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WO2018186365A1 - Agent inducteur de lecture et application pharmaceutique correspondante - Google Patents

Agent inducteur de lecture et application pharmaceutique correspondante 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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WO
WIPO (PCT)
Prior art keywords
group
compound
mmol
added
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2018/014162
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English (en)
Japanese (ja)
Inventor
滋充 武田
弘明 白波瀬
俊輔 高嶋
達哉 北尾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyoto Pharmaceutical Industries Ltd
Original Assignee
Kyoto Pharmaceutical Industries Ltd
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Filing date
Publication date
Application filed by Kyoto Pharmaceutical Industries Ltd filed Critical Kyoto Pharmaceutical Industries Ltd
Publication of WO2018186365A1 publication Critical patent/WO2018186365A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • 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 
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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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    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/22—Oxygen atoms attached in position 2 or 4
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—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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    • C07D271/00—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
    • 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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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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.

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Abstract

La présente invention concerne un nouvel agent inducteur de lecture, ainsi qu'un composé représenté par la formule générale (I) (les symboles étant tels que définis dans la description) ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique contenant le composé en tant que composant actif. L'invention concerne un composé qui présente une activité de lecture, et peut également fournir un médicament destiné à être utilisé en tant qu'agent pour la prévention ou le traitement de maladies génétiques à médiation non-sens, telles que, la dystrophie musculaire, la dystrophie musculaire de Duchenne, la fibrose kystique, la mucopolysaccharidose, la lipofuscinose ceroïde et la maladie de Niemann-Pick.
PCT/JP2018/014162 2017-04-03 2018-04-02 Agent inducteur de lecture et application pharmaceutique correspondante Ceased WO2018186365A1 (fr)

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WO2019225625A1 (fr) * 2018-05-23 2019-11-28 京都薬品工業株式会社 Inducteur de translecture et utilisation pharmaceutique associée
KR20210036281A (ko) * 2019-09-25 2021-04-02 한국원자력의학원 신규 트리플루오로메틸페닐피라졸 유도체를 유효성분으로 함유하는 암 예방 또는 치료용 조성물
WO2021060888A3 (fr) * 2019-09-25 2021-09-02 한국원자력의학원 Composition pour prévenir ou traiter le cancer, contenant un dérivé à base de trifluorométhylphényl pyrazole comme principe actif
WO2021228945A1 (fr) * 2020-05-12 2021-11-18 Centre National De La Recherche Scientifique Composés de quinazoline utilisés en tant qu'inhibiteurs de codons stop prématurés
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
AU2022283883B2 (en) * 2021-06-01 2025-07-24 Azcuris Co., Ltd. Novel oxazole derivative and pharmaceutical composition containing same for prevention or treatment of allergic disease

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WO2019225625A1 (fr) * 2018-05-23 2019-11-28 京都薬品工業株式会社 Inducteur de translecture et utilisation pharmaceutique associée
KR20210036281A (ko) * 2019-09-25 2021-04-02 한국원자력의학원 신규 트리플루오로메틸페닐피라졸 유도체를 유효성분으로 함유하는 암 예방 또는 치료용 조성물
WO2021060888A3 (fr) * 2019-09-25 2021-09-02 한국원자력의학원 Composition pour prévenir ou traiter le cancer, contenant un dérivé à base de trifluorométhylphényl pyrazole comme principe actif
JP2022550109A (ja) * 2019-09-25 2022-11-30 コリア インスティチュート オブ レディオロジカル アンド メディカル サイエンシズ 新規なトリフルオロメチルフェニルピラゾール誘導体を有効成分として含有する癌の予防または治療用組成物
KR102663365B1 (ko) 2019-09-25 2024-05-08 한국원자력의학원 신규 트리플루오로메틸페닐피라졸 유도체를 유효성분으로 함유하는 암 예방 또는 치료용 조성물
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US12247021B2 (en) 2019-12-06 2025-03-11 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
WO2021228945A1 (fr) * 2020-05-12 2021-11-18 Centre National De La Recherche Scientifique Composés de quinazoline utilisés en tant qu'inhibiteurs de codons stop prématurés
JP2023526315A (ja) * 2020-05-12 2023-06-21 サントル ナシオナル ドゥ ラ ルシェルシェ サイアンティフィク 未成熟終止コドンの阻害剤としてのキナゾリン化合物
AU2022283883B2 (en) * 2021-06-01 2025-07-24 Azcuris Co., Ltd. Novel oxazole derivative and pharmaceutical composition containing same for prevention or treatment of allergic disease
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US12258333B2 (en) 2021-06-04 2025-03-25 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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