WO2014123203A1 - Agent thérapeutique destiné à traiter le diabète - Google Patents

Agent thérapeutique destiné à traiter le diabète Download PDF

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Publication number
WO2014123203A1
WO2014123203A1 PCT/JP2014/052803 JP2014052803W WO2014123203A1 WO 2014123203 A1 WO2014123203 A1 WO 2014123203A1 JP 2014052803 W JP2014052803 W JP 2014052803W WO 2014123203 A1 WO2014123203 A1 WO 2014123203A1
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Prior art keywords
optionally substituted
compound
diyl
alkyl
phenyl
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PCT/JP2014/052803
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English (en)
Japanese (ja)
Inventor
俊吉 田中
正樹 福井
一弥 小竹
正恭 笠井
弘明 白波瀬
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京都薬品工業株式会社
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Priority to JP2014560808A priority Critical patent/JPWO2014123203A1/ja
Publication of WO2014123203A1 publication Critical patent/WO2014123203A1/fr

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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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Definitions

  • the present invention relates to a compound having a protein tyrosine phosphatase-1B (PTP-1B; Protein Tyrosine Phosphatase-1B) inhibitory activity, a blood glucose lowering action, a blood lipid lowering action and / or an insulin resistance improving action, or a pharmaceutical thereof Relates to acceptable salts.
  • PTP-1B protein tyrosine phosphatase-1B
  • the present invention also relates to a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention provides a therapeutic agent for diabetes, an insulin resistance improving agent, a glucose intolerance improving agent, a therapeutic agent for diabetic complications, an antiobesity agent, an antihyperglycemia comprising the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a prophylactic agent, a therapeutic agent for fatty liver, an antihyperlipidemic agent, an anti-arteriosclerosis agent, an anti-inflammatory agent, an anticancer agent, a prophylactic / therapeutic agent for diseases mediated by PTP-1B, and a prophylactic / therapeutic agent for metabolic syndrome.
  • Diabetes is a disease that causes various metabolic abnormalities, mainly chronic hyperglycemia, and causes various complications such as retinopathy, nephropathy, peripheral neuropathy, myocardial infarction based on arteriosclerosis, and cerebral infarction. cause.
  • Metabolic syndrome is a state in which visceral fat obesity is combined with two or more of hyperglycemia, hypertension, and hyperlipidemia, and mortality due to coronary artery disease is high.
  • Diabetes is type I diabetes (insulin-dependent diabetes mellitus; IDDM) characterized by impaired insulin secretion mainly caused by islet cell destruction caused by autoantibody production against the islets, reduced insulin secretion from the pancreas, or skeletal muscle, Type II diabetes caused by insulin resistance in the liver, adipocytes, etc. (non-insulin dependent diabetes mellitus; NIDDM) is roughly classified.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • type II diabetic patients are rapidly increasing, accounting for over 90% of diabetic patients in Japan.
  • Representative therapeutic agents for type II diabetes include insulin secretagogues (sulfonylurea compounds, sulfonamide compounds, phenylalanine derivatives, GLP-1 analogs, DPP-4 inhibitors, etc.), biguanide compounds, ⁇ -glucosidase inhibition Agents, Peroxisome Proliferator-activated Receptor ⁇ (PPAR ⁇ ) activators (thiazolidinedione derivatives, etc.).
  • biguanide compounds and PPAR ⁇ activators increase the sensitivity of insulin and lower blood sugar independently of insulin secretion.
  • biguanide compounds cause lactic acidosis, diarrhea, and vomiting
  • PPAR ⁇ activators can cause side effects such as liver damage, weight gain, fluid retention, hemodilution, edema, cardiac hypertrophy, and increased risk of fracture.
  • the development of a therapeutic agent for insulin-sensitized diabetes that has been reported and is more effective and safe is desired.
  • Insulin is a hormone related to blood glucose regulation made by pancreatic ⁇ cells.
  • insulin receptors on the surface of membranes such as skeletal muscle cells, hepatocytes, and adipocytes
  • tyrosine kinases phosphorylate tyrosine residues in the intracellular domain of insulin receptors .
