ、ナフチルアミノ、アセナフチレニルアミノ、アズレニルアミノ、アントリルアミノ、フェナントリルアミノ、ジフェニルアミノ等が挙げられる。 As used herein, "mono- or di -C 6-14 arylamino" means one or two of the "C 6-14 aryl" monovalent radical group is substituted to an amino group. Examples of the “mono or di-C 6-14 arylamino” include phenylamino, naphthylamino, acenaphthylenylamino, azulenylamino, anthrylamino, phenanthrylamino, diphenylamino and the like.
　本明細書において、「モノまたはジ－Ｃ６－１４アリール－カルバモイル基」は、カルバモイル基に１個または２個の前記「Ｃ６－１４アリール」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ６－１４アリール－カルバモイル基」としては、例えば、フェニルカルバモイル、ナフチルカルバモイル、アセナフチレニルカルバモイル、アズレニルカルバモイル、アントリルカルバモイル、フェナントリルカルバモイル、ジフェニルカルバモイル等が挙げられる。 In the present specification, the “mono or di-C 6-14 aryl-carbamoyl group” means a monovalent group in which one or two of the “C 6-14 aryl” groups are substituted on the carbamoyl group. Examples of the “mono or di-C 6-14 aryl-carbamoyl group” include phenylcarbamoyl, naphthylcarbamoyl, acenaphthylenylcarbamoyl, azulenylcarbamoyl, anthrylcarbamoyl, phenanthrylcarbamoyl, diphenylcarbamoyl and the like.
　本明細書において、「モノまたはジ－Ｃ６－１４アリール－チオカルバモイル基」は、チオカルバモイル基に１個または２個の前記「Ｃ６－１４アリール」基が置換した一価の基を意味する。該「モノまたはジ－Ｃ６－１４アリール－チオカルバモイル基」としては、例えば、フェニルチオカルバモイル、ナフチルチオカルバモイル、アセナフチレニルチオカルバモイル、アズレニルチオカルバモイル、アントリルチオカルバモイル、フェナントリルチオカルバモイル、ジフェニルチオカルバモイル等が挙げられる。 In the present specification, the “mono or di-C 6-14 aryl-thiocarbamoyl group” means a monovalent group in which one or two “C 6-14 aryl” groups are substituted on the thiocarbamoyl group. To do. Examples of the “mono or di-C 6-14 aryl-thiocarbamoyl group” include phenylthiocarbamoyl, naphthylthiocarbamoyl, acenaphthylenylthiocarbamoyl, azulenylthiocarbamoyl, anthrylthiocarbamoyl, phenanthrylthiocarbamoyl, And diphenylthiocarbamoyl.
　本明細書において、「Ｃ６－１４アリール－カルボニル」は、カルボニルに前記「Ｃ６－１４アリール」基が結合した一価の基を意味する。該「Ｃ６－１４アリール－カルボニル」としては、例えば、ベンゾイル、ナフチルカルボニル、アセナフチレニルカルボニル、アズレニルカルボニル、アントリルカルボニル、フェナントリルカルボニル等が挙げられる。 In the present specification, “C 6-14 aryl-carbonyl” means a monovalent group in which the above “C 6-14 aryl” group is bonded to carbonyl. Examples of the “C 6-14 aryl-carbonyl” include benzoyl, naphthylcarbonyl, acenaphthylenylcarbonyl, azulenylcarbonyl, anthrylcarbonyl, phenanthrylcarbonyl and the like.
　本明細書において、「Ｃ６－１４アリールオキシ－カルボニル」は、カルボニルに前記「Ｃ６－１４アリールオキシ」基が結合した一価の基を意味する。該「Ｃ６－１４アリールオキシ－カルボニル」としては、例えば、フェノキシカルボニル、ナフチルオキシカルボニル、アセナフチレニルオキシカルボニル、アズレニルオキシカルボニル、アントリルオキシカルボニル、フェナントリルオキシカルボニル等が挙げられる。 In the present specification, “C 6-14 aryloxy-carbonyl” means a monovalent group in which the “C 6-14 aryloxy” group is bonded to carbonyl. Examples of the “C 6-14 aryloxy-carbonyl” include phenoxycarbonyl, naphthyloxycarbonyl, acenaphthylenyloxycarbonyl, azulenyloxycarbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl and the like.
　本明細書において、「Ｃ６－１４アリールオキシ－カルボニルオキシ」は、酸素原子に前記「Ｃ６－１４アリールオキシ－カルボニル」基が結合した一価の基を意味する。該「Ｃ６－１４アリールオキシ－カルボニルオキシ」としては、例えば、フェノキシカルボニルオキシ、ナフチルオキシカルボニルオキシ、アセナフチレニルオキシカルボニルオキシ、アズレニルオキシカルボニルオキシ、アントリルオキシカルボニルオキシ、フェナントリルオキシカルボニルオキシ等が挙げられる。 In the present specification, “C 6-14 aryloxy-carbonyloxy” means a monovalent group in which the “C 6-14 aryloxy-carbonyl” group is bonded to an oxygen atom. Examples of the “C 6-14 aryloxy-carbonyloxy” include phenoxycarbonyloxy, naphthyloxycarbonyloxy, acenaphthylenylcarbonyloxy, azulenyloxycarbonyloxy, anthryloxycarbonyloxy, phenanthryloxy And carbonyloxy.
　本明細書において、「アリールＣ１－６アルキル」は、前記「Ｃ１－６アルキル」に前記「アリール」基が置換した一価の基を意味する。該「アリールＣ１－６アルキル」としては、例えば、ベンジル、ナフチルメチル、２－フェニルエチル、１－フェニルエチル、１－フェニルプロピル等が挙げられる。 In the present specification, “aryl C 1-6 alkyl” means a monovalent group in which the “aryl” group is substituted on the “C 1-6 alkyl”. Examples of the “aryl C 1-6 alkyl” include benzyl, naphthylmethyl, 2-phenylethyl, 1-phenylethyl, 1-phenylpropyl and the like.
　本明細書において、「アリールＣ１－６アルコキシ」は、酸素原子に前記「アリールＣ１－６アルキル」基が結合した一価の基を意味する。該「アリールＣ１－６アルコキシ」としては、例えば、ベンジルオキシ、ナフチルメチルオキシ、２－フェニルエチルオキシ、１－フェニルエチルオキシ、１－フェニルプロピルオキシ等が挙げられる。 In the present specification, “aryl C 1-6 alkoxy” means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to an oxygen atom. Examples of the “aryl C 1-6 alkoxy” include benzyloxy, naphthylmethyloxy, 2-phenylethyloxy, 1-phenylethyloxy, 1-phenylpropyloxy and the like.
　本明細書において、「アリールＣ１－６アルキルスルファニル」は、硫黄原子に前記「アリールＣ１－６アルキル」基が結合した一価の基を意味する。該「アリールＣ１－６アルキルスルファニル」としては、例えば、ベンジルスルファニル、ナフチルメチルスルファニル、２－フェニルエチルスルファニル、１－フェニルエチルスルファニル、１－フェニルプロピルスルファニル等が挙げられる。 In the present specification, “aryl C 1-6 alkylsulfanyl” means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to a sulfur atom. Examples of the “aryl C 1-6 alkylsulfanyl” include benzylsulfanyl, naphthylmethylsulfanyl, 2-phenylethylsulfanyl, 1-phenylethylsulfanyl, 1-phenylpropylsulfanyl and the like.
　本明細書において、「アリールＣ１－６アルキルスルフィニル」は、スルフィニル基に前記「アリールＣ１－６アルキル」基が結合した一価の基を意味する。該「アリールＣ１－６アルキルスルフィニル」としては、例えば、ベンジルスルフィニル、ナフチルメチルスルフィニル、２－フェニルエチルスルフィニル、１－フェニルエチルスルフィニル、１－フェニルプロピルスルフィニル等が挙げられる。 In the present specification, “aryl C 1-6 alkylsulfinyl” means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to a sulfinyl group. Examples of the “aryl C 1-6 alkylsulfinyl” include benzylsulfinyl, naphthylmethylsulfinyl, 2-phenylethylsulfinyl, 1-phenylethylsulfinyl, 1-phenylpropylsulfinyl and the like.
　本明細書において、「アリールＣ１－６アルキルスルホニル」は、スルホニル基に前記「アリールＣ１－６アルキル」基が結合した一価の基を意味する。該「アリールＣ１－６アルキルスルホニル」としては、例えば、ベンジルスルホニル、ナフチルメチルスルホニル、２－フェニルエチルスルホニル、１－フェニルエチルスルホニル、１－フェニルプロピルスルホニル等が挙げられる。 As used herein, "aryl C 1-6 alkylsulfonyl" means the sulfonyl group "aryl C 1-6 alkyl" monovalent radical group is bonded. Examples of the “aryl C 1-6 alkylsulfonyl” include benzylsulfonyl, naphthylmethylsulfonyl, 2-phenylethylsulfonyl, 1-phenylethylsulfonyl, 1-phenylpropylsulfonyl and the like.
　本明細書において、「アリールＣ１－６アルキルスルホニルオキシ」は、酸素原子に前記「アリールＣ１－６アルキルスルホニル」基が結合した一価の基を意味する。該「アリールＣ１－６アルキルスルホニルオキシ」としては、例えば、ベンジルスルホニルオキシ、ナフチルメチルスルホニルオキシ、２－フェニルエチルスルホニルオキシ、１－フェニルエチルスルホニルオキシ、１－フェニルプロピルスルホニルオキシ等が挙げられる。 In the present specification, “aryl C 1-6 alkylsulfonyloxy” means a monovalent group in which the “aryl C 1-6 alkylsulfonyl” group is bonded to an oxygen atom. Examples of the “aryl C 1-6 alkylsulfonyloxy” include benzylsulfonyloxy, naphthylmethylsulfonyloxy, 2-phenylethylsulfonyloxy, 1-phenylethylsulfonyloxy, 1-phenylpropylsulfonyloxy and the like.
　本明細書において、「モノまたはジ－アリールＣ１－６アルキルアミノ」は、アミノ基に１個または２個の前記「アリールＣ１－６アルキル」基が置換した一価の基を意味する。該「モノまたはジ－アリールＣ１－６アルキルアミノ」としては、例えば、ベンジルアミノ、ナフチルメチルアミノ、２－フェニルエチルアミノ、１－フェニルエチルアミノ、１－フェニルプロピルアミノ、ジベンジルアミノ等が挙げられる。 In the present specification, “mono or di-aryl C 1-6 alkylamino” means a monovalent group in which one or two “aryl C 1-6 alkyl” groups are substituted on the amino group. Examples of the “mono or di-aryl C 1-6 alkylamino” include benzylamino, naphthylmethylamino, 2-phenylethylamino, 1-phenylethylamino, 1-phenylpropylamino, dibenzylamino and the like. It is done.
　本明細書において、「モノまたはジ－アリールＣ１－６アルキル－カルバモイル」は、カルバモイル基に１個または２個の前記「アリールＣ１－６アルキル」基が置換した一価の基を意味する。該「モノまたはジ－アリールＣ１－６アルキル－カルバモイル」としては、例えば、ベンジルカルバモイル、ナフチルメチルカルバモイル、２－フェニルエチルカルバモイル、１－フェニルエチルカルバモイル、１－フェニルプロピルカルバモイル、ジベンジルカルバモイル等が挙げられる。 In the present specification, “mono or di-aryl C 1-6 alkyl-carbamoyl” means a monovalent group in which one or two “aryl C 1-6 alkyl” groups are substituted on the carbamoyl group. . Examples of the “mono- or di-aryl C 1-6 alkyl-carbamoyl” include benzylcarbamoyl, naphthylmethylcarbamoyl, 2-phenylethylcarbamoyl, 1-phenylethylcarbamoyl, 1-phenylpropylcarbamoyl, dibenzylcarbamoyl and the like. It is done.
　本明細書において、「モノまたはジ－アリールＣ１－６アルキル－チオカルバモイル」は、チオカルバモイル基に１個または２個の前記「アリールＣ１－６アルキル」基が置換した一価の基を意味する。該「モノまたはジ－アリールＣ１－６アルキル－チオカルバモイル」としては、例えば、ベンジルチオカルバモイル、ナフチルメチルチオカルバモイル、２－フェニルエチルチオカルバモイル、１－フェニルエチルチオカルバモイル、１－フェニルプロピルチオカルバモイル、ジベンジルチオカルバモイル等が挙げられる。 In the present specification, “mono or di-aryl C 1-6 alkyl-thiocarbamoyl” is a monovalent group in which one or two “aryl C 1-6 alkyl” groups are substituted on a thiocarbamoyl group. means. Examples of the “mono- or di-arylC 1-6 alkyl-thiocarbamoyl” include benzylthiocarbamoyl, naphthylmethylthiocarbamoyl, 2-phenylethylthiocarbamoyl, 1-phenylethylthiocarbamoyl, 1-phenylpropylthiocarbamoyl, di Examples thereof include benzylthiocarbamoyl.
　本明細書において、「アリールＣ１－６アルコキシ－カルボニル」は、カルボニルに前記「アリールＣ１－６アルコキシ」基が結合した一価の基を意味する。該「アリールＣ１－６アルコキシ－カルボニル」としては、例えば、ベンジルオキシカルボニル、ナフチルメチルオキシカルボニル、２－フェニルエチルオキシカルボニル、１－フェニルエチルオキシカルボニル、１－フェニルプロピルオキシカルボニル等が挙げられる。 In the present specification, “arylC 1-6 alkoxy-carbonyl” means a monovalent group in which the “arylC 1-6 alkoxy” group is bonded to carbonyl. Examples of the “aryl C 1-6 alkoxy-carbonyl” include benzyloxycarbonyl, naphthylmethyloxycarbonyl, 2-phenylethyloxycarbonyl, 1-phenylethyloxycarbonyl, 1-phenylpropyloxycarbonyl and the like.
　本明細書において、「アリールＣ１－６アルコキシ－カルボニルオキシ」は、酸素原子に前記「アリールＣ１－６アルコキシ－カルボニル」基が結合した一価の基を意味する。該「アリールＣ１－６アルコキシ－カルボニルオキシ」としては、例えば、ベンジルオキシカルボニルオキシ、ナフチルメチルオキシカルボニルオキシ、２－フェニルエチルオキシカルボニルオキシ、１－フェニルエチルオキシカルボニルオキシ、１－フェニルプロピルオキシカルボニルオキシ等が挙げられる。 In the present specification, “aryl C 1-6 alkoxy-carbonyloxy” means a monovalent group in which the “aryl C 1-6 alkoxy-carbonyl” group is bonded to an oxygen atom. Examples of the “aryl C 1-6 alkoxy-carbonyloxy” include benzyloxycarbonyloxy, naphthylmethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 1-phenylpropyloxycarbonyl Examples include oxy.
　本明細書において、「アリールＣ１－６アルキル－カルボニル基」は、カルボニルに前記「アリールＣ１－６アルキル」基が結合した一価の基を意味する。該「アリールＣ１－６アルキル－カルボニル」としては、例えば、ベンジルカルボニル、ナフチルメチルカルボニル、２－フェニルエチルカルボニル、１－フェニルエチルカルボニル、１－フェニルプロピルカルボニル等が挙げられる。 In the present specification, the “aryl C 1-6 alkyl-carbonyl group” means a monovalent group in which the “aryl C 1-6 alkyl” group is bonded to carbonyl. Examples of the “aryl C 1-6 alkyl-carbonyl” include benzylcarbonyl, naphthylmethylcarbonyl, 2-phenylethylcarbonyl, 1-phenylethylcarbonyl, 1-phenylpropylcarbonyl and the like.
　本明細書において、「アリールＣ１－６アルキル－カルボニルオキシ基」は、酸素原子に前記「アリールＣ１－６アルキル－カルボニル」基が結合した一価の基を意味する。該「アリールＣ１－６アルキル－カルボニルオキシ」としては、例えば、ベンジルカルボニルオキシ、ナフチルメチルカルボニルオキシ、２－フェニルエチルカルボニルオキシ、１－フェニルエチルカルボニルオキシ、１－フェニルプロピルカルボニルオキシ等が挙げられる。 In the present specification, the “aryl C 1-6 alkyl-carbonyloxy group” means a monovalent group in which the “aryl C 1-6 alkyl-carbonyl” group is bonded to an oxygen atom. Examples of the “aryl C 1-6 alkyl-carbonyloxy” include benzylcarbonyloxy, naphthylmethylcarbonyloxy, 2-phenylethylcarbonyloxy, 1-phenylethylcarbonyloxy, 1-phenylpropylcarbonyloxy and the like. .
　本明細書において、「複素環基」は、酸素原子、窒素原子および硫黄原子からなる群より選択されるヘテロ原子を少なくとも１つ含有する３～１４員（単環、２環または３環系）複素環基を意味し、芳香族複素環基および非芳香族複素環基が挙げられる。
　本明細書において、「芳香族複素環基」は、酸素原子、窒素原子および硫黄原子からなる群より選択されるヘテロ原子を少なくとも１つ含有する一価または二価の５～１４員の単環式芳香族複素環基および縮合芳香族複素環基を意味する。本発明における縮合芳香族複素環基は２または３環系であり、複数の環にヘテロ原子を有していてもよい。単環式芳香族複素環基としては、５または６員環基が挙げられ、縮合芳香族複素環基としては、該基を構成する各環が５または６員環である基が挙げられる。該「芳香族複素環基」としては、例えば、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソキサゾリル、チアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、オキサジアゾリル、ピリジル、ピラジニル、ピリダジニル、ピリミジニル等の５または６員の単環式芳香族複素環基、インドリル、イソインドリル、インダゾリル、ベンゾフラニル、ベンゾチオフェニル、ベンゾイミダゾリル（例、５－ベンゾイミダゾリル）、ベンゾオキサゾリル、ベンゾチアゾリル、キノリル、イソキノリル、ベンゾオキサジニル、ベンゾチアジニル、フロ［２，３－ｂ］ピリジル、チエノ［２，３－ｂ］ピリジル、ナフチリジニル、イミダゾピリジル、オキサゾロピリジル、チアゾロピリジル、キノキサリニル、キナゾリニル、ピリドピラジニル、カルバゾリル、ジベンゾチオフェニル等の８ないし１４員縮合芳香族複素環基が挙げられる。 In the present specification, the “heterocyclic group” is a 3 to 14 member (monocyclic, bicyclic or tricyclic system) containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. A heterocyclic group means an aromatic heterocyclic group and a non-aromatic heterocyclic group.
In the present specification, the “aromatic heterocyclic group” means a monovalent or divalent 5- to 14-membered monocyclic ring containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Means an aromatic heterocyclic group and a fused aromatic heterocyclic group. The condensed aromatic heterocyclic group in the present invention is a 2 or 3 ring system, and a plurality of rings may have heteroatoms. The monocyclic aromatic heterocyclic group includes a 5- or 6-membered ring group, and the condensed aromatic heterocyclic group includes a group in which each ring constituting the group is a 5- or 6-membered ring. Examples of the “aromatic heterocyclic group” include 5- or 6-membered members such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like. A monocyclic aromatic heterocyclic group, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl (eg, 5-benzoimidazolyl), benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, Furo [2,3-b] pyridyl, thieno [2,3-b] pyridyl, naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, quinoxalinyl, quinazoly Le, pyridopyrazinyl, carbazolyl, include 8-14 membered fused aromatic heterocyclic groups such as a dibenzothiophenyl.
　本明細書において、「非芳香族複素環基」は、酸素原子、窒素原子および硫黄原子からなる群より選択されるヘテロ原子を少なくとも１つ含有する一価または二価の３～１４員の単環式非芳香族複素環基および縮合非芳香族複素環基を意味する。本発明における縮合非芳香族複素環基は２または３環系であり、両環にヘテロ原子を有していてもよい。単環式非芳香族複素環基としては、３～９員環基（好ましくは、４～７員環基）が挙げられ、縮合非芳香族複素環基としては、該基を構成する各環が５または６員環である基が挙げられる。該「非芳香族複素環基」としては、例えば、オキセタニル（例、３－オキセタニル）、テトラヒドロフリル（例、テトラヒドロフラン－３－イル）、ジオキソリル（例、１，３－ジオキソール－４－イル）、ジオキソラニル（例、１，３－ジオキソラン－４－イル）、オキサゾリジニル、イミダゾリニル（例、１－イミダゾリニル、２－イミダゾリニル、４－イミダゾリニル）、アジリジニル（例、１－アジリジニル、２－アジリジニル）、アゼチジニル（例、１－アゼチジニル、２－アゼチジニル、３－アゼチジニル）、ピロリジニル（例、１－ピロリジニル、２－ピロリジニル、３－ピロリジニル）、ピペリジル（例、１－ピペリジル、２－ピペリジル、３－ピペリジル、４－ピペリジル）、ジオキサニル（例、１，４－ジオキサン－２－イル）、アゼパニル（例、１－アゼパニル、２－アゼパニル、３－アゼパニル、４－アゼパニル）、アゾカニル（例、１－アゾカニル、２－アゾカニル、３－アゾカニル、４－アゾカニル）、アゾナニル（例、１－アゾナニル、２－アゾナニル、３－アゾナニル、４－アゾナニル、５－アゾナニル）、ピペラジニル（例、ピペラジン－１－イル、ピペラジン－２－イル）、ジアゼピニル（例、１，４－ジアゼピン－１－イル、１，４－ジアゼピン－２－イル、１，４－ジアゼピン－５－イル、１，４－ジアゼピン－６－イル）、ジアゾカニル（例、１，４－ジアゾカン－１－イル、１，４－ジアゾカン－２－イル、１，４－ジアゾカン－５－イル、１，４－ジアゾカン－６－イル、１，５－ジアゾカン－１－イル、１，５－ジアゾカン－２－イル、１，５－ジアゾカン－３－イル）、テトラヒドロピラニル（例、テトラヒドロピラン－４－イル、テトラヒドロピラン－２－イル）、モルホリニル（例、４－モルホリニル）、チオモルホリニル（例、４－チオモルホリニル）、２－オキサゾリジニル、ジヒドロフリル、ジヒドロピラニル等の３ないし９員の単環式非芳香族複素環基、ベンゾピラニル、ジヒドロキノリル、ジヒドロイソキノリル（例、３，４－ジヒドロイソキノリン－２－イル）、ジヒドロインドリル（例、２，３－ジヒドロインドール－５－イル、２，３－ジヒドロインドール－１－イル）、ジヒドロイソインドリル（例、２，３－ジヒドロイソインドール－２－イル）等の８ないし１４員の縮合非芳香族複素環基等が挙げられる。 In the present specification, the “non-aromatic heterocyclic group” is a monovalent or divalent 3- to 14-membered single atom containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. It means a cyclic non-aromatic heterocyclic group and a fused non-aromatic heterocyclic group. The fused non-aromatic heterocyclic group in the present invention is a 2 or 3 ring system and may have a hetero atom in both rings. Examples of the monocyclic non-aromatic heterocyclic group include 3- to 9-membered cyclic groups (preferably 4- to 7-membered cyclic groups), and the condensed non-aromatic heterocyclic group includes each ring constituting the group. Group in which is a 5- or 6-membered ring. Examples of the “non-aromatic heterocyclic group” include oxetanyl (eg, 3-oxetanyl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), Dioxolanyl (eg, 1,3-dioxolan-4-yl), oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl (eg, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl) ), Dioxanyl (eg, 1,4-dioxane-2) Yl), azepanyl (eg, 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (eg, 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl), azonanyl (eg, 1 -Azonanyl, 2-azonanyl, 3-azonanyl, 4-azonanyl, 5-azonanyl), piperazinyl (eg, piperazin-1-yl, piperazin-2-yl), diazepinyl (eg, 1,4-diazepin-1-yl) 1,4-diazepin-2-yl, 1,4-diazepin-5-yl, 1,4-diazepin-6-yl), diazocanyl (eg, 1,4-diazocan-1-yl, 1,4- Diazocan-2-yl, 1,4-diazocan-5-yl, 1,4-diazocan-6-yl, 1,5-diazocan-1-yl, 1,5-diazocan-2 Yl, 1,5-diazocan-3-yl), tetrahydropyranyl (eg, tetrahydropyran-4-yl, tetrahydropyran-2-yl), morpholinyl (eg, 4-morpholinyl), thiomorpholinyl (eg, 4-thiomorpholinyl) ), 3-oxazolidinyl, dihydrofuryl, dihydropyranyl, etc., 3- to 9-membered monocyclic non-aromatic heterocyclic group, benzopyranyl, dihydroquinolyl, dihydroisoquinolyl (eg, 3,4-dihydroisoquinoline-2) -Yl), dihydroindolyl (eg, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-1-yl), dihydroisoindolyl (eg, 2,3-dihydroisoindole-2- 8) to 14-membered condensed non-aromatic heterocyclic group and the like.
　本明細書において、「含窒素複素環基」としては、「複素環基」のうち、環構成原子として少なくとも１個以上の窒素原子を含有するものが挙げられる。 In the present specification, examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic group”.
　本明細書において、「複素環カルボニル」は、カルボニルに前記「複素環基」が結合した一価の基を意味する。該「複素環カルボニル」の好適な例としては、例えば、モルホリノカルボニル、ピぺリジノカルボニル等が挙げられる。 In this specification, “heterocyclic carbonyl” means a monovalent group in which the “heterocyclic group” is bonded to carbonyl. Preferable examples of the “heterocyclic carbonyl” include morpholinocarbonyl, piperidinocarbonyl and the like.
　本明細書において、「複素環カルボニルオキシ」は、酸素原子に前記「複素環カルボニル」基が結合した一価の基を意味する。該「複素環カルボニルオキシ」の好適な例としては、例えば、テトラヒドロピラン－４－イルカルボニルオキシ、ピぺリジン－４－イルカルボニルオキシ、ピロリジン－２－イルカルボニルオキシ、アゼチジン－３－イルカルボニルオキシ等が挙げられる。 In the present specification, “heterocyclic carbonyloxy” means a monovalent group in which the “heterocyclic carbonyl” group is bonded to an oxygen atom. Suitable examples of the “heterocyclic carbonyloxy” include, for example, tetrahydropyran-4-ylcarbonyloxy, piperidin-4-ylcarbonyloxy, pyrrolidin-2-ylcarbonyloxy, azetidin-3-ylcarbonyloxy Etc.
　本明細書において、「Ｃ１－６アルキル－カルボニル」は、カルボニルに前記「Ｃ１－６アルキル」基が結合した一価の基を意味する。該「Ｃ１－６アルキル－カルボニル」としては、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、イソペンタノイル、１－メチルブチリル、ピバロイル、ヘキサノイル、イソヘキサノイル、３，３－ジメチルブチリル、１－エチルブチリル、４－メチルヘキサノイル、ヘプタノイル等が挙げられる。 In the present specification, “C 1-6 alkyl-carbonyl” means a monovalent group in which the “C 1-6 alkyl” group is bonded to carbonyl. Examples of the “C 1-6 alkyl-carbonyl” include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isopentanoyl, 1-methylbutyryl, pivaloyl, hexanoyl, isohexanoyl, 3,3-dimethylbutyryl, 1 -Ethylbutyryl, 4-methylhexanoyl, heptanoyl and the like.
　本明細書において、「Ｃ１－６アルキル－カルボニルオキシ」は、酸素原子に前記「Ｃ１－６アルキル－カルボニル」基が結合した一価の基を意味する。該「Ｃ１－６アルキル－カルボニルオキシ」としては、例えば、アセチルオキシ、プロピオニルオキシ、ブチリルオキシ、イソブチリルオキシ、ペンタノイルオキシ、イソペンタノイルオキシ、１－メチルブチリルオキシ、ピバロイルオキシ、ヘキサノイルオキシ、イソヘキサノイルオキシ、３，３－ジメチルブチリルオキシ、１－エチルブチリルオキシ、４－メチルヘキサノイルオキシ、ヘプタノイルオキシ等が挙げられる。 In the present specification, “C 1-6 alkyl-carbonyloxy” means a monovalent group in which the “C 1-6 alkyl-carbonyl” group is bonded to an oxygen atom. Examples of the “C 1-6 alkyl-carbonyloxy” include acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, isopentanoyloxy, 1-methylbutyryloxy, pivaloyloxy, hexanoyloxy Isohexanoyloxy, 3,3-dimethylbutyryloxy, 1-ethylbutyryloxy, 4-methylhexanoyloxy, heptanoyloxy and the like.
　本明細書において、「アリール－カルボニルオキシ」は、酸素原子に前記「アリール－カルボニル」基が結合した一価の基を意味する。該「アリール－カルボニルオキシ」の好適な例としては、例えば、ベンゾイルオキシ等のＣ６－１４アリール－カルボニルオキシが挙げられる。 In the present specification, “aryl-carbonyloxy” means a monovalent group in which the “aryl-carbonyl” group is bonded to an oxygen atom. Preferable examples of the “aryl-carbonyloxy” include C 6-14 aryl-carbonyloxy such as benzoyloxy.
　本明細書において、「Ｃ１－６アルコキシ－カルボニルオキシ」は、酸素原子に前記「Ｃ１－６アルコキシ－カルボニル」基が結合した一価の基を意味する。該「Ｃ１－６アルコキシ－カルボニルオキシ」としては、例えば、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、イソプロポキシカルボニルオキシ、ブトキシカルボニルオキシ、イソブトキシカルボニルオキシ、ｓｅｃ－ブトキシカルボニルオキシ、ｔｅｒｔ－ブトキシカルボニルオキシ、ペンチルオキシカルボニルオキシ、イソペンチルオキシカルボニルオキシ、ネオペンチルオキシカルボニルオキシ、１－エチルプロピルオキシカルボニルオキシ、へキシルオキシカルボニルオキシ等が挙げられる。 In the present specification, “C 1-6 alkoxy-carbonyloxy” means a monovalent group in which the “C 1-6 alkoxy-carbonyl” group is bonded to an oxygen atom. Examples of the “C 1-6 alkoxy-carbonyloxy” include, for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert- Examples include butoxycarbonyloxy, pentyloxycarbonyloxy, isopentyloxycarbonyloxy, neopentyloxycarbonyloxy, 1-ethylpropyloxycarbonyloxy, hexyloxycarbonyloxy and the like.
　本明細書において、「Ｃ３－８シクロアルキル－カルボニルオキシ」は、酸素原子に前記「Ｃ３－８シクロアルキル－カルボニル」基が結合した一価の基を意味する。該「Ｃ３－８シクロアルキル－カルボニルオキシ」としては、例えば、シクロプロピルカルボニルオキシ、シクロブチルカルボニルオキシ、シクロペンチルカルボニルオキシ、シクロヘキシルカルボニルオキシ、シクロヘプチルカルボニルオキシ等が挙げられる。 In the present specification, “C 3-8 cycloalkyl-carbonyloxy” means a monovalent group in which the “C 3-8 cycloalkyl-carbonyl” group is bonded to an oxygen atom. Examples of the “C 3-8 cycloalkyl-carbonyloxy” include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, cycloheptylcarbonyloxy and the like.
　本明細書において、「Ｃ３－８シクロアルキルオキシ」は、酸素原子に前記「Ｃ３－８シクロアルキル基」が結合した一価の基を意味する。該「Ｃ３－８シクロアルキルオキシ」としては、例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ等が挙げられる。 In the present specification, “C 3-8 cycloalkyloxy” means a monovalent group in which the “C 3-8 cycloalkyl group” is bonded to an oxygen atom. Examples of the “C 3-8 cycloalkyloxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like.
　本明細書において、「Ｃ３－８シクロアルキルオキシ－カルボニル」は、カルボニルに前記「Ｃ３－８シクロアルキルオキシ基」が結合した一価の基を意味する。該「Ｃ３－８シクロアルキルオキシ－カルボニル」としては、例えば、シクロプロピルオキシカルボニル、シクロブチルオキシカルボニル、シクロペンチルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロヘプチルオキシカルボニル等が挙げられる。 In the present specification, “C 3-8 cycloalkyloxy-carbonyl” means a monovalent group in which the “C 3-8 cycloalkyloxy group” is bonded to carbonyl. Examples of the “C 3-8 cycloalkyloxy-carbonyl” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl and the like.
　本明細書において、「Ｃ３－８シクロアルキルオキシ－カルボニルオキシ」は、酸素原子に前記「Ｃ３－８シクロアルキルオキシ－カルボニル」基が結合した一価の基を意味する。該「Ｃ３－８シクロアルキルオキシ－カルボニルオキシ」としては、例えば、シクロプロピルオキシカルボニルオキシ、シクロブチルオキシカルボニルオキシ、シクロペンチルオキシカルボニルオキシ、シクロヘキシルオキシカルボニルオキシ、シクロヘプチルオキシカルボニルオキシ等が挙げられる。 In the present specification, “C 3-8 cycloalkyloxy-carbonyloxy” means a monovalent group in which the “C 3-8 cycloalkyloxy-carbonyl” group is bonded to an oxygen atom. Examples of the “C 3-8 cycloalkyloxy-carbonyloxy” include cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy and the like.
　本明細書において、「複素環Ｃ１－６アルキル」は、前記「Ｃ１－６アルキル」に前記「複素環基」が置換した一価の基を意味する。該「複素環Ｃ１－６アルキル」の好適な例としては、例えば、アゼチジン－１－イルメチル、モルフホリン－４－イルメチル、ピロリジン－１－イルメチル、ピペリジン－１－イルメチル、テトラヒドロピラン－４－イル等が挙げられる。 In the present specification, the “heterocyclic C 1-6 alkyl” means a monovalent group in which the “heterocyclic group” is substituted on the “C 1-6 alkyl”. Suitable examples of the “heterocyclic C 1-6 alkyl” include, for example, azetidin-1-ylmethyl, morpholin-4-ylmethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, tetrahydropyran-4-yl and the like. Is mentioned.
　本明細書において、「複素環オキシ」は、酸素原子に前記「複素環基」が結合した一価の基を意味する。該「複素環オキシ」の好適な例としては、例えば、テトラヒドロピラン－２－イルオキシ等が挙げられる。 In the present specification, “heterocyclic oxy” means a monovalent group in which the “heterocyclic group” is bonded to an oxygen atom. Preferable examples of the “heterocyclic oxy” include, for example, tetrahydropyran-2-yloxy and the like.
　本明細書において、「複素環スルファニル」は、硫黄原子に前記「複素環基」が結合した一価の基を意味する。該「複素環スルファニル」の好適な例としては、例えば、テトラヒドロピラン－２－イルスルファニル等が挙げられる。 In this specification, “heterocyclic sulfanyl” means a monovalent group in which the “heterocyclic group” is bonded to a sulfur atom. Preferable examples of the “heterocyclic sulfanyl” include, for example, tetrahydropyran-2-ylsulfanyl and the like.
　本明細書において、「複素環スルフィニル」は、スルフィニル基に前記「複素環基」が結合した一価の基を意味する。該「複素環スルフィニル」の好適な例としては、例えば、テトラヒドロピラン－２－イルスルフィニル等が挙げられる。 In the present specification, “heterocyclic sulfinyl” means a monovalent group in which the “heterocyclic group” is bonded to a sulfinyl group. Preferable examples of the “heterocyclic sulfinyl” include, for example, tetrahydropyran-2-ylsulfinyl and the like.
　本明細書において、「複素環スルホニル」は、スルホニル基に前記「複素環基」が結合した一価の基を意味する。該「複素環スルホニル」の好適な例としては、例えば、テトラヒドロピラン－２－イルスルホニル等が挙げられる。 In the present specification, “heterocyclic sulfonyl” means a monovalent group in which the “heterocyclic group” is bonded to a sulfonyl group. Preferable examples of the “heterocyclic sulfonyl” include, for example, tetrahydropyran-2-ylsulfonyl and the like.
　本明細書において、「複素環スルホニルオキシ」は、酸素原子に前記「複素環スルホニル」基が結合した一価の基を意味する。該「複素環スルホニルオキシ」としては、例えば、テトラヒドロピラン－２－イルスルホニルオキシ等が挙げられる。 In the present specification, “heterocyclic sulfonyloxy” means a monovalent group in which the “heterocyclic sulfonyl” group is bonded to an oxygen atom. Examples of the “heterocyclic sulfonyloxy” include tetrahydropyran-2-ylsulfonyloxy and the like.
　本明細書において、「複素環オキシカルボニル」は、カルボニルに前記「複素環オキシ基」が結合した一価の基を意味する。該「複素環オキシカルボニル」としては、例えば、テトラヒドロピラン－４－イルオキシカルボニル等が挙げられる。 In the present specification, “heterocyclic oxycarbonyl” means a monovalent group in which the “heterocyclic oxy group” is bonded to carbonyl. Examples of the “heterocyclic oxycarbonyl” include tetrahydropyran-4-yloxycarbonyl and the like.
　本明細書において、「モノまたはジ－複素環アミノ」は、アミノ基に１個または２個の前記「複素環基」が置換した一価の基を意味する。該「モノまたはジ－複素環アミノ」としては、例えば、ピロリジニルアミノ、ピペリジルアミノ等が挙げられる。 In the present specification, “mono or di-heterocyclic amino” means a monovalent group in which one or two “heterocyclic groups” are substituted on the amino group. Examples of the “mono or di-heterocyclic amino” include pyrrolidinylamino, piperidylamino and the like.
　本明細書において、「モノまたはジ－複素環カルバモイル」は、カルバモイル基に１個または２個の前記「複素環基」が置換した一価の基を意味する。該「モノまたはジ－複素環カルバモイル」としては、例えば、ピロリジニルカルバモイル、ピペリジルカルバモイル等が挙げられる。 In the present specification, “mono or di-heterocyclic carbamoyl” means a monovalent group in which one or two “heterocyclic groups” are substituted on a carbamoyl group. Examples of the “mono or di-heterocyclic carbamoyl” include pyrrolidinylcarbamoyl, piperidylcarbamoyl and the like.
　本明細書において、「モノまたはジ－複素環チオカルバモイル」は、チオカルバモイル基に１個または２個の前記「複素環基」が置換した一価の基を意味する。該「モノまたはジ－複素環チオカルバモイル」としては、例えば、ピロリジニルチオカルバモイル、ピペリジルチオカルバモイル等が挙げられる。 In the present specification, “mono or di-heterocyclic thiocarbamoyl” means a monovalent group in which one or two “heterocyclic groups” are substituted on a thiocarbamoyl group. Examples of the “mono or di-heterocyclic thiocarbamoyl” include pyrrolidinylthiocarbamoyl, piperidylthiocarbamoyl and the like.
　本明細書において、「複素環オキシカルボニルオキシ」は、複素環部分が前記「複素環基」である「複素環オキシカルボニルオキシ」を意味する。該「複素環オキシカルボニルオキシ」の好適な例としては、例えば、テトラヒドロピラン－４－イルオキシカルボニルオキシ等が挙げられる。 In the present specification, “heterocyclic oxycarbonyloxy” means “heterocyclic oxycarbonyloxy” in which the heterocyclic moiety is the “heterocyclic group”. Preferable examples of the “heterocyclic oxycarbonyloxy” include, for example, tetrahydropyran-4-yloxycarbonyloxy and the like.
　以下では、本発明の化合物（Ｉ）に包含される態様について順に説明する。 Hereinafter, embodiments included in the compound (I) of the present invention will be described in order.