  • tyrosine residues such as IRS (insulin receptor substrate) and APS (adapter protein containing PH and SH2 domain), which are insulin receptor substrates, are phosphorylated, and the PI3 kinase-Akt pathway is activated. Is transferred onto the cell membrane, glucose uptake occurs, and the sugar concentration in the blood decreases.
  • tyrosine phosphatase that negatively regulates intracellular signal transduction by insulin by dephosphorylating phosphorylated tyrosine, suppressing the action of insulin. That is, tyrosine phosphorylation in insulin signaling is regulated by the balance between tyrosine kinase and tyrosine phosphatase. Thus, insulin action is enhanced by inhibiting tyrosine phosphatase.
  • insulin resistance can be improved by inhibiting tyrosine phosphatase.
  • Tyrosine phosphatase is also involved in signal transduction of leptin, a peptide hormone secreted from adipocytes.
  • Leptin is a hormone involved in the suppression of obesity, which has a strong inhibitory effect on food intake and energy consumption.
  • the leptin signal like the insulin signal, is regulated by tyrosine kinases and tyrosine phosphatases to phosphorylate tyrosine residues in the intracellular domain of the leptin receptor. Therefore, when tyrosine phosphatase activity is enhanced, dephosphorylation of phosphorylated tyrosine is enhanced, leading to leptin resistance (Non-patent Document 1).
  • PTP-1B is considered to be a major phosphatase involved in insulin and leptin signaling.
  • PTP-1B gene expression is increased in high glucose culture, and its intracellular localization is changed to reduce insulin receptor and IRS-1 tyrosine phosphorylation, thereby inducing insulin resistance (non-patented).
  • Non-Patent Document 4 introduction of wild-type PTP-1B impairs translocation of the sugar transporter GLUT4, and further enhances insulin sensitivity in PTP-1B knockout mice, and also against high-fat diet It becomes obesity resistant (Non-Patent Document 4), and PTP-1B knockout mice exhibit increased insulin sensitivity, increased energy metabolism, and decreased white adipose fine tissue weight (Non-Patent Document 5). It has been reported. Therefore, a drug that suppresses and / or inhibits the activation of PTP-1B inhibits dephosphorylation by PTP-1B and enhances insulin and leptin signaling, thereby causing diabetes due to insulin resistance and leptin resistance. It is thought to improve obesity and the like. Since this PTP-1B inhibitor has a novel action of normalizing and enhancing intracellular signal transduction, it can be a new type of diabetes therapeutic agent that avoids the problems of existing diabetes therapeutic agents.
  • Non-patent Documents 6 to 9 and Patent Documents 1 to 12 disclose a compound having a structure such as the compound of the present invention, nor a statement to suggest it.
  • a compound represented by the following general formula (I) having a novel structure or a pharmaceutically acceptable salt thereof is PTP-1B. Since it has an inhibitory action and exhibits such actions as a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, etc., it has been found to be an extremely excellent compound as a pharmaceutical, and the present invention has been completed. It was.
  • A represents an optionally substituted carbocyclic group, an optionally substituted biaryl, or an optionally substituted heterocyclic group
  • B represents an optionally substituted divalent carbocyclic group, an optionally substituted biarylene, or an optionally substituted divalent heterocyclic group
  • C is an optionally substituted carbocyclic group, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted alkyl, a substituted An optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic alkenyl;
  • X is an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted * — (CH 2 ) m —O— (CH 2 ) n
  • X is optionally substituted * — (CH 2 ) 3 — **, optionally substituted * — (CH 2 ) m —O— (CH 2 ) n — **, substituted * — (CH 2 ) m —S (O) p — (CH 2 ) n — **, optionally substituted * — (CH 2 ) m —N (R 1 ) — (CH 2 ) N -**, optionally substituted *-(CH 2 ) m -CO- (CH 2 ) n -**, optionally substituted *-(CH 2 ) q -CO-N (R 1 ) — (CH 2 ) r — **, optionally substituted * — (CH 2 ) q —N (R 1 ) —CO— (CH 2 ) r — **, optionally substituted * — (CH 2 ) q —N (R 1 ) —CO— (CH 2 ) r — **,
  • the compound represented by the general formula (I) is: (1) N- [4- (biphenyl-4-ylmethylsulfanylmethyl) benzoyl] octane-1-sulfonamide, (2) N- [4- (biphenyl-4-ylmethoxymethyl) benzoyl] -2,4-dichlorobenzenesulfonamide, (3) N- [4- (biphenyl-4-ylmethoxymethyl) benzoyl] octane-1-sulfonamide, (4) N- [4- (biphenyl-4-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide, (5) N- [4- (biphenyl-4-ylmethylsulfanylmethyl) benzoyl] -4-cyclopropylbutane-1-sulfonamide, (6) N- [4- (biphenyl-4-ylmeth
  • the compound represented by the above general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a PTP-1B inhibitory action, it has a blood glucose lowering action, a blood lipid lowering action and / or an insulin resistance improvement.
  • Antihyperglycemic agent, antihyperlipidemic agent, insulin resistance improving agent, diabetes treatment agent, diabetic complication treatment agent, glucose intolerance improving agent, anti-arteriosclerosis agent, anti-obesity agent, anti-hyperglycemic agent It is useful as an inflammatory agent, a prophylactic / therapeutic agent for diseases mediated by PTP-1B, and a prophylactic / therapeutic agent for metabolic syndrome.
  • the pharmaceutical which contains this invention compound as an active ingredient has few side effects, it can become a highly safe therapeutic agent for diabetes.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the term “lower” for an organic group such as an alkyl group means that the number of carbon atoms is 1 to 6.
  • alkyl refers to a linear or branched monovalent saturated hydrocarbon group having 1 to 12 carbon atoms (hereinafter sometimes referred to as C 1-12 alkyl. The same applies to others. .)
  • Examples of the “alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 4-methylpentyl, hexyl, heptyl, octyl, nonyl, decyl. , Undecyl, dodecyl and the like.
  • cycloalkyl means a monovalent group derived from a saturated hydrocarbon ring having 3 to 10 carbon atoms. Further, “cycloalkyl” may be bridged. Examples of the “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
  • alkenyl means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 10 carbon atoms.
  • alkenyl include vinyl, 1-propenyl (allyl), 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and 2-butene-2.
  • cycloalkenyl means a monovalent group derived from a partially unsaturated hydrocarbon ring having 3 to 10 carbon atoms. Further, “cycloalkenyl” may be cross-linked. Examples of the “cycloalkenyl” include cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclopentenyl (eg, 1-cyclopenten-1-yl).
  • alkynyl means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 10 carbon atoms.
  • the “alkynyl” may have one or more carbon-carbon double bonds in addition to one or more carbon-carbon triple bonds.
  • Examples of the “alkynyl” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and 1-hexynyl.
  • cycloalkylalkyl means a monovalent group in which the “cycloalkyl” group is bonded to the “alkyl” group.
  • examples of the “cycloalkylalkyl” include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl.
  • Cyclooctylethyl cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctylpropyl, cyclopropylbutyl, cyclopropylpentyl and the like.
  • alkylene means a linear or branched divalent saturated hydrocarbon group having 1 to 10 carbon atoms. Examples include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, 2,2-dimethylethylene, 2,2-dimethylpropylene and the like.
  • alkenylene means a linear or branched divalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 10 carbon atoms.
  • alkenylene include vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the like.
  • alkynylene means a linear or branched divalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 10 carbon atoms.
  • alkynylene examples include ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the like.
  • carbocyclic group means aryl and non-aromatic carbocyclic groups.
  • aryl means a monovalent aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • examples of the “aryl” include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl, phenanthryl and the like.
  • the “aromatic hydrocarbon” includes a ring corresponding to the above “aryl”.
  • non-aromatic carbocyclic group means a monovalent saturated or partially saturated cyclic hydrocarbon group having 3 to 14 carbon atoms.
  • examples of the “non-aromatic carbocyclic group” include cycloalkyl, cycloalkenyl, condensed non-aromatic carbocyclic group and the like.
  • the “fused non-aromatic carbocyclic group” means a carbocyclic group in which an cycloalkyl or cycloalkenyl and an aromatic hydrocarbon are condensed, for example, indanyl (eg, 2-indanyl, 5-indanyl). , Indenyl (eg, 2-indenyl, 5-indenyl), fluorenyl (eg, 2-fluorenyl, 9-fluorenyl) and the like.
  • arylalkyl means a monovalent group in which the “aryl” group is bonded to the “alkyl” group.