　式（Ｉ）における環Ａ、Ｘおよび環Ｂの定義における、「さらに置換されていてもよい」の各基の置換基としては、下記置換基群αから選択される置換基が挙げられる。置換基の数は、置換可能な数であれば特に限定されないが、好ましくは１ないし５個、より好ましくは１ないし３個である。複数の置換基が存在する場合、各置換基は、同一でも異なっていてもよい。
（置換基群α）
ハロゲン原子；
ヒドロキシ基；
カルボキシ基；
シアノ基；
ニトロ基；
オキソ基；
チオキソ基；
Ｃ１－６アルキル基；
Ｃ２－６アルケニル基；
Ｃ２－６アルキニル基；
Ｃ３－８シクロアルキル基；
Ｃ６－１４アリール基；
アリールＣ１－６アルキル基；
複素環Ｃ１－６アルキル基；
Ｃ１－６アルコキシ基；
Ｃ３－８シクロアルキルオキシ基；
アリールＣ１－６アルコキシ基；
複素環基；
複素環オキシ基；
ホルミル基；
Ｃ１－６アルキル－カルボニル基；
Ｃ３－８シクロアルキル－カルボニル基；
Ｃ６－１４アリール－カルボニル基；
アリールＣ１－６アルキル－カルボニル基；
複素環カルボニル基；
Ｃ１－６アルコキシ－カルボニル基；
Ｃ３－８シクロアルキルオキシ－カルボニル基；
Ｃ６－１４アリールオキシ－カルボニル基；
アリールＣ１－６アルコキシ－カルボニル基；
複素環オキシカルボニル基；
Ｃ１－６アルキル－カルボニルオキシ基；
Ｃ３－８シクロアルキル－カルボニルオキシ基；
Ｃ６－１４アリール－カルボニルオキシ基；
アリールＣ１－６アルキル－カルボニルオキシ基；
複素環カルボニルオキシ基；
Ｃ１－６アルコキシ－カルボニルオキシ基；
Ｃ３－８シクロアルキルオキシ－カルボニルオキシ基；
Ｃ６－１４アリールオキシ－カルボニルオキシ基；
アリールＣ１－６アルコキシ－カルボニルオキシ基；
複素環オキシカルボニルオキシ基；
スルファニル基；
Ｃ１－６アルキルスルファニル基；
Ｃ３－８シクロアルキルスルファニル基；
Ｃ６－１４アリールスルファニル基；
アリールＣ１－６アルキルスルファニル基；
複素環スルファニル基；
スルフィノ基；
Ｃ１－６アルキルスルフィニル基；
Ｃ３－８シクロアルキルスルフィニル基；
Ｃ６－１４アリールスルフィニル基；
アリールＣ１－６アルキルスルフィニル基；
複素環スルフィニル基；
スルホ基；
Ｃ１－６アルキルスルホニル基；
Ｃ３－８シクロアルキルスルホニル基；
Ｃ６－１４アリールスルホニル基；
アリールＣ１－６アルキルスルホニル基；
複素環スルホニル基；
Ｃ１－６アルキルスルホニルオキシ基；
Ｃ３－８シクロアルキルスルホニルオキシ基；
Ｃ６－１４アリールスルホニルオキシ基；
アリールＣ１－６アルキルスルホニルオキシ基；
複素環スルホニルオキシ基；
アミノ基；
モノまたはジ－Ｃ１－６アルキルアミノ基；
モノまたはジ－Ｃ３－８シクロアルキルアミノ基；
モノまたはジ－Ｃ６－１４アリールアミノ基；
モノまたはジ－アリールＣ１－６アルキルアミノ基；
モノまたはジ－複素環アミノ基；
カルバモイル基；
モノまたはジ－Ｃ１－６アルキル－カルバモイル基；
モノまたはジ－Ｃ３－８シクロアルキル－カルバモイル基；
モノまたはジ－Ｃ６－１４アリール－カルバモイル基；
モノまたはジ－アリールＣ１－６アルキル－カルバモイル基；
モノまたはジ－複素環カルバモイル基；
チオカルバモイル基；
モノまたはジ－Ｃ１－６アルキル－チオカルバモイル基；
モノまたはジ－Ｃ３－８シクロアルキル－チオカルバモイル基；
モノまたはジ－Ｃ６－１４アリール－チオカルバモイル基；
モノまたはジ－アリールＣ１－６アルキル－チオカルバモイル基；または
モノまたはジ－複素環チオカルバモイル基。 Examples of the substituent of each group of “which may be further substituted” in the definition of ring A, X and ring B in formula (I) include substituents selected from the following substituent group α. The number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
(Substituent group α)
A halogen atom;
A hydroxy group;
A carboxy group;
A cyano group;
A nitro group;
An oxo group;
A thioxo group;
A C 1-6 alkyl group;
A C 2-6 alkenyl group;
A C 2-6 alkynyl group;
A C 3-8 cycloalkyl group;
A C 6-14 aryl group;
An aryl C 1-6 alkyl group;
A heterocyclic C 1-6 alkyl group;
A C 1-6 alkoxy group;
A C 3-8 cycloalkyloxy group;
An aryl C 1-6 alkoxy group;
A heterocyclic group;
A heterocyclic oxy group;
Formyl group;
A C 1-6 alkyl-carbonyl group;
A C 3-8 cycloalkyl-carbonyl group;
A C 6-14 aryl-carbonyl group;
An aryl C 1-6 alkyl-carbonyl group;
A heterocyclic carbonyl group;
A C 1-6 alkoxy-carbonyl group;
A C 3-8 cycloalkyloxy-carbonyl group;
A C 6-14 aryloxy-carbonyl group;
An aryl C 1-6 alkoxy-carbonyl group;
A heterocyclic oxycarbonyl group;
A C 1-6 alkyl-carbonyloxy group;
A C 3-8 cycloalkyl-carbonyloxy group;
A C 6-14 aryl-carbonyloxy group;
An aryl C 1-6 alkyl-carbonyloxy group;
A heterocyclic carbonyloxy group;
A C 1-6 alkoxy-carbonyloxy group;
A C 3-8 cycloalkyloxy-carbonyloxy group;
A C 6-14 aryloxy-carbonyloxy group;
An aryl C 1-6 alkoxy-carbonyloxy group;
A heterocyclic oxycarbonyloxy group;
A sulfanyl group;
A C 1-6 alkylsulfanyl group;
A C 3-8 cycloalkylsulfanyl group;
A C 6-14 arylsulfanyl group;
An aryl C 1-6 alkylsulfanyl group;
A heterocyclic sulfanyl group;
A sulfino group;
A C 1-6 alkylsulfinyl group;
A C 3-8 cycloalkylsulfinyl group;
A C 6-14 arylsulfinyl group;
An aryl C 1-6 alkylsulfinyl group;
A heterocyclic sulfinyl group;
A sulfo group;
A C 1-6 alkylsulfonyl group;
A C 3-8 cycloalkylsulfonyl group;
A C 6-14 arylsulfonyl group;
An aryl C 1-6 alkylsulfonyl group;
A heterocyclic sulfonyl group;
A C 1-6 alkylsulfonyloxy group;
A C 3-8 cycloalkylsulfonyloxy group;
A C 6-14 arylsulfonyloxy group;
An aryl C 1-6 alkylsulfonyloxy group;
A heterocyclic sulfonyloxy group;
An amino group;
A mono- or di-C 1-6 alkylamino group;
A mono- or di-C 3-8 cycloalkylamino group;
A mono- or di-C 6-14 arylamino group;
A mono- or di-aryl C 1-6 alkylamino group;
A mono- or di-heterocyclic amino group;
A carbamoyl group;
A mono- or di-C 1-6 alkyl-carbamoyl group;
A mono- or di-C 3-8 cycloalkyl-carbamoyl group;
A mono- or di-C 6-14 aryl-carbamoyl group;
A mono- or di-aryl C 1-6 alkyl-carbamoyl group;
A mono- or di-heterocyclic carbamoyl group;
A thiocarbamoyl group;
A mono- or di-C 1-6 alkyl-thiocarbamoyl group;
A mono- or di-C 3-8 cycloalkyl-thiocarbamoyl group;
A mono- or di-C 6-14 aryl-thiocarbamoyl group;
A mono or di-aryl C 1-6 alkyl-thiocarbamoyl group; or a mono or di-heterocyclic thiocarbamoyl group.
　上記置換基は、さらに上記置換基で置換されていてもよい。置換基の数は、置換可能な数であれば特に限定されないが、好ましくは１ないし５個、より好ましくは１ないし３個である。複数の置換基が存在する場合、各置換基は、同一でも異なっていてもよい。当該置換基はまたさらにＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ３－８シクロアルキル基、Ｃ１－６アルコキシ基、Ｃ６－１４アリール基、複素環基、ハロゲン原子、ヒドロキシ基、カルボキシ基、ホルミル基、アミノ基、カルバモイル基、シアノ基、ニトロ基、オキソ基、Ｃ１－６アルキルスルホニル基、Ｃ６－１４アリールスルホニル基、Ｃ１－６アルキル－カルボニル基、Ｃ１－６アルコキシ－カルボニル基等（好ましくは、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、ハロゲン原子、ヒドロキシ基、カルボキシ基、ホルミル基、アミノ基、ジ－Ｃ１－６アルキルアミノ基、カルバモイル基、シアノ基、ニトロ基、オキソ基、Ｃ１－６アルキルスルホニル基、Ｃ６－１４アリールスルホニル基、Ｃ１－６アルキル－カルボニル基、Ｃ１－６アルコキシ－カルボニル基、複素環基、アリールＣ１－６アルコキシ－カルボニル基等）で置換されていてもよい。置換基の数は、置換可能な数であれば特に限定されないが、好ましくは１ないし５個、より好ましくは１ないし３個である。複数の置換基が存在する場合、各置換基は、同一でも異なっていてもよい。 The above substituent may be further substituted with the above substituent. The number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different. The substituent may further include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a C 6-14 aryl group, a complex Ring group, halogen atom, hydroxy group, carboxy group, formyl group, amino group, carbamoyl group, cyano group, nitro group, oxo group, C 1-6 alkylsulfonyl group, C 6-14 arylsulfonyl group, C 1-6 Alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group and the like (preferably C 1-6 alkyl group, C 1-6 alkoxy group, halogen atom, hydroxy group, carboxy group, formyl group, amino group, di-C 1-6 alkylamino group, a carbamoyl group, a cyano group, a nitro group, an oxo group, C 1-6 alkylsulfonyl group, C 6-14 aryl sulfonyl Group, C 1-6 alkyl - carbonyl group, C 1-6 alkoxy - carbonyl group, a heterocyclic group, an aryl C 1-6 alkoxy - optionally substituted with a carbonyl group). The number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
　環Ａは、それぞれさらに置換されていてもよい、フェニル基または６員の単環式含窒素複素環基（例、ピリジル基、ピペリジル基、ピペラジニル基等）を示す。 Ring A represents a phenyl group or a 6-membered monocyclic nitrogen-containing heterocyclic group (eg, pyridyl group, piperidyl group, piperazinyl group, etc.) which may be further substituted.
　環Ａは、好ましくは、それぞれさらに置換されていてもよい、フェニル基またはピリジル基であり、より好ましくは、さらに置換されていてもよいフェニル基である。 Ring A is preferably a phenyl group or a pyridyl group, each of which may be further substituted, and more preferably a phenyl group that may be further substituted.
　環Ａの好適な具体例は、
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
　 (b)カルボキシ基、
　 (c)ヒドロキシ基、
　 (d)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
　 (e)オキソ基、および
　 (f)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)Ｃ６－１４アリール基（好ましくはフェニル）
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルファニル基（好ましくはメチルスルファニル）、
(5)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルホニル基（好ましくはメチルスルホニル）、
(6)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(7)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(8)(a)Ｃ１－６アルキル基、
   (b)Ｃ３－８シクロアルキル基、
   (c)Ｃ６－１４アリール基、
   (d)アリールＣ１－６アルキル基、および
   (e)複素環基
から選択される置換基でモノまたはジ置換されていてもよいカルバモイル基、
(9)シアノ基、
(10)カルボキシ基、
(11)ヒドロキシ基、
(12)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、および
(13)ニトロ基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、フェニル基またはピリジル基である。 A preferred example of ring A is:
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a carboxy group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl)
A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
(4) a C 1-6 alkylsulfanyl group (preferably methylsulfanyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(5) a C 1-6 alkylsulfonyl group (preferably methylsulfonyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(6) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(7) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(8) (a) a C 1-6 alkyl group,
(b) a C 3-8 cycloalkyl group,
(c) a C 6-14 aryl group,
(d) an aryl C 1-6 alkyl group, and (e) a carbamoyl group optionally mono- or disubstituted with a substituent selected from a heterocyclic group,
(9) a cyano group,
(10) a carboxy group,
(11) hydroxy group,
(12) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group, and
(13) A phenyl group or a pyridyl group, each of which may be further substituted with 1 to 3 substituents selected from a nitro group.
　環Ａのより好適な具体例は、
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ヒドロキシ基、
   (c)オキソ基、および
   (d)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)フェニル基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(5)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(6)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
(7)シアノ基、
(8)カルボキシ基、
(9)ヒドロキシ基、
(10)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、および
(11)ニトロ基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、フェニル基またはピリジル基である。 A more preferred specific example of ring A is
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy),
(4) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(6) a carbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group,
(7) cyano group,
(8) a carboxy group,
(9) hydroxy group,
(10) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group, and
(11) A phenyl group or a pyridyl group, each of which may be further substituted with 1 to 3 substituents selected from a nitro group.
　環Ａの特に好適な具体例は、
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、および
   (b)ヒドロキシ基、
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル）、および
(3)シアノ基
から選択される１ないし３個の置換基で、さらに置換されていてもよいフェニル基である。 Particularly preferred examples of ring A are:
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group,
A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted with 1 to 3 substituents selected from
(3) A phenyl group which may be further substituted with 1 to 3 substituents selected from a cyano group.
　Ｘは、単結合、さらに置換されていてもよい二価の４ないし７員の単環式複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、ピリジル基、ピリミジル基、ピペリジル基、ピペラジニル基等から誘導される二価の基）またはさらに置換されていてもよいＣ２－６アルキニレン基（例、エチニレン基）を示す。 X represents a single bond, a divalent 4- to 7-membered monocyclic heterocyclic group which may be further substituted (eg, oxadiazolyl group, furyl group, thienyl group, triazolyl group, oxazolyl group, pyrazolyl group, imidazolyl group) , A divalent group derived from a thiazolyl group, a pyridyl group, a pyrimidyl group, a piperidyl group, a piperazinyl group, etc.) or a C 2-6 alkynylene group (eg, an ethynylene group) which may be further substituted.
　Ｘは、好ましくは、単結合、またはさらに置換されていてもよい二価の５または６員の単環式芳香族複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、ピリジル基、ピリミジル基等から誘導される二価の基）であり、より好ましくは、単結合、またはさらに置換されていてもよい二価の５員の単環式芳香族複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基等から誘導される二価の基）である。 X is preferably a single bond or an optionally substituted divalent 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxadiazolyl group, furyl group, thienyl group, triazolyl group, oxazolyl group) A divalent group derived from a pyrazolyl group, an imidazolyl group, a thiazolyl group, a pyridyl group, a pyrimidyl group, etc., more preferably a single bond or a divalent 5-membered single group which may be further substituted. A cyclic aromatic heterocyclic group (eg, a divalent group derived from an oxadiazolyl group, a furyl group, a thienyl group, a triazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, and the like).
　Ｘの好適な具体例は、単結合、または
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
　 (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
   (e)オキソ基、および
   (f)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)Ｃ６－１４アリール基（好ましくはフェニル）
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(5)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(6)(a)Ｃ１－６アルキル基、
  (b)Ｃ３－８シクロアルキル基、
   (c)Ｃ６－１４アリール基、
   (d)アリールＣ１－６アルキル基、および
   (e)複素環基
から選択される置換基でモノまたはジ置換されていてもよいカルバモイル基、
(7)シアノ基、
(8)カルボキシ基、
(9)ヒドロキシ基、
(10)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、および
(11)ニトロ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい二価の５または６員の単環式芳香族複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、ピリジル基、ピリミジル基等から誘導される二価の基）である。 Suitable examples of X are a single bond, or
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a carboxy group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl)
A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
(4) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(6) (a) a C 1-6 alkyl group,
(b) a C 3-8 cycloalkyl group,
(c) a C 6-14 aryl group,
(d) an aryl C 1-6 alkyl group, and (e) a carbamoyl group optionally mono- or disubstituted with a substituent selected from a heterocyclic group,
(7) cyano group,
(8) a carboxy group,
(9) hydroxy group,
(10) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group, and
(11) A divalent 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxadiazolyl group, furyl group, optionally substituted with 1 to 3 substituents selected from nitro groups) A divalent group derived from a thienyl group, a triazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a pyridyl group, a pyrimidyl group, and the like.
　Ｘのより好適な具体例は、単結合、または
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ヒドロキシ基、
   (c)オキソ基、および
   (d)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)フェニル基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルコキシ－カルボニル基、
(5)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
(6)シアノ基、
(7)カルボキシ基、
(8)ヒドロキシ基、および
(9)ニトロ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい二価の５または６員の単環式芳香族複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、ピリジル基、ピリミジル、ピラジニル基等から誘導される二価の基）である。 A more preferred specific example of X is a single bond, or
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy),
(4) a C 1-6 alkoxy-carbonyl group,
(5) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group,
(6) a cyano group,
(7) a carboxy group,
(8) a hydroxy group, and
(9) A divalent 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxadiazolyl group, furyl group, optionally substituted with 1 to 3 substituents selected from nitro groups) A divalent group derived from thienyl, triazolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl and the like.
　Ｘの特に好適な具体例は、単結合、または
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、および
   (b)ヒドロキシ基、
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル）、
(3)Ｃ１－６アルコキシ－カルボニル基、
(4)カルバモイル基、
(5)シアノ基、および
(6)カルボキシ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい二価の５員の単環式芳香族複素環基（好ましくは、オキサジアゾリル基、オキサゾリル基、チアゾリル基、トリアゾリル基、ピラゾリル基から誘導される二価の基）である。 A particularly preferred example of X is a single bond, or
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group,
A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from:
(3) a C 1-6 alkoxy-carbonyl group,
(4) a carbamoyl group,
(5) a cyano group, and
(6) A divalent 5-membered monocyclic aromatic heterocyclic group (preferably an oxadiazolyl group, an oxazolyl group, a thiazolyl group) which may be further substituted with 1 to 3 substituents selected from a carboxy group A divalent group derived from a group, a triazolyl group and a pyrazolyl group).
　環Ｂは、それぞれさらに置換されていてもよい、アリール基（例、フェニル基、ナフチル基、アントラニル基等）または複素環基を示す。 Ring B represents an aryl group (eg, phenyl group, naphthyl group, anthranyl group, etc.) or heterocyclic group, each of which may be further substituted.
　環Ｂは、好ましくは、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基（例、フェニル基、ナフチル基）、５または６員の単環式複素環基（例、ピリジル基、ピラジニル基）あるいは８ないし１４員の縮合複素環基（例、ピラゾロピリジル基、キノリル基、キノキサリニル基、キナゾリニル基、ベンゾピラニル基、ベンゾオキサゾリル基、ピリドピラジニル基等）であり、より好ましくは、それぞれさらに置換されていてもよい、フェニル基または８ないし１４員の縮合芳香族複素環基（例、ピラゾロピリジル基、キノリル基、キノキサリニル基、キナゾリニル基、ベンゾピラニル基、ベンゾオキサゾリル基、ピリドピラジニル基等）である。 Ring B is preferably a C 6-10 aryl group (eg, phenyl group, naphthyl group), 5- or 6-membered monocyclic heterocyclic group (eg, pyridyl group, pyrazinyl group), each of which may be further substituted. Group) or an 8- to 14-membered condensed heterocyclic group (eg, pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzooxazolyl group, pyridopyrazinyl group, etc.), more preferably Further substituted phenyl group or 8- to 14-membered condensed aromatic heterocyclic group (eg, pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzoxazolyl group, pyridopyrazinyl group) Etc.).
　環Ｂの好適な具体例は、
(1)ハロゲン原子（好ましくはフッ素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
　 (b)カルボキシ基、
   (c)ヒドロキシ基、
(d)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
   (e)オキソ基、
　 (f)シアノ基、および
   (g)複素環基
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)Ｃ６－１４アリール基（好ましくはフェニル）
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルファニル基（好ましくはメチルスルファニル）、
(5)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルホニル基（好ましくはメチルスルホニル）、
(6)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(7)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(8)(a)Ｃ１－６アルキル基、
   (b)Ｃ３－８シクロアルキル基、
   (c)Ｃ６－１４アリール基、
   (d)アリールＣ１－６アルキル基、および
   (e)複素環基
から選択される置換基でモノまたはジ置換されていてもよいカルバモイル基、
(9)シアノ基、
(10)カルボキシ基、
(11)ヒドロキシ基、
(12)オキソ基、
(13)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、
(14)ニトロ基、および
(15)複素環基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基（例、フェニル基、ナフチル基）、５または６員の単環式複素環基（例、ピリジル基、ピラジニル基）あるいは８ないし１４員の縮合複素環基（例、ピラゾロピリジル基、キノリル基、キノキサリニル基、キナゾリニル基、ベンゾピラニル基、ベンゾオキサゾリル基、ピリドピラジニル基）である。 Suitable examples of ring B are:
(1) a halogen atom (preferably a fluorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a carboxy group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) an oxo group,
(f) a cyano group, and (g) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-) optionally substituted with 1 to 3 substituents selected from a heterocyclic group Butyl, tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl)
A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
(4) a C 1-6 alkylsulfanyl group (preferably methylsulfanyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(5) a C 1-6 alkylsulfonyl group (preferably methylsulfonyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(6) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(7) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(8) (a) a C 1-6 alkyl group,
(b) a C 3-8 cycloalkyl group,
(c) a C 6-14 aryl group,
(d) an aryl C 1-6 alkyl group, and (e) a carbamoyl group optionally mono- or disubstituted with a substituent selected from a heterocyclic group,
(9) a cyano group,
(10) a carboxy group,
(11) hydroxy group,
(12) an oxo group,
(13) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group,
(14) a nitro group, and
(15) A C 6-10 aryl group (eg, phenyl group, naphthyl group), which may be further substituted with 1 to 3 substituents selected from a heterocyclic group, each of which is a 5- or 6-membered single group Cyclic heterocyclic group (eg, pyridyl group, pyrazinyl group) or 8- to 14-membered condensed heterocyclic group (eg, pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzoxazolyl group, Pyridopyrazinyl group).
　環Ｂのより好適な具体例は、
(1)ハロゲン原子（好ましくはフッ素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ヒドロキシ基、
   (c)ジメチルアミノ基、
   (d)オキソ基、
　 (e)シアノ基、および
   (f)４ないし７員の単環式含窒素複素環基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)フェニル基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(5)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(6)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
(7)シアノ基、
(8)カルボキシ基、
(9)オキソ基、
(10)ヒドロキシ基、
(11)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、
(12)ニトロ基、および
(13)Ｃ１－６アルキル基で置換されていてもよい４ないし７員の単環式含窒素複素環基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基（例、フェニル基、ナフチル基）、５または６員の単環式複素環基（例、ピリジル基、ピラジニル基）あるいは８ないし１４員の縮合複素環基（例、ピラゾロピリジル基、キノリル基、キノキサリニル基、キナゾリニル基、ベンゾピラニル基、ベンゾオキサゾリル基、ピリドピラジニル基）である。 A more preferred specific example of ring B is
(1) a halogen atom (preferably a fluorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) a dimethylamino group,
(d) an oxo group,
(e) a cyano group, and (f) a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from 4- to 7-membered monocyclic nitrogen-containing heterocyclic groups (preferably Methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy),
(4) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(6) a carbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group,
(7) cyano group,
(8) a carboxy group,
(9) an oxo group,
(10) a hydroxy group,
(11) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group,
(12) a nitro group, and
(13) 1 to 3 substituents selected from 4- to 7-membered monocyclic nitrogen-containing heterocyclic groups which may be substituted with C 1-6 alkyl groups, and each may be further substituted , C 6-10 aryl group (eg, phenyl group, naphthyl group), 5- or 6-membered monocyclic heterocyclic group (eg, pyridyl group, pyrazinyl group) or 8- to 14-membered condensed heterocyclic group (eg, Pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzoxazolyl group, pyridopyrazinyl group).
　環Ｂの特に好適な具体例は、
(1)ハロゲン原子（好ましくはフッ素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ジメチルアミノ基、
   (c)ヒドロキシ基、および
   (d)４ないし７員の単環式含窒素複素環基（好ましくは、アゼチジニル基、モルホリニル基、ピロリジニル基）
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル）、
(3)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(4)ヒドロキシ基、
(5)オキソ基、
(6)シアノ基、
(7)ニトロ基、および
(8)Ｃ１－６アルキル基で置換されていてもよい４ないし７員の単環式含窒素複素環基（好ましくは、４－メチルピペラジン－１－イル基）
から選択される１ないし３個の置換基で、さらに置換されていてもよいフェニル基である。 A particularly preferred embodiment of ring B is
(1) a halogen atom (preferably a fluorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a dimethylamino group,
(c) a hydroxy group, and (d) a 4- to 7-membered monocyclic nitrogen-containing heterocyclic group (preferably an azetidinyl group, a morpholinyl group, a pyrrolidinyl group)
A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from:
(3) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(4) hydroxy group,
(5) an oxo group,
(6) a cyano group,
(7) a nitro group, and
(8) a 4- to 7-membered monocyclic nitrogen-containing heterocyclic group (preferably a 4-methylpiperazin-1-yl group) optionally substituted with a C 1-6 alkyl group
A phenyl group which may be further substituted with 1 to 3 substituents selected from:
　好適な化合物（Ｉ）としては、以下の化合物が挙げられる。
［化合物Ｉ－Ａ］
　環Ａが、
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
   (e)オキソ基、および
   (f)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)Ｃ６－１４アリール基（好ましくはフェニル）
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルファニル基（好ましくはメチルスルファニル）、
(5)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルホニル基（好ましくはメチルスルホニル）、
(6)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(7)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(8)(a)Ｃ１－６アルキル基、
   (b)Ｃ３－８シクロアルキル基、
   (c)Ｃ６－１４アリール基、
   (d)アリールＣ１－６アルキル基、および
   (e)複素環基
から選択される置換基でモノまたはジ置換されていてもよいカルバモイル基、
(9)シアノ基、
(10)カルボキシ基、
(11)ヒドロキシ基、
(12)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、および
(13)ニトロ基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、フェニル基またはピリジル基であり；
　Ｘが、単結合、または
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
　 (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
   (e)オキソ基、および
　 (f)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)Ｃ６－１４アリール基（好ましくはフェニル）
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(5)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(6)(a)Ｃ１－６アルキル基、
   (b)Ｃ３－８シクロアルキル基、
   (c)Ｃ６－１４アリール基、
   (d)アリールＣ１－６アルキル基、および
   (e)複素環基
から選択される置換基でモノまたはジ置換されていてもよいカルバモイル基、
(7)シアノ基、
(8)カルボキシ基、
(9)ヒドロキシ基、
(10)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、および
(11)ニトロ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい二価の５または６員の単環式芳香族複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、ピリジル基、ピリミジル基等から誘導される二価の基）であり；かつ
　環Ｂが、
(1)ハロゲン原子（好ましくはフッ素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
　 (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
   (e)オキソ基、
   (f)シアノ基、および
   (g)複素環基
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)Ｃ６－１４アリール基（好ましくはフェニル）
から選択される１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルファニル基（好ましくはメチルスルファニル）、
(5)１～３個のハロゲン原子（好ましくはフッ素原子）で置換されていてもよいＣ１－６アルキルスルホニル基（好ましくはメチルスルホニル）、
(6)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(7)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(8)(a)Ｃ１－６アルキル基、
   (b)Ｃ３－８シクロアルキル基、
   (c)Ｃ６－１４アリール基、
   (d)アリールＣ１－６アルキル基、および
   (e)複素環基
から選択される置換基でモノまたはジ置換されていてもよいカルバモイル基、
(9)シアノ基、
(10)カルボキシ基、
(11)ヒドロキシ基、
(12)オキソ基、
(13)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、
(14)ニトロ基、および
(15)複素環基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基（例、フェニル基、ナフチル基）、５または６員の単環式複素環基（例、ピリジル基、ピラジニル基）あるいは８ないし１４員の縮合複素環基（例、ピラゾロピリジル基、キノリル基、キノキサリニル基、キナゾリニル基、ベンゾピラニル基、ベンゾオキサゾリル基、ピリドピラジニル基）である、
化合物（Ｉ）。 Suitable compounds (I) include the following compounds.
[Compound IA]
Ring A is
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a carboxy group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl)
A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
(4) a C 1-6 alkylsulfanyl group (preferably methylsulfanyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(5) a C 1-6 alkylsulfonyl group (preferably methylsulfonyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(6) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(7) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(8) (a) a C 1-6 alkyl group,
(b) a C 3-8 cycloalkyl group,
(c) a C 6-14 aryl group,
(d) an aryl C 1-6 alkyl group, and (e) a carbamoyl group optionally mono- or disubstituted with a substituent selected from a heterocyclic group,
(9) a cyano group,
(10) a carboxy group,
(11) hydroxy group,
(12) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group, and
(13) a phenyl group or a pyridyl group, each of which may be further substituted with 1 to 3 substituents selected from a nitro group;
X is a single bond, or
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a carboxy group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) an oxo group, and (f) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl)
A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
(4) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(6) (a) a C 1-6 alkyl group,
(b) a C 3-8 cycloalkyl group,
(c) a C 6-14 aryl group,
(d) an aryl C 1-6 alkyl group, and (e) a carbamoyl group optionally mono- or disubstituted with a substituent selected from a heterocyclic group,
(7) cyano group,
(8) a carboxy group,
(9) hydroxy group,
(10) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group, and
(11) A divalent 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxadiazolyl group, furyl group, optionally substituted with 1 to 3 substituents selected from nitro groups) A divalent group derived from thienyl, triazolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, etc .; and ring B is
(1) a halogen atom (preferably a fluorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a carboxy group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) an oxo group,
(f) a cyano group, and (g) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-) optionally substituted with 1 to 3 substituents selected from a heterocyclic group Butyl, tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 6-14 aryl group (preferably phenyl)
A C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from:
(4) a C 1-6 alkylsulfanyl group (preferably methylsulfanyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(5) a C 1-6 alkylsulfonyl group (preferably methylsulfonyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom),
(6) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(7) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(8) (a) a C 1-6 alkyl group,
(b) a C 3-8 cycloalkyl group,
(c) a C 6-14 aryl group,
(d) an aryl C 1-6 alkyl group, and (e) a carbamoyl group optionally mono- or disubstituted with a substituent selected from a heterocyclic group,
(9) a cyano group,
(10) a carboxy group,
(11) hydroxy group,
(12) an oxo group,
(13) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group,
(14) a nitro group, and
(15) A C 6-10 aryl group (eg, phenyl group, naphthyl group), which may be further substituted with 1 to 3 substituents selected from a heterocyclic group, each of which is a 5- or 6-membered single group Cyclic heterocyclic groups (eg, pyridyl group, pyrazinyl group) or 8- to 14-membered condensed heterocyclic groups (eg, pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzoxazolyl group, A pyridopyrazinyl group)
Compound (I).
［化合物Ｉ－Ｂ］
　環Ａが、
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ヒドロキシ基、
   (c)オキソ基、および
   (d)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)フェニル基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(5)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(6)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
(7)シアノ基、
(8)カルボキシ基、
(9)ヒドロキシ基、
(10)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、および
(11)ニトロ基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、フェニル基またはピリジル基であり；
Ｘが、単結合、または
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ヒドロキシ基、
   (c)オキソ基、および
   (d)シアノ基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)フェニル基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルコキシ－カルボニル基、
(5)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
(6)シアノ基、
(7)カルボキシ基、
(8)ヒドロキシ基、および
(9)ニトロ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい二価の５または６員の単環式芳香族複素環基（例、オキサジアゾリル基、フリル基、チエニル基、トリアゾリル基、オキサゾリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、ピリジル基、ピリミジル、ピラジニル基等から誘導される二価の基）であり；かつ
　環Ｂが、
(1)ハロゲン原子（好ましくはフッ素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ヒドロキシ基、
   (c)ジメチルアミノ基、
   (d)オキソ基、
　 (e)シアノ基、および
   (f)４ないし７員の単環式含窒素複素環基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル、sec-ブチル、tert-ブチル）、
(3)(a)ハロゲン原子（好ましくはフッ素原子）、および
　 (b)フェニル基
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルコキシ基（好ましくはメトキシ、エトキシ、プロポキシ）、
(4)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(5)Ｃ１－６アルコキシ－カルボニル基（好ましくはメトキシカルボニル）、
(6)Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
(7)シアノ基、
(8)カルボキシ基、
(9)オキソ基、
(10)ヒドロキシ基、
(11)(a)Ｃ１－６アルキル基、
    (b)Ｃ１－６アルキルスルホニル基、
    (c)Ｃ６－１４アリールスルホニル基、
    (d)ホルミル基、
    (e)Ｃ１－６アルキル－カルボニル基、
    (f)Ｃ１－６アルコキシ－カルボニル基、および
    (g)アリールＣ１－６アルコキシ－カルボニル基
から選択される置換基でモノまたはジ置換されていてもよいアミノ基、
(12)ニトロ基、および
(13)Ｃ１－６アルキル基で置換されていてもよい４ないし７員の単環式含窒素複素環基
から選択される１ないし３個の置換基で、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基（例、フェニル基、ナフチル基）、５または６員の単環式複素環基（例、ピリジル基、ピラジニル基）あるいは８ないし１４員の縮合複素環基（例、ピラゾロピリジル基、キノリル基、キノキサリニル基、キナゾリニル基、ベンゾピラニル基、ベンゾオキサゾリル基、ピリドピラジニル基）である、
化合物（Ｉ）。 [Compound IB]
Ring A is
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy),
(4) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(6) a carbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group,
(7) cyano group,
(8) a carboxy group,
(9) hydroxy group,
(10) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group, and
(11) a phenyl group or a pyridyl group, each of which may be further substituted with 1 to 3 substituents selected from a nitro group;
X is a single bond, or
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) an oxo group, and (d) a C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl, sec-butyl) optionally substituted with 1 to 3 substituents selected from a cyano group Tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy),
(4) a C 1-6 alkoxy-carbonyl group,
(5) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group,
(6) a cyano group,
(7) a carboxy group,
(8) a hydroxy group, and
(9) A divalent 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxadiazolyl group, furyl group, optionally substituted with 1 to 3 substituents selected from nitro groups) A divalent group derived from thienyl, triazolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, etc .; and ring B is
(1) a halogen atom (preferably a fluorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) a dimethylamino group,
(d) an oxo group,
(e) a cyano group, and (f) a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from 4- to 7-membered monocyclic nitrogen-containing heterocyclic groups (preferably Methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl),
(3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-4 alkoxy group (preferably methoxy, optionally substituted with 1 to 3 substituents selected from a phenyl group) Ethoxy, propoxy),
(4) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(5) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl),
(6) a carbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group,
(7) cyano group,
(8) a carboxy group,
(9) an oxo group,
(10) a hydroxy group,
(11) (a) a C 1-6 alkyl group,
(b) a C 1-6 alkylsulfonyl group,
(c) a C 6-14 arylsulfonyl group,
(d) a formyl group,
(e) a C 1-6 alkyl-carbonyl group,
(f) a C 1-6 alkoxy-carbonyl group, and (g) an amino group optionally mono- or di-substituted with a substituent selected from an aryl C 1-6 alkoxy-carbonyl group,
(12) a nitro group, and
(13) 1 to 3 substituents selected from 4- to 7-membered monocyclic nitrogen-containing heterocyclic groups which may be substituted with C 1-6 alkyl groups, and each may be further substituted , C 6-10 aryl group (eg, phenyl group, naphthyl group), 5- or 6-membered monocyclic heterocyclic group (eg, pyridyl group, pyrazinyl group) or 8- to 14-membered condensed heterocyclic group (eg, Pyrazolopyridyl group, quinolyl group, quinoxalinyl group, quinazolinyl group, benzopyranyl group, benzooxazolyl group, pyridopyrazinyl group)
Compound (I).
［化合物Ｉ－Ｃ］
　環Ａが、
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、および
   (b)ヒドロキシ基、
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル）、および
(3)シアノ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい、フェニル基であり；
　Ｘが、単結合、または
(1)ハロゲン原子（好ましくはフッ素原子、塩素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、および
   (b)ヒドロキシ基、
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル）、
(3)Ｃ１－６アルコキシ－カルボニル基、
(4)カルバモイル基、
(5)シアノ基、および
(6)カルボキシ基
から選択される１ないし３個の置換基で、さらに置換されていてもよい二価の５員の単環式芳香族複素環基（好ましくは、オキサジアゾリル基、オキサゾリル基、チアゾリル基、トリアゾリル基、ピラゾリル基から誘導される二価の基）であり；かつ
　環Ｂが、
(1)ハロゲン原子（好ましくはフッ素原子）、
(2)(a)ハロゲン原子（好ましくはフッ素原子）、
   (b)ジメチルアミノ基、
   (c)ヒドロキシ基、および
   (d)４ないし７員の単環式含窒素複素環基（好ましくは、アゼチジニル基、モルホリニル基、ピロリジニル基）
から選択される１～３個の置換基で置換されていてもよいＣ１－４アルキル基（好ましくはメチル、エチル、プロピル、イソプロピル）、
(3)Ｃ１－６アルキル－カルボニル基（好ましくはアセチル）、
(4)ヒドロキシ基、
(5)オキソ基、
(6)シアノ基、
(7)ニトロ基、および
(8)Ｃ１－６アルキル基で置換されていてもよい４ないし７員の単環式含窒素複素環基（好ましくは、４－メチルピペラジン－１－イル基）
から選択される１ないし３個の置換基で、さらに置換されていてもよい、フェニル基である、
化合物（Ｉ）。 [Compound IC]
Ring A is
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group,
A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted with 1 to 3 substituents selected from
(3) a phenyl group which may be further substituted with 1 to 3 substituents selected from a cyano group;
X is a single bond, or
(1) a halogen atom (preferably a fluorine atom or a chlorine atom),
(2) (a) a halogen atom (preferably a fluorine atom), and (b) a hydroxy group,
A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from:
(3) a C 1-6 alkoxy-carbonyl group,
(4) a carbamoyl group,
(5) a cyano group, and
(6) A divalent 5-membered monocyclic aromatic heterocyclic group (preferably an oxadiazolyl group, an oxazolyl group, a thiazolyl group) which may be further substituted with 1 to 3 substituents selected from a carboxy group A divalent group derived from a group, triazolyl group, pyrazolyl group); and ring B is
(1) a halogen atom (preferably a fluorine atom),
(2) (a) a halogen atom (preferably a fluorine atom),
(b) a dimethylamino group,
(c) a hydroxy group, and (d) a 4- to 7-membered monocyclic nitrogen-containing heterocyclic group (preferably an azetidinyl group, a morpholinyl group, a pyrrolidinyl group)
A C 1-4 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from:
(3) a C 1-6 alkyl-carbonyl group (preferably acetyl),
(4) hydroxy group,
(5) an oxo group,
(6) a cyano group,
(7) a nitro group, and
(8) a 4- to 7-membered monocyclic nitrogen-containing heterocyclic group (preferably a 4-methylpiperazin-1-yl group) optionally substituted with a C 1-6 alkyl group
A phenyl group which may be further substituted with 1 to 3 substituents selected from:
Compound (I).
　化合物（Ｉ）の好ましい具体例としては、例えば、下記実施例および表１－１～表１－５に記載の実施例１～５９の化合物（以下、化合物１～５９ともいう。）が挙げられ、中でも、
（１）N-(4-{5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル}フェニル)スルファミド（化合物１）、
（２）N-{4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニル}スルファミド（化合物２）、
（３）N-[4-{2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル}フェニル]スルファミド（化合物３）、
（４）N-{4-[4-(2-フルオロフェニル)イミダゾール-1-イル]フェニル}スルファミド（化合物５）、
（５）N-[4-｛5-(2-フルオロフェニル)オキサゾール-2-イル｝フェニル]スルファミド（化合物７）、
（６）N-{4-[2-(2-フルオロフェニル)オキサゾール-4-イル]フェニル}スルファミド（化合物８）、
（７）N-{4-[2-(2-フルオロフェニル)オキサゾール-5-イル]フェニル}スルファミド（化合物１１）、
（８）N-(4-キナゾリン-2-イルフェニル)スルファミド（化合物１４）、
（９）N-[4-(4-オキソ-4H-クロメン-2-イル)フェニル]スルファミド（化合物１５）、
（１０）N-{4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニル}スルファミド（化合物１８）、
（１１）N-{4-[2-(2-シアノフェニル)[1,2,3]トリアゾール-4-イル]フェニル}スルファミド（化合物２１）、
（１２）N-(4-キノキサリン-2-イルフェニル)スルファミド（化合物２３）、
（１３）N-{4-[5-(2-フルオロフェニル)オキサゾール-5-イル]フェニル}スルファミド（化合物２７）、
（１４）N-[4-(6-シアノキノキサリン-2-イル)フェニル]スルファミド（化合物２９）、
（１５）N-[4-(7-シアノキノキサリン-2-イル)フェニル]スルファミド（化合物３０）、
（１６）N-{4-[2-(2-シアノフェニル)オキサゾール-5-イル]フェニル}スルファミド（化合物３５）、
（１７）N-[4-(6-シアノ-4-オキソ-4H-クロメン-2-イル)フェニル]スルファミド（化合物４０）、
（１８）N-[4-(6-シアノキナゾリン-2-イル)フェニル]スルファミド（化合物４２）、
（１９）N-{4-[2-(2-フルオロフェニル)-2H-[1,2,3]トリアゾール-4-イル]フェニル}スルファミド（化合物４５）、または
（２０）N-{4-[2-(2-トリフルオロメチルフェニル)-2H-[1,2,3]トリアゾール-4-イル]フェニル}スルファミド（化合物４６）
が特に好ましい。 Preferable specific examples of compound (I) include, for example, the following examples and the compounds of Examples 1 to 59 described in Table 1-1 to Table 1-5 (hereinafter also referred to as compounds 1 to 59). , Among others
(1) N- (4- {5- (2-fluorophenyl) [1,2,4] oxadiazol-3-yl} phenyl) sulfamide (compound 1),
(2) N- {4- [1- (2-fluorophenyl) -1H-pyrazol-4-yl] phenyl} sulfamide (Compound 2),
(3) N- [4- {2- (2-fluorophenyl) -4-methyloxazol-5-yl} phenyl] sulfamide (Compound 3),
(4) N- {4- [4- (2-fluorophenyl) imidazol-1-yl] phenyl} sulfamide (Compound 5),
(5) N- [4- {5- (2-fluorophenyl) oxazol-2-yl} phenyl] sulfamide (Compound 7),
(6) N- {4- [2- (2-fluorophenyl) oxazol-4-yl] phenyl} sulfamide (Compound 8),
(7) N- {4- [2- (2-fluorophenyl) oxazol-5-yl] phenyl} sulfamide (Compound 11),
(8) N- (4-quinazolin-2-ylphenyl) sulfamide (Compound 14),
(9) N- [4- (4-oxo-4H-chromen-2-yl) phenyl] sulfamide (Compound 15),
(10) N- {4- [5- (2-fluorophenyl) [1,3,4] oxadiazol-2-yl] phenyl} sulfamide (Compound 18),
(11) N- {4- [2- (2-cyanophenyl) [1,2,3] triazol-4-yl] phenyl} sulfamide (Compound 21),
(12) N- (4-quinoxalin-2-ylphenyl) sulfamide (Compound 23),
(13) N- {4- [5- (2-fluorophenyl) oxazol-5-yl] phenyl} sulfamide (Compound 27),
(14) N- [4- (6-cyanoquinoxalin-2-yl) phenyl] sulfamide (Compound 29),
(15) N- [4- (7-cyanoquinoxalin-2-yl) phenyl] sulfamide (Compound 30),
(16) N- {4- [2- (2-cyanophenyl) oxazol-5-yl] phenyl} sulfamide (Compound 35),
(17) N- [4- (6-cyano-4-oxo-4H-chromen-2-yl) phenyl] sulfamide (Compound 40),
(18) N- [4- (6-cyanoquinazolin-2-yl) phenyl] sulfamide (Compound 42),
(19) N- {4- [2- (2-fluorophenyl) -2H- [1,2,3] triazol-4-yl] phenyl} sulfamide (Compound 45) or (20) N- {4- [2- (2-Trifluoromethylphenyl) -2H- [1,2,3] triazol-4-yl] phenyl} sulfamide (Compound 46)
Is particularly preferred.
　化合物（Ｉ）が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物（Ｉ）として含有される。 When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I).
　本発明の化合物（Ｉ）は自体公知の方法によって、その医薬上許容される塩にすることができる。本発明の化合物（Ｉ）が、酸性基または塩基性基を有する場合に、塩基または酸と反応させることにより、塩基性塩または酸性塩にすることができる。 Compound (I) of the present invention can be converted to a pharmaceutically acceptable salt thereof by a method known per se. When the compound (I) of the present invention has an acidic group or basic group, it can be converted into a basic salt or acidic salt by reacting with a base or acid.
　本発明の化合物（Ｉ）の医薬上許容される「塩基性塩」としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩；マグネシウム塩、カルシウム塩のようなアルカリ土類金属塩；Ｎ－メチルモルホリン塩、エタノールアミン塩、ピペラジン塩、ジエチルアミン塩、トリエチルアミン塩、トリブチルアミン塩、ｔｅｒｔ－ブチルアミン塩、ジイソプロピルエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ－メチルピペリジン塩、メグルミン塩、トロメタミン塩、コリン塩、ベンザチン塩、４－フェニルシクロヘキシルアミン塩、ピリジン塩、４－ピロリジノピリジン塩、ピコリン塩のような有機塩基塩類またはグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、好適には、アルカリ金属塩である。 The pharmaceutically acceptable “basic salt” of the compound (I) of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; alkaline earth salt such as magnesium salt or calcium salt. Metal salts: N-methylmorpholine salt, ethanolamine salt, piperazine salt, diethylamine salt, triethylamine salt, tributylamine salt, tert-butylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, meglumine salt, tromethamine Salt, choline salt, benzathine salt, 4-phenylcyclohexylamine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salt such as picoline salt or glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, asparagine Like salt A Bruno acid salt, preferably an alkali metal salt.
　本発明の化合物（Ｉ）の医薬上許容される「酸性塩」としては、好適には、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、トリフルオロ酢酸塩、リンゴ酸塩、フマール酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；および、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、最も好適には、ハロゲン化水素酸塩（特に、塩酸塩）である。 The pharmaceutically acceptable “acid salt” of the compound (I) of the present invention is preferably a hydrogen halide such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide. Inorganic acid salts such as acid salts, nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate Aryl sulfonates such as p-toluenesulfonate, acetate, trifluoroacetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, Organic acid salts such as maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalic acid (Particularly hydrochloride) it is.
　以下、本発明の化合物の製造法について説明する。
　化合物（Ｉ）の製造法の例として、代表的な製造法を以下に述べるが、製造法はこれらに限定されない。 Hereafter, the manufacturing method of the compound of this invention is demonstrated.
As examples of the production method of compound (I), typical production methods are described below, but the production methods are not limited to these.
（製造方法）
　本発明の化合物は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、各種の公知の製造方法を適用して製造することができる。公知の方法としては、例えば、「ORGANIC FUNCTIONAL GROUP PREPARATIONS」、第2版、ACADEMIC PRESS,INC.、1989年、「Comprehensive Organic Transformations」、VCHPublishers Inc.、1989年等に記載された方法がある。
　その際、官能基の種類によっては、当該官能基を原料ないし中間体の段階で適当な保護基で保護、または当該官能基に容易に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。
　このような官能基としては、例えば、アミノ基、水酸基、カルボキシ基等があり、それらの保護基としては、例えば、T.W.GreeneおよびP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の保護基があり、これらの反応条件に応じて適宜選択して用いればよい。このような方法によれば、当該置換基を導入して反応を行った後、必要に応じて保護基を除去、あるいは所望の基に転化することにより、所望の化合物を得ることができる。
　また、本発明の化合物のプロドラッグは、上記保護基と同様に、原料ないし中間体の段階で特定の基を導入し、あるいは得られた本発明の化合物を用いて、反応を行うことで製造できる。反応は、通常のエステル化、アミド化、脱水、水素添加等、当業者により公知の方法を適用することにより行うことができる。
　以下に本発明の化合物の製造方法について述べる。ただし、製造方法は、下記の方法に何ら限定されるものではない。
　なお、各反応における原料化合物は、具体的製法を述べない場合、市販されているものを容易に入手して用いることができるか、または自体公知の方法、またはそれに準ずる方法に従って製造することもできる。 (Production method)
The compound of the present invention can be produced by applying various known production methods utilizing characteristics based on the basic skeleton or the type of substituent. Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
At that time, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases.
Examples of such a functional group include an amino group, a hydroxyl group, and a carboxy group. Examples of protective groups for these functional groups include Protective Groups in Organic Synthesis (3rd edition, 1999) by TW Greene and PG Wuts. May be appropriately selected depending on these reaction conditions. According to such a method, after carrying out the reaction by introducing the substituent, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
In addition, the prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
The production method of the compound of the present invention is described below. However, the manufacturing method is not limited to the following method.
In addition, when not mentioning a specific manufacturing method, the raw material compound in each reaction can obtain and use a commercially available thing easily, or can also manufacture it according to a method known per se, or a method according to it. .
（製法１） (Production method 1)
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
［上記式中、Ｘ、ＡおよびＢは、前記と同意義である。］ [Wherein, X, A and B are as defined above. ]
　製法１は、化合物（１）の-ＮＨ２を-ＮＨＳＯ２ＮＨ２に変換し、本発明の化合物 (Ｉ)を製造する方法である。 Production Method 1 is a method for producing Compound (I) of the present invention by converting —NH 2 of Compound (1) into —NHSO 2 NH 2 .
　本製法は、自体公知の方法にて、化合物（１）と化合物（２）とを不活性溶媒中で反応させ、化合物（３）を得、次いで化合物（３）のｔ－ブトキシカルボニル基を自体公知の方法にて脱離させ、化合物 (Ｉ)を製造する方法である。　 In this production method, compound (1) and compound (2) are reacted in an inert solvent by a method known per se to obtain compound (3), and then the t-butoxycarbonyl group of compound (3) is itself In this method, compound (I) is produced by desorption by a known method. *
　化合物（１）と化合物（２）の反応は、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、４－ジメチルアミノピリジン、１，８－ジアザビシクロ［５，４，０］ウンデカ－７－エンなどの有機塩基；炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸セシウムなどアルカリ金属炭酸塩などの塩基の存在下に行ってもよい。
　使用される不活性溶媒は、例えばメタノール、エタノール、プロパノール、２－プロパノールまたはブタノールのようなアルコール類；ベンゼン、トルエン、またはキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンまたは１,２ジメトキシエタンのようなエーテル類；Ｎ,Ｎ－ジメチルホルムアミド、Ｎ,Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、Ｎ－メチルピロリジノンまたはヘキサメチルホスホロトリアミドのようなアミド類；或いはメチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、o－ジクロロベンゼン、m－ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼンまたはトリフルオロメチルベンゼンのようなハロゲン化炭化水素類、あるいはこれらの混合物である。 The reaction of compound (1) and compound (2) is carried out by using triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene Organic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate and other alkali metal carbonates may be used in the presence of a base.
Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Halogenated hydrocarbons, or mixtures thereof.
　化合物（２）の使用量は、化合物（１）１モルに対して、通常１～５モル、好ましくは１～３モルである。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 The amount of compound (2) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
　ｔ－ブトキシカルボニル基の脱離は、例えば、T.W. GreeneおよびP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。 The elimination of the t-butoxycarbonyl group can be performed, for example, according to the method described in T.W. Greene and P.G. Wuts, "Protective Group Organic.Synthesis (3rd edition, 1999)".
　本製法において用いられる化合物（２）は、クロロスルホニルイソシアネートとｔ－ブチルアルコールとを反応させる自体公知の方法またはそれに準じた方法に従って製造することができる。 The compound (2) used in this production method can be produced according to a method known per se in which chlorosulfonyl isocyanate and t-butyl alcohol are reacted or a method analogous thereto.
　製法１において用いられる化合物（１）の製造法を以下に示す。 The manufacturing method of the compound (1) used in the manufacturing method 1 is shown below.
（製法２） (Manufacturing method 2)
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法２は、化合物（１）中のＸが、１，２，４－オキサジアゾールである本発明の化合物 (１ａ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.4」に記載の方法が挙げられる。 Production Method 2 is a method for producing Compound (1a) of the present invention in which X in Compound (1) is 1,2,4-oxadiazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
　本製法は、化合物（４）と化合物（５）を反応させ、得られた化合物（６）を化合物（７）と反応させ、次いで得られた化合物（８）のニトロ基を自体公知の方法にて還元し、化合物（１ａ）を製造する方法である。 In this production method, the compound (4) and the compound (5) are reacted, the obtained compound (6) is reacted with the compound (7), and then the nitro group of the obtained compound (8) is converted to a method known per se. Reduction to produce compound (1a).
　化合物（４）と化合物（５）との反応は、自体公知の方法にて不活性溶媒中で行われる。使用される不活性溶媒は、前述のものが挙げられる。 The reaction between the compound (4) and the compound (5) is carried out in an inert solvent by a method known per se. Examples of the inert solvent used include those described above.
　化合物（５）の使用量は、化合物（４）１モルに対して、通常１～５モル、好ましくは１～３モルである。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 The amount of compound (5) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (4).
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
　化合物（６）と化合物（７）との反応は、自体公知の方法、例えば、化合物（６）と化合物（７）とを直接縮合させる方法、あるいは化合物（６）と化合物（７）の反応性誘導体とを反応させる方法等を用いて行われる。 The reaction between the compound (6) and the compound (7) is a method known per se, for example, a method in which the compound (6) and the compound (7) are directly condensed, or the reactivity between the compound (6) and the compound (7). This is performed using a method of reacting with a derivative.
　化合物（６）と化合物（７）とを直接縮合させる方法は、縮合剤の存在下、不活性溶媒中で行われる。縮合剤としては、例えばＮ，Ｎ’－ジシクロヘキシルカルボジイミド、１－エチル－３－（３’－ジメチルアミノプロピル）カルボジイミド、Ｎ－シクロヘキシル－Ｎ’－モルホリノエチルカルボジイミド、Ｎ－シクロヘキシル－Ｎ’－（４－ジエチルアミノシクロヘキシル）カルボジイミドなどのカルボジイミド化合物；Ｎ，Ｎ’－カルボニルジイミダゾール、Ｎ，Ｎ’－チオニルジイミダゾールなどのアゾライド化合物；シアノリン酸ジエチル、アジ化ジフェニルホスホリルなどのリン化合物などの縮合剤が挙げられる。
　使用される不活性溶媒は、例えばメタノール、エタノール、プロパノール、２－プロパノールまたはブタノールのようなアルコール類；ベンゼン、トルエン、またはキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンまたは１,２ジメトキシエタンのようなエーテル類；Ｎ,Ｎ－ジメチルホルムアミド、Ｎ,Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、Ｎ－メチルピロリジノンまたはヘキサメチルホスホロトリアミドのようなアミド類；或いはメチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、o－ジクロロベンゼン、m－ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼンまたはトリフルオロメチルベンゼンのようなハロゲン化炭化水素類、あるいはこれらの混合物である。 The method of directly condensing the compound (6) and the compound (7) is performed in an inert solvent in the presence of a condensing agent. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4 Carbodiimide compounds such as -diethylaminocyclohexyl) carbodiimide; azolide compounds such as N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole; condensing agents such as phosphorus compounds such as diethyl cyanophosphate and diphenylphosphoryl azide It is done.
Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Halogenated hydrocarbons, or mixtures thereof.
　化合物（７）の使用量は、化合物（６）１モルに対して、通常１～５モル、好ましくは１～３モルである。
　縮合剤の使用量は、化合物（７）１モルに対して、通常１～５モル、好ましくは１～３モルである。 The amount of compound (7) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (6).
The amount of the condensing agent to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (7).
　縮合剤として上記カルボジイミド化合物を用いる場合、必要に応じて縮合促進剤（例えば、１－ヒドロキシ－７－アザベンゾトリアゾール、１－ヒドロキシベンゾトリアゾール、Ｎ－ヒドロキシこはく酸イミド、Ｎ－ヒドロキシフタルイミドなど）を用いることにより、反応収率を向上させることができる。また、縮合剤として上記リン化合物を用いる場合、必要に応じてトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどの有機塩基を添加することにより、反応収率を向上させることができる。さらに、縮合剤として上記アゾライド化合物を用いる場合、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、４－ジメチルアミノピリジン、１，８－ジアザビシクロ［５，４，０］ウンデカ－７－エンなどの有機塩基；炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸セシウムなどアルカリ金属炭酸塩などの塩基の存在下に反応させることが望ましい。 When the carbodiimide compound is used as a condensing agent, a condensation accelerator (for example, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.) is optionally used. By using it, the reaction yield can be improved. When the above phosphorus compound is used as a condensing agent, the reaction yield can be improved by adding an organic base such as triethylamine or N, N-diisopropylethylamine as necessary. Further, when the above azolide compound is used as a condensing agent, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, etc. It is desirable to carry out the reaction in the presence of a base such as an alkali metal carbonate such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, or cesium carbonate.
　上記縮合促進剤、有機塩基およびアルカリ金属炭酸塩の使用量は、化合物（７）１モルに対して、通常１～５モル、好ましくは１～３モルである。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 The amount of the above condensation accelerator, organic base and alkali metal carbonate to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (7).
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
　化合物（６）と化合物（７）の反応性誘導体とを反応させる方法において、化合物（７）の反応性誘導体としては、例えば、酸クロライド、酸ブロマイドなどの酸ハライド；酸無水物；ジアルキルリン酸などの置換リン酸、クロロ炭酸メチル、クロロ炭酸エチルまたはクロロ炭酸イソブチルなどのクロロ炭酸エステルとの混合酸無水物；イミダゾールなどとの活性アミド；シアノメチルエステル、４－ニトロフェニルエステルなどのエステルなどが挙げられる。 In the method of reacting the compound (6) and the reactive derivative of the compound (7), examples of the reactive derivative of the compound (7) include acid halides such as acid chloride and acid bromide; acid anhydrides; dialkyl phosphoric acid Such as substituted phosphoric acid, mixed acid anhydride with chlorocarbonate such as methyl chlorocarbonate, ethyl chlorocarbonate or isobutyl chlorocarbonate; active amide with imidazole; ester such as cyanomethyl ester, 4-nitrophenyl ester, etc. Can be mentioned.
　化合物（７）の反応性誘導体として上記酸ハライドを用いる場合、通常、塩基の存在下、不活性溶媒中で行われる。
　当該反応において使用される塩基としては特に限定はなく、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、４－ジメチルアミノピリジンなどの有機塩基；炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸セシウムなどのアルカリ金属炭酸塩などが挙げられる。
　使用される不活性溶媒は、例えばメタノール、エタノール、プロパノール、２－プロパノールまたはブタノールのようなアルコール類；ベンゼン、トルエン、またはキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサンまたは１,２ジメトキシエタンのようなエーテル類；Ｎ,Ｎ－ジメチルホルムアミド、Ｎ,Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、Ｎ－メチルピロリジノンまたはヘキサメチルホスホロトリアミドのようなアミド類；或いはメチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、o－ジクロロベンゼン、m－ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼンまたはトリフルオロメチルベンゼンのようなハロゲン化炭化水素類、あるいはこれらの混合物である。 When the acid halide is used as the reactive derivative of compound (7), it is usually carried out in an inert solvent in the presence of a base.
The base used in the reaction is not particularly limited, and is an organic base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine; sodium carbonate, sodium hydrogen carbonate, potassium carbonate, hydrogen carbonate Examples include alkali metal carbonates such as potassium and cesium carbonate.
Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2 dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene. Halogenated hydrocarbons, or mixtures thereof.
　化合物（７）の使用量は、化合物（６）１モルに対して、通常１～５モル、好ましくは１～３モルである。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 The amount of compound (7) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (6).
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
　化合物（７）の反応性誘導体として混合酸無水物を用いる場合、化合物（７）と置換リン酸またはクロロ炭酸エステルとを塩基（例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジメチルアニリンなどの有機塩基；炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムなどのアルカリ金属炭酸塩など）の存在下に反応させて反応性誘導体とし、さらに化合物（６）と反応させる。
　化合物（７）の使用量は、化合物（６）１モルに対して、通常１～５モル、好ましくは１～３モルである。 When a mixed acid anhydride is used as the reactive derivative of the compound (7), the compound (7) and the substituted phosphoric acid or chlorocarbonate are converted into a base (for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N , N-dimethylaniline; an organic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) to make a reactive derivative, and further react with compound (6).
The amount of compound (7) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (6).
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 The reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually −30 to 150 ° C. and the reaction time is 30 minutes to 20 hours.
（製法３） (Manufacturing method 3)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法３は、化合物（１）中のＸが、１，２，３－トリアゾールである化合物 (１ｂ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.4」に記載の方法が挙げられる。 Production method 3 is a method for producing compound (1b) in which X in compound (1) is 1,2,3-triazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
　製法３は、化合物（９)とアジ化ナトリウムを不活性溶媒中、自体公知の方法にて反応させることによって化合物（１０）を得、得られた化合物（１０）に化合物（１１）を前述の不活性溶媒中、自体公知の方法にて反応させることによって化合物（１２）を得、次いで化合物（１２）のニトロ基を自体公知の方法にて還元し、化合物（１ｂ）を製造する方法である。化合物（９)とアジ化ナトリウムの反応においては、アスコルビン酸および硫酸銅の存在下に行ってもよい。 In production method 3, compound (9) is reacted with sodium azide in an inert solvent by a method known per se to obtain compound (10), and the obtained compound (10) is compounded with compound (11) as described above. In this method, compound (12) is obtained by reacting in an inert solvent by a method known per se, and then reducing the nitro group of compound (12) by a method known per se. . The reaction between compound (9) and sodium azide may be performed in the presence of ascorbic acid and copper sulfate.
　アジ化ナトリウムの使用量は、化合物（９）１モルに対して、通常１～５モル、好ましくは１～３モルである。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 The amount of sodium azide to be used is generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound (9).
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
（製法４） (Manufacturing method 4)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法４は、化合物（１）中のＸが、１，２，３－トリアゾールである化合物（１ｃ）を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.4」に記載の方法が挙げられる。 Production method 4 is a method for producing compound (1c) in which X in compound (1) is 1,2,3-triazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
　製法４は、化合物（１３)と化合物（１４)を不活性溶媒中、自体公知の方法にて反応させることによって化合物（１ｃ）を製造する方法である。本製法は、製法３に記載した反応と同様の反応に付すことによって行われる。 Production method 4 is a method for producing compound (1c) by reacting compound (13) and compound (14) in an inert solvent by a method known per se. This production method is carried out by subjecting the reaction to the same reaction as described in Production Method 3.
（製法５） (Manufacturing method 5)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法５は、化合物（１）中のＸが、オキサゾールである化合物 (１ｄ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.3」に記載の方法が挙げられる。 Production Method 5 is a method for producing Compound IV (1d) in which X in Compound (1) is oxazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
　本製法は、化合物（１５）と化合物（１６）とをトリフルオロメタンスルホン酸銀の存在下、反応させ化合物 (１７)を得るか、化合物（１５）をヘキサメチレンテトラミン等でアミノ化し、得られた化合物（１８）と化合物（７）とを反応させ、化合物（１９）を得、得られた化合物（１９）をオキシ塩化リンで閉環し、化合物 (１７)を得、次いで化合物（１７)のニトロ基を自体公知の方法にて還元し、化合物（１ｄ）を製造する方法である。 This production method was obtained by reacting compound (15) and compound (16) in the presence of silver trifluoromethanesulfonate to obtain compound (17) or amination of compound (15) with hexamethylenetetramine or the like. Compound (18) and compound (7) are reacted to obtain compound (19), and the obtained compound (19) is cyclized with phosphorus oxychloride to obtain compound (17), and then nitro of compound (17) This is a method for producing a compound (1d) by reducing a group by a method known per se.
　本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。また、化合物（１８）と化合物（７）との反応は、製法２に記載の化合物（６）と化合物（７）との反応と同様の条件にて行うことができる。 Each step of the production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above. Moreover, reaction of a compound (18) and a compound (7) can be performed on the conditions similar to reaction with the compound (6) and the compound (7) of the manufacturing method 2.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　化合物（１）中のＸが、オキサゾールである化合物 (１ｄ＊)および化合物（１ｄ＊＊）は、製法５に準じて製造することができる。 The compound (1d * ) and the compound (1d ** ) in which X in the compound (1) is oxazole can be produced according to production method 5.
（製法６） (Production method 6)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法６は、化合物（１）中のＸが、イミダゾールである化合物 (１ｅ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.3」に記載の方法が挙げられる。 Production method 6 is a method for producing compound (1e) in which X in compound (1) is imidazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
　本製法は、化合物（２０）とホルムアミドとを反応させ、得られた化合物（２１）を化合物（２２）と反応させ、化合物 (２３)を得、次いで化合物（２３)のニトロ基を自体公知の方法にて還元し、化合物（１ｅ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the compound (20) is reacted with formamide, the obtained compound (21) is reacted with the compound (22) to obtain a compound (23), and then the nitro group of the compound (23) is known per se. This is a method for producing a compound (1e) by reduction by a method. Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
（製法７） (Manufacturing method 7)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法７は、化合物（１）中のＸが、イミダゾールである化合物 (１ｆ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.3」に記載の方法が挙げられる。 Production method 7 is a method for producing compound (1f) in which X in compound (1) is imidazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
　本製法は、化合物（１５）と化合物（２４）を反応させ、化合物（２５）を得、次いで化合物（２５)のニトロ基を自体公知の方法にて還元し、化合物（１ｆ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, compound (15) and compound (24) are reacted to obtain compound (25), and then the nitro group of compound (25) is reduced by a method known per se to produce compound (1f). It is. Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
（製法８） (Manufacturing method 8)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法８は、化合物（１）中のＸが、１，３，４－オキサジアゾールである化合物 (１ｇ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.4」に記載の方法が挙げられる。 Production Method 8 is a method for producing Compound (1g) in which X in Compound (1) is 1,3,4-oxadiazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
　本製法は、化合物（２６）と化合物（２７）とを反応させ、次いで、得られた化合物（２８）を塩化チオニルで閉環し、化合物 (２９)を得、次いで化合物（２９)のニトロ基を自体公知の方法にて還元し、化合物（１ｇ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the compound (26) and the compound (27) are reacted, and then the obtained compound (28) is cyclized with thionyl chloride to obtain a compound (29), and then the nitro group of the compound (29) is removed. This is a method for producing a compound (1 g) by reduction by a method known per se. Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
（製法９） (Manufacturing method 9)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法９は、化合物（１）中のＸが、イソキサゾールである化合物 (１ｈ)を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.3」に記載の方法が挙げられる。 Production Method 9 is a method for producing Compound IV (1h) in which X in Compound (1) is isoxazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.3”.
　本製法は、化合物（３０）にヒドロキシルアミンを反応させ、得られた化合物（３１）をＮ－クロロスクシンイミドで塩素化し、得られた化合物（３２）と化合物（３３）を反応させ、化合物 (３４)を得、次いで化合物（３４)のニトロ基を自体公知の方法にて還元し、化合物（１ｈ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the compound (30) is reacted with hydroxylamine, the obtained compound (31) is chlorinated with N-chlorosuccinimide, the obtained compound (32) and the compound (33) are reacted, and the compound (34 Then, the nitro group of compound (34) is reduced by a method known per se to produce compound (1h). Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
（製法１０） (Manufacturing method 10)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法１０は、化合物（１）中のＸが、イソキサゾール－３－オンである化合物 (１ｉ)を製造する方法である。 Production method 10 is a method for producing compound (1i) in which X in compound (1) is isoxazol-3-one.
　本製法は、化合物（３５）とホスホノ酢酸トリエチルとを反応させ、得られた化合物（３６）を臭素で臭素化し、得られた化合物（３７）にヒドロキシルアミンを反応させ、得られた化合物（３８）と化合物（２２）を反応させ、化合物 (３９)を得、次いで化合物（３９)のニトロ基を自体公知の方法にて還元し、化合物（１ｉ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the compound (35) is reacted with triethyl phosphonoacetate, the obtained compound (36) is brominated with bromine, the obtained compound (37) is reacted with hydroxylamine, and the obtained compound (38 ) And compound (22) are obtained to obtain compound (39), and then the nitro group of compound (39) is reduced by a method known per se to produce compound (1i). Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
（製法１１） (Manufacturing method 11)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法１１は、化合物（１）中のＸがピラゾールである化合物 (１ｊ)を製造する方法である。 Production method 11 is a method for producing compound (1j) in which X in compound (1) is pyrazole.
　本製法は、化合物（４０）とピラゾールを反応させ、得られた化合物（４１）を臭素で臭素化し、次いで、得られた化合物（４２）と化合物（４３）を有機金属触媒を用いたカップリング反応に付し、化合物（１ｊ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the compound (40) is reacted with pyrazole, the obtained compound (41) is brominated with bromine, and then the obtained compound (42) and the compound (43) are coupled using an organometallic catalyst. This is a method for producing a compound (1j) by subjecting to a reaction. Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
　本製法において、化合物（４２）と化合物（４３）の反応は、不活性溶媒中、必要により塩基の存在下で行われる。また、化合物（４２）と化合物（４３）の反応は、必要に応じて、ホスフィンリガンドの存在下に行ってもよい。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the reaction of the compound (42) and the compound (43) is carried out in an inert solvent, if necessary, in the presence of a base. Moreover, you may perform reaction of a compound (42) and a compound (43) in presence of a phosphine ligand as needed. Examples of the inert solvent used include those described above.
　有機金属触媒としては、酢酸パラジウム(II)、テトラキス（トリフェニルホスフィン）パラジウム(0)、トリス（ジベンジリデンアセトン）ジパラジウム(0)、ジクロロビス（トリフェニルホスフィン）パラジウム(II)などが挙げられる。 Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
　塩基としては、例えば、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸セシウムなどアルカリ金属炭酸塩；水素化カリウム、水素化ナトリウム等の金属水素化物などが挙げられる。 Examples of the base include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate; metal hydrides such as potassium hydride and sodium hydride.
　ホスフィンリガンドとしては、２，２’－ビス(ジフェニルホスフィノ)－１，１’－ビナフチル（ＢＩＮＡＰ）、トリス（２－メチルフェニル）ホスフィン、１，１’－ビス（ジフェニルホスフィノ）フェロセン、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル等が挙げられる。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 Examples of the phosphine ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl and the like.
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
（製法１２） (Manufacturing method 12)
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法１２は、化合物（１）中のＸが単結合であり、Ｂがイミダゾ［１，２－ａ］ピリジンである化合物 (１ｋ)を製造する方法である。 Production method 12 is a method for producing compound (1k) in which X in compound (1) is a single bond and B is imidazo [1,2-a] pyridine.
　本製法は、化合物（１５）と化合物（４４）を反応させ、化合物 (４５)を得、次いで化合物（４５)のニトロ基を自体公知の方法にて還元し、化合物（１ｋ）を製造する方法である。本製法の各工程は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, compound (15) and compound (44) are reacted to obtain compound (45), and then the nitro group of compound (45) is reduced by a method known per se to produce compound (1k). It is. Each process of this manufacturing method can be performed by an itself well-known method in an inert solvent. Examples of the inert solvent used include those described above.
（製法１３） (Manufacturing method 13)
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法１３は、化合物（１）中のＸが単結合であり、Ｂがキナゾリンである化合物 (１ｌ)を製造する方法である。 Production method 13 is a method for producing compound (1 l) in which X in compound (1) is a single bond and B is quinazoline.
　本製法は、化合物（３０）と化合物（４６）を反応させ、化合物 (４７)を得、次いで化合物（４７)のニトロ基を自体公知の方法にて還元し、化合物（１ｌ）を製造する方法である。本製法は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, compound (30) and compound (46) are reacted to obtain compound (47), and then the nitro group of compound (47) is reduced by a method known per se to produce compound (1l). It is. This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
（製法１４） (Manufacturing method 14)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法１４は、化合物（１）中のＸが単結合であり、Ｂがクロメン－４－オンである化合物 (１ｍ)を製造する方法である。 Production method 14 is a method for producing compound (1 m) in which X in compound (1) is a single bond and B is chromen-4-one.
　本製法は、化合物（４８）と化合物（４９）を反応させ、化合物 (５０)を得、次いで化合物（５０)のニトロ基を自体公知の方法にて還元し、化合物（１ｍ）を製造する方法である。本製法は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, compound (48) and compound (49) are reacted to obtain compound (50), and then the nitro group of compound (50) is reduced by a method known per se to produce compound (1m). It is. This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
（製法１５） (Manufacturing method 15)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法１５は、化合物（１）中のＸがエチニレンである化合物 (１ｎ)を製造する方法である。 Production method 15 is a method for producing compound (1n) in which X in compound (1) is ethynylene.
　本製法は、化合物（９）と化合物（４０）を、有機金属触媒を用いたカップリング反応に付し、化合物 (５１)を得、次いで化合物（５１)のニトロ基を自体公知の方法にて還元し、化合物（１ｎ）を製造する方法である。 In this production method, compound (9) and compound (40) are subjected to a coupling reaction using an organometallic catalyst to obtain compound (51), and then the nitro group of compound (51) is obtained by a method known per se. Reduction is a method for producing a compound (1n).
　本製法は、不活性溶媒中、必要により塩基の存在下で行われる。また、本製法は、必要に応じて、ホスフィンリガンドの存在下に行ってもよい。使用される不活性溶媒は、前述のものが挙げられる。 This production method is carried out in an inert solvent, if necessary, in the presence of a base. Moreover, you may perform this manufacturing method in presence of a phosphine ligand as needed. Examples of the inert solvent used include those described above.
　有機金属触媒としては、酢酸パラジウム(II)、テトラキス（トリフェニルホスフィン）パラジウム(0)、トリス（ジベンジリデンアセトン）ジパラジウム(0)、ジクロロビス（トリフェニルホスフィン）パラジウム(II)などが挙げられる。 Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
　塩基としては、例えば、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸セシウムなどアルカリ金属炭酸塩；水素化カリウム、水素化ナトリウム等の金属水素化物などが挙げられる。 Examples of the base include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate; metal hydrides such as potassium hydride and sodium hydride.
　ホスフィンリガンドとしては、２，２’－ビス(ジフェニルホスフィノ)－１，１’－ビナフチル（ＢＩＮＡＰ）、トリス（２－メチルフェニル）ホスフィン、１，１’－ビス（ジフェニルホスフィノ）フェロセン、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル等が挙げられる。
　反応温度や反応時間などの反応条件は、用いられる反応試薬、反応溶媒などによって異なるが、通常、反応温度は－３０から１５０℃であり、反応時間は３０分から２０時間である。 Examples of the phosphine ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl and the like.
Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but the reaction temperature is usually from −30 to 150 ° C., and the reaction time is from 30 minutes to 20 hours.
（製法１６） (Manufacturing method 16)
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法１６は、化合物（１）中のＸが単結合であり、Ｂがナフタレンである本発明の化合物 (１ｏ)を製造する方法である。 Production method 16 is a method for producing compound (1o) of the present invention in which X in compound (1) is a single bond and B is naphthalene.
　本製法は、化合物（５２）と化合物（５３）を、有機金属触媒を用いたカップリング反応に付し、化合物 (５４)を得、次いで化合物（５４)のニトロ基を自体公知の方法にて還元するか、化合物（４３）と化合物（５５）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｏ）を製造する方法である。本製法は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 In this production method, compound (52) and compound (53) are subjected to a coupling reaction using an organometallic catalyst to obtain compound (54), and then the nitro group of compound (54) is obtained by a method known per se. In this method, compound (43) and compound (55) are subjected to a coupling reaction using an organometallic catalyst to produce compound (1o). This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
（製法１７） (Manufacturing method 17)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法１７は、化合物（１）中のＸが単結合であり、Ｂがキノリンである化合物 (１ｐ)を製造する方法である。 Production method 17 is a method for producing compound (1p) in which X in compound (1) is a single bond and B is quinoline.
　本製法は、化合物（４３）と化合物（５６）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｐ）を製造する方法である。本製法は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 This production method is a method for producing the compound (1p) by subjecting the compound (43) and the compound (56) to a coupling reaction using an organometallic catalyst. This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
（製法１８） (Manufacturing method 18)
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法１８は、化合物（１）中のＸがピリミジンである化合物 (１ｑ)を製造する方法である。 Production method 18 is a method for producing compound (1q) in which X in compound (1) is pyrimidine.
　本製法は、化合物（５７）と化合物（５８）を、有機金属触媒を用いたカップリング反応に付し、得られた化合物（５９）と化合物（４３）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｑ）を製造する方法である。本製法の各工程は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 In this production method, the compound (57) and the compound (58) are subjected to a coupling reaction using an organometallic catalyst, and the resulting compound (59) and the compound (43) are coupled using an organometallic catalyst. This is a method for producing a compound (1q) by subjecting to a reaction. Each process of this manufacturing method is performed by attaching | subjecting to reaction similar to reaction of the compound (42) described in the manufacturing method 11, and a compound (43).
（製法１９） (Manufacturing method 19)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法１９は、化合物（１）中のＸが単結合であり、Ｂがキノキサリンである化合物 (１ｒ)を製造する方法である。 Production method 19 is a method for producing compound (1r) in which X in compound (1) is a single bond and B is quinoxaline.
　本製法は、化合物（４３）と化合物（６０）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｒ）を製造する方法である。本製法は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 This production method is a method for producing compound (1r) by subjecting compound (43) and compound (60) to a coupling reaction using an organometallic catalyst. This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
（製法２０） (Manufacturing method 20)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法２０は、化合物（１）中のＸがピラジンである化合物 (１ｓ)を製造する方法である。 Production method 20 is a method for producing compound (1s) in which X in compound (1) is pyrazine.
　本製法は、化合物（６１）と化合物（５８）を、有機金属触媒を用いたカップリング反応に付し、さらに得られた化合物（６２）と化合物（４３）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｓ）を製造する方法である。本製法の各工程は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 In this production method, the compound (61) and the compound (58) are subjected to a coupling reaction using an organometallic catalyst, and the obtained compound (62) and the compound (43) are further combined with a cup using an organometallic catalyst. This is a method for producing a compound (1s) by subjecting it to a ring reaction. Each process of this manufacturing method is performed by attaching | subjecting to reaction similar to reaction of the compound (42) described in the manufacturing method 11, and a compound (43).
（製法２１） (Manufacturing method 21)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法２１は、化合物（１）中のＸが単結合であり、Ｂがベンゾオキサゾールである化合物 (１ｔ)を製造する方法である。 Production method 21 is a method for producing compound (1t) in which X in compound (1) is a single bond and B is benzoxazole.
　本製法は、化合物（４３）と化合物（６３）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｔ）を製造する方法である。本製法は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 This production method is a method for producing compound (1t) by subjecting compound (43) and compound (63) to a coupling reaction using an organometallic catalyst. This production method is carried out by subjecting the compound (42) and the compound (43) described in the production method 11 to the same reaction.