  • examples of the “arylalkyl” include benzyl, naphthylmethyl, phenylethyl, naphthylethyl, phenylpropyl, naphthylpropyl and the like.
  • arylalkenyl means a monovalent group in which the “aryl” group is bonded to the “alkenyl” group.
  • examples of the “arylalkenyl” include phenylvinyl, naphthylvinyl, phenylbutadienyl (eg, 4-phenylbuta-1,3-dien-1-yl) and the like.
  • arylalkynyl means a monovalent group in which the “aryl” group is bonded to the “alkynyl” group.
  • examples of the “arylalkynyl” include phenylethynyl, naphthylethynyl and the like.
  • alkoxy means a group in which the “alkyl” group is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 10 carbon atoms.
  • alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • cycloalkoxy means a group in which the “cycloalkyl” group is bonded to an oxygen atom.
  • examples of the “cycloalkoxy” include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • arylalkyloxy means a monovalent group in which the “arylalkyl” group is bonded to an oxygen atom.
  • the “arylalkyloxy” is a monovalent group in which the “arylalkyl” is bonded to an oxygen atom, and examples thereof include benzyloxy, naphthylmethoxy, phenylethoxy, naphthylethoxy, phenylpropoxy, naphthylpropoxy and the like.
  • “mono or di-alkylamino” means a group in which one or two “alkyl” groups are bonded to an amino group, that is, mono or di (straight or branched having 1 to 10 carbon atoms). Means a chain alkyl) amino group.
  • Examples of the “mono or di-alkylamino” include methylamino, ethylamino, dimethylamino, diethylamino and the like.
  • alkylsulfanyl means a group in which the “alkyl” group is bonded to a sulfur atom, that is, a linear or branched alkylsulfanyl group having 1 to 10 carbon atoms.
  • alkylsulfanyl examples include, for example, methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, Xylsulfanyl and the like.
  • alkylcarbonyl means a group in which the “alkyl” group is bonded to a carbonyl group, that is, a linear or branched alkylcarbonyl group having 1 to 10 carbon atoms.
  • alkylcarbonyl include acetyl, propionyl 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” is a monovalent 5- to 14-membered monocyclic aromatic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. It means a heterocyclic group and a condensed aromatic heterocyclic group.
  • the fused 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 monocyclic aromatic heterocyclic rings such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and the like.
  • indolyl isoindolyl, indazolyl, benzofuryl, benzothiophenyl, benzoimidazolyl (eg, 5-benzoimidazolyl), benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, furo [2,3-b] Pyridyl, thieno [2,3-b] pyridyl, naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, quinolyl, carbazolyl, dibenzothiophenyl, etc. It includes ring aromatic heterocyclic group.
  • non-aromatic heterocyclic group means a monovalent 3- to 14-membered monocyclic non-cyclic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • An aromatic heterocyclic group and a fused non-aromatic heterocyclic group are meant.
  • 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.
  • the monocyclic non-aromatic heterocyclic group includes a 5- to 9-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.
  • non-aromatic heterocyclic group examples include tetrahydrofuryl, oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (Eg, 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl (eg, 1-piperidyl, 2-piperidyl, 3-piperidyl), azepanyl (eg, 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (eg, 1-azocanyl, 2-azocanyl, 3-azocanyl,
  • Aromatic heterocyclic groups dihydrobenzofuryl, dihydroquinolyl, dihydroisoquinolyl (eg, 3,4-dihydroisoquinolin-2-yl), dihydroindolyl (eg, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-1-yl), dihydroisoindolyl (eg, 2,3-dihydroisoindol-2-yl), benzodioxanyl (eg, 1,4-benzodioxan-6-yl) And condensed non-aromatic heterocyclic groups such as benzodioxolyl (eg, 1,3-benzodioxol-5-yl).
  • biasing is a monovalent group in which the “aryl” groups are directly bonded, a monovalent group in which the “aromatic heterocyclic” groups are directly bonded, or the “aryl” group. It means a monovalent group to which the “aromatic heterocycle” group is directly bonded.
  • Examples of the “biaryl” include biphenylyl (eg, 4-biphenylyl, 3-biphenylyl), bipyridyl, pyridylphenyl, phenylpyridyl and the like.