（製法２２） (Manufacturing method 22)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法２２は、化合物（１）中のＸが単結合であり、Ｂが４－オキソ－１，４－ジヒドロキノリンである化合物 (１ｕ)を製造する方法である。 Production method 22 is a method for producing compound (1u) in which X in compound (1) is a single bond and B is 4-oxo-1,4-dihydroquinoline.
　本製法は、化合物（９）と化合物（６４）を反応させ、化合物 (６５)を得、次いで化合物（６５)のニトロ基を自体公知の方法にて還元し、化合物（１ｕ）を製造する方法である。本製法は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, compound (9) and compound (64) are reacted to obtain compound (65), and then the nitro group of compound (65) is reduced by a method known per se to produce compound (1u). It is. This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
（製法２３） (Manufacturing method 23)
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法２３は、化合物（１）中のＸがチアゾールである化合物 (１ｖ)を製造する方法である。 Production Method 23 is a method for producing Compound IV (1v) in which X in Compound (1) is thiazole.
　本製法は、化合物（６６）と化合物（５８）を、有機金属触媒を用いたカップリング反応に付し、得られた化合物（６７）をＮ－ブロモスクシンイミドで臭素化し、次いで、得られた化合物（６８）と化合物（４３）を、有機金属触媒を用いたカップリング反応に付し、化合物（１ｖ）を製造する方法である。本製法において、化合物（６６）と化合物（５８）の反応および化合物（６８）と化合物（４３）の反応は、製法１１に記載した化合物（４２）と化合物（４３）との反応と同様の反応に付すことによって行われる。 In this production method, the compound (66) and the compound (58) are subjected to a coupling reaction using an organometallic catalyst, the obtained compound (67) is brominated with N-bromosuccinimide, and then the obtained compound (68) and compound (43) are subjected to a coupling reaction using an organometallic catalyst to produce compound (1v). In this production method, the reaction between compound (66) and compound (58) and the reaction between compound (68) and compound (43) are the same as the reaction between compound (42) and compound (43) described in production method 11. It is done by attaching to.
（製法２４） (Manufacturing method 24)
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
［上記式中、ＡおよびＢは、前記と同意義である。］ [In the above formula, A and B are as defined above. ]
　製法２４は、化合物（１）中のＸが、１，２，４－トリアゾールである化合物（１ｗ）を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.4」に記載の方法が挙げられる。 Production method 24 is a method for producing compound (1w) in which X in compound (1) is 1,2,4-triazole. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
　本製法は、化合物（６９）と化合物（３５）を反応させ、化合物 (７０)を得、次いで化合物（７０)のニトロ基を自体公知の方法にて還元し、化合物（１ｗ）を製造する方法である。本製法は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, compound (69) and compound (35) are reacted to obtain compound (70), and then the nitro group of compound (70) is reduced by a method known per se to produce compound (1w). It is. This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
（製法２５） (Manufacturing method 25)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
［上記式中、Ａは、前記と同意義である。］ [In the above formula, A is as defined above. ]
　製法２５は、化合物（１）中のＸが単結合であり、Ｂがピリド［３，４－ｂ］ピラジンである本化合物（１ｘ）を製造する方法である。その他の方法としては、例えば、「Comprehensive Heterocyclic Chemistry II，Vol.4」に記載の方法が挙げられる。 Production method 25 is a method for producing the present compound (1x) in which X in compound (1) is a single bond and B is pyrido [3,4-b] pyrazine. Examples of other methods include the method described in “ComprehensivehenHeterocyclic Chemistry II, Vol.4”.
　本製法は、化合物（７１）を二酸化セレンで酸化し、得られた化合物（７２）と化合物（７３）を反応させ、化合物 (７４)を得、次いで化合物（７４)のニトロ基を自体公知の方法にて還元し、化合物（１ｘ）を製造する方法である。本製法は、不活性溶媒中、自体公知の方法にて行うことができる。使用される不活性溶媒は、前述のものが挙げられる。 In this production method, the compound (71) is oxidized with selenium dioxide, the resulting compound (72) and the compound (73) are reacted to obtain a compound (74), and then the nitro group of the compound (74) is known per se. This is a method for producing a compound (1x) by reduction by a method. This production method can be carried out by a method known per se in an inert solvent. Examples of the inert solvent used include those described above.
　上記の方法において化合物（Ｉ）が遊離化合物として得られる場合、常法に従って、例えば、無機酸（塩酸、硫酸、臭化水素酸など）、有機酸（メタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、シュウ酸、フマル酸、マレイン酸、酒石酸など）、無機塩基（ナトリウム、カリウムなどのアルカリ金属、カルシウム、マグネシウムなどのアルカリ土類金属、アルミニウムまたはアンモニウムなど）または有機塩基（トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミンまたはＮ，Ｎ’－ジベンジルエチレンジアミンなど）などとの塩を生成させることもでき、化合物（Ｉ）が塩の形態で得られる場合は、常法に従って、遊離の化合物または他の塩に変換することもできる。 When compound (I) is obtained as a free compound in the above method, according to a conventional method, for example, inorganic acid (hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acid (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid) , Oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium) or organic bases (trimethylamine, triethylamine, pyridine, A salt with picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine, etc.) can be formed. When compound (I) is obtained in the form of a salt, According to the law, free It can also be converted to compounds or other salts.
　また、前記の各反応において、原料化合物が塩を形成し得る場合、該化合物を塩として用いてもよい。このような塩としては、例えば、化合物（Ｉ）の塩（医薬上許容される塩）として例示したものが使用される。 In each of the reactions described above, when the raw material compound can form a salt, the compound may be used as a salt. As such salt, for example, those exemplified as the salt of compound (I) (pharmaceutically acceptable salt) are used.
上記の方法で製造された本発明の化合物（Ｉ）は、公知の方法、例えば、抽出、沈殿、蒸留、クロマトグラフィー、分別再結晶、再結晶等により単離、精製することができる。
　また、本発明の化合物（Ｉ）または製造の中間体が不斉炭素を有する場合には光学異性体が存在する。これらの光学異性体は、適切な塩と再結晶する分別再結晶（塩分割）やカラムクロマトグラフィー等の常法によって、それぞれの異性体を単離、精製することができる。また、不斉合成によっても上記異性体を製造することができる。上記異性体をラセミ体から光学異性体を分割する方法の参考文献としては、J.Jacquesらの、「Enantiomers, Racemates and Resolution, John Wiley And Sons,Inc.」を挙げることができる。 The compound (I) of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
Further, when the compound (I) of the present invention or the intermediate of production has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography. The isomer can also be produced by asymmetric synthesis. As a reference for a method for resolving an optical isomer from a racemate, there can be mentioned “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.
　化合物（Ｉ）は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても化合物（Ｉ）に包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　化合物（Ｉ）は、水和物、非水和物、溶媒和物、無溶媒和物のいずれであってもよい。 Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. The crystal can be produced by crystallization by applying a crystallization method known per se.
Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
　本発明の化合物（Ｉ）は、毒性が低く、単独で、または医薬上許容し得る担体等と混合して医薬組成物とすることにより、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト等）に投与することができる。本発明化合物を哺乳動物（特にヒト）に投与する場合には、全身的または局所的に、経口または非経口で投与することができる。 The compound (I) of the present invention has low toxicity, and can be used alone or in admixture with a pharmaceutically acceptable carrier to make a pharmaceutical composition so that mammals (eg, mice, rats, hamsters, rabbits, cats) , Dogs, cows, sheep, monkeys, humans, etc.). When the compound of the present invention is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
　本発明の医薬組成物に配合される医薬上許容される担体としては、例えば、賦形剤（例えば、デンプン、乳糖、砂糖、炭酸カルシウム、リン酸カルシウム等）、結合剤（例えば、デンプン、アラビアゴム、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、結晶セルロース等）、滑沢剤（例えば、ステアリン酸マグネシウム、タルク等）、崩壊剤（例えば、カルボキシメチルセルロース、タルク等）等が挙げられる。
　化合物（Ｉ）および必要に応じて医薬上許容される担体を混合した後、混合物を自体公知の手段に従い、例えば、カプセル剤、錠剤、細粒剤、顆粒剤、ドライシロップ等の経口投与用、または注射剤、坐剤等の非経口投与用の製剤とすることができる。
　本発明の医薬組成物中の化合物（Ｉ）の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし１００重量％の範囲であり、好ましくは約０．１ないし５０重量％の範囲であり、さらに好ましくは約０．５ないし２０重量％程度の範囲である。 Examples of the pharmaceutically acceptable carrier to be blended in the pharmaceutical composition of the present invention include, for example, excipients (for example, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (for example, starch, gum arabic, Carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.), disintegrating agents (eg, carboxymethyl cellulose, talc, etc.) and the like.
After mixing Compound (I) and, if necessary, a pharmaceutically acceptable carrier, the mixture is used for oral administration such as capsules, tablets, fine granules, granules, dry syrup, etc., according to a method known per se, or It can be set as the formulation for parenteral administration, such as an injection and a suppository.
The content of compound (I) in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 100% by weight, preferably about 0.1 to the total preparation. The range is from about 50 to 50% by weight, and more preferably about 0.5 to 20% by weight.
　本発明の医薬組成物は、投与方法に応じて適当な形態を選択し、通常用いられている各種製剤の調製法によって製造できる。
　経口用の医薬組成物の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている賦形剤、結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、希釈剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 The pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.
　非経口用の医薬組成物の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤、吸入剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている安定化剤、防腐剤、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、溶解補助剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. The preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives. Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
　本発明の化合物（Ｉ）の投与量は、症状、年齢、体重、組み合わせて投与する薬剤の種類や投与量等によって異なるが、通常、化合物（Ｉ）の換算量で、成人一人（体重約６０ｋｇとして）一回につき０．００１－１０００ｍｇの範囲で、全身的または局所的に、月：一回から数回、週：一回から数回、一日：一回から数回、経口または非経口投与されるか、或いは一日に１－２４時間の範囲で静脈内に持続投与されるのが好ましい。 The dose of the compound (I) of the present invention varies depending on the symptoms, age, body weight, type of drug to be administered in combination and the dose, etc., but is usually an equivalent amount of the compound (I) and one adult (body weight of about 60 kg). As) in the range of 0.001-1000 mg at a time, systemically or locally, month: once to several times, week: once to several times, day: once to several times, oral or parenteral Preferably, it is administered or administered intravenously in the range of 1-24 hours per day.
　次に、実施例、試験例および製剤例を挙げて本発明を詳細に説明するが、本発明はこれらに限定されるものではない。 Next, the present invention will be described in detail with reference to Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.
実施例１: 
N-(4-{5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル}フェニル)スルファミド Example 1:
N- (4- {5- (2-fluorophenyl) [1,2,4] oxadiazol-3-yl} phenyl) sulfamide
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
(1-1) (Z)-O-(2-フルオロベンゾイル)-4-ニトロベンズアミドオキシム (1-1) (Z) -O- (2-Fluorobenzoyl) -4-nitrobenzamide oxime
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　4-ニトロベンゾニトリル5.00 g (33.8 mmol) をt-ブタノール 70 mLに懸濁し、50％ ヒドロキシルアミン水溶液2.45 g (37 mmol) を加え、3 時間加熱還流した。放冷後、反応液に水を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣に t-ブチルメチルエーテル 30 mL を加え、不溶物をろ取し、黄色粉末 3.55 g を得た。
　得られた黄色粉末 2.00 gを塩化メチレン20 mL に溶解し、トリエチルアミン1.44 mL (12.1 mmol) および2-フルオロベンゾイルクロリド 1.68 mL (12.1 mmol) を加え、室温にて30 分間撹拌した。反応液に水および 酢酸エチルを加え、不溶物をろ取し、(Z)-O-(2-フルオロベンゾイル)-4-ニトロベンズアミドオキシムの淡黄色粉末 1.79 g (収率31％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.10-7.25 (2H, br), 7.31-7.45 (2H, m), 7.66-7.77 (1H, m,), 8.01-8.15 (3H, m), 8.29-8.40 (2H, m). 4-Nitrobenzonitrile 5.00 g (33.8 mmol) was suspended in t-butanol 70 mL, 50% hydroxylamine aqueous solution 2.45 g (37 mmol) was added, and the mixture was heated to reflux for 3 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, 30 mL of t-butyl methyl ether was added to the resulting residue, and the insoluble material was collected by filtration to obtain 3.55 g of a yellow powder.
2.00 g of the obtained yellow powder was dissolved in 20 mL of methylene chloride, 1.44 mL (12.1 mmol) of triethylamine and 1.68 mL (12.1 mmol) of 2-fluorobenzoyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the insoluble material was collected by filtration to obtain 1.79 g (yield 31%) of a pale yellow powder of (Z) -O- (2-fluorobenzoyl) -4-nitrobenzamide oxime. .
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.10-7.25 (2H, br), 7.31-7.45 (2H, m), 7.66-7.77 (1H, m,), 8.01-8.15 (3H, m) , 8.29-8.40 (2H, m).
 (1-2) 5-(2-フルオロフェニル)-3-(4-ニトロフェニル)[1,2,4]オキサジアゾール (1-2) 5- (2-Fluorophenyl) -3- (4-nitrophenyl) [1,2,4] oxadiazole
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　(1-1) で製造した (Z)-O-(2-フルオロベンゾイル)-4-ニトロベンズアミドオキシム1.00 g (3.30mmol) をテトラヒドロフラン7 mLに懸濁し、1.0 M テトラブチルアンモニウムヒドロキシド－メタノール溶液3.3 mL (3.3 mmol) を加え、室温にて 15 分間撹拌した。反応液に1.0 M 塩酸 10 mL を加え、析出物をろ取し、5-(2-フルオロフェニル)-3-(4-ニトロフェニル)[1,2,4]オキサジアゾールの白色粉末 790 mg (収率84％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.28-7.42 (2H, m), 7.60-7.70 (1H, m), 8.20-8.27 (1H, m,), 8.36-8.42 (4H, m). 1.00 g (3.30 mmol) of (Z) -O- (2-fluorobenzoyl) -4-nitrobenzamidooxime prepared in (1-1) was suspended in 7 mL of tetrahydrofuran, and 1.0 M tetrabutylammonium hydroxide-methanol solution 3.3 mL (3.3 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 10 mL of 1.0 M hydrochloric acid, and the precipitate was collected by filtration. A white powder of 5- (2-fluorophenyl) -3- (4-nitrophenyl) [1,2,4] oxadiazole 790 mg (84% yield) was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 7.28-7.42 (2H, m), 7.60-7.70 (1H, m), 8.20-8.27 (1H, m,), 8.36-8.42 (4H, m).
(1-3) 4-[5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル]フェニルアミン (1-3) 4- [5- (2-Fluorophenyl) [1,2,4] oxadiazol-3-yl] phenylamine
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　(1-2) で製造した5-(2-フルオロフェニル)-3-(4-ニトロフェニル)[1,2,4]オキサジアゾール250 mg (0.876 mmol) をエタノール5 mL に懸濁し、塩化スズ（II）二水和物989 mg (4.38 mmol) を加え、30 分間加熱還流した。同様に5-(2-フルオロフェニル)-3-(4-ニトロフェニル)[1,2,4]オキサジアゾール 528 mg (1.85mmol) をエタノール10 mL に懸濁し、塩化スズ（II）二水和物2.09 g (9.26 mmol) を加え、30 分間加熱還流した。反応液を合わせ、28％アンモニア水を加え、不溶物をろ別し、ろ液を酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、4-[5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル]フェニルアミンの白色粉末 700 mgを定量的に得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.80-4.20 (2H, br), 6.73-6.80 (2H, m), 7.26-7.36 (2H, m,), 7.54-7.62 (1H, m), 7.95-8.02 (2H, m), 8.15-8.25 (1H, m). 250 mg (0.876 mmol) of 5- (2-fluorophenyl) -3- (4-nitrophenyl) [1,2,4] oxadiazole prepared in (1-2) was suspended in 5 mL of ethanol and chlorinated. Tin (II) dihydrate 989 mg (4.38 mmol) was added, and it heated and refluxed for 30 minutes. Similarly, 528 mg (1.85 mmol) of 5- (2-fluorophenyl) -3- (4-nitrophenyl) [1,2,4] oxadiazole was suspended in 10 mL of ethanol, and tin (II) chloride dihydrate was added. The product 2.09 g (9.26 mmol) was added, and the mixture was heated to reflux for 30 minutes. The reaction solutions were combined, 28% aqueous ammonia was added, insolubles were filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to quantitatively obtain 700 mg of white powder of 4- [5- (2-fluorophenyl) [1,2,4] oxadiazol-3-yl] phenylamine.
1 H-NMR (CDCl3, 400 MHz) δ; 3.80-4.20 (2H, br), 6.73-6.80 (2H, m), 7.26-7.36 (2H, m,), 7.54-7.62 (1H, m), 7.95 -8.02 (2H, m), 8.15-8.25 (1H, m).
(1-4) N-(4-{5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル}フェニル)スルファミド  (1-4) N- (4- {5- (2-Fluorophenyl) [1,2,4] oxadiazol-3-yl} phenyl) sulfamide
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　クロロスルホニルイソシアネート 0.35 mL (4.0 mmol) を塩化メチレン3.2 mLに溶解し、氷冷下t-ブタノール0.39 mL (4.1 mmol) を加え、同温にて20 分間撹拌し、約1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液を調製した。
　(1-3) で製造した4-[5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル]フェニルアミン700 mg (2.73 mmol) を塩化メチレン5 mLに溶解し、トリエチルアミン1.2 mL (8.2 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液3.3 mL (3.3 mmol) を加え、室温にて 2 時間撹拌した。反応液に5％ クエン酸水を加え、クロロホルムにて抽出後、有機層を乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡黄色油状物 980 mg を得た。
　得られた淡黄色油状物 980 mgをトリフルオロ酢酸5 mLに溶解し、室温にて 30 分間撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出後、有機層を水および飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣にt-ブチルメチルエーテル5 mLを加え、不溶物をろ取し、N-(4-{5-(2-フルオロフェニル)[1,2,4]オキサジアゾール-3-イル}フェニル)スルファミドの微褐色粉末 140 mg (収率5％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.30-7.40 (4H, m), 7.44-7.63 (2H, m), 7.74-7.85 (1H, m), 7.95-8.05 (2H, m), 8.18-8.30 (1H, m), 10.00-10.15 (1H, br).
MS ; ESI m/z 333 [M-H]-. Dissolve 0.35 mL (4.0 mmol) of chlorosulfonyl isocyanate in 3.2 mL of methylene chloride, add 0.39 mL (4.1 mmol) of t-butanol under ice-cooling, stir at the same temperature for 20 minutes, and add about 1.0 M t-butyl N- A chlorosulfonyl carbamate-methylene chloride solution was prepared.
Dissolve 700 mg (2.73 mmol) of 4- [5- (2-fluorophenyl) [1,2,4] oxadiazol-3-yl] phenylamine prepared in (1-3) in 5 mL of methylene chloride. , 1.2 mL (8.2 mmol) of triethylamine and 3.3 mL (3.3 mmol) of 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 5% aqueous citric acid, and the mixture was extracted with chloroform. The organic layer was dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 980 mg of a pale yellow oil.
980 mg of the obtained pale yellow oil was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, 5 mL of t-butyl methyl ether was added to the resulting residue, the insoluble material was collected by filtration, and N- (4- {5- (2-fluorophenyl) [1,2,4 A fine brown powder of 140 mg (yield 5%) of oxadiazol-3-yl} phenyl) sulfamide was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.30-7.40 (4H, m), 7.44-7.63 (2H, m), 7.74-7.85 (1H, m), 7.95-8.05 (2H, m), 8.18-8.30 (1H, m), 10.00-10.15 (1H, br).
MS; ESI m / z 333 [MH] - .
実施例２: 
N-{4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニル}スルファミド Example 2:
N- {4- [1- (2-Fluorophenyl) -1H-pyrazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
(2-1) 1-(2-フルオロフェニル)-1H-ピラゾール (2-1) 1- (2-Fluorophenyl) -1H-pyrazole
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　ヨウ化銅 190 mg (1.00 mmol)、L-プロリン115 mg (1.00 mmol) および炭酸カリウム 1.38 g (10.0 mmol) をジメチルスルホキシド 10 mL に懸濁し、2-フルオロヨードベンゼン0.58 mL (5.0 mmol) および ピラゾール477 mg (7.00 mmol) を加え、室温にて0.5時間撹拌後、120℃ にて16 時間撹拌した。放冷後、反応液に酢酸エチル10 mLを加え、不溶物をろ別後、ろ液を水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→0:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、1-(2-フルオロフェニル)-1H-ピラゾールの赤色油状物323 mg (収率40％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 6.48 (1H, ｔ, J=2.7 Hz), 7.20-7.30 (3H, m,), 7.73-7.77 (1H, m), 7.75 (1H, d, J=2.7 Hz), 7.87-7.92 (1H, m), 8.01 (1H, ｔ, J=2.7 Hz).  Copper iodide 190 mg (1.00 mmol), L-proline 115 mg (1.00 mmol) and potassium carbonate 1.38 g (10.0 mmol) were suspended in dimethyl sulfoxide 10 mL, 2-fluoroiodobenzene 0.58 mL (5.0 mmol) and pyrazole 477 mg (7.00 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr and then stirred at 120 ° C. for 16 hr. After allowing to cool, 10 mL of ethyl acetate was added to the reaction solution, the insoluble material was filtered off, and the filtrate was washed with water and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 0: 1, V / V), and the solvent of the target fraction was distilled under reduced pressure. This gave 323 mg (yield 40%) of red oil of 1- (2-fluorophenyl) -1H-pyrazole.
1 H-NMR (CDCl3, 400 MHz) δ; 6.48 (1H, t, J = 2.7 Hz), 7.20-7.30 (3H, m,), 7.73-7.77 (1H, m), 7.75 (1H, d, J = 2.7 Hz), 7.87-7.92 (1H, m), 8.01 (1H, t, J = 2.7 Hz).
(2-2) 4-ブロモ-1-(2-フルオロフェニル)-1H-ピラゾール (2-2) 4-Bromo-1- (2-fluorophenyl) -1H-pyrazole
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　(2-1) で製造した1-(2-フルオロフェニル)-1H-ピラゾール323 mg (1.99 mmol) をアセトニトリル 4.3 mL に溶解し、N-ブロモスクシンイミド 425 mg (2.39 mmol) を加え、室温にて16 時間撹拌した。反応液に酢酸エチルを加え、水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→0:1、V/V） にて精製後、目的分画の溶媒を減圧下留去し、4-ブロモ-1-(2-フルオロフェニル)-1H-ピラゾールの褐色油状物195 mg (収率41％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.21-7.31 (3H, m), 7.69 (1H, s), 7.86 (1H, td, J=8.0, 1.7 Hz), 8.03 (1H, d, J=2.4 Hz).  Dissolve 323 mg (1.99 mmol) of 1- (2-fluorophenyl) -1H-pyrazole prepared in (2-1) in 4.3 mL of acetonitrile and add 425 mg (2.39 mmol) of N-bromosuccinimide at room temperature. Stir for 16 hours. Ethyl acetate was added to the reaction mixture, washed with water, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 0: 1, V / V), and the solvent of the target fraction was distilled under reduced pressure. This gave 195 mg (yield 41%) of brown oil of 4-bromo-1- (2-fluorophenyl) -1H-pyrazole.
1 H-NMR (CDCl3, 400 MHz) δ; 7.21-7.31 (3H, m), 7.69 (1H, s), 7.86 (1H, td, J = 8.0, 1.7 Hz), 8.03 (1H, d, J = 2.4 Hz).
(2-3) 4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニルアミン (2-3) 4- [1- (2-Fluorophenyl) -1H-pyrazol-4-yl] phenylamine
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　(2-2) で製造した4-ブロモ-1-(2-フルオロフェニル)-1H-ピラゾール294 mg (1.22 mmol) を1,4-ジオキサン 12.2 mLに溶解し、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン 401 mg (1.83 mmol)、テトラキス(トリフェニルホスフィン)パラジウム 141 mg (0.122 mmol)、2.0 M炭酸ナトリウム水溶液 1.83 mL (3.66 mmol) を加え、100℃で2.5 時間撹拌した。反応液に酢酸エチルを加え、飽和塩化アンモニウム水、飽和食塩水で順次洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー （n-ヘキサン：酢酸エチル、1:0→7:3、V/V）にて精製した。目的分画の溶媒を減圧下留去し、4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニルアミンの淡黄色粉末178 mg (y=54％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.65-3.77 (2H, br), 6.70-6.76 (2H, m), 7.20-7.25 (3H, m), 7.33-7.39 (2H, m), 7.90-7.94 (2H, m), 8.14 (1H, d, J=2.7 Hz).  294 mg (1.22 mmol) of 4-bromo-1- (2-fluorophenyl) -1H-pyrazole prepared in (2-2) was dissolved in 12.2 mL of 1,4-dioxane, and 4- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) aniline 401 mg (1.83 mmol), tetrakis (triphenylphosphine) palladium 141 mg (0.122 mmol), 2.0 M aqueous sodium carbonate solution 1.83 mL (3.66 mmol) ) Was added and stirred at 100 ° C. for 2.5 hours. Ethyl acetate was added to the reaction solution, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 7: 3, V / V). The solvent of the objective fraction was distilled off under reduced pressure to obtain 178 mg (y = 54%) of 4- [1- (2-fluorophenyl) -1H-pyrazol-4-yl] phenylamine as a pale yellow powder.
1 H-NMR (CDCl3, 400 MHz) δ; 3.65-3.77 (2H, br), 6.70-6.76 (2H, m), 7.20-7.25 (3H, m), 7.33-7.39 (2H, m), 7.90- 7.94 (2H, m), 8.14 (1H, d, J = 2.7 Hz).
(2-4) N-{4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニル}スルファミド (2-4) N- {4- [1- (2-Fluorophenyl) -1H-pyrazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　(2-3) で製造した4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニルアミン178 mg (0.70 mmol) を塩化メチレン 2 mL に溶解し、氷冷下、トリエチルアミン 0.29 mL (2.1 mmol)、1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 1.05 mL (1.1 mmol) を加え、室温にて30 分間撹拌した。反応液に飽和塩化アンモニウム水 10 mLを加え、酢酸エチル 10 mLで3回抽出し、乾燥 （Na2SO4） した。減圧下溶媒を留去し、淡褐色油状物 354 mgを得た。得られた油状物をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→95:5→90:10、V/V）にて精製した。減圧下溶媒を留去し、白色粉末 50 mgを得た。この白色粉末にt-ブチルメチルエーテル 2 mLを加え、不溶物をろ取し、N-{4-[1-(2-フルオロフェニル)-1H-ピラゾール-4-イル]フェニル}スルファミドの白色粉末40.5 mg (収率18％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.09-7.13 (2H, br), 7.16-7.21 (2H, m), 7.35-7.52 (3H, m), 7.58-7.64 (2H, m), 7.82 (1H, td, J=8.1, 1.7 Hz), 8.20 (1H, s), 8.56 (1H, d, J=2.2 Hz), 9.48-9.52 (1H, br).
MS ; ESI m/z 333 [M+H]+, 355 [M+Na]+, 331 [M-H]-. 4- [1- (2-Fluorophenyl) -1H-pyrazol-4-yl] phenylamine 178 mg (0.70 mmol) prepared in (2-3) was dissolved in 2 mL of methylene chloride, and triethylamine was cooled with ice. 0.29 mL (2.1 mmol), 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution 1.05 mL (1.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (10 mL) and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 354 mg of a light brown oil. The obtained oil was purified by column chromatography (chloroform: methanol, 1: 0 → 95: 5 → 90: 10, V / V). The solvent was distilled off under reduced pressure to obtain 50 mg of white powder. To this white powder was added 2 mL of t-butyl methyl ether, the insoluble material was collected by filtration, and white powder of N- {4- [1- (2-fluorophenyl) -1H-pyrazol-4-yl] phenyl} sulfamide 40.5 mg (18% yield) was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.09-7.13 (2H, br), 7.16-7.21 (2H, m), 7.35-7.52 (3H, m), 7.58-7.64 (2H, m), 7.82 (1H, td, J = 8.1, 1.7 Hz), 8.20 (1H, s), 8.56 (1H, d, J = 2.2 Hz), 9.48-9.52 (1H, br).
MS; ESI m / z 333 [M + H] + , 355 [M + Na] + , 331 [MH] - .
実施例３: 
N-[4-{2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル}フェニル]スルファミド Example 3:
N- [4- {2- (2-Fluorophenyl) -4-methyloxazol-5-yl} phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
(3-1) 2-ブロモ-1-(4-ニトロフェニル)プロパン-1-オン (3-1) 2-Bromo-1- (4-nitrophenyl) propan-1-one
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　1-(4-ニトロフェニル)プロパン-1-オン4.00 g (22.3 mmol) を四塩化炭素 30 mLに溶解し、臭素 1.72 mL (33.5 mmol) の四塩化炭素 15 mLの溶液を加え、室温にて1.5 時間撹拌した。反応液に10％ チオ硫酸ナトリウム水50 mLを加え、塩化メチレンにて2回抽出後、有機層を合わせ、飽和重曹水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、2-ブロモ-1-(4-ニトロフェニル)プロパン-1-オンの黄色油状物5.81 gを定量的に得た。
1H-NMR (CDCl3, 400 MHz) δ; 1.94 (3H, d, J=6.6 Hz), 5.25 (3H, q, J=6.6 Hz), 8.15-8.20 (2H, m), 8.31-8.36 (2H, m). Dissolve 4.00 g (22.3 mmol) of 1- (4-nitrophenyl) propan-1-one in 30 mL of carbon tetrachloride, add a solution of 1.72 mL of bromine (33.5 mmol) in 15 mL of carbon tetrachloride, and Stir for 1.5 hours. To the reaction solution was added 50 mL of 10% aqueous sodium thiosulfate, and the mixture was extracted twice with methylene chloride. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to quantitatively obtain 5.81 g of 2-bromo-1- (4-nitrophenyl) propan-1-one as a yellow oily substance.
1 H-NMR (CDCl3, 400 MHz) δ; 1.94 (3H, d, J = 6.6 Hz), 5.25 (3H, q, J = 6.6 Hz), 8.15-8.20 (2H, m), 8.31-8.36 (2H , m).
(3-2) 2-(2-フルオロフェニル)-4-メチル-5-(4-ニトロフェニル)オキサゾール (3-2) 2- (2-Fluorophenyl) -4-methyl-5- (4-nitrophenyl) oxazole
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　(3-1) で製造した2-ブロモ-1-(4-ニトロフェニル)プロパン-1-オン 2.31 g (8.95 mmol) をN, N-ジメチルホルムアミド 35.8 mLに溶解し、2-フルオロベンジルアミン1.23 mL (10.7 mmol)、炭酸カリウム 4.95 g (35.8 mmol) およびヨウ素 5.00 g (19.7 mmol) を加え、80℃ にて5 時間撹拌した。放冷後、反応液に酢酸エチル 120 mLを加え、10％ チオ硫酸ナトリウム水にて2回、水にて2回、飽和食塩水にて1回洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、4:1→1:3、V/V）にて精製した。目的分画の溶媒を減圧下留去し、2-(2-フルオロフェニル)-4-メチル-5-(4-ニトロフェニル)オキサゾールの褐色粉末2.34 g (収率88％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 2.55 (3H, s), 7.38-7.49 (2H, m), 7.59-7.66 (1H, m), 7.95-8.00 (2H, m), 8.11-8.17 (1H, m), 8.34-8.39 (2H, m). 2-Bromo-1- (4-nitrophenyl) propan-1-one prepared in (3-1) was dissolved in 35.8 mL of N, N-dimethylformamide and dissolved in 2-fluorobenzylamine 1.23 mL (10.7 mmol), potassium carbonate 4.95 g (35.8 mmol) and iodine 5.00 g (19.7 mmol) were added, and the mixture was stirred at 80 ° C. for 5 hours. After allowing to cool, 120 mL of ethyl acetate was added to the reaction solution, washed twice with 10% aqueous sodium thiosulfate, twice with water, and once with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1 → 1: 3, V / V). The solvent of the objective fraction was distilled off under reduced pressure to obtain 2.34 g (yield 88%) of 2- (2-fluorophenyl) -4-methyl-5- (4-nitrophenyl) oxazole brown powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 2.55 (3H, s), 7.38-7.49 (2H, m), 7.59-7.66 (1H, m), 7.95-8.00 (2H, m), 8.11- 8.17 (1H, m), 8.34-8.39 (2H, m).
(3-3) 4-[2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル]フェニルアミン (3-3) 4- [2- (2-Fluorophenyl) -4-methyloxazol-5-yl] phenylamine
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　(3-2) で製造した2-(2-フルオロフェニル)-4-メチル-5-(4-ニトロフェニル)オキサゾール 609 mg (2.04 mmol) をエタノール 20 mLに懸濁し、塩化すず(II)二水和物 2.30 g (10.2 mmol) を加え、1.5 時間加熱還流した。放冷後、反応液に飽和重層水および酢酸エチルを加え、不溶物をセライトにてろ別し、ろ液の二層を分液した。有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（酢酸エチル：クロロホルム、0:1→1:9、V/V）にて精製した。目的分画の溶媒を減圧下留去し、4-[2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル]フェニルアミンの黄色粉末333 mg (収率61％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 2.36 (3H, s), 5.45-5.59 (2H, br), 6.65-6.70 (2H, m), 7.32-7.42 (4H, m), 7.50-7.57 (1H, m), 8.00-8.06 (1H, m). 609 mg (2.04 mmol) of 2- (2-fluorophenyl) -4-methyl-5- (4-nitrophenyl) oxazole prepared in (3-2) was suspended in 20 mL of ethanol, and tin (II) chloride Hydrate 2.30 g (10.2 mmol) was added, and the mixture was heated to reflux for 1.5 hours. After standing to cool, saturated multistory water and ethyl acetate were added to the reaction solution, the insoluble material was filtered off through Celite, and the two layers of the filtrate were separated. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: chloroform, 0: 1 → 1: 9, V / V). The solvent of the objective fraction was distilled off under reduced pressure to obtain 333 mg (yield 61%) of 4- [2- (2-fluorophenyl) -4-methyloxazol-5-yl] phenylamine as a yellow powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 2.36 (3H, s), 5.45-5.59 (2H, br), 6.65-6.70 (2H, m), 7.32-7.42 (4H, m), 7.50- 7.57 (1H, m), 8.00-8.06 (1H, m).
(3-4) N-[4-{2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル}フェニル]スルファミド (3-4) N- [4- {2- (2-Fluorophenyl) -4-methyloxazol-5-yl} phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　t-ブタノール 0.16 mL (1.74 mmol) を塩化メチレン 2 mLに溶解し、氷冷下、クロロスルホニルイソシアネート 0.13 mL (1.5 mmol) を加え、同温にて20 分間撹拌後、(3-3) で製造した4-[2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル]フェニルアミン 333 mg (1.24 mmol) およびトリエチルアミン 0.52 mL (3.7 mmol) の塩化メチレン 10 mL溶液を加え、室温にて2 時間撹拌した。反応液に飽和塩化アンモニウム水30 mLを加え、酢酸エチルにて3回抽出後、有機層を合わせ飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、黄色粉末621 mgを得た。得られた黄色粉末621 mgを塩化メチレン 5 mLに懸濁し、氷冷下トリフルオロ酢酸 5 mLを加え、室温にて2 時間撹拌した。反応液に飽和重曹水を加え、酢酸エチル-テトラヒドロフランの混液にて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（酢酸エチル：クロロホルム、1:9→1:3、V/V）にて精製した。目的分画の溶媒を減圧下留去し、得られた黄色粉末に酢酸エチル-t-ブチルメチルエーテル (1:4) 5 mLを加え、不溶物をろ取し、N-[4-{2-(2-フルオロフェニル)-4-メチルオキサゾール-5-イル}フェニル]スルファミドの白色粉末 76.7 mg (収率18％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 2.42 (3H, s), 7.19-7.25 (2H, m), 7.27-7.32 (2H, m), 7.34-7.45 (2H, m), 7.53-7.65 (3H, m), 8.04-8.10 (1H, m), 9.77 (1H, s).
MS ; ESI m/z 348 [M+H]+, 346 [M-H]-. Dissolve 0.16 mL (1.74 mmol) of t-butanol in 2 mL of methylene chloride, add 0.13 mL (1.5 mmol) of chlorosulfonyl isocyanate under ice-cooling, stir at the same temperature for 20 minutes, and then prepare in (3-3) 4- [2- (2-fluorophenyl) -4-methyloxazol-5-yl] phenylamine 333 mg (1.24 mmol) and triethylamine 0.52 mL (3.7 mmol) in 10 mL of methylene chloride were added at room temperature. Stir for 2 hours. Saturated aqueous ammonium chloride (30 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 621 mg of yellow powder. 621 mg of the obtained yellow powder was suspended in 5 mL of methylene chloride, 5 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: chloroform, 1: 9 → 1: 3, V / V). The solvent of the target fraction was distilled off under reduced pressure, 5 mL of ethyl acetate-t-butylmethyl ether (1: 4) was added to the obtained yellow powder, the insoluble material was collected by filtration, and N- [4- {2 A white powder of 76.7 mg (yield 18%) of-(2-fluorophenyl) -4-methyloxazol-5-yl} phenyl] sulfamide was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 2.42 (3H, s), 7.19-7.25 (2H, m), 7.27-7.32 (2H, m), 7.34-7.45 (2H, m), 7.53- 7.65 (3H, m), 8.04-8.10 (1H, m), 9.77 (1H, s).
MS; ESI m / z 348 [M + H] + , 346 [MH] - .
実施例４: 
N-[4-{2-(2-フルオロフェニル)チアゾール-5-イル}フェニル]スルファミド Example 4:
N- [4- {2- (2-Fluorophenyl) thiazol-5-yl} phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
(4-1) 2-(2-フルオロフェニル)チアゾール (4-1) 2- (2-Fluorophenyl) thiazole
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　2-フルオロフェニルボロン酸 2.05 g (14.6 mmol) を1,4-ジオキサン 50 mL に溶解し、2-ブロモチアゾール 1.08 mL (12.2 mmol)、テトラキス（トリフェニルホスフィン）パラジウム 0.70 g (0.61 mmol) および 2.0 M炭酸ナトリウム水 18.3 mL (36 mmol) を加え、窒素雰囲気下、100℃ にて2 時間撹拌した。放冷後、反応液に酢酸エチルを加え、飽和塩化アンモニウム水および飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→95:5、V/V）にて精製後、目的分画の溶媒を減圧下留去し、2-(2-フルオロフェニル)チアゾールの無色油状物 1.39 g (収率64％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.16-7.33 (2H, m), 7.35-7.44 (1H, m), 7.47 (1H, d, J=3.2 Hz), 7.90-8.00 (1H, m), 8.30 (1H, dt, J=7.6, 1.4 Hz). Dissolve 2.05 g (14.6 mmol) of 2-fluorophenylboronic acid in 50 mL of 1,4-dioxane, add 1.08 mL (12.2 mmol) of 2-bromothiazole, 0.70 g (0.61 mmol) of tetrakis (triphenylphosphine) palladium and 2.0 18.3 mL (36 mmol) of M sodium carbonate water was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. After allowing to cool, ethyl acetate was added to the reaction mixture, washed with saturated aqueous ammonium chloride and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 95: 5, V / V), and the solvent of the target fraction was distilled under reduced pressure. On leaving, 1.39 g (yield 64%) of 2- (2-fluorophenyl) thiazole colorless oil was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 7.16-7.33 (2H, m), 7.35-7.44 (1H, m), 7.47 (1H, d, J = 3.2 Hz), 7.90-8.00 (1H, m) , 8.30 (1H, dt, J = 7.6, 1.4 Hz).
(4-2) 5-ブロモ-2-(2-フルオロフェニル)チアゾール (4-2) 5-Bromo-2- (2-fluorophenyl) thiazole
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　(4-1) で製造した2-(2-フルオロフェニル)チアゾール 1.39 g (7.76 mmol) をN, N-ジメチルホルムアミド 10 mL に溶解し、N-ブロモスクシンイミド 2.76 g (15.5 mmol) を加え、50℃ にて12 時間撹拌した。放冷後、反応液に酢酸エチルを加え、水および飽和重層水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→97:3、V/V）にて精製後、目的分画の溶媒を減圧下留去し、5-ブロモ-2-(2-フルオロフェニル)チアゾールの淡褐色油状物1.90 g (収率95％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.13-7.32 (2H, m), 7.37-7.46 (1H, m), 7.81 (1H, d, J=2.2 Hz), 8.23 (1H, dt, J=7.4, 1.5 Hz). 1.39 g (7.76 mmol) of 2- (2-fluorophenyl) thiazole prepared in (4-1) was dissolved in 10 mL of N, N-dimethylformamide, and 2.76 g (15.5 mmol) of N-bromosuccinimide was added. The mixture was stirred at ° C for 12 hours. After allowing to cool, ethyl acetate was added to the reaction solution, washed with water and saturated multistory water, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 97: 3, V / V), and the solvent of the target fraction was distilled under reduced pressure. This gave 1.90 g (yield 95%) of a light brown oil of 5-bromo-2- (2-fluorophenyl) thiazole.
1 H-NMR (CDCl3, 400 MHz) δ; 7.13-7.32 (2H, m), 7.37-7.46 (1H, m), 7.81 (1H, d, J = 2.2 Hz), 8.23 (1H, dt, J = (7.4, 1.5 Hz).
(4-3) 4-[2-(2-フルオロフェニル)チアゾール-5-イル]フェニルアミン (4-3) 4- [2- (2-Fluorophenyl) thiazol-5-yl] phenylamine
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　(4-2) で製造した5-ブロモ-2-(2-フルオロフェニル)チアゾール 1.00 g (3.87 mmol) を1,4-ジオキサン 20 mL に溶解し、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン 1.02 g (4.65 mmol)、テトラキス（トリフェニルホスフィン）パラジウム 0.22 g (0.61 mmol) および 2.0 M 炭酸ナトリウム水 5.8 mL (12 mmol) を加え、窒素雰囲気下、100℃ にて2 時間撹拌した。放冷後、反応液に酢酸エチルを加え、飽和塩化アンモニウム水および飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→4:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-[2-(2-フルオロフェニル)チアゾール-5-イル]フェニルアミンの黄色粉末1.03 g (収率98％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.72-3.90 (2H, br), 6.66-6.78 (2H, m), 7.13-7.29 (2H, m), 7.31-7.48 (3H, m), 7.94 (1H, d, J=2.2 Hz), 8.26 (1H, dt, J=7.6, 1.5 Hz). 1.00 g (3.87 mmol) of 5-bromo-2- (2-fluorophenyl) thiazole prepared in (4-2) was dissolved in 20 mL of 1,4-dioxane, and 4- (4,4,5,5- Add tetramethyl-1,3,2-dioxaborolan-2-yl) aniline 1.02 g (4.65 mmol), tetrakis (triphenylphosphine) palladium 0.22 g (0.61 mmol) and 2.0 M sodium carbonate water 5.8 mL (12 mmol) The mixture was stirred at 100 ° C. for 2 hours in a nitrogen atmosphere. After allowing to cool, ethyl acetate was added to the reaction mixture, washed with saturated aqueous ammonium chloride and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 4: 1, V / V), and the solvent of the target fraction was distilled under reduced pressure. This gave 1.03 g (yield 98%) of 4- [2- (2-fluorophenyl) thiazol-5-yl] phenylamine as a yellow powder.
1 H-NMR (CDCl3, 400 MHz) δ; 3.72-3.90 (2H, br), 6.66-6.78 (2H, m), 7.13-7.29 (2H, m), 7.31-7.48 (3H, m), 7.94 ( 1H, d, J = 2.2 Hz), 8.26 (1H, dt, J = 7.6, 1.5 Hz).
(4-4) N-[4-{2-(2-フルオロフェニル)チアゾール-5-イル}フェニル]スルファミド (4-4) N- [4- {2- (2-Fluorophenyl) thiazol-5-yl} phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　(4-3) で製造した4-[2-(2-フルオロフェニル)チアゾール-5-イル]フェニルアミン 246 mg (0.910 mmol) を塩化メチレン 5 mLに溶解し、氷冷下トリエチルアミン 0.38 mL (2.7 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液1.36 mL (1.4 mmol) を加え、室温にて40 分間撹拌した。反応液に飽和塩化アンモニウム水を加え、酢酸エチルにて抽出後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、微褐色粉末0.40 gを得た。得られた微褐色粉末0.40 gを塩化メチレン 5 mLに懸濁し、氷冷下トリフルオロ酢酸 1 mLを加え、同温にて10 分間撹拌後、室温にて5.5 時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出後、水および飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→9:1、V/V）にて精製後、目的分画の溶媒を減圧下留去した。得られた粉末にt-ブチルメチルエーテル 3 mL を加え、不溶物をろ取後、t-ブチルメチルエーテル3 mL にて洗浄し、N-[4-{2-(2-フルオロフェニル)チアゾール-5-イル}フェニル]スルファミドの微褐色粉末 210 mg (収率66％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.18-7.30 (4H, m), 7.34-7.49 (2H, m), 7.49-7.59 (1H, m), 7.63-7.71 (2H, m), 8.24 (1H, dt, J=7.6, 1.5 Hz), 8.31 (1H, d, J=2.2 Hz), 9.77 (1H, s).
MS ; ESI m/z350 [M+H]+, 348 [M-H]-. (4-3) 4- [2- (2-fluorophenyl) thiazol-5-yl] phenylamine 246 mg (0.910 mmol) was dissolved in methylene chloride 5 mL, and triethylamine 0.38 mL (2.7 mmol) and 1.36 mL (1.4 mmol) of 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution were added, and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.40 g of a fine brown powder. 0.40 g of the obtained fine brown powder was suspended in 5 mL of methylene chloride, 1 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol, 1: 0 → 9: 1, V / V), and then the solvent of the target fraction was distilled off under reduced pressure. Add 3 mL of t-butyl methyl ether to the obtained powder, filter the insoluble matter, wash with 3 mL of t-butyl methyl ether, and wash with N- [4- {2- (2-fluorophenyl) thiazole- There was obtained 210 mg (66% yield) of a slightly brown powder of 5-yl} phenyl] sulfamide.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.18-7.30 (4H, m), 7.34-7.49 (2H, m), 7.49-7.59 (1H, m), 7.63-7.71 (2H, m), 8.24 (1H, dt, J = 7.6, 1.5 Hz), 8.31 (1H, d, J = 2.2 Hz), 9.77 (1H, s).
MS; ESI m / z350 [M + H] + , 348 [MH] - .
実施例５: 
N-{4-[4-(2-フルオロフェニル)イミダゾール-1-イル]フェニル}スルファミド Example 5:
N- {4- [4- (2-Fluorophenyl) imidazol-1-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
(5-1) 4-(2-フルオロフェニル)-1H-イミダゾール (5-1) 4- (2-Fluorophenyl) -1H-imidazole
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　1-(2-フルオロフェニル)エタノン 3.00 g (21.7 mmol) をジエチルエーテル 87.0 mLに溶解し、臭素 1.11 mL (21.7 mmol) のジエチルエーテル溶液 7.00 mL をゆっくり滴下し、室温にて16 時間撹拌した。ジエチルエーテル 200 mLを反応溶液に加え、飽和重曹水 100 mLで3回洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡褐色油状物4.67 gを得た。得られた淡褐色油状物 4.67 gにホルムアミド 11.0 mL、水 1.00 mLを加え懸濁し、140℃ にて2.5 時間撹拌した。室温まで冷却したのち、不溶物をろ別後、1 M 水酸化ナトリウム水 30 mLを加え、pH 10に調製した。水層を酢酸エチルにて3回抽出し、有機層を合わせ、飽和食塩水で洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→95:5、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-(2-フルオロフェニル)-1H-イミダゾールの淡褐色粉末 1.43 g (収率41％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.40-7.61 (3H, m), 7.71 (1H, d, J=3.6 Hz), 8.01 (1H, s), 8.26-8.34 (1H, m), 12.42-12.63 (1H, br). 1- (2-Fluorophenyl) ethanone (3.00 g, 21.7 mmol) was dissolved in diethyl ether (87.0 mL), bromine (1.11 mL, 21.7 mmol) in diethyl ether (7.00 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. 200 mL of diethyl ether was added to the reaction solution, washed 3 times with 100 mL of saturated aqueous sodium bicarbonate, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 4.67 g of a light brown oil. Formamide 11.0 mL and water 1.00 mL were added and suspended in 4.67 g of the obtained light brown oily substance, and the mixture was stirred at 140 ° C. for 2.5 hours. After cooling to room temperature, the insoluble material was filtered off, and 30 mL of 1 M aqueous sodium hydroxide was added to adjust to pH 10. The aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (chloroform: methanol, 1: 0 → 95: 5, V / V), and then the solvent of the target fraction was evaporated under reduced pressure to give 4- ( 1.43 g (41% yield) of a light brown powder of 2-fluorophenyl) -1H-imidazole was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.40-7.61 (3H, m), 7.71 (1H, d, J = 3.6 Hz), 8.01 (1H, s), 8.26-8.34 (1H, m) , 12.42-12.63 (1H, br).
(5-2) 4-(2-フルオロフェニル)-1-(4-ニトロフェニル)-1H-イミダゾール (5-2) 4- (2-Fluorophenyl) -1- (4-nitrophenyl) -1H-imidazole
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　(5-1) で製造した4-(2-フルオロフェニル)-1H-イミダゾール 1.43 g (8.84 mmol) をジメチルスルホキシド 17.7 mL に溶解し、1-フルオロ-4-ニトロベンゼン　1.12 mL (10.6 mmol)、炭酸カリウム 1.47 g (10.6 mmol) を加え懸濁し、室温にて1 時間、40℃ にて3時間、60℃ にて1時間撹拌した。反応液に水 30 mLを加え、不溶物をろ取し、水で洗浄した。得られた粉末をクロロホルムおよびメタノールの混液に加熱溶解し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、99:1→97:3→96:4、V/V）にて精製した。目的分画の溶媒を減圧下留去し、4-(2-フルオロフェニル)-1-(4-ニトロフェニル)-1H-イミダゾールの黄色粉末1.60 g (収率64％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.24-7.38 (3H, m), 8.03-8.14 (3H, m), 8.19 (1H, d, J=2.9 Hz), 8.33-8.40 (2H, m), 8.63 (1H, s). 4- (2-Fluorophenyl) -1H-imidazole prepared in (5-1) is dissolved in 17.7 mL of dimethyl sulfoxide, and 1.12 mL (10.6 mmol) of 1-fluoro-4-nitrobenzene is added to carbonic acid. Potassium 1.47 g (10.6 mmol) was added and suspended, and the mixture was stirred at room temperature for 1 hour, at 40 ° C for 3 hours, and at 60 ° C for 1 hour. 30 mL of water was added to the reaction solution, and the insoluble material was collected by filtration and washed with water. The obtained powder was dissolved by heating in a mixed solution of chloroform and methanol and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 99: 1 → 97: 3 → 96: 4, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 1.60 g (yield 64%) of 4- (2-fluorophenyl) -1- (4-nitrophenyl) -1H-imidazole powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.24-7.38 (3H, m), 8.03-8.14 (3H, m), 8.19 (1H, d, J = 2.9 Hz), 8.33-8.40 (2H, m), 8.63 (1H, s).
(5-3) N-{4-[4-(2-フルオロフェニル)イミダゾール-1-イル]フェニル}スルファミド (5-3) N- {4- [4- (2-Fluorophenyl) imidazol-1-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　(5-2) で製造した4-(2-フルオロフェニル)-1-(4-ニトロフェニル)-1H-イミダゾール 700 mg (2.47 mmol) をエタノール 25.0 mLに懸濁し、塩化すず(II)二水和物 2.79 g (12.4 mmol) を加え、1.5 時間加熱還流した。放冷後、反応液に飽和重曹水25 mLおよび酢酸エチル 25 mLを加え、不溶物をセライトにてろ別し、ろ液を分液した。有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) 後、減圧下溶媒を留去し、黄色粉末を得た。
　得られた黄色粉末 740 mg (2.47 mmolとして計算) を塩化メチレン 25 mLに懸濁し、氷冷下トリエチルアミン 1.03 mL (7.41 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液3.7 mL (3.7 mmol) を加え、室温にて0.5 時間撹拌した。反応液に飽和塩化アンモニウム水を加え、酢酸エチルにて抽出し、乾燥 (Na2SO4) 後、減圧下溶媒を留去し、黄色粉末 0.87 gを得た。
　得られた黄色粉末 0.87 gを塩化メチレン 5 mLに懸濁し、トリフルオロ酢酸 5 mLを加え、室温にて2.5 時間撹拌した。反応液に飽和重曹水50 mL、酢酸エチル 15 mLを加え、さらにテトラヒドロフラン 10 mLを加え、二層を分離した。水層を酢酸エチル 15 mLで3回抽出し、有機層を合わせ飽和食塩水で洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→9:1、V/V）にて精製した。目的分画の溶媒を減圧下留去し、淡褐色粉末を得た。得られた淡褐色粉末にt-ブチルメチルエーテル 8 mLを加え、不溶物をろ取し、更にｎ-ヘキサン 5 mLで2回洗浄し、N-{4-[4-(2-フルオロフェニル)イミダゾール-1-イル]フェニル}スルファミドの淡褐色粉末208 mg (収率25％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.13-7.35 (2H, br), 7.23-7.35 (5H, m), 7.59-7.67 (2H, m), 7.88-7.94 (1H, m), 8.06-8.14 (1H, m), 8.29 (1H, s), 9.65-9.73 (1H, br).
MS ; ESI m/z 333 [M+H]+, 331 [M-H]-. 700 mg (2.47 mmol) of 4- (2-fluorophenyl) -1- (4-nitrophenyl) -1H-imidazole prepared in (5-2) was suspended in 25.0 mL of ethanol, and tin (II) chloride dihydrate 2.79 g (12.4 mmol) of the Japanese product was added and heated to reflux for 1.5 hours. After allowing to cool, 25 mL of saturated aqueous sodium hydrogen carbonate and 25 mL of ethyl acetate were added to the reaction solution, insoluble material was filtered off through celite, and the filtrate was separated. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure to give a yellow powder.
The obtained yellow powder 740 mg (calculated as 2.47 mmol) was suspended in 25 mL of methylene chloride, and triethylamine 1.03 mL (7.41 mmol) and 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution 3.7 mL ( 3.7 mmol) was added and stirred at room temperature for 0.5 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure to give 0.87 g of a yellow powder.
0.87 g of the obtained yellow powder was suspended in 5 mL of methylene chloride, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution were added 50 mL of saturated aqueous sodium bicarbonate and 15 mL of ethyl acetate, and 10 mL of tetrahydrofuran was further added to separate the two layers. The aqueous layer was extracted three times with 15 mL of ethyl acetate, the organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 1: 0 → 9: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain a light brown powder. To the obtained light brown powder, 8 mL of t-butyl methyl ether was added, the insoluble material was collected by filtration, and further washed twice with 5 mL of n-hexane to give N- {4- [4- (2-fluorophenyl) 208 mg (25% yield) of a light brown powder of imidazol-1-yl] phenyl} sulfamide was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.13-7.35 (2H, br), 7.23-7.35 (5H, m), 7.59-7.67 (2H, m), 7.88-7.94 (1H, m), 8.06-8.14 (1H, m), 8.29 (1H, s), 9.65-9.73 (1H, br).
MS; ESI m / z 333 [M + H] + , 331 [MH] - .
実施例６: 
N-{4-[2-(2-フルオロフェニル)-3H-イミダゾール-4-イル]フェニル}スルファミド Example 6:
N- {4- [2- (2-Fluorophenyl) -3H-imidazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
(6-1) 2-(2-フルオロフェニル)-5-(4-ニトロフェニル)-1H-イミダゾール (6-1) 2- (2-Fluorophenyl) -5- (4-nitrophenyl) -1H-imidazole
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　2-フルオロベンゾニトリル 4.00 g (33.0 mmol) をエタノール 23.6 mLに溶解し、氷冷下塩化アセチル 18.7 mL (264 mmol) をゆっくり滴下し、室温にて22 時間撹拌した。溶媒を減圧下留去し、残渣にジエチルエーテル 20 mLを加え、不溶物をろ取し、白色粉末2.81 gを得た。
　得られた白色粉末 2.81 gをエタノール 13.8 mLに溶解し、7.0 M アンモニアのメタノール溶液 13.8 mL (97 mmol) をゆっくり滴下し、室温にて22 時間撹拌した。溶媒を減圧下留去し、淡赤色粉末 2.87 gを得た。
　得られた淡赤色粉末 2.75 gをテトラヒドロフラン 58 mLおよび水 14 mLの混液に懸濁させ、2-ブロモ-1-(4-ニトロフェニル)エタノン 3.49 g (13.2 mmol)、炭酸水素ナトリウム 4.81 g (48.0 mmol) を加え、2.5 時間加熱還流した。放冷後、水を加え、酢酸エチルで2回抽出し、有機層を合わせ、飽和食塩水で洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、1:0→90:10→83:17、V/V）にて精製後、目的分画の溶媒を減圧下留去し、2-(2-フルオロフェニル)-5-(4-ニトロフェニル)-1H-イミダゾールの橙色粉末 180 mg (収率2％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.17-7.40 (3H, m), 7.59 (1H, d, J=1.9 Hz), 8.01-8.06 (2H, m), 8.25-8.29 (2H, m), 8.39-8.41 (1H, m), 9.89-10.00 (1H, br). 4.00 g (33.0 mmol) of 2-fluorobenzonitrile was dissolved in 23.6 mL of ethanol, and 18.7 mL (264 mmol) of acetyl chloride was slowly added dropwise under ice cooling, followed by stirring at room temperature for 22 hours. The solvent was distilled off under reduced pressure, 20 mL of diethyl ether was added to the residue, and the insoluble material was collected by filtration to obtain 2.81 g of a white powder.
The obtained white powder (2.81 g) was dissolved in ethanol (13.8 mL), 7.0 M ammonia in methanol (13.8 mL, 97 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure to obtain 2.87 g of a pale red powder.
The obtained pale red powder (2.75 g) was suspended in a mixture of tetrahydrofuran (58 mL) and water (14 mL), and 2-bromo-1- (4-nitrophenyl) ethanone 3.49 g (13.2 mmol), sodium hydrogen carbonate 4.81 g (48.0 mmol) was added and heated to reflux for 2.5 hours. After allowing to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 90: 10 → 83: 17, V / V). Distillation gave 180 mg (yield 2%) of 2- (2-fluorophenyl) -5- (4-nitrophenyl) -1H-imidazole orange powder.
1 H-NMR (CDCl3, 400 MHz) δ; 7.17-7.40 (3H, m), 7.59 (1H, d, J = 1.9 Hz), 8.01-8.06 (2H, m), 8.25-8.29 (2H, m) , 8.39-8.41 (1H, m), 9.89-10.00 (1H, br).
(6-2) 4-[2-(2-フルオロフェニル)-3H-イミダゾール-4-イル]フェニルアミン (6-2) 4- [2- (2-Fluorophenyl) -3H-imidazol-4-yl] phenylamine
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　(6-1) で製造した2-(2-フルオロフェニル)-5-(4-ニトロフェニル)-1H-イミダゾール0.18 g (0.64 mmol) をエタノール 40 mLに懸濁し、塩化すず(II)二水和物 0.72 g (3.2 mmol) を加え、3 時間加熱還流した。放冷後、反応液に飽和重曹水および酢酸エチルを加え、不溶物をセライトにてろ別し、ろ液を分液した。有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、1:0→90:10→55:45、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-[2-(2-フルオロフェニル)-3H-イミダゾール-4-イル]フェニルアミンの黄色油状物116 mg (収率72％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.50-4.00 (2H, br), 6.68-6.82 (2H, m), 7.09-7.45 (5H, m), 7.57-7.81 (1H, m), 8.23-8.50 (1H, m), 9.59-9.98 (1H, m). 2- (2-Fluorophenyl) -5- (4-nitrophenyl) -1H-imidazole 0.18 g (0.64 mmol) prepared in (6-1) was suspended in 40 mL of ethanol, and tin (II) chloride dihydrate The Japanese product 0.72 g (3.2 mmol) was added, and it heated and refluxed for 3 hours. After allowing to cool, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, the insoluble material was filtered off through celite, and the filtrate was separated. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 90: 10 → 55: 45, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give 4- [2 116 mg (yield 72%) of a yellow oily substance of-(2-fluorophenyl) -3H-imidazol-4-yl] phenylamine was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 3.50-4.00 (2H, br), 6.68-6.82 (2H, m), 7.09-7.45 (5H, m), 7.57-7.81 (1H, m), 8.23- 8.50 (1H, m), 9.59-9.98 (1H, m).
(6-3) 4-[2-(2-フルオロフェニル)-3H-イミダゾール-4-イル]フェニルスルファミド (6-3) 4- [2- (2-Fluorophenyl) -3H-imidazol-4-yl] phenylsulfamide
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　(6-2) で製造した4-[2-(2-フルオロフェニル)-3H-イミダゾール-4-イル]フェニルアミン 116 mg (0.458 mmol) を塩化メチレン 5 mLに懸濁し、氷冷下トリエチルアミン 0.19 mL (1.4 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液0.50 mL (0.50 mmol) を加え、氷冷下50 分間撹拌した。反応液に水を加え、酢酸エチルにて抽出後、有機層を乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡褐色粉末 0.19 gを得た。
　得られた淡褐色粉末 0.19 gを塩化メチレン 3 mLに懸濁し、トリフルオロ酢酸 3 mLを加え、室温にて1.5 時間撹拌した。反応液に飽和重曹水を加えて中和し、水層を酢酸エチルにて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、1:0→9:1→1:1、V/V）にて精製した。目的分画の溶媒を減圧下留去し、残渣に塩化メチレン 5 mLを加え、不溶物をろ取し、塩化メチレン 10 mLで洗浄した。更に、ｔ-ブチルメチルエーテル 10 mLにて洗浄し、4-[2-(2-フルオロフェニル)-3H-イミダゾール-4-イル]フェニルスルファミドの灰色粉末70 mg (収率46％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.03-7.11 (2H, br), 7.13-7.22 (2H, m), 7.28-7.48 (3H, m), 7.65 (1H, s), 7.73-7.80 (2H, m), 8.02-8.13 (1H, m), 9.39-9.49 (1H, br), 12.21-12.29 (1H, br).
MS ; ESI m/z 333 [M+H]+, 331 [M-H]-. 116 mg (0.458 mmol) of 4- [2- (2-fluorophenyl) -3H-imidazol-4-yl] phenylamine prepared in (6-2) was suspended in 5 mL of methylene chloride, and triethylamine 0.19 was added under ice cooling. mL (1.4 mmol) and 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution 0.50 mL (0.50 mmol) were added, and the mixture was stirred for 50 minutes under ice cooling. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.19 g of a light brown powder.
0.19 g of the obtained light brown powder was suspended in 3 mL of methylene chloride, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution for neutralization, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 9: 1 → 1: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure, 5 mL of methylene chloride was added to the residue, the insoluble material was collected by filtration, and washed with 10 mL of methylene chloride. Further, it was washed with 10 mL of t-butyl methyl ether, and 70 mg (yield 46%) of 4- [2- (2-fluorophenyl) -3H-imidazol-4-yl] phenylsulfamide as a gray powder was obtained. Obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.03-7.11 (2H, br), 7.13-7.22 (2H, m), 7.28-7.48 (3H, m), 7.65 (1H, s), 7.73- 7.80 (2H, m), 8.02-8.13 (1H, m), 9.39-9.49 (1H, br), 12.21-12.29 (1H, br).
MS; ESI m / z 333 [M + H] + , 331 [MH] - .
実施例７: 
N-[4-｛5-(2-フルオロフェニル)オキサゾール-2-イル｝フェニル]スルファミド Example 7:
N- [4- {5- (2-Fluorophenyl) oxazol-2-yl} phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
(7-1) 5-(2-フルオロフェニル)オキサゾール (7-1) 5- (2-Fluorophenyl) oxazole
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　2-フルオロベンズアルデヒド 2.08 mL (19.9 mmol) をメタノール 50 mL に溶解し、1-イソシアノメタンスルホニル-4-メチルベンゼン4.28 g (21.9 mmol) および炭酸カリウム 3.58 g (25.9 mmol) を加え、室温にて2 時間撹拌した。反応液に水40 mL を加え、酢酸エチルにて2回抽出後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→9:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、5-(2-フルオロフェニル)オキサゾールの無色油状物0.67 g (収率21％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.11-7.39 (3H, m), 7.51 (1H, d, J=3.9 Hz), 7.77 (1H, dt, J=7.6 Hz, 1.7 Hz), 7.95 (1H, s). Dissolve 2.08 mL (19.9 mmol) of 2-fluorobenzaldehyde in 50 mL of methanol, add 4.28 g (21.9 mmol) of 1-isocyanomethanesulfonyl-4-methylbenzene and 3.58 g (25.9 mmol) of potassium carbonate at room temperature. Stir for 2 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 9: 1, V / V), and the solvent of the target fraction was distilled under reduced pressure. This gave 0.67 g (yield 21%) of a colorless oily product of 5- (2-fluorophenyl) oxazole.
1 H-NMR (CDCl3, 400 MHz) δ; 7.11-7.39 (3H, m), 7.51 (1H, d, J = 3.9 Hz), 7.77 (1H, dt, J = 7.6 Hz, 1.7 Hz), 7.95 ( 1H, s).
(7-2) 5-(2-フルオロフェニル)-2-(4-ニトロフェニル)オキサゾール (7-2) 5- (2-Fluorophenyl) -2- (4-nitrophenyl) oxazole
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　(7-1) で製造した5-(2-フルオロフェニル)オキサゾール286 mg (1.75 mmol) を1,4-ジオキサン10 mL に溶解し、1-ブロモ-4-ニトロベンゼン) 531 mg (2.63 mmol)、テトラキス（トリフェニルホスフィン）パラジウム 0.10 g (0.088 mmol) およびリチウムt-ブトキシド 0.21 g (2.6 mmol) を加え、120℃ にて200 分間撹拌後、テトラキス（トリフェニルホスフィン）パラジウム0.07 g (0.06 mmol) およびリチウムt-ブトキシド 0.20 g (2.5 mmol) を加え、120℃ にてさらに1 時間撹拌した。放冷後、反応液に飽和塩化アンモニウム水を加え、酢酸エチルにて2回抽出し、有機層を合せ、飽和食塩水にて洗浄した。乾燥 (Na2SO4) 後、減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→3:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、5-(2-フルオロフェニル)-2-(4-ニトロフェニル)オキサゾールの黄色粉末0.18 g (収率36％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.18-7.41 (2H, m), 7.50-7.58 (1H, m), 7.68 (1H, d, J=3.9 Hz), 7.89 (1H, dt, J=7.6, 1.3 Hz), 8.25-8.32 (2H, m), 8.33-8.38 (2H, m). 286 mg (1.75 mmol) of 5- (2-fluorophenyl) oxazole prepared in (7-1) was dissolved in 10 mL of 1,4-dioxane, 1-bromo-4-nitrobenzene) 531 mg (2.63 mmol), Add tetrakis (triphenylphosphine) palladium (0.10 g, 0.088 mmol) and lithium t-butoxide (0.21 g, 2.6 mmol), and stir at 120 ° C for 200 minutes, then tetrakis (triphenylphosphine) palladium (0.07 g, 0.06 mmol) and Lithium t-butoxide 0.20 g (2.5 mmol) was added, and the mixture was further stirred at 120 ° C. for 1 hour. After allowing to cool, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated brine. After drying (Na 2 SO 4 ), the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 3: 1, V / V), The solvent of the target fraction was distilled off under reduced pressure to obtain 0.18 g (yield 36%) of 5- (2-fluorophenyl) -2- (4-nitrophenyl) oxazole as a yellow powder.
1 H-NMR (CDCl3, 400 MHz) δ; 7.18-7.41 (2H, m), 7.50-7.58 (1H, m), 7.68 (1H, d, J = 3.9 Hz), 7.89 (1H, dt, J = 7.6, 1.3 Hz), 8.25-8.32 (2H, m), 8.33-8.38 (2H, m).
(7-3) 4-[5-(2-フルオロフェニル)オキサゾール-2-イル]フェニルアミン (7-3) 4- [5- (2-Fluorophenyl) oxazol-2-yl] phenylamine
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　(7-2) で製造した5-(2-フルオロフェニル)-2-(4-ニトロフェニル)オキサゾール 0.18 g (0.63 mmol) を エタノール 20 mL に懸濁し、塩化すず(II)二水和物 714 mg (3.17 mmol) を加え、40 分間加熱還流した。放冷後、反応液に飽和重曹水および酢酸エチルを加え、不溶物をろ別後、ろ液を分液し、有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、1:0→2:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-[5-(2-フルオロフェニル)オキサゾール-2-イル]フェニルアミンの淡褐色粉末117 mg (収率73％) を得た。 
1H-NMR (CDCl3, 400 MHz) δ; 3.88-4.05 (2H, br), 6.71-6.79 (2H, m), 7.11-7.34 (3H, m), 7.52 (1H, d, J=4.1 Hz), 7.84 (1H, ddd, J=7.6, 7.3, 1.3 Hz), 7.89-7.98 (2H, m). 0.18 g (0.63 mmol) of 5- (2-fluorophenyl) -2- (4-nitrophenyl) oxazole prepared in (7-2) was suspended in 20 mL of ethanol and tin (II) chloride dihydrate 714 mg (3.17 mmol) was added, and it heated and refluxed for 40 minutes. After allowing to cool, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, the insoluble material was filtered off, the filtrate was separated, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 2: 1, V / V), and then the solvent of the target fraction was distilled under reduced pressure. This gave 117 mg (yield 73%) of 4- [5- (2-fluorophenyl) oxazol-2-yl] phenylamine as a light brown powder.
1 H-NMR (CDCl3, 400 MHz) δ; 3.88-4.05 (2H, br), 6.71-6.79 (2H, m), 7.11-7.34 (3H, m), 7.52 (1H, d, J = 4.1 Hz) , 7.84 (1H, ddd, J = 7.6, 7.3, 1.3 Hz), 7.89-7.98 (2H, m).
(7-4) N-[4-｛5-(2-フルオロフェニル)オキサゾール-2-イル｝フェニル]スルファミド (7-4) N- [4- {5- (2-Fluorophenyl) oxazol-2-yl} phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　t-ブタノール 0.060 mL (0.64 mmol) を塩化メチレン 2 mL に溶解し、氷冷下、クロロスルホニルイソシアネート 0.048 mL (0.55 mmol) を加え、同温にて20 分間撹拌後、同温にて、(7-3) で製造した4-[5-(2-フルオロフェニル)オキサゾール-2-イル]フェニルアミン 117 mg (0.460 mmol) およびトリエチルアミン 0.19 mL (1.4 mmol) の塩化メチレン 5 mL の溶液を滴下し、室温にて1 時間撹拌した。反応液に飽和塩化アンモニウム水を加え、酢酸エチルにて抽出後、乾燥(Na2SO4) した。減圧下溶媒を留去し、黄色粉末0.21 gを得た。
　得られた黄色粉末0.21 gを塩化メチレン 3 mLに懸濁し、氷冷下トリフルオロ酢酸 3 mLを加え、室温にて40 分間撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出し、水および飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣に酢酸エチル-t-ブチルメチルエーテル (1:4) の混液 10 mLを加え、不溶物をろ取後、酢酸エチル-t-ブチルメチルエーテル (1:4) の混液 10 mLにて洗浄し、N-[4-｛5-(2-フルオロフェニル)オキサゾール-2-イル｝フェニル]スルファミドの黄色粉末110 mg (収率72％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.18-7.49 (7H, m), 7.52-7.68 (1H, m), 7.88-8.12 (3H, m), 9.90-10.08 (1H, br).
MS ; ESI m/z 334 [M+H]+, 356 [M+Na]+, 332 [M-H]-. Dissolve 0.060 mL (0.64 mmol) of t-butanol in 2 mL of methylene chloride, add 0.048 mL (0.55 mmol) of chlorosulfonyl isocyanate under ice-cooling, and stir at the same temperature for 20 minutes. -3) 4- [5- (2-fluorophenyl) oxazol-2-yl] phenylamine 117 mg (0.460 mmol) and triethylamine 0.19 mL (1.4 mmol) in 5 mL of methylene chloride was added dropwise, Stir at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.21 g of a yellow powder.
0.21 g of the obtained yellow powder was suspended in 3 mL of methylene chloride, 3 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and 10 mL of a mixed solution of ethyl acetate-t-butylmethyl ether (1: 4) was added to the resulting residue. The insoluble material was filtered off, and then ethyl acetate-t-butylmethyl ether (1 : 4) was washed with 10 mL of the mixture to obtain 110 mg (yield 72%) of yellow powder of N- [4- {5- (2-fluorophenyl) oxazol-2-yl} phenyl] sulfamide.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.18-7.49 (7H, m), 7.52-7.68 (1H, m), 7.88-8.12 (3H, m), 9.90-10.08 (1H, br).
MS; ESI m / z 334 [M + H] + , 356 [M + Na] + , 332 [MH] - .
実施例８: 
N-{4-[2-(2-フルオロフェニル)オキサゾール]-4-イルフェニル}スルファミド Example 8:
N- {4- [2- (2-Fluorophenyl) oxazol] -4-ylphenyl} sulfamide
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
(8-1) 2-(2-フルオロフェニル)-4-(4-ニトロフェニル)オキサゾール (8-1) 2- (2-Fluorophenyl) -4- (4-nitrophenyl) oxazole
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　2-ブロモ-1-(4-ニトロフェニル)エタノン 1.00 g (4.10 mmol) および2-フルオロベンズアミド 713 mg (5.12 mmol) を酢酸エチル 6 mLに懸濁し、トリフルオロメタンスルホン酸銀 1.32 g (5.12 mmol) を加え、60℃ にて 1 時間撹拌後、トリフルオロメタンスルホン酸銀 421 mg (1.64 mmol) を追加し、同温にてさらに 1.5 時間撹拌した。反応液に酢酸エチル 20 mL および 飽和食塩水 20 mL を加え、室温にて 10 分間撹拌後、不溶物をろ別し、ろ液を分液した。有機層を水、飽和重曹水、1.0 M 塩酸、水および飽和食塩水にて順次洗浄し、乾燥 (Na2SO4) 後、減圧下溶媒を留去した。得られた残渣に t-ブチルメチルエーテル 10 mL を加え、不溶物をろ取し、2-(2-フルオロフェニル)-4-(4-ニトロフェニル)オキサゾールの微黄色粉末458 mg (収率39％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.20-7.34 (2H, m), 7.45-7.56 (1H, m), 7.95-8.07 (2H, m), 8.10-8.20 (2H, m), 8.27-8.35 (2H, m). 2-Bromo-1- (4-nitrophenyl) ethanone 1.00 g (4.10 mmol) and 2-fluorobenzamide 713 mg (5.12 mmol) are suspended in 6 mL of ethyl acetate, and silver trifluoromethanesulfonate 1.32 g (5.12 mmol) After stirring at 60 ° C. for 1 hour, 421 mg (1.64 mmol) of silver trifluoromethanesulfonate was added, and the mixture was further stirred at the same temperature for 1.5 hours. Ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The insoluble material was filtered off, and the filtrate was separated. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate, 1.0 M hydrochloric acid, water and saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. To the resulting residue was added 10 mL of t-butyl methyl ether, and the insoluble material was collected by filtration to give 458 mg of 2- (2-fluorophenyl) -4- (4-nitrophenyl) oxazole as a slightly yellow powder (yield 39 %).
1 H-NMR (CDCl3, 400 MHz) δ; 7.20-7.34 (2H, m), 7.45-7.56 (1H, m), 7.95-8.07 (2H, m), 8.10-8.20 (2H, m), 8.27- 8.35 (2H, m).
(8-2) 4-[2-(2-フルオロフェニル)オキサゾール-4-イル]フェニルアミン (8-2) 4- [2- (2-Fluorophenyl) oxazol-4-yl] phenylamine
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　(8-1) で製造した2-(2-フルオロフェニル)-4-(4-ニトロフェニル)オキサゾール 458 mg (1.61 mmol) をエタノール 10 mLに懸濁し、塩化すず(II)二水和物 1.82 g (8.05 mmol) を加え、4 時間加熱還流した。放冷後、反応液に飽和重曹水50 mLおよび酢酸エチル 100 mLを加え、不溶物をセライトにてろ別し、ろ液を分液した。有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、4:1→2:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-[2-(2-フルオロフェニル)オキサゾール-4-イル]フェニルアミンの微黄色粉末277 mg (収率59％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.65-3.85 (2H, m), 6.71-6.79 (2H, m), 7.15-7.30 (2H, m), 7.38-7.50 (1H, m), 7.59-7.67 (2H, m), 7.89 (1H, s), 8.08-8.18 (1H, m). 458 mg (1.61 mmol) of 2- (2-fluorophenyl) -4- (4-nitrophenyl) oxazole prepared in (8-1) was suspended in 10 mL of ethanol, and tin (II) chloride dihydrate 1.82 g (8.05 mmol) was added, and it heated and refluxed for 4 hours. After allowing to cool, 50 mL of saturated aqueous sodium bicarbonate and 100 mL of ethyl acetate were added to the reaction solution, insoluble material was filtered off through Celite, and the filtrate was separated. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1 → 2: 1, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give 4- [2- This gave 277 mg (yield 59%) of (2-fluorophenyl) oxazol-4-yl] phenylamine as a slightly yellow powder.
1 H-NMR (CDCl3, 400 MHz) δ; 3.65-3.85 (2H, m), 6.71-6.79 (2H, m), 7.15-7.30 (2H, m), 7.38-7.50 (1H, m), 7.59- 7.67 (2H, m), 7.89 (1H, s), 8.08-8.18 (1H, m).
(8-3) N-{4-[2-(2-フルオロフェニル)オキサゾール-4-イル]フェニル}スルファミド (8-3) N- {4- [2- (2-Fluorophenyl) oxazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　t-ブタノール 0.14 mL (1.5 mmol) を塩化メチレン 5 mLに溶解し、氷冷下クロロスルホニルイソシアネート 0.11 mL (1.3 mmol) を加え、同温にて30 分間撹拌後、(8b) で製造した4-[2-(2-フルオロフェニル)オキサゾール-4-イル]フェニルアミン 277 mg (1.09 mmol) およびトリエチルアミン 0.45 mL (3.3 mmol) の塩化メチレン 10 mL溶液を加え、室温にて30 分間撹拌した。反応液に飽和塩化アンモニウム水10 mLを加え、酢酸エチルにて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、微黄色粉末510 mgを得た。
　得られた微黄色粉末510 mgを塩化メチレン 5 mLに懸濁し、氷冷下トリフルオロ酢酸 5 mLを加え、室温にて1 時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣にt-ブチルメチルエーテル 10 mLを加え、不溶物をろ取し、N-{4-[2-(2-フルオロフェニル)オキサゾール-4-イル]フェニル}スルファミドの微褐色粉末 124 mg (収率34％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.15-7.30 (4H, m), 7.35-7.50 (2H, m), 7.54-7.66 (1H, m), 7.72-7.80 (2H, m), 8.05-8.17 (1H, m), 8.67 (1H, s), 9.68 (1H, s).