  • the “aromatic heterocyclic alkyl” means a monovalent group in which the “aromatic heterocyclic group” is bonded to the “alkyl” group.
  • the “aromatic heterocyclic alkyl” include pyridylmethyl and the like.
  • the “aromatic heterocyclic alkenyl” means a monovalent group in which the “aromatic heterocyclic group” is bonded to the “alkenyl” group.
  • Examples of the “aromatic heterocyclic alkenyl” include furylbutadienyl (eg, 4- (2-furyl) buta-1,3-dien-1-yl) and the like.
  • aromatic heterocyclic alkynyl means a monovalent group in which the “aromatic heterocyclic group” is bonded to the “alkynyl” group.
  • aromatic heterocyclic alkynyl examples include thiazolylethynyl (eg, thiazol-2-ylethynyl) and the like.
  • divalent carbocyclic group means arylene and a divalent non-aromatic carbocyclic group.
  • arylene means a divalent aromatic hydrocarbon group derived from the “aryl” group.
  • examples of the “arylene” include benzene-1,4-diyl (hereinafter also referred to as 1,4-phenylene), benzene-1,3-diyl, benzene-1,2-diyl (hereinafter, 1,2-phenylene).
  • Phenylene), naphthalene-1,8-diyl hereinafter also referred to as 1,8-naphthylene
  • naphthalene-1,5-diyl hereinafter also referred to as 1,5-naphthylene
  • anthracene-1,4-diyl Etc anthracene-1,4-diyl Etc.
  • the “divalent non-aromatic carbocyclic group” means a cycloalkylene, cycloalkenylene, divalent fused non-aromatic carbocyclic group.
  • cycloalkylene means a divalent saturated carbocyclic group derived from the “cycloalkyl” group. Examples of the “cycloalkylene” include cyclopropylene, cyclobutane-diyl, cyclopentane-diyl, cyclohexane-diyl and the like.
  • cycloalkenylene means a divalent partially saturated carbocyclic group derived from the “cycloalkenyl” group.
  • examples of the “cycloalkenylene” include cyclopropene-diyl, cyclobutene-diyl, cyclopentene-diyl, cyclohexene-diyl and the like.
  • the “divalent fused non-aromatic carbocyclic group” means a divalent carbocyclic group derived from the “fused non-aromatic carbocyclic group”.
  • Examples of the “divalent fused non-aromatic carbocyclic group” include indan-diyl and the like.
  • the “divalent heterocyclic group” is a 3- to 14-membered (monocyclic, bicyclic or tricyclic) containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • Ring system means a divalent group derived from a heterocyclic ring, and includes a divalent aromatic heterocyclic group and a divalent non-aromatic heterocyclic group.
  • the “divalent aromatic heterocyclic group” means a monocyclic aromatic heterocyclic ring or condensed aromatic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Means a divalent group derived from a heterocyclic group.
  • Examples of the “divalent aromatic heterocyclic group” include furan-2,5-diyl (hereinafter also referred to as 2,5-furylene), thiophene-2,4-diyl, thiophene-2,5-diyl.
  • the “divalent non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic ring containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, or It means a divalent group derived from a fused non-aromatic heterocyclic ring.
  • Examples of the “divalent non-aromatic heterocyclic group” include piperidine-diyl, dihydroindole-diyl and the like.
  • biaslene means a divalent group derived from the “biaryl”.
  • examples of the “biarylene” include biphenylene (eg, 4,4′-biphenylene, 2,4′-biphenylene), phenylpyridine-diyl, phenylpyrazole-diyl, phenylpyridazine-diyl, phenylpyrazine-diyl, pyrazolylpyridazine -Diyl, pyrazolylpyrazine-diyl and the like.
  • A represents an optionally substituted carbocyclic group, an optionally substituted biaryl, or an optionally substituted heterocyclic group.
  • the “carbocyclic group” of the “optionally substituted carbocyclic group” represented by A is preferably a C 6-14 aryl or condensed non-aromatic carbocyclic group, more preferably phenyl, naphthyl ( Examples, 1-naphthyl), indanyl (eg, 2-indanyl, 5-indanyl), fluorenyl (eg, 2-fluorenyl) and the like.
  • the “carbocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the following substituent group A. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • [Substituent group A] (1) a halogen atom, (2) hydroxy, (3) Carboxy, (4) Cyano, (5) Nitro, (6) (i) a halogen atom, and (ii) an alkyl optionally substituted with 1 to 5 substituents selected from arylalkoxy optionally substituted with alkyl, (7) arylalkyl, (8) aromatic heterocyclic alkyl, (9) Alkenyl, (10) arylalkenyl, (11) aromatic heterocyclic alkenyl, (12) alkynyl, (13) arylalkynyl, (14) aromatic heterocyclic alkynyl, (15) alkoxy, (16) aryloxy, (17) aromatic heterocyclic oxy, (18) amino, (19) mono- or di-alkylamino, (20) cycloalkyl, (21) cycloalkoxy, (22) (i) a halogen atom, and (ii) aryl optionally substituted with 1 to 3 substituents
  • the “optionally substituted carbocyclic group” is preferably (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, methyl, isopropyl, tert-butyl, hexyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) arylalkynyl (eg, phenylethynyl), (h) heterocyclic alkynyl [eg, thiazolylethynyl (eg, thiazol-5-ylethynyl)],
  • the “optionally substituted carbocyclic group” is preferably (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, methyl, isopropyl, tert-butyl, hexyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) arylalkynyl (eg, phenylethynyl), (h) heterocyclic alkynyl [eg, thiazolylethynyl (eg, thiazol-5-ylethynyl),
  • the “biaryl” of the “optionally substituted biaryl” represented by A is preferably biphenylyl, a monovalent substituent in which a 5- or 6-membered aromatic heterocyclic ring and phenyl are directly bonded, or 5 or 6 Monovalent substituents in which member aromatic heterocycles are directly bonded to each other, and more preferably biphenylyl (eg, 4-biphenylyl, 3-biphenylyl, etc.), pyridylphenyl (eg, 2-pyridylphenyl, 3-pyridyl).
  • biphenylyl eg, 4-biphenylyl, 3-biphenylyl, etc.
  • furylphenyl e.g, 4-biphenylyl, 3-biphenylyl, etc.
  • furylphenyl eg, 4-biphenylyl, 3-biphenylyl, etc.
  • furylphenyl eg, pyrazolylthiazolyl, thiadiazolylphenyl, phenyloxadiazolyl, thienylphenyl, pyrrolylphenyl
  • biphenylyl eg, 4-biphenylyl, 3-biphenylyl, etc.
  • furylphenyl e.g., 4-biphenylyl, 3-biphenylyl, etc.
  • pyrazolylthiazolyl e.g., thiadiazolylphenyl, phenyloxadiazolyl, thienylphenyl, pyrrolylphenyl
  • Phenylpyridyl pyridylphenyl
  • triazolylphenyl oxazolylphenyl (eg, isoxazol-5-ylphenyl) and the like.
  • the “biaryl” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted biaryl” is preferably (a) a halogen atom (eg, fluorine atom, chlorine atom), and (b) Alkyl (eg, methyl, isopropyl) optionally substituted with 1 to 7 halogen atoms (eg, fluorine atom) Biaryl optionally substituted with 1 to 3 (preferably 1 or 2) substituents selected from [eg, biphenylyl (eg, 4-biphenylyl, 3-biphenylyl), furylphenyl, pyrazolylthiazolyl , Thiadiazolylphenyl, phenyloxadiazolyl, thienylphenyl, pyrrolylphenyl].