MS ; ESI m/z 334 [M+H]+, 356 [M+Na]+, 332 [M-H]-. Dissolve 0.14 mL (1.5 mmol) of t-butanol in 5 mL of methylene chloride, add 0.11 mL (1.3 mmol) of chlorosulfonyl isocyanate under ice-cooling, and stir at the same temperature for 30 minutes. A solution of [2- (2-fluorophenyl) oxazol-4-yl] phenylamine (277 mg, 1.09 mmol) and triethylamine (0.45 mL, 3.3 mmol) in methylene chloride (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 510 mg of a slightly yellow powder.
510 mg of the obtained pale yellow powder was suspended in 5 mL of methylene chloride, 5 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, 10 mL of t-butyl methyl ether was added to the resulting residue, the insoluble material was collected by filtration, and N- {4- [2- (2-fluorophenyl) oxazol-4-yl] 124 mg (34% yield) of a fine brown powder of phenyl} sulfamide was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.15-7.30 (4H, m), 7.35-7.50 (2H, m), 7.54-7.66 (1H, m), 7.72-7.80 (2H, m), 8.05-8.17 (1H, m), 8.67 (1H, s), 9.68 (1H, s).
MS; ESI m / z 334 [M + H] + , 356 [M + Na] + , 332 [MH] - .
実施例９: 
N-[4-[3-(2-フルオロフェニル)[1,2,4]トリアゾール-1-イル]フェニル]スルファミド Example 9:
N- [4- [3- (2-Fluorophenyl) [1,2,4] triazol-1-yl] phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
(9-1) 3-(2-フルオロフェニル)-1-(4-ニトロフェニル)-1H-[1,2,4]トリアゾール (9-1) 3- (2-Fluorophenyl) -1- (4-nitrophenyl) -1H- [1,2,4] triazole
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　(4-ニトロフェニル)ヒドラジン 5.0 g (33 mmol) を2.0 M 硫酸 33 mLおよびエタノール 20 mL の混液に懸濁し、2-フルオロベンズアルデヒド 3.58 mL (34.3 mmol) およびエタノール 50 mLを加え、室温にて4.5 時間撹拌した。不溶物をろ取し、水、エタノールおよびt-ブチルメチルエーテルにて順次洗浄し、橙色粉末11.50 g を得た。
　N-ブロモスクシンイミド 1.2 g (6.8 mmol) を塩化メチレン 25 mLに溶解し、氷冷下ジメチルスルフィド 0.92 mL (12.4 mol) を加え、-20℃ にて、先に得られた橙色粉末 1.4 g (4.0 mmolとして計算) の塩化メチレン 25 mLの溶液を滴下し、室温にて3 時間撹拌した。反応液に塩化メチレン 200 mLを加え、水および飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、褐色粉末1.18 g を得た。
　得られた褐色粉末1.18 g をエタノール 35 mLに懸濁し、トリエチルアミン 0.33 mL (2.4 mmol) およびテトラゾール 0.17 g (2.4 mmol) を加え、4.25 時間加熱還流した。放冷後、反応液に水を加え、析出物をろ取した。得られた粉末をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、1:0→4:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、3-(2-フルオロフェニル)-1-(4-ニトロフェニル)-1H-[1,2,4] トリアゾールの淡褐色粉末325 mg (収率29％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.15-7.36 (2H, m), 7.42-7.52 (1H, m), 7.93-8.09 (2H, m), 8.11-8.19 (1H, m), 8.35-8.47 (2H, m), 8.76 (1H, s). (4-Nitrophenyl) hydrazine (5.0 g, 33 mmol) was suspended in a mixture of 2.0 M sulfuric acid (33 mL) and ethanol (20 mL), and 2-fluorobenzaldehyde (3.58 mL, 34.3 mmol) and ethanol (50 mL) were added. Stir for hours. The insoluble material was collected by filtration and washed successively with water, ethanol and t-butyl methyl ether to obtain 11.50 g of an orange powder.
Dissolve 1.2 g (6.8 mmol) of N-bromosuccinimide in 25 mL of methylene chloride, add 0.92 mL (12.4 mol) of dimethyl sulfide under ice cooling, and then add 1.4 g (4.0 A solution of 25 mL of methylene chloride (calculated as mmol) was added dropwise and stirred at room temperature for 3 hours. Methylene chloride (200 mL) was added to the reaction mixture, washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 1.18 g of a brown powder.
1.18 g of the obtained brown powder was suspended in 35 mL of ethanol, 0.33 mL (2.4 mmol) of triethylamine and 0.17 g (2.4 mmol) of tetrazole were added, and the mixture was heated to reflux for 4.25 hours. After allowing to cool, water was added to the reaction solution, and the precipitate was collected by filtration. The obtained powder was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 4: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to give 3- (2- 325 mg (29% yield) of a light brown powder of fluorophenyl) -1- (4-nitrophenyl) -1H- [1,2,4] triazole was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 7.15-7.36 (2H, m), 7.42-7.52 (1H, m), 7.93-8.09 (2H, m), 8.11-8.19 (1H, m), 8.35- 8.47 (2H, m), 8.76 (1H, s).
(9-2) 4-[3-(2-フルオロフェニル)[1,2,4]トリアゾール-1-イル]フェニルアミン (9-2) 4- [3- (2-Fluorophenyl) [1,2,4] triazol-1-yl] phenylamine
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　(9-1) で製造した3-(2-フルオロフェニル)-1-(4-ニトロフェニル)-1H-[1,2,4] トリアゾール 325 mg (1.14 mmol) を エタノール 35 mL に懸濁し、塩化すず(II)二水和物 1.29 g (5.72 mmol) を加え、35 分間加熱還流した。放冷後、反応液に飽和重層水および酢酸エチルを加え、不溶物をろ別後、ろ液を分液し、有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、1:0→3:2、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-[3-(2-フルオロフェニル)[1,2,4]トリアゾール-1-イル]フェニルアミンの褐色粉末200 mg (収率69％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.68-3.98 (2H, br), 6.72-6.83 (2H, m), 7.15-7.31 (2H, m), 7.35-7.45 (1H, m), 7.46-7.54 (2H, m), 8.12 (1H, td, J=7.6, 1.4 Hz), 8.46 (1H, s). 325 mg (1.14 mmol) of 3- (2-fluorophenyl) -1- (4-nitrophenyl) -1H- [1,2,4] triazole prepared in (9-1) was suspended in 35 mL of ethanol, Tin (II) chloride dihydrate 1.29 g (5.72 mmol) was added, and the mixture was heated to reflux for 35 minutes. After allowing to cool, saturated multistory water and ethyl acetate were added to the reaction solution, the insoluble material was filtered off, the filtrate was separated, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 3: 2, V / V), and the solvent of the target fraction was distilled under reduced pressure. This gave 200 mg (69% yield) of brown powder of 4- [3- (2-fluorophenyl) [1,2,4] triazol-1-yl] phenylamine.
1 H-NMR (CDCl3, 400 MHz) δ; 3.68-3.98 (2H, br), 6.72-6.83 (2H, m), 7.15-7.31 (2H, m), 7.35-7.45 (1H, m), 7.46- 7.54 (2H, m), 8.12 (1H, td, J = 7.6, 1.4 Hz), 8.46 (1H, s).
(9-3) N-[4-[3-(2-フルオロフェニル)[1,2,4]トリアゾール-1-イル]フェニル]スルファミド (9-3) N- [4- [3- (2-Fluorophenyl) [1,2,4] triazol-1-yl] phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　t-ブタノール 0.10 mL (1.1 mmol) を塩化メチレン 2 mL に溶解し、氷冷下クロロスルホニルイソシアネート 0.081 mL (0.94 mmol) を加え、同温にて20 分間撹拌した。同温にて、(9b) で製造した4-[3-(2-フルオロフェニル)[1,2,4] トリアゾール-1-イル]フェニルアミン 200 mg (0.787 mmol) およびトリエチルアミン 0.33 mL (2.4 mmol) の塩化メチレン 8 mL の溶液を滴下し、室温にて40 分間撹拌した。反応液に飽和塩化アンモニウム水を加え、酢酸エチルにて抽出後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡褐色粉末0.39 gを得た。
　得られた淡褐色粉末0.39 gを塩化メチレン 3 mLに懸濁し、氷冷下トリフルオロ酢酸 3 mLを加え、室温にて1 時間撹拌した。反応液に飽和重層水を加え、酢酸エチルにて抽出し、水および飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣に酢酸エチル-t-ブチルメチルエーテル (1:4) 10 mLを加え、不溶物をろ取後、酢酸エチル-t-ブチルメチルエーテル (1:4) 15 mLにて洗浄し、N-[4-[3-(2-フルオロフェニル)[1,2,4]トリアゾール-1-イル]フェニル]スルファミドの微褐色粉末197 mg (収率75％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.24 (2H, s), 7.29-7.40 (4H, m), 7.47-7.57 (1H, m), 7.75-7.86 (2H, m), 8.07 (1H, td, J=7.6, 1.5 Hz), 9.27 (1H, s), 9.79 (1H, s).
MS ; ESI m/z 334 [M+H]+, 356 [M+Na]+. 0.10 mL (1.1 mmol) of t-butanol was dissolved in 2 mL of methylene chloride, 0.081 mL (0.94 mmol) of chlorosulfonyl isocyanate was added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. At the same temperature, 4- [3- (2-fluorophenyl) [1,2,4] triazol-1-yl] phenylamine prepared in (9b) 200 mg (0.787 mmol) and triethylamine 0.33 mL (2.4 mmol) ) In 8 mL of methylene chloride was added dropwise and stirred at room temperature for 40 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.39 g of a light brown powder.
0.39 g of the obtained light brown powder was suspended in 3 mL of methylene chloride, 3 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated multistory water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and 10 mL of ethyl acetate-t-butylmethyl ether (1: 4) was added to the resulting residue. The insoluble material was filtered off, and then ethyl acetate-t-butylmethyl ether (1: 4) was collected. ) Washed with 15 mL, 197 mg of N- [4- [3- (2-fluorophenyl) [1,2,4] triazol-1-yl] phenyl] sulfamide as a slightly brown powder (yield 75%) Got.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.24 (2H, s), 7.29-7.40 (4H, m), 7.47-7.57 (1H, m), 7.75-7.86 (2H, m), 8.07 ( 1H, td, J = 7.6, 1.5 Hz), 9.27 (1H, s), 9.79 (1H, s).
MS; ESI m / z 334 [M + H] + , 356 [M + Na] + .
実施例１０: 
N-{4-[5-(2-フルオロフェニル)ピラジン-2-イル]フェニル}スルファミド Example 10:
N- {4- [5- (2-Fluorophenyl) pyrazin-2-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
(10-1) 2-ブロモ-5-(2-フルオロフェニル)ピラジン (10-1) 2-Bromo-5- (2-fluorophenyl) pyrazine
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　2,5-ジブロモピラジン1.70 g (7.15 mmol) を1,4-ジオキサン 20 mLに溶解し、2-フルオロフェニルボラン酸1.00 g (7.15 mmol)、テトラキス(トリフェニルホスフィン)パラジウム826 mg (0.715 mmol) および2.0 M炭酸カリウム水溶液7.2 mL (14 mmol) を加え、100℃ にて6 時間撹拌した。放冷後、反応液に水を加え、酢酸エチルにて2回抽出した。有機層を合わせ飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（n-ヘキサン：クロロホルム、1:1→0:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、2-ブロモ-5-(2-フルオロフェニル)ピラジンの白色粉末1.08 g (収率60％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.17-7.24 (1H, m), 7.28-7.33 (1H, m), 7.43-7.50 (1H, m), 7.97-8.03 (1H, m), 8.77 (1H, d, J=1.5 Hz), 8.85-8.88 (1H, m). Dissolve 1.70 g (7.15 mmol) of 2,5-dibromopyrazine in 20 mL of 1,4-dioxane, 1.00 g (7.15 mmol) of 2-fluorophenylboranoic acid, 826 mg (0.715 mmol) of tetrakis (triphenylphosphine) palladium Then, 7.2 mL (14 mmol) of 2.0 M potassium carbonate aqueous solution was added, and the mixture was stirred at 100 ° C. for 6 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. After the residue was purified by column chromatography (n-hexane: chloroform, 1: 1 → 0: 1, V / V), the solvent of the target fraction was distilled off under reduced pressure to give 2-bromo-5- (2- A white powder of fluorophenyl) pyrazine (1.08 g, yield 60%) was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 7.17-7.24 (1H, m), 7.28-7.33 (1H, m), 7.43-7.50 (1H, m), 7.97-8.03 (1H, m), 8.77 ( 1H, d, J = 1.5 Hz), 8.85-8.88 (1H, m).
(10-2) 4-[5-(2-フルオロフェニル)ピラジン-2-イル]フェニルアミン (10-2) 4- [5- (2-Fluorophenyl) pyrazin-2-yl] phenylamine
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　(10-1) で製造した2-ブロモ-5-(2-フルオロフェニル)ピラジン1.08 g (4.27 mmol) を1,4-ジオキサン 15 mLに溶解し、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン935 mg (4.27 mmol)、テトラキス(トリフェニルホスフィン)パラジウム493 mg (0.427 mmol) および2.0 M炭酸カリウム水溶液 4.3 mL (8.6 mmol) を加え、100℃ にて6 時間撹拌した。放冷後、反応液に水を加え、酢酸エチルにて2回抽出した。有機層を合わせ飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、2:1→1:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-[5-(2-フルオロフェニル)ピラジン-2-イル]フェニルアミンの橙色粉末 1.04 g (収率92％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.88-4.01 (2H, br), 6.77-6.82 (2H, m), 7.26-7.34 (2H, m), 7.38-7.45 (1H, m), 7.89-7.94 (2H, m), 8.00-8.06 (1H, m), 9.01-9.07 (2H, m). 1.08 g (4.27 mmol) of 2-bromo-5- (2-fluorophenyl) pyrazine prepared in (10-1) was dissolved in 15 mL of 1,4-dioxane, and 4- (4,4,5,5- Add 935 mg (4.27 mmol) of tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, 493 mg (0.427 mmol) of tetrakis (triphenylphosphine) palladium and 4.3 mL (8.6 mmol) of 2.0 M aqueous potassium carbonate solution. And stirred at 100 ° C. for 6 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 → 1: 1, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give 4- [5- (2- An orange powder of fluorophenyl) pyrazin-2-yl] phenylamine (1.04 g, yield 92%) was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 3.88-4.01 (2H, br), 6.77-6.82 (2H, m), 7.26-7.34 (2H, m), 7.38-7.45 (1H, m), 7.89- 7.94 (2H, m), 8.00-8.06 (1H, m), 9.01-9.07 (2H, m).
(10-3) N-{4-[5-(2-フルオロフェニル)ピラジン-2-イル]フェニル}スルファミド (10-3) N- {4- [5- (2-Fluorophenyl) pyrazin-2-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　t-ブタノール0.44 mL (2.2 mmol) を塩化メチレン 10 mLに溶解し、氷冷下クロロスルホニルイソシアネート0.40 mL (4.6 mmol) を加え、同温にて15 分間撹拌後、(10-2) で製造した4-[5-(2-フルオロフェニル)ピラジン-2-イル]フェニルアミン1.03 g (3.80 mmol) およびトリエチルアミン0.79 mL (5.7 mmol) を加え、室温にてさらに0.5 時間撹拌した。反応液に水100 mLを加え、酢酸エチル-テトラヒドロフラン (1:1) にて2回抽出後、有機層を合わせ飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、黄色粉末1.95 gを得た。
　得られた黄色粉末1.95 gを塩化メチレン 10 mLに懸濁し、トリフルオロ酢酸10 mLを加え、室温にて1 時間撹拌した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、20:1→10:1、V/V）にて精製した。目的分画の溶媒を減圧下留去し、N-{4-[5-(2-フルオロフェニル)ピラジン-2-イル]フェニル}スルファミドの微黄色粉末 368 mg (収率28％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.26-7.34 (4H, m), 7.38-7.45 (2H, m), 7.53-7.60 (1H, m), 7.98-8.04 (1H, m), 8.12-8.17 (2H, m), 9.03-9.06 (1H, m), 9.34 (1H, d, J=1.5 Hz), 9.84-9.96 (1H, br).
MS ; ESI m/z 345 [M+H]+. Dissolve 0.44 mL (2.2 mmol) of t-butanol in 10 mL of methylene chloride, add 0.40 mL (4.6 mmol) of chlorosulfonyl isocyanate under ice-cooling, stir at the same temperature for 15 minutes, and then prepare in (10-2) 4- [5- (2-Fluorophenyl) pyrazin-2-yl] phenylamine (1.03 g, 3.80 mmol) and triethylamine (0.79 mL, 5.7 mmol) were added, and the mixture was further stirred at room temperature for 0.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate-tetrahydrofuran (1: 1). The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 1.95 g of a yellow powder.
The obtained yellow powder (1.95 g) was suspended in methylene chloride (10 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 20: 1 → 10: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 368 mg (yield 28%) of a slightly yellow powder of N- {4- [5- (2-fluorophenyl) pyrazin-2-yl] phenyl} sulfamide. .
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.26-7.34 (4H, m), 7.38-7.45 (2H, m), 7.53-7.60 (1H, m), 7.98-8.04 (1H, m), 8.12-8.17 (2H, m), 9.03-9.06 (1H, m), 9.34 (1H, d, J = 1.5 Hz), 9.84-9.96 (1H, br).
MS; ESI m / z 345 [M + H] + .
実施例１１: 
N-{4-[2-(2-フルオロフェニル)オキサゾール-5-イル]フェニル}スルファミド Example 11
N- {4- [2- (2-Fluorophenyl) oxazol-5-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
(11-1) 2-アミノ-1-(4-ニトロフェニル)エタノン塩酸塩 (11-1) 2-amino-1- (4-nitrophenyl) ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　2-ブロモ-1-(4-ニトロフェニル)エタノン 5.00 g (20.5 mmol) を塩化メチレン 50 mLに溶解し、ヘキサメチレンテトラミン4.02 g (28.7 mmol) を加え、室温にて 14 時間撹拌した。不溶物をろ取し、得られた微黄色粉末をエタノール 35 mL に懸濁後、濃塩酸 10 mL を加え、室温にて 3 時間撹拌した。不溶物をろ取後、水 20 mL にて洗浄し、2-アミノ-1-(4-ニトロフェニル)エタノン塩酸塩の微褐色粉末 3.96 g (収率89％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 4.65-4.74 (2H, br), 8.23-8.29 (2H, m), 8.37-8.43 (2H, m), 8.44-8.57 (3H, br). 2-Bromo-1- (4-nitrophenyl) ethanone 5.00 g (20.5 mmol) was dissolved in 50 mL of methylene chloride, 4.02 g (28.7 mmol) of hexamethylenetetramine was added, and the mixture was stirred at room temperature for 14 hours. The insoluble material was collected by filtration, and the resulting pale yellow powder was suspended in 35 mL of ethanol, 10 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hr. The insoluble material was collected by filtration and washed with 20 mL of water to obtain 3.96 g (yield 89%) of 2-amino-1- (4-nitrophenyl) ethanone hydrochloride as a pale brown powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 4.65-4.74 (2H, br), 8.23-8.29 (2H, m), 8.37-8.43 (2H, m), 8.44-8.57 (3H, br).
(11-2) 2-(2-フルオロフェニル)-5-(4-ニトロフェニル)オキサゾール (11-2) 2- (2-Fluorophenyl) -5- (4-nitrophenyl) oxazole
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　(11-1) で製造した2-アミノ-1-(4-ニトロフェニル)エタノン塩酸塩3.96 g (18.3 mmol) および2-フルオロ安息香酸2.56 g (18.3 mmol) を塩化メチレン 50 mLに懸濁し、1-エチル-3-(3-ジメチルアミノプロピル) カルボジイミド塩酸塩 4.21 g (21.9 mmol)、1-ヒドロキシベンゾトリアゾール 2.96 g (21.9 mmol) およびトリエチルアミン 3.8 mL (27 mmol) を加え、室温にて13 時間撹拌した。反応液に水およびクロロホルムを加え、不溶物をろ別し、二層を分離した。有機層を 5％ クエン酸水、飽和重曹水および飽和食塩水にて順次洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣に酢酸エチルを加え、不溶物をろ取し、黄色粉末 1.31 gを得た。
　得られた黄色粉末 300 mg をオキシ塩化リン 13 mL に懸濁し、2 時間加熱還流した。放冷後、反応液に水を加え、酢酸エチルにて抽出後、有機層を水、飽和重曹水および飽和食塩水にて順次洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（ｎ-ヘキサン：酢酸エチル、1:0→4:1、V/V）にて精製し、2-(2-フルオロフェニル)-5-(4-ニトロフェニル)オキサゾールの黄色粉末 258 mg (収率8％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.26-7.34 (2H, m), 7.45-7.56 (1H, m), 7.70 (1H, s), 7.86-7.92 (2H, m), 8.10-8.17 (1H, m), 8.29-8.36 (2H, m). 2-amino-1- (4-nitrophenyl) ethanone hydrochloride prepared in (11-1) 3.96 g (18.3 mmol) and 2-fluorobenzoic acid 2.56 g (18.3 mmol) were suspended in 50 mL of methylene chloride, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 4.21 g (21.9 mmol), 1-hydroxybenzotriazole 2.96 g (21.9 mmol) and triethylamine 3.8 mL (27 mmol) were added. Stir. Water and chloroform were added to the reaction solution, the insoluble material was filtered off, and the two layers were separated. The organic layer was washed successively with 5% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting residue, and the insoluble material was collected by filtration to obtain 1.31 g of a yellow powder.
300 mg of the obtained yellow powder was suspended in 13 mL of phosphorus oxychloride and heated to reflux for 2 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 4: 1, V / V) to give 2- (2-fluorophenyl)- A yellow powder of 258 mg of 5- (4-nitrophenyl) oxazole was obtained (yield 8%).
1 H-NMR (CDCl3, 400 MHz) δ; 7.26-7.34 (2H, m), 7.45-7.56 (1H, m), 7.70 (1H, s), 7.86-7.92 (2H, m), 8.10-8.17 ( 1H, m), 8.29-8.36 (2H, m).
 (11-3) 4-[2-(2-フルオロフェニル)オキサゾール-5-イル]フェニルアミン (11-3) 4- [2- (2-Fluorophenyl) oxazol-5-yl] phenylamine
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　(11-2) で製造した2-(2-フルオロフェニル)-5-(4-ニトロフェニル)オキサゾール 197 mg (0.693mmol) をエタノール 20 mL に懸濁し、塩化すず(II)二水和物 0.78 g (3.5 mmol) を加え、45分間加熱還流した。反応液に飽和重層水および酢酸エチルを加え、不溶物をろ別後、二層を分離し、有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、4-[2-(2-フルオロフェニル)オキサゾール-5-イル] フェニルアミンの淡褐色粉末 0.17 g (収率96％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 5.53 (2H, s), 6.59-6.72 (2H, m), 7.31-7.62 (6H, m), 8.02-8.13 (1H, m). 197 mg (0.693 mmol) of 2- (2-fluorophenyl) -5- (4-nitrophenyl) oxazole prepared in (11-2) was suspended in 20 mL of ethanol, and tin (II) chloride dihydrate 0.78 g (3.5 mmol) was added and heated to reflux for 45 minutes. Saturated multistory water and ethyl acetate were added to the reaction solution, the insoluble material was filtered off, the two layers were separated, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.17 g (yield 96%) of 4- [2- (2-fluorophenyl) oxazol-5-yl] phenylamine as a light brown powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 5.53 (2H, s), 6.59-6.72 (2H, m), 7.31-7.62 (6H, m), 8.02-8.13 (1H, m).
(11-4)N-{4-[2-(2-フルオロフェニル)オキサゾール-5-イル]フェニル}スルファミド (11-4) N- {4- [2- (2-Fluorophenyl) oxazol-5-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　(11-3) で製造した4-[2-(2-フルオロフェニル)オキサゾール-5-イル] フェニルアミン 0.12 g (0.47 mmol) を塩化メチレン 3 mLに懸濁し、氷冷下トリエチルアミン 0.20 mL (1.4 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液0.71 mL (0.71 mmol) を加え、室温にて45 分間撹拌した。反応液に飽和塩化アンモニウム水を加え、酢酸エチル 30 mLにて抽出後、有機層を乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡褐色粉末 0.20 gを得た。
　得られた淡褐色粉末 0.20 gを塩化メチレン 5 mLに懸濁し、トリフルオロ酢酸 1 mLを加え、同温にて10 分間撹拌後、室温にて 2 時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出後、有機層を水および飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→95:5、V/V）にて精製した。目的分画の溶媒を減圧下留去し、得られた残渣にｔ-ブチルメチルエーテル 3 mLを加え、不溶物をろ取し、ｔ-ブチルメチルエーテル 3 mLにて洗浄し、N-{4-[2-(2-フルオロフェニル)オキサゾール-5-イル]フェニル}スルファミドの淡褐色粉末60 mg (収率38％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.19-7.32 (4H, m), 7.35-7.48 (2H, m), 7.55-7.65 (1H, m), 7.67-7.82 (3H, m), 8.05-8.18 (1H, m), 9.81 (1H, s).
MS ; ESI m/z 334 [M+H]+, 332 [M+H]-, 356 [M+Na]+. 4- [2- (2-fluorophenyl) oxazol-5-yl] phenylamine prepared in (11-3) 0.12 g (0.47 mmol) was suspended in 3 mL of methylene chloride, and 0.20 mL (1.4 mmol) and a 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution 0.71 mL (0.71 mmol) were added, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with 30 mL of ethyl acetate, and the organic layer was dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.20 g of a light brown powder.
0.20 g of the obtained light brown powder was suspended in 5 mL of methylene chloride, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 1: 0 → 95: 5, V / V). The solvent of the target fraction was distilled off under reduced pressure, 3 mL of t-butyl methyl ether was added to the resulting residue, the insoluble material was collected by filtration, washed with 3 mL of t-butyl methyl ether, and N- {4 A pale brown powder 60 mg (yield 38%) of-[2- (2-fluorophenyl) oxazol-5-yl] phenyl} sulfamide was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.19-7.32 (4H, m), 7.35-7.48 (2H, m), 7.55-7.65 (1H, m), 7.67-7.82 (3H, m), 8.05-8.18 (1H, m), 9.81 (1H, s).
MS; ESI m / z 334 [M + H] + , 332 [M + H] - , 356 [M + Na] + .
実施例１２: 
N-(4-キノリン-2-イルフェニル)スルファミド Example 12:
N- (4-Quinolin-2-ylphenyl) sulfamide
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
(12-1) 4-キノリン-2-イルフェニルアミン (12-1) 4-Quinolin-2-ylphenylamine
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　2-ブロモキノリン 285 mg (1.37 mmol) を1,4-ジオキサン 5 mLに溶解し、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン 300 mg (1.37 mmol)、テトラキス（トリフェニルホスフィン）パラジウム158 mg (0.137 mmol) および2.0 M 炭酸カリウム水 1.4 mL (2.8 mmol) を加え、100℃ にて4 時間撹拌した。放冷後、反応液に酢酸エチルを加え、水および飽和食塩水にて洗浄後、乾燥(Na2SO4) し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、2:1→1:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、4-キノリン-2-イルフェニルアミンの淡黄色粉末 177 mg (収率59％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.78-3.96 (2H, br), 6.78-6.83 (2H, m), 7.43-7.49 (1H, m,), 7.65-7.71 (1H, m), 7.75-7.82 (2H, m), 8.00-8.05 (2H, m), 8.08-8.15 (2H, m). 2- (bromoquinoline) 285 mg (1.37 mmol) was dissolved in 1,4-dioxane (5 mL) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline 300 mg (1.37 mmol), tetrakis (triphenylphosphine) palladium 158 mg (0.137 mmol) and 2.0 M potassium carbonate water 1.4 mL (2.8 mmol) were added, and the mixture was stirred at 100 ° C. for 4 hours. After allowing to cool, ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 → 1: 1, V / V), and then the solvent of the target fraction was distilled off under reduced pressure to give 4-quinolin-2-ylphenyl. A light yellow powder 177 mg (59% yield) of amine was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 3.78-3.96 (2H, br), 6.78-6.83 (2H, m), 7.43-7.49 (1H, m,), 7.65-7.71 (1H, m), 7.75 -7.82 (2H, m), 8.00-8.05 (2H, m), 8.08-8.15 (2H, m).
(12-2) N-(4-キノリン-2-イルフェニル)スルファミド (12-2) N- (4-Quinolin-2-ylphenyl) sulfamide
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　(12-1) で製造した4-キノリン-2-イルフェニルアミン 172 mg (0.781 mmol) を塩化メチレン 3 mLに溶解し、氷冷下トリエチルアミン 0.16 mL (1.2 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 0.94 mL (0.94 mmol) を加え、同温にて0.5 時間撹拌した。反応液に酢酸エチル 30 mLおよびテトラヒドロフラン 30 mLを加え、0.5 M塩酸および飽和食塩水にて順次洗浄後、有機層にメタノールを加え、不溶物を溶解させた後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、黄色粉末332 mgを得た。
　得られた黄色粉末332 mgを塩化メチレン 3 mLに懸濁し、トリフルオロ酢酸 3 mLを加え、室温にて0.5 時間撹拌した。減圧下溶媒を留去し、残渣に水を加え、クロロホルム-テトラヒドロフラン-エタノール(10:5:1) にて5回抽出した。有機層を合わせ、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、19:1→9:1、V/V）にて精製後、目的分画の溶媒を減圧下留去した。得られた粉末にエタノール 2 mLを加え、不溶物をろ取し、N-(4-キノリン-2-イルフェニル)スルファミドの黄色粉末 198 mg (収率85％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.33-7.43 (4H, m), 7.65-7.73 (1H, m), 7.86-7.93 (1H, m), 8.07-8.14 (1H, m), 8.22-8.52 (4H, m), 8.63-8.77 (1H, br), 10.02-10.17 (1H, br).
MS ; ESI m/z 300 [M+H]+, 298 [M-H]-. 172 mg (0.781 mmol) of 4-quinolin-2-ylphenylamine prepared in (12-1) was dissolved in 3 mL of methylene chloride, and 0.16 mL (1.2 mmol) of triethylamine and 1.0 M t-butyl N- 0.94 mL (0.94 mmol) of a chlorosulfonylcarbamate-methylene chloride solution was added, and the mixture was stirred at the same temperature for 0.5 hour. 30 mL of ethyl acetate and 30 mL of tetrahydrofuran were added to the reaction solution, washed sequentially with 0.5 M hydrochloric acid and saturated brine, methanol was added to the organic layer to dissolve insoluble matters, and then dried (Na 2 SO 4 ). . The solvent was distilled off under reduced pressure to obtain 332 mg of a yellow powder.
The obtained yellow powder (332 mg) was suspended in methylene chloride (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 0.5 hr. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted 5 times with chloroform-tetrahydrofuran-ethanol (10: 5: 1). Combine the organic layers, evaporate the solvent under reduced pressure, purify the residue by column chromatography (chloroform: methanol, 19: 1 → 9: 1, V / V), and evaporate the solvent of the target fraction under reduced pressure. did. 2 mL of ethanol was added to the obtained powder, and insoluble matters were collected by filtration to obtain 198 mg (yield 85%) of N- (4-quinolin-2-ylphenyl) sulfamide as a yellow powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.33-7.43 (4H, m), 7.65-7.73 (1H, m), 7.86-7.93 (1H, m), 8.07-8.14 (1H, m), 8.22-8.52 (4H, m), 8.63-8.77 (1H, br), 10.02-10.17 (1H, br).
MS; ESI m / z 300 [M + H] + , 298 [MH] - .
実施例１３: 
4-イミダゾ[1,2-a]ピリジン-2-イルフェニルスルファミド Example 13:
4-Imidazo [1,2-a] pyridin-2-ylphenylsulfamide
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
(13-1） 2-(4-ニトロフェニル)イミダゾ[1,2-a]ピリジン (13-1) 2- (4-Nitrophenyl) imidazo [1,2-a] pyridine
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　2-ブロモ-1-(4-ニトロフェニル)エタノン 2.44 g (10.0 mmol) をアセトン 60 mL に溶解し、2-アミノピリジン 942 mg (10.0 mmol) を加え、2 時間加熱還流した。放冷後、不溶物をろ取し、ジイソプロピルエーテルにて3回、エタノールにて1回洗浄した。得られた粉末をクロロホルムに溶解し、2.0 M 炭酸ナトリウム水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、2-(4-ニトロフェニル)イミダゾ[1,2-a]ピリジンの淡褐色粉末2.03 g (収率85％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.94 (1H, dd, J=6.8, 6.6 Hz), 7.30 (1H, dd, J=9.0, 6.8 Hz), 7.61 (1H, d, J=9.0 Hz), 8.17-8.26 (2H, m), 8.16-8.33 (2H, m), 8.55 (1H, d, J=6.6 Hz), 8.63 (1H, s). 2-Bromo-1- (4-nitrophenyl) ethanone 2.44 g (10.0 mmol) was dissolved in acetone 60 mL, 2-aminopyridine 942 mg (10.0 mmol) was added, and the mixture was heated to reflux for 2 hours. After standing to cool, the insoluble material was collected by filtration and washed 3 times with diisopropyl ether and once with ethanol. The obtained powder was dissolved in chloroform, washed with 2.0 M aqueous sodium carbonate solution, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 2.03 g (yield 85%) of 2- (4-nitrophenyl) imidazo [1,2-a] pyridine as a light brown powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.94 (1H, dd, J = 6.8, 6.6 Hz), 7.30 (1H, dd, J = 9.0, 6.8 Hz), 7.61 (1H, d, J = 9.0 Hz), 8.17-8.26 (2H, m), 8.16-8.33 (2H, m), 8.55 (1H, d, J = 6.6 Hz), 8.63 (1H, s).
(13-2) 4-イミダゾ[1,2-a]ピリジン-2-イルフェニルアミン (13-2) 4-Imidazo [1,2-a] pyridin-2-ylphenylamine
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　(13-1) で製造した2-(4-ニトロフェニル)イミダゾ[1,2-a]ピリジン 957 mg (4.00 mmol) を 水 15 mL および濃塩酸 7 mLに懸濁し、塩化すず(II)二水和物 3.25 g (14.4 mmol) を加え、60℃ にて7 時間撹拌した。放冷後、反応液を水に加え、2.0 M 炭酸ナトリウム水にてpH 9～10とした。不溶物をろ取し、得られた粉末を酢酸エチルに溶解後、水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、4-イミダゾ[1,2-a]ピリジン-2-イルフェニルアミンの淡褐色粉末 439 mg (収率52％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.63-3.88 (2H, br), 6.66-6.84 (3H, m), 7.06-7.19 (1H, m), 7.59 (1H, d, J=9.0 Hz), 7.54-7.86 (3H, m), 8.08 (1H, d, J=6.6 Hz). Suspend 957 mg (4.00 mmol) of 2- (4-nitrophenyl) imidazo [1,2-a] pyridine prepared in (13-1) in 15 mL of water and 7 mL of concentrated hydrochloric acid. The hydrate 3.25 g (14.4 mmol) was added, and it stirred at 60 degreeC for 7 hours. After allowing to cool, the reaction mixture was added to water and adjusted to pH 9-10 with 2.0 M aqueous sodium carbonate. Insoluble matter was collected by filtration, and the resulting powder was dissolved in ethyl acetate, washed with water, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 439 mg (yield 52%) of 4-imidazo [1,2-a] pyridin-2-ylphenylamine as a light brown powder.
1 H-NMR (CDCl3, 400 MHz) δ; 3.63-3.88 (2H, br), 6.66-6.84 (3H, m), 7.06-7.19 (1H, m), 7.59 (1H, d, J = 9.0 Hz) , 7.54-7.86 (3H, m), 8.08 (1H, d, J = 6.6 Hz).
(13-3) 4-イミダゾ[1,2-a]ピリジン-2-イルフェニルスルファミド (13-3) 4-Imidazo [1,2-a] pyridin-2-ylphenylsulfamide
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　(13-2) で製造した4-イミダゾ[1,2-a]ピリジン-2-イルフェニルアミン　287 mg (1.37 mmol) を塩化メチレン 8 mLに溶解し、氷冷下トリエチルアミン 0.57 mL (4.1 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 2.06 mL (2.1 mmol) を加え、室温にて25 分間撹拌した。反応液に飽和塩化アンモニウム水を加え、酢酸エチルにて抽出後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、微褐色粉末0.70 gを得た。
　得られた微褐色粉末0.70 gを塩化メチレン 5 mLに懸濁し、氷冷下トリフルオロ酢酸 1 mLを加え、同温にて10 分間撹拌後、室温にて5.5 時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出後、水および飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた残渣をカラムクロマトグラフィー（クロロホルム：メタノール、10:0→9:1、V/V）にて精製後、目的分画の溶媒を減圧下留去した。得られた粉末にt-ブチルメチルエーテルを加え、不溶物をろ取後、t-ブチルメチルエーテルにて洗浄し、4-イミダゾ[1,2-a]ピリジン-2-イルフェニルスルファミドの微黄色粉末 97 mg (収率25％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.88 (1H, dd, J=6.8, 6.4 Hz), 7.15 (2H, s), 7.18-7.28 (3H, m), 7.55 (1H, d, J=9.0 Hz), 7.80-7.92 (2H, m), 8.30 (1H, s), 8.50 (1H, d, J=6.8 Hz), 9.61 (1H, s).
MS ; ESI m/z 289 [M+H]+, 287 [M+H]-. (13-2) 4-Imidazo [1,2-a] pyridin-2-ylphenylamine 287 mg (1.37 mmol) was dissolved in 8 mL of methylene chloride, and triethylamine 0.57 mL (4.1 mmol) was cooled with ice. Then, 2.06 mL (2.1 mmol) of 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution was added, and the mixture was stirred at room temperature for 25 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 0.70 g of a fine brown powder.
0.70 g of the obtained fine brown powder was suspended in 5 mL of methylene chloride, 1 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol, 10: 0 → 9: 1, V / V), and then the solvent of the target fraction was distilled off under reduced pressure. T-Butyl methyl ether was added to the obtained powder, and the insoluble matter was collected by filtration and washed with t-butyl methyl ether to obtain 4-imidazo [1,2-a] pyridin-2-ylphenylsulfamide. A pale yellow powder 97 mg (yield 25%) was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.88 (1H, dd, J = 6.8, 6.4 Hz), 7.15 (2H, s), 7.18-7.28 (3H, m), 7.55 (1H, d, J = 9.0 Hz), 7.80-7.92 (2H, m), 8.30 (1H, s), 8.50 (1H, d, J = 6.8 Hz), 9.61 (1H, s).
MS; ESI m / z 289 [M + H] + , 287 [M + H] - .
実施例１４: 
N-(4-キナゾリン-2-イルフェニル)スルファミド Example 14
N- (4-Quinazolin-2-ylphenyl) sulfamide
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
(14-1) 2-(4-ニトロフェニル)キナゾリン (14-1) 2- (4-Nitrophenyl) quinazoline
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　4-ニトロベンズアルデヒド 1.00 g (6.62 mmol) をメタノール 20 mLに溶解し、2-アミノベンジルアミン 808 mg (6.61 mmol) を加え、室温にて5 時間撹拌後、アンチホルミン（NaOCl : 8.5-13.5％） 1.3 mLを加え、同温にてさらに15 時間撹拌した。反応液にアンチホルミン（NaOCl : 8.5-13.5％） 2.6 mLを追加し、室温にて1.5 時間撹拌後、さらにアンチホルミン（NaOCl : 8.5-13.5％） 2.6 mLを追加し、室温にて3.5 時間撹拌した。反応液に水40 mLを加え、析出物をろ取後、得られた橙色粉末をカラムクロマトグラフィー（クロロホルム：酢酸エチル、1:0→3:2、V/V）にて精製した。目的分画の溶媒を減圧下留去し、2-(4-ニトロフェニル)キナゾリンの淡褐色粉末 287 mg (収率17％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.68-7.73 (1H, m), 7.95-8.02 (2H, m), 8.11-8.16 (1H, m), 8.35-8.40 (2H, m), 8.80-8.85 (2H, m), 9.51 (1H, s) Dissolve 1.00 g (6.62 mmol) of 4-nitrobenzaldehyde in 20 mL of methanol, add 808 mg (6.61 mmol) of 2-aminobenzylamine, stir at room temperature for 5 hours, and then antiformin (NaOCl: 8.5-13.5%) 1.3 mL was added, and the mixture was further stirred at the same temperature for 15 hours. Add 2.6 mL of antiformin (NaOCl: 8.5-13.5%) to the reaction mixture and stir at room temperature for 1.5 hours, then add 2.6 mL of antiformin (NaOCl: 8.5-13.5%) and stir at room temperature for 3.5 hours. did. 40 mL of water was added to the reaction solution, and the precipitate was collected by filtration, and the resulting orange powder was purified by column chromatography (chloroform: ethyl acetate, 1: 0 → 3: 2, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 287 mg (17% yield) of 2- (4-nitrophenyl) quinazoline as a light brown powder.
1 H-NMR (CDCl3, 400 MHz) δ; 7.68-7.73 (1H, m), 7.95-8.02 (2H, m), 8.11-8.16 (1H, m), 8.35-8.40 (2H, m), 8.80- 8.85 (2H, m), 9.51 (1H, s)
(14-2) 4-キナゾリン-2-イルフェニルアミン (14-2) 4-Quinazolin-2-ylphenylamine
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　(14-1) で製造した2-(4-ニトロフェニル)キナゾリン 287 mg (1.14 mmol) をエタノール 10 mLに懸濁し、塩化すず(II)二水和物 1.29 g (5.72 mmol) を加え、1 時間加熱還流した。放冷後、反応液に28％ アンモニア水15 mLおよび酢酸エチル 30 mLを加え、不溶物をろ別後、ろ液を分液し、有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた黄色粉末にt-ブチルメチルエーテル 5 mLを加え、不溶物をろ取し、4-キナゾリン-2-イルフェニルアミンの黄色粉末 160 mg (収率64％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.90-4.00 (2H, br), 6.78-6.83 (2H, m), 7.51-7.56 (1H, m), 7.82-7.89 (2H, m), 7.88-8.03 (1H, m), 8.42-8.47 (2H, m), 9.38 (1H, s) 287 mg (1.14 mmol) of 2- (4-nitrophenyl) quinazoline prepared in (14-1) was suspended in 10 mL of ethanol, and 1.29 g (5.72 mmol) of tin (II) chloride dihydrate was added. Heated to reflux for hours. After allowing to cool, 15 mL of 28% aqueous ammonia and 30 mL of ethyl acetate were added to the reaction mixture, the insoluble material was filtered off, the filtrate was separated, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, 5 mL of t-butyl methyl ether was added to the resulting yellow powder, and the insoluble material was collected by filtration to give 160 mg of 4-quinazolin-2-ylphenylamine yellow powder (yield: 64% )
1 H-NMR (CDCl3, 400 MHz) δ; 3.90-4.00 (2H, br), 6.78-6.83 (2H, m), 7.51-7.56 (1H, m), 7.82-7.89 (2H, m), 7.88- 8.03 (1H, m), 8.42-8.47 (2H, m), 9.38 (1H, s)
(14-3) N-(4-キナゾリン-2-イルフェニル)スルファミド (14-3) N- (4-Quinazolin-2-ylphenyl) sulfamide
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　(14-2) で製造した4-キナゾリン-2-イルフェニルアミン 155 mg (0.707 mmol) を塩化メチレン 3 mLに懸濁し、氷冷下トリエチルアミン 0.15 mL (1.1 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 0.85 mL (0.85 mmol) を加え、同温にて0.5 時間撹拌した。反応液に水20 mLおよび飽和塩化アンモニウム水20 mLを加え、酢酸エチルにて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、黄色粉末310 mgを得た。
　得られた黄色粉末310 mgを塩化メチレン 2 mLに懸濁し、トリフルオロ酢酸 2 mLを加え、室温にて0.5 時間撹拌した。減圧下溶媒を留去し、残渣に水を加え、酢酸エチルにて2回抽出した。有機層を合わせ飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、3:2→1:4、V/V）にて精製後、目的分画の溶媒を減圧下留去した。得られた粉末160 mgに酢酸エチル 3 mLを加え、不溶物をろ取し、N-(4-キナゾリン-2-イルフェニル)スルファミドの淡黄色粉末129 mg (収率61％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.28-7.35 (4H, m), 7.66-7.74 (1H, m), 7.98-7.84 (2H, m), 8.12-8.17 (1H, m), 8.45-8.50 (2H, m), 9.65 (1H, m), 9.95 (1H, s)
MS ; ESI m/z 301 [M+H]+, 299 [M-H]-. 155 mg (0.707 mmol) of 4-quinazolin-2-ylphenylamine prepared in (14-2) was suspended in 3 mL of methylene chloride and triethylamine 0.15 mL (1.1 mmol) and 1.0 M t-butyl N- Chlorosulfonylcarbamate-methylene chloride solution 0.85 mL (0.85 mmol) was added, and the mixture was stirred at the same temperature for 0.5 hour. Water (20 mL) and saturated aqueous ammonium chloride (20 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 310 mg of a yellow powder.
310 mg of the obtained yellow powder was suspended in 2 mL of methylene chloride, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 0.5 hour. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 2 → 1: 4, V / V), and the solvent of the target fraction was evaporated under reduced pressure. To 160 mg of the obtained powder, 3 mL of ethyl acetate was added, and insoluble matter was collected by filtration to obtain 129 mg (yield 61%) of a pale yellow powder of N- (4-quinazolin-2-ylphenyl) sulfamide.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.28-7.35 (4H, m), 7.66-7.74 (1H, m), 7.98-7.84 (2H, m), 8.12-8.17 (1H, m), 8.45-8.50 (2H, m), 9.65 (1H, m), 9.95 (1H, s)
MS; ESI m / z 301 [M + H] + , 299 [MH] - .
実施例１５: 
N-[4-(4-オキソ-4H-クロメン-2-イル)フェニル]スルファミド Example 15:
N- [4- (4-Oxo-4H-chromen-2-yl) phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
(15-1) 2-(4-ニトロフェニル)クロメン-4-オン (15-1) 2- (4-Nitrophenyl) chromen-4-one
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
 塩化4-ニトロベンゾイル1.50 g (8.00 mmol) をアセトン 20 mLに溶解し、2’-ヒドロキシアセトフェノン 1.00 g (7.34 mmol) および炭酸カリウム 5.07 g (36.6 mmol) を加え、室温にて15分間撹拌後、7 時間加熱還流した。放冷後、反応液に水50 mLを加え、不溶物をろ取した。得られた粉末を水、エタノールおよびt-ブチルメチルエーテルにて順次洗浄し、2-(4-ニトロフェニル)クロメン-4-オンの橙色粉末 1.77 g を定量的に得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.20-6.33 (1H, m), 6.63-6.70 (2H, m), 7.14-7.21 (1H, m), 7.73-7.79 (1H, m), 7.94-8.00 (2H, m), 8.16-8.21 (2H, m). 4-Nitrobenzoyl chloride 1.50 g (8.00 mmol) was dissolved in acetone 20 mL, 2'-hydroxyacetophenone 1.00 g (7.34 mmol) and potassium carbonate 5.07 g (36.6 mmol) were added, and after stirring at room temperature for 15 minutes, Heated to reflux for 7 hours. After allowing to cool, 50 mL of water was added to the reaction solution, and insoluble material was collected by filtration. The obtained powder was washed successively with water, ethanol and t-butyl methyl ether to quantitatively obtain 1.77 g of 2- (4-nitrophenyl) chromen-4-one orange powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.20-6.33 (1H, m), 6.63-6.70 (2H, m), 7.14-7.21 (1H, m), 7.73-7.79 (1H, m), 7.94-8.00 (2H, m), 8.16-8.21 (2H, m).
(15-2) 4-(4-オキソ-4H-クロメン-2-イル)フェニルアミン (15-2) 4- (4-Oxo-4H-chromen-2-yl) phenylamine
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　(15-1) で製造した2-(4-ニトロフェニル)クロメン-4-オン 1.77 g (7.34 mmolとして計算) をエタノール 20 mLに懸濁し、塩化すず(II)二水和物 8.28 g (36.7 mmol) を加え、2.5 時間加熱還流した。放冷後、反応液に28％ アンモニア水30 mLおよびクロロホルム 30 mLを加え、不溶物をろ別後、ろ液を分液し、有機層を乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた橙色粉末にt-ブチルメチルエーテル 10 mLを加え、不溶物をろ取し、4-(4-オキソ-4H-クロメン-2-イル)フェニルアミンの橙色粉末1.03 g (収率59％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 4.04-4.17 (2H, br), 6.69 (1H, s), 6.73-6.78 (2H, m), 7.36-7.42 (1H, m), 7.50-7.55 (1H, m), 7.63-7.69 (1H, m), 7.73-7.78 (2H, m), 8.19-8.24 (1H, m). 2- (4-Nitrophenyl) chromen-4-one 1.77 g (calculated as 7.34 mmol) prepared in (15-1) was suspended in 20 mL of ethanol and tin (II) chloride dihydrate 8.28 g (36.7 mmol) was added and heated to reflux for 2.5 hours. After allowing to cool, 28% aqueous ammonia (30 mL) and chloroform (30 mL) were added to the reaction solution, the insoluble material was filtered off, the filtrate was separated, and the organic layer was dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and 10 mL of t-butyl methyl ether was added to the resulting orange powder, and the insoluble material was collected by filtration to give 4- (4-oxo-4H-chromen-2-yl) phenylamine orange. 1.03 g (59% yield) of powder was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 4.04-4.17 (2H, br), 6.69 (1H, s), 6.73-6.78 (2H, m), 7.36-7.42 (1H, m), 7.50-7.55 ( 1H, m), 7.63-7.69 (1H, m), 7.73-7.78 (2H, m), 8.19-8.24 (1H, m).
(15-3) N-[4-(4-オキソ-4H-クロメン-2-イル)フェニル]スルファミド (15-3) N- [4- (4-Oxo-4H-chromen-2-yl) phenyl] sulfamide
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　(15-2) で製造した4-(4-オキソ-4H-クロメン-2-イル)フェニルアミン 300 mg (1.26 mmol) を塩化メチレン5 mLに懸濁し、氷冷下トリエチルアミン 0.26 mL (1.9 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 1.5 mL (1.5 mmol) を加え、室温にて1 時間撹拌した。反応液に水20 mLおよび飽和塩化アンモニウム水20 mLを加え、酢酸エチル-テトラヒドロフラン (1:1) にて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、橙色粉末547 mgを得た。
　得られた橙色粉末547 mgを塩化メチレン 4 mLに懸濁し、トリフルオロ酢酸 4 mLを加え、室温にて0.5 時間撹拌した。減圧下溶媒を留去し、残渣にクロロホルム 10 mLを加え、不溶物をろ取した。得られた黄色粉末に酢酸エチル 5 mLを加え、不溶物をろ取し、N-[4-(4-オキソ-4H-クロメン-2-イル)フェニル]スルファミドの黄色粉末 336 mg (収率85％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.97 (1H, s), 7.28-7.34 (2H, m), 7.38 (2H, s), 7.47-7.53 (1H, m), 7.75-7.86 (2H, m), 8.02-8.08 (3H, m), 10.11 (1H, s).
MS ; ESI m/z 317 [M+H]+, 339 [M+Na]+, 315 [M-H]-. (15-2) 4- (4-oxo-4H-chromen-2-yl) phenylamine 300 mg (1.26 mmol) was suspended in 5 mL of methylene chloride, and triethylamine 0.26 mL (1.9 mmol) was cooled with ice. Then, 1.5 mL (1.5 mmol) of 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution was added, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) and saturated aqueous ammonium chloride (20 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 547 mg of orange powder.
The resulting orange powder (547 mg) was suspended in methylene chloride (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 0.5 hr. The solvent was distilled off under reduced pressure, 10 mL of chloroform was added to the residue, and insolubles were collected by filtration. To the obtained yellow powder, 5 mL of ethyl acetate was added, the insoluble material was filtered, and N- [4- (4-oxo-4H-chromen-2-yl) phenyl] sulfamide yellow powder 336 mg (yield 85 %).
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.97 (1H, s), 7.28-7.34 (2H, m), 7.38 (2H, s), 7.47-7.53 (1H, m), 7.75-7.86 ( 2H, m), 8.02-8.08 (3H, m), 10.11 (1H, s).
MS; ESI m / z 317 [M + H] + , 339 [M + Na] + , 315 [MH] - .
実施例１６: 
2-(2-フルオロフェニル)-5-(4-スルファモイルアミノフェニル)オキサゾール-4-カルボン酸エチル Example 16:
2- (2-Fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4-carboxylic acid ethyl
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
(16-1) 2-(2-フルオロフェニル)-5-(4-ニトロフェニル)オキサゾール-4-カルボン酸エチル (16-1) 2- (2-Fluorophenyl) -5- (4-nitrophenyl) oxazole-4-carboxylic acid ethyl
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　2-フルオロベンジルアミン 7.2 mL (64 mmol) をN, N-ジメチルホルムアミド 100 mLに溶解し、3-(4-ニトロフェニル)-3-オキソプロピオン酸エチル 10.0 g (42.2 mmol)、ヨード 12.9 g (50.8 mmol)、酢酸第二銅 766 mg (4.22 mmol) および5.5 M t-ブチルヒドロペルオキシドのデカン溶液 15.3 mL (84 mmol) を加え、室温にて1 時間撹拌後、2-フルオロベンジルアミン 2.4 mL (21.3 mmol) を追加し、室温にてさらに1 時間撹拌した。反応液に水を加え、酢酸エチルにて2回抽出後、有機層を合わせ、10％ チオ硫酸ナトリウム水および飽和食塩水にて順次洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、4:1→7:3、V/V）にて精製後、目的分画の溶媒を減圧下留去し、得られた残渣を再度カラムクロマトグラフィー（n-ヘキサン：酢酸エチル、9:1→7:3、V/V）にて精製した。目的分画の溶媒を減圧下留去し、2-(2-フルオロフェニル)-5-(4-ニトロフェニル)オキサゾール-4-カルボン酸エチルの黄色粉末 2.66 g (収率18％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 1.46 (3H, t, J=7.1 Hz), 4.50 (2H, q, J=7.1 Hz), 7.22-7.23 (2H, m), 7.49-7.57 (1H, m), 8.16-8.22 (1H, m), 8.32-8.37 (2H, m), 8.38-8.44 (2H, m). Dissolve 7.2 mL (64 mmol) of 2-fluorobenzylamine in 100 mL of N, N-dimethylformamide, 10.0 g (42.2 mmol) of ethyl 3- (4-nitrophenyl) -3-oxopropionate, 12.9 g of iodo ( 50.8 mmol), cupric acetate 766 mg (4.22 mmol) and 5.5 M t-butyl hydroperoxide in decane solution 15.3 mL (84 mmol) were added, and the mixture was stirred at room temperature for 1 hour, and then 2-fluorobenzylamine 2.4 mL ( 21.3 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with 10% aqueous sodium thiosulfate and saturated brine, and dried (Na 2 SO 4 ). After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1 → 7: 3, V / V), and then the solvent of the target fraction was evaporated under reduced pressure. The obtained residue was purified again by column chromatography (n-hexane: ethyl acetate, 9: 1 → 7: 3, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 2.66 g (yield 18%) of a yellow powder of ethyl 2- (2-fluorophenyl) -5- (4-nitrophenyl) oxazole-4-carboxylate. .
1 H-NMR (CDCl3, 400 MHz) δ; 1.46 (3H, t, J = 7.1 Hz), 4.50 (2H, q, J = 7.1 Hz), 7.22-7.23 (2H, m), 7.49-7.57 (1H , m), 8.16-8.22 (1H, m), 8.32-8.37 (2H, m), 8.38-8.44 (2H, m).
(16-2) 5-(4-アミノフェニル)-2-(2-フルオロフェニル)オキサゾール-4-カルボン酸エチル (16-2) ethyl 5- (4-aminophenyl) -2- (2-fluorophenyl) oxazole-4-carboxylate
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　(16-1) で製造した2-(2-フルオロフェニル)-5-(4-ニトロフェニル)オキサゾール-4-カルボン酸エチル 1.40 g (3.93 mmol) をエタノール 20 mLに懸濁し、塩化すず(II)二水和物 3.82 g (16.9 mmol) を加え、0.5 時間加熱還流した。放冷後、反応液に28％ アンモニア水30 mLを加え、不溶物をセライトにてろ別し、ろ液を酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。残渣にt-ブチルメチルエーテル 10 mLを加え、不溶物をろ取し、5-(4-アミノフェニル)- 2-(2-フルオロフェニル)オキサゾール-4-カルボン酸エチルの淡黄色粉末 838 mg (収率65％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 1.44 (3H, t, J=7.1 Hz), 3.85-4.05 (2H, br), 4.45 (2H, q, J=7.1 Hz), 6.72-6.77 (2H, m), 7.17-7.28 (2H, m), 7.42-7.49 (1H, m), 8.01-8.06 (2H, m), 8.11-8.17 (1H, m). The ethyl 2- (2-fluorophenyl) -5- (4-nitrophenyl) oxazole-4-carboxylate prepared in (16-1) (1.40 g, 3.93 mmol) was suspended in ethanol (20 mL) and tin chloride (II ) 3.82 g (16.9 mmol) of dihydrate was added and heated under reflux for 0.5 hour. After allowing to cool, 30 mL of 28% aqueous ammonia was added to the reaction solution, the insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. To the residue was added 10 mL of t-butyl methyl ether, and the insoluble material was collected by filtration. 838 mg of a light yellow powder of ethyl 5- (4-aminophenyl) -2- (2-fluorophenyl) oxazole-4-carboxylate ( Yield 65%).
1 H-NMR (CDCl3, 400 MHz) δ; 1.44 (3H, t, J = 7.1 Hz), 3.85-4.05 (2H, br), 4.45 (2H, q, J = 7.1 Hz), 6.72-6.77 (2H , m), 7.17-7.28 (2H, m), 7.42-7.49 (1H, m), 8.01-8.06 (2H, m), 8.11-8.17 (1H, m).
(16-3) 2-(2-フルオロフェニル)-5-(4-スルファモイルアミノフェニル)オキサゾール-4-カルボン酸エチル (16-3) 2- (2-Fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4-carboxylate
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　t-ブタノール 0.30 mL (3.1 mmol) を塩化メチレン 5 mLに溶解し、氷冷下クロロスルホニルイソシアネート 0.27 mL (3.1 mmol) を加え、同温にて15 分間撹拌後、(16-2) で製造した5-(4-アミノフェニル)- 2-(2-フルオロフェニル)オキサゾール-4-カルボン酸エチル 835 mg (2.56 mmol) およびトリエチルアミン 0.54 mL (3.9 mmol) の塩化メチレン 5 mL懸濁液を加え、室温にてさらに0.5 時間撹拌した。反応液に水100 mLを加え、酢酸エチル-テトラヒドロフラン (2:1) にて2回抽出後、有機層を合わせ、飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、黄色粉末1.50 gを得た。
　得られた黄色粉末1.50 gを塩化メチレン 5 mLに懸濁し、トリフルオロ酢酸 5 mLを加え、室温にて0.5 時間撹拌した。減圧下溶媒を留去し、残渣に酢酸エチル 30 mLを加え、減圧下溶媒を留去した。得られた淡褐色粉末にt-ブチルメチルエーテル 30 mLを加え、不溶物をろ取し、2-(2-フルオロフェニル)-5-(4-スルファモイルアミノフェニル)オキサゾール-4-カルボン酸エチルの微褐色粉末 903 mg (収率87％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 1.31 (3H, t, J=7.1 Hz), 4.34 (2H, q, J=7.1 Hz), 7.26-7.36 (4H, m), 7.39-7.50 (2H, m), 7.61-7.68 (1H, m), 7.98-8.03 (2H, m), 8.09-8.15 (1H, m), 10.01 (1H, s).
MS ; ESI m/z 406 [M+H]+, 428 [M+Na]+, 404 [M-H]-. Dissolve 0.30 mL (3.1 mmol) of t-butanol in 5 mL of methylene chloride, add 0.27 mL (3.1 mmol) of chlorosulfonyl isocyanate under ice-cooling, stir at the same temperature for 15 minutes, and then prepare in (16-2) Add a suspension of ethyl 5- (4-aminophenyl) -2- (2-fluorophenyl) oxazole-4-carboxylate 835 mg (2.56 mmol) and triethylamine 0.54 mL (3.9 mmol) in methylene chloride at room temperature. The mixture was further stirred for 0.5 hour. 100 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate-tetrahydrofuran (2: 1). The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 1.50 g of a yellow powder.
The obtained yellow powder (1.50 g) was suspended in methylene chloride (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 0.5 hr. The solvent was distilled off under reduced pressure, 30 mL of ethyl acetate was added to the residue, and the solvent was distilled off under reduced pressure. To the resulting light brown powder, add 30 mL of t-butyl methyl ether, filter the insoluble matter, and add 2- (2-fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4-carboxylic acid. As a result, 903 mg (yield 87%) of a fine brown powder of ethyl was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 1.31 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 7.26-7.36 (4H, m), 7.39-7.50 (2H, m), 7.61-7.68 (1H, m), 7.98-8.03 (2H, m), 8.09-8.15 (1H, m), 10.01 (1H, s).
MS; ESI m / z 406 [M + H] + , 428 [M + Na] + , 404 [MH] - .
実施例１７:
2-(2-フルオロフェニル)-5-(4-スルファモイルアミノフェニル)オキサゾール-4-カルボン酸 Example 17:
2- (2-Fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4-carboxylic acid
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　実施例16 (16-3) で製造した2-(2-フルオロフェニル)-5-(4-スルファモイルアミノフェニル)オキサゾール-4-カルボン酸エチル 673 mg (1.66 mmol) をメタノール 7 mLに懸濁し、テトラヒドロフラン 7 mLおよび5.0 M 水酸化ナトリウム水 1.0 mL (5.0 mmol) を加え、室温にて20 分間撹拌後、40℃ にてさらに1.5 時間撹拌した。氷冷下反応液に6.0 M塩酸1.0 mL (6.0 mmol) を加え、減圧下溶媒を留去後、残渣に水10 mLを加え、不溶物をろ取した。得られた淡褐色粉末をt-ブチルメチルエーテル-エタノール(1:1) 2 mLにて洗浄し、2-(2-フルオロフェニル)-5-(4-スルファモイルアミノフェニル)オキサゾール-4-カルボン酸の淡黄色粉末444 mg (収率71％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.25-7.35 (4H, m), 7.39-7.50 (2H, m), 7.60-7.67 (1H, m), 8.00-8.06 (2H, m), 8.08-8.15 (1H, m), 9.98 (1H, s), 13.00-13.45 (1H, br).
MS ; ESI m/z 378 [M+H]+, 400 [M+Na]+, 376 [M-H]-. Example 16 673 mg (1.66 mmol) of ethyl 2- (2-fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4-carboxylate prepared in (16-3) was suspended in 7 mL of methanol. The mixture became cloudy, 7 mL of tetrahydrofuran and 1.0 mL (5.0 mmol) of 5.0 M aqueous sodium hydroxide were added, and the mixture was stirred at room temperature for 20 minutes, and further stirred at 40 ° C. for 1.5 hours. Under ice-cooling, 1.0 M (6.0 mmol) of 6.0 M hydrochloric acid was added, the solvent was distilled off under reduced pressure, 10 mL of water was added to the residue, and insolubles were collected by filtration. The obtained light brown powder was washed with 2 mL of t-butyl methyl ether-ethanol (1: 1) to give 2- (2-fluorophenyl) -5- (4-sulfamoylaminophenyl) oxazole-4- As a result, 444 mg (yield 71%) of a pale yellow powder of carboxylic acid was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.25-7.35 (4H, m), 7.39-7.50 (2H, m), 7.60-7.67 (1H, m), 8.00-8.06 (2H, m), 8.08-8.15 (1H, m), 9.98 (1H, s), 13.00-13.45 (1H, br).
MS; ESI m / z 378 [M + H] + , 400 [M + Na] + , 376 [MH] - .
実施例１８ :
N-{4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニル}スルファミド Example 18:
N- {4- [5- (2-Fluorophenyl) [1,3,4] oxadiazol-2-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
(18-1) 2-フルオロベンズヒドラジド (18-1) 2-Fluorobenzhydrazide
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　2-フルオロ安息香酸エチル 1.50 g (8.92 mmol) にヒドラジン一水和物 2.2 mL (45 mmol) を加え、80℃ にて2 時間撹拌した。放冷後、反応液に水10 mLを加え、塩化メチレンにて3回抽出し、有機層を合わせ、水および飽和食塩水にて順次洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、2-フルオロベンズヒドラジドの白色粉末 1.06 g (収率77％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 4.10-4.20 (2H, br), 7.13 (1H, dd, J=12.0, 8.3 Hz), 7.28 (1H, t, J=7.8 Hz), 7.45-7.53 (1H, m), 7.82-8.04 (1H, br), 8.07-8.13 (1H, m). Hydrazine monohydrate (2.2 mL, 45 mmol) was added to ethyl 2-fluorobenzoate (1.50 g, 8.92 mmol), and the mixture was stirred at 80 ° C for 2 hours. After allowing to cool, 10 mL of water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, washed successively with water and saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 1.06 g (yield 77%) of 2-fluorobenzhydrazide white powder.
1 H-NMR (CDCl3, 400 MHz) δ; 4.10-4.20 (2H, br), 7.13 (1H, dd, J = 12.0, 8.3 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.45-7.53 (1H, m), 7.82-8.04 (1H, br), 8.07-8.13 (1H, m).
(18-2) N'-(2-フルオロベンゾイル)-4-ニトロベンズヒドラジド (18-2) N '-(2-Fluorobenzoyl) -4-nitrobenzhydrazide
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　(18-1) で製造した2-フルオロベンズヒドラジド 1.06 g (6.88 mmol) を1,4-ジオキサン 28 mLに懸濁し、塩化 4-ニトロベンゾイル 1.28 g (6.88 mmol) および炭酸ナトリウム 365 mg (3.44 mmol) を加え、室温にて1 時間撹拌した。減圧下溶媒を留去し、残渣に水20 mLを加え、不溶物をろ取した。得られた粉末を水30 mL、1.0 M 水酸化ナトリウム水2 mLと水10 mLの混液、1.0 M 塩酸2 mLと水10 mLの混液、水5 mLの順で洗浄し、N'-(2-フルオロベンゾイル)-4-ニトロベンズヒドラジドの黄色粉末 1.31 g (収率63％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.31-7.38 (2H, m), 7.55-7.63 (1H, m), 7.69-7.75 (1H, m), 8.12-8.17 (2H, m), 8.31-8.36 (2H, m), 10.40-11.00 (2H, br). 1.06 g (6.88 mmol) of 2-fluorobenzhydrazide prepared in (18-1) was suspended in 28 mL of 1,4-dioxane, and 4-nitrobenzoyl chloride 1.28 g (6.88 mmol) and sodium carbonate 365 mg (3.44 mmol) ) Was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 20 mL of water was added to the residue, and the insoluble material was collected by filtration. Wash the resulting powder with 30 mL of water, a mixture of 2 mL of 1.0 M aqueous sodium hydroxide and 10 mL of water, a mixture of 2 mL of 1.0 M hydrochloric acid and 10 mL of water, and 5 mL of water in this order. This gave 1.31 g (yield 63%) of a yellow powder of -fluorobenzoyl) -4-nitrobenzhydrazide.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.31-7.38 (2H, m), 7.55-7.63 (1H, m), 7.69-7.75 (1H, m), 8.12-8.17 (2H, m), 8.31-8.36 (2H, m), 10.40-11.00 (2H, br).
(18-3) 2-(2-フルオロフェニル)-5-(4-ニトロフェニル)[1,3,4]オキサジアゾール (18-3) 2- (2-Fluorophenyl) -5- (4-nitrophenyl) [1,3,4] oxadiazole
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　(18-2) で製造したN'-(2-フルオロベンゾイル)-4-ニトロベンズヒドラジド 1.31 g (4.32 mmol) に塩化チオニル 1.23 mL (17.0 mmol) およびピリジン 2.1 mL を加え、80℃ にて0.5 時間撹拌した。放冷後、氷冷下反応液にメタノール 1 mLおよび水20 mLを加え、酢酸エチルにて10回抽出後、有機層を合わせ乾燥 (Na2SO4) し、減圧下溶媒を留去した。得られた粉末1.12 gに酢酸エチル 5 mLを加え、不溶物をろ取し、2-(2-フルオロフェニル)-5-(4-ニトロフェニル)[1,3,4]オキサジアゾールの黄色粉末 501 mg (収率41％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.46-7.58 (2H, m), 7.71-7.78 (1H, m), 8.19-8.25 (1H, m), 8.34-8.39 (2H, m), 8.44-8.49 (2H, m). Add 1.23 mL (17.0 mmol) of thionyl chloride and 2.1 mL of pyridine to 1.31 g (4.32 mmol) of N '-(2-fluorobenzoyl) -4-nitrobenzhydrazide prepared in (18-2), and add 0.5 mL at 80 ° C. Stir for hours. After cooling, 1 mL of methanol and 20 mL of water was added under ice-cooling the reaction mixture, and the mixture was extracted 10 times with ethyl acetate, the organic layers were combined dried (Na 2 SO 4) and the solvent was evaporated under reduced pressure. To 1.12 g of the obtained powder, 5 mL of ethyl acetate was added, the insoluble material was collected by filtration, and 2- (2-fluorophenyl) -5- (4-nitrophenyl) [1,3,4] oxadiazole yellow 501 mg (41% yield) of powder was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.46-7.58 (2H, m), 7.71-7.78 (1H, m), 8.19-8.25 (1H, m), 8.34-8.39 (2H, m), 8.44-8.49 (2H, m).
(18-4) 4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニルアミン (18-4) 4- [5- (2-Fluorophenyl) [1,3,4] oxadiazol-2-yl] phenylamine
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　(18-3) で製造した2-(2-フルオロフェニル)-5-(4-ニトロフェニル)[1,3,4]オキサジアゾール 501 mg (1.76 mmol) をエタノール18 mLに懸濁し、塩化すず(II)二水和物 1.99 g (8.82 mmol) を加え、0.5 時間加熱還流した。放冷後、反応液に飽和重層水 10 mLおよび酢酸エチル 10 mLを加え、不溶物をセライトにてろ別し、ろ液を分液した。有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。得られた粉末に酢酸エチル 5 mLを加え、不溶物をろ取し、4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニルアミンの淡褐色粉末 253 mg (収率56％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.70-6.75 (2H, m), 7.41-7.52 (2H, m), 7.64-7.71 (1H, m), 7.73-7.78 (2H, m), 8.07-8.13 (1H, m). 2- (2-Fluorophenyl) -5- (4-nitrophenyl) [1,3,4] oxadiazole 501 mg (1.76 mmol) prepared in (18-3) was suspended in 18 mL of ethanol and chlorinated. Tin (II) dihydrate 1.99 g (8.82 mmol) was added, and the mixture was heated to reflux for 0.5 hour. After allowing to cool, 10 mL of saturated multistory water and 10 mL of ethyl acetate were added to the reaction solution, the insoluble material was filtered off through celite, and the filtrate was separated. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. To the obtained powder was added 5 mL of ethyl acetate, the insoluble material was collected by filtration, and 4- [5- (2-fluorophenyl) [1,3,4] oxadiazol-2-yl] phenylamine light brown 253 mg (56% yield) of powder was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.70-6.75 (2H, m), 7.41-7.52 (2H, m), 7.64-7.71 (1H, m), 7.73-7.78 (2H, m), 8.07-8.13 (1H, m).
(18-5) N-{4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニル}スルファミド (18-5) N- {4- [5- (2-Fluorophenyl) [1,3,4] oxadiazol-2-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　(18-4) で製造した4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニルアミン 253 mg (0.991 mmol) を塩化メチレン 4.5 mLに懸濁し、氷冷下トリエチルアミン0.41 mL (3.0 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 1.5 mL (1.5 mmol) を加え、室温1 時間撹拌した。反応液に飽和塩化アンモニウム水10 mLを加え、減圧下塩化メチレンを留去後、不溶物をろ取した。得られた粉末を水10 mLおよびクロロホルム-ｎ-ヘキサン (1:1) 10 mLにて順次洗浄し、淡褐色粉末339 mgを得た。
　得られた微褐色粉末339 mgを塩化メチレン 2 mLに懸濁し、トリフルオロ酢酸 1 mLを加え、室温にて18 時間撹拌した。反応液に飽和重曹水10 mLを加え、析出物をろ取後、得られた粉末を2.0 M 水酸化ナトリウム水に溶解し、クロロホルムにて3回洗浄した。水層の不溶物をろ別し、6.0 M塩酸を加え、酸性とした後、析出物をろ取し、N-{4-[5-(2-フルオロフェニル)[1,3,4]オキサジアゾール-2-イル]フェニル}スルファミドの褐色粉末 84.8 mg (収率28％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.32-7.37 (2H, m), 7.37-7.43 (2H, m), 7.43-7.55 (2H, m), 7.67-7.75 (1H, m), 7.98-8.04 (2H, m), 8.12-8.18 (1H, m), 10.15 (1H, s).
MS ; ESI m/z 335 [M+H]+, 357 [M+Na]+, 333 [M-H]-. The suspension of 4- [5- (2-fluorophenyl) [1,3,4] oxadiazol-2-yl] phenylamine prepared in (18-4) in 253 mg (0.991 mmol) in 4.5 mL of methylene chloride was suspended. Under ice-cooling, 0.41 mL (3.0 mmol) of triethylamine and 1.5 mL (1.5 mmol) of 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and methylene chloride was distilled off under reduced pressure. Insoluble material was collected by filtration. The obtained powder was washed successively with 10 mL of water and 10 mL of chloroform-n-hexane (1: 1) to obtain 339 mg of a light brown powder.
339 mg of the obtained fine brown powder was suspended in 2 mL of methylene chloride, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the precipitate was collected by filtration. The obtained powder was dissolved in 2.0 M aqueous sodium hydroxide and washed 3 times with chloroform. Insoluble matter in the aqueous layer was filtered off, 6.0 M hydrochloric acid was added to make it acidic, and then the precipitate was collected by filtration to give N- {4- [5- (2-fluorophenyl) [1,3,4] oxacin. As a result, 84.8 mg (yield 28%) of a brown powder of diazol-2-yl] phenyl} sulfamide was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.32-7.37 (2H, m), 7.37-7.43 (2H, m), 7.43-7.55 (2H, m), 7.67-7.75 (1H, m), 7.98-8.04 (2H, m), 8.12-8.18 (1H, m), 10.15 (1H, s).
MS; ESI m / z 335 [M + H] + , 357 [M + Na] + , 333 [MH] - .
実施例１９:
N-{4-[1-(2-フルオロフェニル)-1H-[1,2,3]トリアゾール-4-イル]フェニル}スルファミド Example 19
N- {4- [1- (2-Fluorophenyl) -1H- [1,2,3] triazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
(19-1) 1-アジド-2-フルオロベンゼン (19-1) 1-Azido-2-fluorobenzene
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　2-フルオロアニリン1.20 g (10.8 mmol) を6.0 M塩酸43.2 mLに懸濁し、氷冷下亜硝酸ナトリウム 745 mg (10.8 mmol) を加え、同温にて10 分間撹拌後、アジ化ナトリウム 843 mg (13.0 mmol) を加え、室温にて3 時間撹拌した。反応液を酢酸エチルにて抽出し、有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、1-アジド-2-フルオロベンゼンの褐色油状物1.08 g (収率79％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 7.04-7.15 (4H, m). 1.20 g (10.8 mmol) of 2-fluoroaniline was suspended in 43.2 mL of 6.0 M hydrochloric acid, and 745 mg (10.8 mmol) of sodium nitrite was added under ice cooling, followed by stirring at the same temperature for 10 minutes, and then 843 mg of sodium azide ( 13.0 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 1.08 g (yield 79%) of a brown oil of 1-azido-2-fluorobenzene.
1 H-NMR (CDCl3, 400 MHz) δ; 7.04-7.15 (4H, m).
(19-2) 4-[1-(2-フルオロフェニル)-1H-[1,2,3]トリアゾール-4-イル]フェニルアミン (19-2) 4- [1- (2-Fluorophenyl) -1H- [1,2,3] triazol-4-yl] phenylamine
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　(19-1) で製造した1-アジド-2-フルオロベンゼン 1.08 g (7.89 mmol) をt-ブタノール 10 mLに溶解し、水10 mL、4-エチニルアニリン 924 mg (7.89 mmol)、L-アスコルビン酸ナトリウム156 mg (0.789 mmol) および硫酸銅五水和物 20 mg (0.079 mmol) を加え、60℃ にて27 時間撹拌した。放冷後、反応液に水20 mLを加え、不溶物をろ取し、4-[1-(2-フルオロフェニル)-1H-[1,2,3]トリアゾール-4-イル]フェニルアミンの褐色粉末 1.52 g (収率76％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 5.25-5.37 (2H, br), 6.63-6.68 (2H, m), 7.42-7.48 (1H, m), 7.55-7.65 (4H, m), 7.84-7.89 (1H, m), 8.75 (1H, d, J=2.0 Hz). 1-azido-2-fluorobenzene prepared in (19-1) 1.08 g (7.89 mmol) was dissolved in 10 mL of t-butanol, 10 mL of water, 924 mg (7.89 mmol) of 4-ethynylaniline, L-ascorbine Sodium 156 mg (0.789 mmol) and copper sulfate pentahydrate 20 mg (0.079 mmol) were added, and the mixture was stirred at 60 ° C. for 27 hours. After allowing to cool, 20 mL of water was added to the reaction solution, and the insoluble material was collected by filtration to give 4- [1- (2-fluorophenyl) -1H- [1,2,3] triazol-4-yl] phenylamine. A brown powder of 1.52 g (yield 76%) was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 5.25-5.37 (2H, br), 6.63-6.68 (2H, m), 7.42-7.48 (1H, m), 7.55-7.65 (4H, m), 7.84-7.89 (1H, m), 8.75 (1H, d, J = 2.0 Hz).
(19-3) N-{4-[1-(2-フルオロフェニル)-1H-[1,2,3]トリアゾール-4-イル]フェニル}スルファミド (19-3) N- {4- [1- (2-Fluorophenyl) -1H- [1,2,3] triazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　(19-2) で製造した4-[1-(2-フルオロフェニル)-1H-[1,2,3]トリアゾール-4-イル]フェニルアミン 500 mg (2.60 mmol) を塩化メチレン 9 mLに懸濁し、氷冷下トリエチルアミン 0.82 mL (5.9 mmol) および1.0 M t-ブチル N-クロロスルホニルカルバメート－塩化メチレン溶液 3.0 mL (3.0 mmol) を加え、室温1 時間撹拌した。反応液に飽和塩化アンモニウム水10 mLを加え、酢酸エチルにて3回抽出後、有機層を合わせ飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡褐色粉末548 mgを得た。
　得られた淡褐色粉末548 mgを塩化メチレン 4 mLに懸濁し、氷冷下トリフルオロ酢酸 2 mLを加え、室温にて20 時間撹拌後、トリフルオロ酢酸 6 mLを追加し、室温にて9 時間、40℃ にて0.5 時間撹拌した。その後、60℃ にて塩化メチレンを留去し、室温にてさらに14 時間撹拌した。反応液に飽和重曹水70 mLを加え、酢酸エチルにて3回抽出後、有機層を合わせ飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、得られた粉末にクロロホルム 5 mLを加え、不溶物をろ取した。得られた粉末をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→9:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、褐色粉末を得た。得られた褐色粉末に酢酸エチル 5 mLを加え、不溶物をろ取し、N-{4-[1-(2-フルオロフェニル)-1H-[1,2,3] トリアゾール-4-イル]フェニル}スルファミドの褐色粉末39.5 mg (収率6.0％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.15-7.22 (2H, br), 7.23-7.28 (2H, m), 7.44-7.50 (1H, m), 7.56-7.67 (2H, m), 7.82-7.92 (3H, m), 8.75 (1H, d, J=2.0 Hz), 9.65-9.72 (1H, br).
MS ; ESI m/z 334 [M+H]+, 356 [M+Na]+, 332 [M-H]-. (19-2) 4- [1- (2-fluorophenyl) -1H- [1,2,3] triazol-4-yl] phenylamine 500 mg (2.60 mmol) was suspended in 9 mL of methylene chloride. The solution became cloudy, and 0.82 mL (5.9 mmol) of triethylamine and 3.0 mL (3.0 mmol) of 1.0 M t-butyl N-chlorosulfonylcarbamate-methylene chloride solution were added under ice-cooling, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 548 mg of a light brown powder.
Suspend 548 mg of the resulting light brown powder in 4 mL of methylene chloride, add 2 mL of trifluoroacetic acid under ice cooling, stir at room temperature for 20 hours, add 6 mL of trifluoroacetic acid, and add 9 mL at room temperature. And stirred at 40 ° C. for 0.5 hour. Thereafter, methylene chloride was distilled off at 60 ° C., and the mixture was further stirred at room temperature for 14 hours. 70 mL of saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, 5 mL of chloroform was added to the obtained powder, and insolubles were collected by filtration. The obtained powder was purified by column chromatography (chloroform: methanol, 1: 0 → 9: 1, V / V), and then the solvent of the target fraction was distilled off under reduced pressure to obtain a brown powder. To the obtained brown powder was added 5 mL of ethyl acetate, and the insoluble material was collected by filtration, and N- {4- [1- (2-fluorophenyl) -1H- [1,2,3] triazol-4-yl] Phenyl} sulfamide brown powder 39.5 mg (yield 6.0%) was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.15-7.22 (2H, br), 7.23-7.28 (2H, m), 7.44-7.50 (1H, m), 7.56-7.67 (2H, m), 7.82-7.92 (3H, m), 8.75 (1H, d, J = 2.0 Hz), 9.65-9.72 (1H, br).
MS; ESI m / z 334 [M + H] + , 356 [M + Na] + , 332 [MH] - .
実施例２０ : 
N-{4-[5-(2-フルオロフェニル)-3-オキソ-3H-イソキサゾール-2-イル]フェニル}スルファミド Example 20:
N- {4- [5- (2-Fluorophenyl) -3-oxo-3H-isoxazol-2-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
(20-1) (E)-3-(2-フルオロフェニル)アクリル酸エチル (20-1) (E) -3- (2-Fluorophenyl) ethyl acrylate
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　水素化ナトリウム(P=60％) 1.38 g (35 mmol) をテトラヒドロフラン 100 mLに懸濁し、氷冷下ホスホノ酢酸トリエチル 6.9 mL (34 mmol) を加え、同温にて15 分間撹拌後、2-フルオロベンズアルデヒド 3.0 mL (29 mmol) を加え、室温にてさらに1 時間撹拌した。氷冷下、反応液に飽和塩化アンモニウム水100 mLを加え、酢酸エチルにて2回抽出後、有機層を合わせ飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、(E)-3-(2-フルオロフェニル)アクリル酸エチルの無色油状物7.54 g (収率quant.) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 1.34 (3H, t, J=7.1 Hz), 4.27 (2H, q, J=7.1 Hz), 6.53 (1H, d, J=16.1 Hz), 7.06-7.18 (2H, m), 7.31-7.39 (1H, m), 7.50-7.56 (1H, m), 7.81 (1H, d, J=16.1 Hz). 1.38 g (35 mmol) of sodium hydride (P = 60%) was suspended in 100 mL of tetrahydrofuran, 6.9 mL (34 mmol) of phosphonoacetic acid triethyl was added under ice-cooling, and the mixture was stirred at the same temperature for 15 min. Benzaldehyde (3.0 mL, 29 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Under ice-cooling, 100 mL of saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 7.54 g (yield quant.) Of a colorless oily ethyl (E) -3- (2-fluorophenyl) acrylate.
1 H-NMR (CDCl3, 400 MHz) δ; 1.34 (3H, t, J = 7.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 6.53 (1H, d, J = 16.1 Hz), 7.06- 7.18 (2H, m), 7.31-7.39 (1H, m), 7.50-7.56 (1H, m), 7.81 (1H, d, J = 16.1 Hz).
(20-2) 2,3-ジブロモ-3-(2-フルオロフェニル)プロピオン酸エチル (20-2) 2,3-Dibromo-3- (2-fluorophenyl) ethyl propionate
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　(20-1) で製造した(E)-3-(2-フルオロフェニル)アクリル酸エチル 7.54 g (29.8 mmolとして計算) を四塩化炭素 20 mLに溶解し、氷冷下臭素 1.55 mL (30.0 mmol) を加え、室温にて63 時間撹拌した。減圧下溶媒を留去し、2,3-ジブロモ-3-(2-フルオロフェニル)プロピオン酸エチルの淡褐色油状物12.9 g (収率quant.) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 1.38 (3H, t, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 4.97 (1H, d, J=11.7 Hz), 5.60 (1H, d, J=11.7 Hz), 7.06-7.13 (1H, m), 7.15-7.22 (1H, m), 7.33-7.42 (2H, m). Dissolve 7.54 g (calculated as 29.8 mmol) of ethyl (E) -3- (2-fluorophenyl) acrylate prepared in (20-1) in 20 mL of carbon tetrachloride, and then add 1.55 mL (30.0 mmol) of bromine under ice-cooling. ) And stirred at room temperature for 63 hours. The solvent was distilled off under reduced pressure to obtain 12.9 g (yield quant.) Of a light brown oily product of ethyl 2,3-dibromo-3- (2-fluorophenyl) propionate.
1 H-NMR (CDCl3, 400 MHz) δ; 1.38 (3H, t, J = 7.1 Hz), 4.36 (2H, q, J = 7.1 Hz), 4.97 (1H, d, J = 11.7 Hz), 5.60 ( 1H, d, J = 11.7 Hz), 7.06-7.13 (1H, m), 7.15-7.22 (1H, m), 7.33-7.42 (2H, m).
(20-3) 5-(2-フルオロフェニル)イソキサゾール-3-オール (20-3) 5- (2-Fluorophenyl) isoxazol-3-ol
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　塩酸ヒドロキシルアミン 5.18 g (74.5 mmol) をメタノール 150 mLに溶解し、氷冷下水酸化ナトリウム 8.34 g (209 mmol) を加え、同温にて20 分間撹拌した後、(20-2) で製造した2,3-ジブロモ-3-(2-フルオロフェニル)プロピオン酸エチル 12.9 g (29.8 mmolとして計算) を5 分間かけて滴下し、氷冷下1 時間撹拌後、3 時間加熱還流した。放冷後、氷冷下反応液に水60 mLを加えた後、6.0 M塩酸40 mL (0.24 mol) および水20 mLを加え、同温にてさらに0.5 時間撹拌した。析出物をろ取後、水にて洗浄し、5-(2-フルオロフェニル)イソキサゾール-3-オールの微褐色粉末3.56 g (収率67％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.38 (1H, d, J=3.4 Hz), 7.34-7.45 (2H, m), 7.52-7.60 (1H, m), 7.83-7.91 (1H, m), 11.49 (1H, s). Dissolve 5.18 g (74.5 mmol) of hydroxylamine hydrochloride in 150 mL of methanol, add 8.34 g (209 mmol) of sodium hydroxide under ice-cooling, and stir at the same temperature for 20 minutes. , 12.9 g of ethyl 3-dibromo-3- (2-fluorophenyl) propionate (calculated as 29.8 mmol) was added dropwise over 5 minutes, stirred for 1 hour under ice-cooling, and then heated to reflux for 3 hours. After allowing to cool, 60 mL of water was added to the reaction mixture under ice-cooling, 40 mL (0.24 mol) of 6.0 M hydrochloric acid and 20 mL of water were added, and the mixture was further stirred at the same temperature for 0.5 hr. The precipitate was collected by filtration and washed with water to obtain 3.56 g (yield 67%) of 5- (2-fluorophenyl) isoxazol-3-ol as a light brown powder.
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.38 (1H, d, J = 3.4 Hz), 7.34-7.45 (2H, m), 7.52-7.60 (1H, m), 7.83-7.91 (1H, m), 11.49 (1H, s).
(20-4) 5-(2-フルオロフェニル)-2-(4-ニトロフェニル)イソキサゾール-3-オン (20-4) 5- (2-Fluorophenyl) -2- (4-nitrophenyl) isoxazol-3-one
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　(20-3) で製造した5-(2-フルオロフェニル)イソキサゾール-3-オール 500 mg (2.79 mmol) をジメチルスルホキシド 5 mLに溶解し、炭酸カリウム 578 mg (4.18 mmol) および4-フルオロニトロベンゼン473 mg (3.35 mmol) を加え、70℃ にて3.5 時間撹拌した。放冷後、反応液に水30 mLを加え、析出物をろ取後、得られた粉末を水10 mL、エタノール 2 mLおよびt-ブチルメチルエーテル 5 mLにて順次洗浄し、5-(2-フルオロフェニル)-2-(4-ニトロフェニル)イソキサゾール-3-オンの微褐色粉末666 mg (収率80％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 6.55 (1H, d, J=3.7 Hz), 7.18-7.25 (1H, m), 7.28-7.34 (1H, m), 7.45-7.52 (3H, m), 7.93-7.99 (1H, m), 8.27-8.32 (2H, m). (20-3) 5- (2-fluorophenyl) isoxazol-3-ol 500 mg (2.79 mmol) was dissolved in dimethyl sulfoxide 5 mL, potassium carbonate 578 mg (4.18 mmol) and 4-fluoronitrobenzene 473 mg (3.35 mmol) was added, and the mixture was stirred at 70 ° C. for 3.5 hours. After allowing to cool, 30 mL of water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained powder was washed successively with 10 mL of water, 2 mL of ethanol and 5 mL of t-butyl methyl ether, There was obtained 666 mg (80% yield) of a slightly brown powder of -fluorophenyl) -2- (4-nitrophenyl) isoxazol-3-one.
1 H-NMR (CDCl3, 400 MHz) δ; 6.55 (1H, d, J = 3.7 Hz), 7.18-7.25 (1H, m), 7.28-7.34 (1H, m), 7.45-7.52 (3H, m) , 7.93-7.99 (1H, m), 8.27-8.32 (2H, m).
(20-5) 2-(4-アミノフェニル)-5-(2-フルオロフェニル)イソキサゾール-3-オン (20-5) 2- (4-Aminophenyl) -5- (2-fluorophenyl) isoxazol-3-one
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　(20-4) で製造した5-(2-フルオロフェニル)-2-(4-ニトロフェニル)イソキサゾール-3-オン 666 mg (2.22 mmol) をエタノール 10 mLに懸濁し、塩化すず(II)二水和物 2.50 g (11.1 mmol) を加え、0.5 時間加熱還流した。放冷後、反応液に28％ アンモニア水15 mLおよび酢酸エチル 10 mLを加え、不溶物をセライトにてろ別し、ろ液を酢酸エチルにて抽出後、有機層を飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（n-ヘキサン：酢酸エチル、4:1→1:1、V/V）にて精製した。目的分画の溶媒を減圧下留去し、2-(4-アミノフェニル)-5-(2-フルオロフェニル)イソキサゾール-3-オンの微黄色粉末545 mg (収率91％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.50-3.80 (2H, br), 6.37 (1H, d, J=3.7 Hz), 6.66-6.71 (2H, m), 7.04-7.09 (2H, m), 7.13-7.19 (1H, m), 7.23-7.28 (1H, m), 7.38-7.45 (1H, m), 7.88-7.93 (1H, m). (20-4) 5- (2-fluorophenyl) -2- (4-nitrophenyl) isoxazol-3-one 666 mg (2.22 mmol) was suspended in ethanol 10 mL, and tin (II) chloride The hydrate 2.50 g (11.1 mmol) was added, and it heated and refluxed for 0.5 hour. After standing to cool, 15 mL of 28% aqueous ammonia and 10 mL of ethyl acetate were added to the reaction mixture, the insoluble material was filtered off through celite, the filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine. And dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1 → 1: 1, V / V). The solvent of the objective fraction was distilled off under reduced pressure to obtain 545 mg (yield 91%) of 2- (4-aminophenyl) -5- (2-fluorophenyl) isoxazol-3-one as a pale yellow powder.
1 H-NMR (CDCl3, 400 MHz) δ; 3.50-3.80 (2H, br), 6.37 (1H, d, J = 3.7 Hz), 6.66-6.71 (2H, m), 7.04-7.09 (2H, m) , 7.13-7.19 (1H, m), 7.23-7.28 (1H, m), 7.38-7.45 (1H, m), 7.88-7.93 (1H, m).
(20-6) N-{4-[5-(2-フルオロフェニル)-3-オキソ-3H-イソキサゾール-2-イル]フェニル}スルファミド (20-6) N- {4- [5- (2-Fluorophenyl) -3-oxo-3H-isoxazol-2-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　t-ブタノール 0.23 mL (2.4 mmol) を塩化メチレン 3 mLに溶解し、氷冷下クロロスルホニルイソシアネート 0.21 mL (2.4 mmol) を加え、同温にて15 分間撹拌後、(20-5) で製造した2-(4-アミノフェニル)-5-(2-フルオロフェニル)イソキサゾール-3-オン 540 mg (2.00 mmol) およびトリエチルアミン 0.42 mL (3.0 mmol) の塩化メチレン 3 mL懸濁液を加え、室温にて0.5 時間撹拌した。反応液を飽和塩化アンモニウム水で洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、淡褐色粉末970 mgを得た。
　得られた淡褐色粉末970 mgを塩化メチレン 3 mLに懸濁し、トリフルオロ酢酸 3 mLを加え、室温にて1 時間撹拌した。減圧下溶媒を留去し、得られた淡褐色粉末にクロロホルム 5 mLを加え、不溶物をろ取し、N-{4-[5-(2-フルオロフェニル)-3-オキソ-3H-イソキサゾール-2-イル]フェニル}スルファミドの白色粉末425 mg (収率61％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 6.67 (1H, d, J=2.9 Hz), 7.08-7.14 (2H, br), 7.20-7.29 (4H, m), 7.37-7.47 (2H, m), 7.57-7.64 (1H, m), 7.88-7.94 (1H, m), 9.53 (1H, s).
MS ; ESI m/z 350 [M+H]+, 372 [M+Na]+, 348 [M-H]-. 0.23 mL (2.4 mmol) of t-butanol was dissolved in 3 mL of methylene chloride, 0.21 mL (2.4 mmol) of chlorosulfonyl isocyanate was added under ice cooling, and the mixture was stirred at the same temperature for 15 minutes, and then prepared in (20-5) Add a suspension of 2- (4-aminophenyl) -5- (2-fluorophenyl) isoxazol-3-one 540 mg (2.00 mmol) and triethylamine 0.42 mL (3.0 mmol) in methylene chloride at room temperature. Stir for 0.5 hour. The reaction solution was washed with saturated aqueous ammonium chloride and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure to obtain 970 mg of a light brown powder.
970 mg of the obtained light brown powder was suspended in 3 mL of methylene chloride, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 5 mL of chloroform was added to the obtained light brown powder, the insoluble material was collected by filtration, and N- {4- [5- (2-fluorophenyl) -3-oxo-3H-isoxazole A white powder of -2-yl] phenyl} sulfamide (425 mg, 61% yield) was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 6.67 (1H, d, J = 2.9 Hz), 7.08-7.14 (2H, br), 7.20-7.29 (4H, m), 7.37-7.47 (2H, m), 7.57-7.64 (1H, m), 7.88-7.94 (1H, m), 9.53 (1H, s).
MS; ESI m / z 350 [M + H] + , 372 [M + Na] + , 348 [MH] - .
実施例２１: 
N-{4-[2-(2-シアノフェニル)[1,2,3]トリアゾール-4-イル]フェニル}スルファミド Example 21:
N- {4- [2- (2-cyanophenyl) [1,2,3] triazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
(21-1) 1-エチニル-4-ニトロベンゼン (21-1) 1-ethynyl-4-nitrobenzene
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　4-ニトロベンズアルデヒド 2.00 g (13.2 mmol) をメタノール 130 mLに溶解し、炭酸カリウム 2.74 g (19.9 mmol) および (1-ジアゾ-2-オキソプロピル)ホスホン酸ジメチル4.77 mL (19.9 mmol) を加え、室温にて1 時間撹拌した。反応液に飽和重曹水150 mLを加え、塩化メチレンにて3回抽出し、有機層を合わせ飽和食塩水にて洗浄後、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：n-ヘキサン、3:1、V/V）にて精製後、目的分画の溶媒を減圧下留去し、1-エチニル-4-ニトロベンゼンの白色粉末 1.64 g (収率84％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.35 (1H, s), 7.61-7.66 (2H, m), 8.17-8.22 (2H, m). Dissolve 2.00 g (13.2 mmol) of 4-nitrobenzaldehyde in 130 mL of methanol, add 2.74 g (19.9 mmol) of potassium carbonate and 4.77 mL (19.9 mmol) of dimethyl (1-diazo-2-oxopropyl) phosphonate, and add room temperature. For 1 hour. 150 mL of saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (chloroform: n-hexane, 3: 1, V / V), and then the solvent of the target fraction was evaporated under reduced pressure to give 1-ethynyl-4 -1.64 g (84% yield) of a white powder of nitrobenzene was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 3.35 (1H, s), 7.61-7.66 (2H, m), 8.17-8.22 (2H, m).
(21-2) 4-(4-ニトロフェニル)-2H-[1,2,3]トリアゾール (21-2) 4- (4-Nitrophenyl) -2H- [1,2,3] triazole
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
　ホルマリン 5.1 mL (68 mmol) および酢酸0.58 mL (10.2 mmol) をテトラヒドロフラン 6.8 mLに溶解し、室温にて15 分間撹拌後、アジ化ナトリウム 663 mg (10.2 mmol) および (21-1) で製造した1-エチニル-4-ニトロベンゼン 1.00 g (6.80 mmol) を加え、室温にて10 分間撹拌後、アスコルビン酸ナトリウム 269 mg (1.36 mmol) および硫酸銅五水和物 85 mg (0.34 mmol) の水0.5 mL溶液を加え、室温にてさらに13.5 時間撹拌した。反応液に水30 mLを加え、不溶物をろ取し、4-(4-ニトロフェニル)-2H-[1,2,3]トリアゾールの褐色粉末1.25 g (収率97％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ(ppm) ; 8.12-8.19 (2H, m), 8.30-8.36 (2H, m), 8.52 (0.8H, s), 8.89 (0.2H, s). Formalin 5.1 mL (68 mmol) and acetic acid 0.58 mL (10.2 mmol) were dissolved in tetrahydrofuran 6.8 mL, stirred at room temperature for 15 minutes, and then prepared with sodium azide 663 mg (10.2 mmol) and (21-1) 1 -Ethynyl-4-nitrobenzene 1.00 g (6.80 mmol) was added, stirred for 10 minutes at room temperature, and then 0.5 mL of water solution of sodium ascorbate 269 mg (1.36 mmol) and copper sulfate pentahydrate 85 mg (0.34 mmol) And stirred at room temperature for an additional 13.5 hours. 30 mL of water was added to the reaction solution, and the insoluble material was collected by filtration to obtain 1.25 g (yield 97%) of 4- (4-nitrophenyl) -2H- [1,2,3] triazole as a brown powder.
1 H-NMR (DMSO-d6, 400 MHz) δ (ppm); 8.12-8.19 (2H, m), 8.30-8.36 (2H, m), 8.52 (0.8H, s), 8.89 (0.2H, s) .
(21-3) 2-[4-(4-ニトロフェニル)[1,2,3]トリアゾール2-イル]ベンゾニトリル (21-3) 2- [4- (4-Nitrophenyl) [1,2,3] triazol-2-yl] benzonitrile
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　(21-2) で製造した4-(4-ニトロフェニル)-2H-[1,2,3]トリアゾール 1.15 g (6.05 mmol) をN, N-ジメチルホルムアミド5.33 mLに溶解し、2-フルオロベンゾニトリル0.84 mL (7.7 mmol) および炭酸カリウム 741 mg (5.36 mmol) を加え、120℃ にて6.5 時間撹拌した。反応液に水50 mLを加え、酢酸エチルにて3回抽出後、水層を食塩で飽和させ、テトラヒドロフランにてさらに2回抽出した。有機層を合わせ飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。得られた褐色粉末に酢酸エチル 10 mLを加え、不溶物をろ取し、褐色粉末889 mgを得た。得られた褐色粉末889 mgをカラムクロマトグラフィー（クロロホルム：メタノール、1:0→91:9、V/V）にて精製後、目的分画の溶媒を減圧下留去し、2-[4-(4-ニトロフェニル)[1,2,3]トリアゾール-2-イル]ベンゾニトリルの淡黄色粉末449 mg (収率32％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.68-7.74 (1H, m), 7.94-7.99 (1H, m), 8.10-8.14 (1H, m), 8.18-8.23 (1H, m), 8.25-8.30 (2H, m), 8.39-8.44 (2H, m), 8.98 (1H, s). 4- (4-Nitrophenyl) -2H- [1,2,3] triazole 1.15 g (6.05 mmol) prepared in (21-2) was dissolved in 5.33 mL of N, N-dimethylformamide, and 2-fluorobenzo Nitrile 0.84 mL (7.7 mmol) and potassium carbonate 741 mg (5.36 mmol) were added, and the mixture was stirred at 120 ° C. for 6.5 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The aqueous layer was saturated with sodium chloride, and extracted twice more with tetrahydrofuran. The organic layers were combined, washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. To the obtained brown powder was added 10 mL of ethyl acetate, and the insoluble material was collected by filtration to obtain 889 mg of a brown powder. After purifying 889 mg of the obtained brown powder by column chromatography (chloroform: methanol, 1: 0 → 91: 9, V / V), the solvent of the target fraction was distilled off under reduced pressure to give 2- [4- A pale yellow powder (449 mg, yield 32%) of (4-nitrophenyl) [1,2,3] triazol-2-yl] benzonitrile was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.68-7.74 (1H, m), 7.94-7.99 (1H, m), 8.10-8.14 (1H, m), 8.18-8.23 (1H, m), 8.25-8.30 (2H, m), 8.39-8.44 (2H, m), 8.98 (1H, s).
(21-4) 2-[4-(4-アミノフェニル)[1,2,3]トリアゾール-2-イル]ベンゾニトリル (21-4) 2- [4- (4-Aminophenyl) [1,2,3] triazol-2-yl] benzonitrile
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　(21-3) で製造した2-[4-(4-ニトロフェニル)[1,2,3]トリアゾール-2-イル]ベンゾニトリル 439 mg (1.51 mmol) をエタノール 15 mLに懸濁し、塩化すず(II)二水和物 1.70 g (7.55 mmol) を加え、45 分間加熱還流した。放冷後、反応液に飽和重曹水 50 mLおよび酢酸エチル 100 mLを加え、不溶物をセライトにてろ別し、ろ液を分液した。有機層を飽和食塩水にて洗浄後、乾燥 (Na2SO4) し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（クロロホルム：メタノール、1:0→93:7、V/V）にて精製後、目的分画の溶媒を減圧下留去し、2-[4-(4-アミノフェニル)[1,2,3]トリアゾール-2-イル]ベンゾニトリルの淡黄色粉末336 mg (収率85％) を得た。
1H-NMR (CDCl3, 400 MHz) δ; 3.81-3.90 (2H, m), 6.74-6.79 (2H, m), 7.39-7.45 (1H, m), 7.67-7.75 (3H, m), 7.80-7.85 (1H, m), 8.05 (1H, s), 8.12-8.17 (1H, m). 2- [4- (4-Nitrophenyl) [1,2,3] triazol-2-yl] benzonitrile 439 mg (1.51 mmol) prepared in (21-3) was suspended in ethanol 15 mL and tin chloride was added. (II) Dihydrate 1.70 g (7.55 mmol) was added, and the mixture was heated to reflux for 45 minutes. After allowing to cool, 50 mL of saturated aqueous sodium bicarbonate and 100 mL of ethyl acetate were added to the reaction solution, insoluble material was filtered off through celite, and the filtrate was separated. The organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 1: 0 → 93: 7, V / V), and the solvent of the target fraction was evaporated under reduced pressure to give 2- [4- (4- A pale yellow powder 336 mg (yield 85%) of aminophenyl) [1,2,3] triazol-2-yl] benzonitrile was obtained.
1 H-NMR (CDCl3, 400 MHz) δ; 3.81-3.90 (2H, m), 6.74-6.79 (2H, m), 7.39-7.45 (1H, m), 7.67-7.75 (3H, m), 7.80- 7.85 (1H, m), 8.05 (1H, s), 8.12-8.17 (1H, m).
(21-5) N-{4-[2-(2-シアノフェニル)[1,2,3]トリアゾール-4-イル]フェニル}スルファミド (21-5) N- {4- [2- (2-Cyanophenyl) [1,2,3] triazol-4-yl] phenyl} sulfamide
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　t-ブタノール 0.17 mL (1.8 mmol) を塩化メチレン 2 mLに溶解し、氷冷下クロロスルホニルイソシアネート 0.13 mL (1.5 mmol) を加え、同温にて20 分間撹拌後、(21-4) で製造した2-[4-(4-アミノフェニル)[1,2,3]トリアゾール-2-イル]ベンゾニトリル 336 mg (1.29 mmol) およびトリエチルアミン 0.54 mL (3.9 mmol) の塩化メチレン 11 mLの溶液を加え、室温にて15 分間撹拌した。反応液に飽和塩化アンモニウム水10 mLを加え、酢酸エチルにて3回抽出後、有機層を合わせ飽和食塩水にて洗浄し、乾燥 (Na2SO4) した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（クロロホルム：メタノール、99:1→91:9、V/V）にて精製した。目的分画の溶媒を減圧下留去し、得られた淡褐色粉末に酢酸エチル-t-ブチルメチルエーテル (1:2) 15 mLを加え、不溶物をろ取し、淡黄色粉末363 mgを得た。
　得られた淡黄色粉末363 mgを塩化メチレン 5 mLに懸濁し、氷冷下トリフルオロ酢酸 5 mLを加え、室温にて1 時間撹拌した。減圧下反応液を濃縮乾固し、残渣にクロロホルムを加え、濃縮乾固する操作を3回繰り返した。残渣にt-ブチルメチルエーテル 8 mLを加え、不溶物をろ取し、N-{4-[2-(2-シアノフェニル)[1,2,3]トリアゾール-4-イル]フェニル}スルファミドの淡黄色粉末 236 mg (収率54％) を得た。
1H-NMR (DMSO-d6, 400 MHz) δ; 7.23-7.27 (2H, br), 7.27-7.32 (2H, m), 7.61-7.67 (1H, m), 7.88-7.96 (3H, m), 8.05-8.10 (1H, m), 8.14-8.18 (1H, m), 8.69 (1H, s), 9.82 (1H, s).
MS ; ESI m/z 363 [M+Na]+, 339 [M-H]-. 0.17 mL (1.8 mmol) of t-butanol was dissolved in 2 mL of methylene chloride, 0.13 mL (1.5 mmol) of chlorosulfonyl isocyanate was added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes and then prepared in (21-4) Add a solution of 2- [4- (4-aminophenyl) [1,2,3] triazol-2-yl] benzonitrile 336 mg (1.29 mmol) and triethylamine 0.54 mL (3.9 mmol) in 11 mL of methylene chloride, Stir at room temperature for 15 minutes. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 99: 1 → 91: 9, V / V). The solvent of the target fraction was distilled off under reduced pressure, and 15 mL of ethyl acetate-t-butylmethyl ether (1: 2) was added to the resulting light brown powder, and the insoluble material was collected by filtration to obtain 363 mg of a pale yellow powder. Obtained.
363 mg of the obtained pale yellow powder was suspended in 5 mL of methylene chloride, 5 mL of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the operation of adding chloroform to the residue and concentrating to dryness was repeated three times. To the residue was added 8 mL of t-butyl methyl ether, and the insoluble material was collected by filtration. N- {4- [2- (2-cyanophenyl) [1,2,3] triazol-4-yl] phenyl} sulfamide A pale yellow powder 236 mg (yield 54%) was obtained.
1 H-NMR (DMSO-d6, 400 MHz) δ; 7.23-7.27 (2H, br), 7.27-7.32 (2H, m), 7.61-7.67 (1H, m), 7.88-7.96 (3H, m), 8.05-8.10 (1H, m), 8.14-8.18 (1H, m), 8.69 (1H, s), 9.82 (1H, s).
MS; ESI m / z 363 [M + Na] + , 339 [MH] - .
　以下の表１－１～表１－５に示す実施例２２～５９は、実施例１～２１に準じて合成した。 Examples 22 to 59 shown in Table 1-1 to Table 1-5 below were synthesized according to Examples 1 to 21.
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
試験例１：ルシフェラーゼアッセイ
　IDUA (NM_000203.4) の Q70X 変異周辺 38 bp の5’末端に Kozak 配列(gccacc)および開始コドン(ATG)を付けた遺伝子を合成した。pNLF1-C [CMV/Hygro] Vector (Promega, Madison, WI) の EcoRV で切断後、合成した遺伝子をライゲーションすることで、ルシフェラーゼ遺伝子の上流にナンセンス変異配列を導入したプラスミドベクター(IDUA-Q70X-Luc)を得た。
　HeLa 細胞を 37℃、5% CO2 条件下、10% 牛胎児血清を含む MEM 培地（ナカライテスク Cat. No. 21443-15）で培養した。この細胞に、プラスミドベクター(IDUA-Q70X-Luc)を、FuGENE HD Transfection Reagent (Promega, Madison, WI) を用いてトランスフェクションした。翌日より、Hygromycin B（ナカライテスク Cat. No. 09287-84）を添加し37℃、5% CO2 条件下約 2 週間培養することで、安定発現細胞を選択した。
　作製した安定発現細胞を、 96 well white half area plate (Greiner)において、10% 牛胎児血清を含む MEM 培地（ナカライテスク Cat. No. 21443-15）中、1×104 cells/50 μL/well の細胞密度で播種した。次いで、各被験化合物を終濃度 0.001～100 μM になるよう添加した。コントロールには最終濃度 0.1% (v/v) の DMSO を添加した。37℃、5% CO2 条件下で 48 時間培養し、Nano-Glo Luciferase Assay (Promega, Madison, WI)によりルシフェラーゼ活性を、マルチプレートリーダー(BioTek)で測定した。実施例化合物の活性値を、コントロールの活性（すなわち、化合物非添加における残存活性（自然発生リードスルーにより生じた蛋白質の活性））を 100% とした相対値で表わし、活性を200% まで増加させた濃度を EC200値 として求めた。
　対照化合物に対する実施例化合物の活性比を以下の式から算出し、表２に示した。 Test Example 1: Luciferase assay A gene having a Kozak sequence (gccacc) and an initiation codon (ATG) at the 5 'end of 38 bp around the Q70X mutation of IDUA (NM_000203.4) was synthesized. After cutting with EcoRV of pNLF1-C [CMV / Hygro] Vector (Promega, Madison, WI) and ligating the synthesized gene, the plasmid vector (IDUA-Q70X-Luc )
HeLa cells were cultured in MEM medium (Nacalai Tesque Cat. No. 21443-15) containing 10% fetal calf serum under conditions of 37 ° C. and 5% CO 2 . The cells were transfected with a plasmid vector (IDUA-Q70X-Luc) using FuGENE HD Transfection Reagent (Promega, Madison, Wis.). From the next day, Hygromycin B (Nacalai Tesque Cat. No. 09287-84) was added and cultured under conditions of 37 ° C. and 5% CO 2 for about 2 weeks to select stably expressing cells.
Prepared stably expressing cells in 96-well white half area plate (Greiner) in MEM medium (Nacalai Tesque Cat. No. 21443-15) containing 10% fetal calf serum 1 × 10 4 cells / 50 μL / well Seeded at a cell density of. Next, each test compound was added to a final concentration of 0.001 to 100 μM. DMSO at a final concentration of 0.1% (v / v) was added to the control. The cells were cultured for 48 hours at 37 ° C. under 5% CO 2 , and luciferase activity was measured with a multi-plate reader (BioTek) by Nano-Glo Luciferase Assay (Promega, Madison, Wis.). The activity value of the Example compound is expressed as a relative value where the activity of the control (that is, the residual activity without addition of the compound (activity of the protein produced by spontaneous read-through)) is 100%, and the activity is increased to 200%. The concentration was determined as the EC 200 value.
The activity ratio of the example compound to the control compound was calculated from the following formula and shown in Table 2.
Figure JPOXMLDOC01-appb-M000128
Figure JPOXMLDOC01-appb-M000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000129
　試験例１の結果から、本発明の化合物（Ｉ）は、公知の対照化合物と比較して、５０倍以上という強力なリードスルー誘導活性を有することが確認された。 From the results of Test Example 1, it was confirmed that the compound (I) of the present invention has a strong lead-through inducing activity of 50 times or more compared to a known control compound.
製剤例１（カプセルの製造）
　１）実施例化合物　　　　　　　　　　　　　　　　　　　　１０　ｍｇ
　２）微粉末セルロース　　　　　　　　　　　　　　　　　　１０　ｍｇ
　３）乳糖　　　　　　　　　　　　　　　　　　　　　　　　１９　ｍｇ
　４）ステアリン酸マグネシウム　　　　　　　　　　　　　　　１　ｍｇ
　　　　　　　　　　　　　　　　　　　　　　　　　　　計　４０　ｍｇ
　１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 Formulation Example 1 (Manufacture of capsules)
1) Example compound 10 mg
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
40 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
製剤例２（錠剤の製造）
　１）実施例化合物　　　　　　　　　　　　　　　　　　　　１０　ｇ
　２）乳糖　　　　　　　　　　　　　　　　　　　　　　　　５０　ｇ
　３）トウモロコシデンプン　　　　　　　　　　　　　　　　１５　ｇ
　４）カルボキシメチルセルロースカルシウム　　　　　　　　４４　ｇ
　５）ステアリン酸マグネシウム　　　　　　　　　　　　　　　１　ｇ
　　　　　　　　　　　　　　　　　　　１０００錠　　計　１２０　ｇ
　１）、２）、３）の全量および３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。この整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたり実施例化合物１０ｍｇを含有する錠剤１０００錠を得る。 Formulation Example 2 (Manufacture of tablets)
1) Example compound 10 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 120 g
The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 10 mg of the example compound per tablet are obtained.
　本発明の化合物またはその医薬上許容される塩は、優れたリードスルー活性を有し、経口投与可能で安全性が高い化合物であり、ナンセンス変異型遺伝子疾患（例えば、筋ジストロフィー、デュシェンヌ型筋ジストロフィー、嚢胞性線維症、ムコ多糖症、セロイドリポフスチン症、ニーマンピック病等）の予防または治療剤となり得る。 The compound of the present invention or a pharmaceutically acceptable salt thereof has excellent read-through activity, is a compound that can be administered orally and is highly safe, and is nonsense mutant gene disease (for example, muscular dystrophy, Duchenne muscular dystrophy, cyst) Sexual fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis, Niemann-Pick disease, etc.).
　本出願は、特願２０１７－０７３９６８を基礎としており、その内容は本明細書に全て包含されるものである。
  This application is based on patent application No. 2017-073968, the contents of which are incorporated in full herein.

Claims (7)

  1. 　一般式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     　　　
    ［式中、
    環Ａは、それぞれさらに置換されていてもよい、フェニル基または６員の単環式含窒素複素環基を示し；
    Ｘは、単結合、さらに置換されていてもよい二価の４ないし７員の単環式複素環基またはさらに置換されていてもよいＣ２－６アルキニレン基を示し；および
    環Ｂは、それぞれさらに置換されていてもよい、アリール基または複素環基を示す。］で表される化合物またはその医薬上許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    Ring A represents a phenyl group or a 6-membered monocyclic nitrogen-containing heterocyclic group, each of which may be further substituted;
    X represents a single bond, a further divalent 4- to 7-membered monocyclic heterocyclic group which may be further substituted, or a C 2-6 alkynylene group which may be further substituted; Furthermore, the aryl group or heterocyclic group which may be further substituted is shown. Or a pharmaceutically acceptable salt thereof.
  2. 　環Ａが、それぞれさらに置換されていてもよい、フェニル基またはピリジル基であり、
    Ｘが、単結合またはさらに置換されていてもよい二価の５または６員の単環式芳香族複素環基であり、ならびに
    環Ｂが、それぞれさらに置換されていてもよい、Ｃ６－１０アリール基、５または６員の単環式複素環基あるいは８ないし１４員の縮合芳香族複素環基である、請求項１に記載の化合物またはその医薬上許容される塩。     Ring A is a phenyl group or a pyridyl group, each of which may be further substituted,
    X is a single bond or a divalent 5- or 6-membered monocyclic aromatic heterocyclic group which may be further substituted, and ring B may be further substituted, respectively, C 6-10 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is an aryl group, a 5- or 6-membered monocyclic heterocyclic group, or an 8- to 14-membered fused aromatic heterocyclic group.
  3. 　環Ａが、さらに置換されていてもよいフェニル基であり、
    Ｘが、単結合またはさらに置換されていてもよい二価の５員の単環式芳香族複素環基であり、ならびに
    環Ｂが、それぞれさらに置換されていてもよい、フェニル基または８ないし１４員の縮合芳香族複素環基である、請求項１に記載の化合物またはその医薬上許容される塩。     Ring A is a phenyl group which may be further substituted,
    X is a single bond or a divalent 5-membered monocyclic aromatic heterocyclic group which may be further substituted, and ring B may be further substituted, respectively, a phenyl group or 8 to 14 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a membered fused aromatic heterocyclic group.
  4. 　請求項１～３のいずれか一項に記載の化合物またはその医薬上許容される塩を有効成分として含有する医薬組成物。  A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 　請求項１～３のいずれか一項に記載の化合物またはその医薬上許容される塩を有効成分として含有するリードスルー誘導剤。 A lead-through inducer comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  6. 　請求項１～３のいずれか一項に記載の化合物またはその医薬上許容される塩を有効成分として含有するナンセンス変異型遺伝子疾患の予防または治療剤。 A preventive or therapeutic agent for a nonsense mutant genetic disease comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  7. 　ナンセンス変異型遺伝子疾患が、筋ジストロフィー、デュシェンヌ型筋ジストロフィー、嚢胞性線維症、ムコ多糖症、セロイドリポフスチン症またはニーマンピック病である、請求項６に記載の剤。 The agent according to claim 6, wherein the nonsense mutant genetic disease is muscular dystrophy, Duchenne muscular dystrophy, cystic fibrosis, mucopolysaccharidosis, ceroid lipofuscinosis or Niemann-Pick disease.
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