  • a halogen atom eg, fluorine atom, chlorine atom
  • Alkyl eg, methyl, isopropyl
  • 1 to 7 halogen atoms eg, fluorine atom
  • Biaryl optionally substituted with 1
  • the “optionally substituted biaryl” is preferably (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) alkyl (eg, methyl, isopropyl) optionally substituted with 1 to 7 halogen atoms (eg, fluorine atom), (c) carboxy, (d) alkoxy (eg, methoxy), (e) cyano, (f) nitro, and (g) Mono- or di-alkylamino (eg dimethylamino) Biaryl optionally substituted with 1 to 3 (preferably 1 or 2) substituents selected from [eg, biphenylyl (eg, 4-biphenylyl, 3-biphenylyl), furylphenyl, pyrazolylthiazolyl , Thiadiazolylphenyl, phenyloxadiazolyl, thienylphenyl, pyrrolylphenyl, phenylpyridyl, pyrrolyl
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by A is preferably oxazolyl (eg, 4-oxazolyl), thiazolyl (eg, 2-thiazolyl, 5-thiazolyl), thienyl ( Examples, 2-thienyl), oxadiazolyl (eg, [1,2,4] oxadiazol-5-yl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), benzoimidazolyl (eg, 5- Benzimidazolyl), indolyl (eg, 5-indolyl), benzothiazolyl (eg, 2-benzothiazolyl), carbazolyl (eg, 3-carbazolyl, 9-carbazolyl), dihydroindolyl (eg, 2,3-dihydroindol-5-yl) , 2,3-dihydroindol-1
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by A is more preferably oxazolyl (eg, 4-oxazolyl), thiazolyl (eg, 2-thiazolyl, 5-thiazolyl), thienyl (Eg, 2-thienyl), oxadiazolyl (eg, [1,2,4] oxadiazol-5-yl), benzimidazolyl (eg, 5-benzoimidazolyl), indolyl (eg, 5-indolyl), dihydroindolyl ( Examples are 2,3-dihydroindol-5-yl, 2,3-dihydroindol-1-yl), benzothiazolyl (eg, 2-benzothiazolyl), carbazolyl (eg, 3-carbazolyl, 9-carbazolyl) and the like.
  • oxazolyl eg, 4-oxazolyl
  • thiazolyl eg
  • the “heterocyclic group” of the “optionally substituted heterocyclic group” is more preferably oxazolyl (eg, 4-oxazolyl), thiazolyl (eg, 2-thiazolyl, 5-thiazolyl), Thienyl (eg, 2-thienyl), oxadiazolyl (eg, [1,2,4] oxadiazol-5-yl), benzimidazolyl (eg, 5-benzimidazolyl), indolyl (eg, 5-indolyl), dihydroindolyl (Eg, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-1-yl), benzothiazolyl (eg, 2-benzothiazolyl), carbazolyl (eg, 3-carbazolyl, 9-carbazolyl), pyridyl ( Examples are 2-pyridyl), benzoxazolyl (eg, 6-benzyl),
  • the “heterocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted heterocyclic group” is preferably (a) alkyl (eg, methyl, ethyl, isopropyl), (b) alkenyl (eg, 4-methyl-1-pentenyl), (c) alkylcarbonyl (eg, acetyl), (d) aryl (eg, phenyl), and (e) Aromatic heterocyclic group (eg, pyrazolyl) 5- to 14-membered heterocyclic group optionally substituted with 1 to 3 (preferably 1 or 2) substituents selected from [eg, oxazolyl (eg, 4-oxazolyl), thiazolyl (eg, , 2-thiazolyl, 5-thiazolyl), thienyl (eg, 2-thienyl), oxadiazolyl (eg, [1,2,4] oxadiazol-5-yl), benzoimidazolyl (eg, 5-benzoimidazolyl), indolyl ( Example
  • A is preferably an optionally substituted 6-14 membered carbocyclic group, an optionally substituted biaryl, or an optionally substituted 5-14 membered heterocyclic group, specifically Is (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, methyl, isopropyl, tert-butyl, hexyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) arylalkynyl (eg, phenylethynyl), (h) heterocyclic alkynyl
  • A is preferably an optionally substituted 6-14 membered carbocyclic group, an optionally substituted biaryl, or an optionally substituted 5-14 membered heterocyclic group.
  • A is (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, methyl, isopropyl, tert-butyl, hexyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) arylalkynyl (eg, phenylethynyl), (h) heterocyclic
  • A is more preferably an optionally substituted phenyl or an optionally substituted dihydroindolyl (eg, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-1-yl).
  • halogen atom eg, chlorine atom
  • alkyl eg, methyl, isopropyl, tert-butyl, hexyl
  • 1 to 5 halogen atoms eg, fluorine atom
  • alkenyl eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl
  • arylalkenyl eg, phenyl vinyl (eg, 2-phenyl vinyl)]
  • alkynyl eg, ethynyl
  • arylalkynyl eg, phenylethynyl
  • heterocyclic alkynyl eg, thiazolylethynyl (eg, thiazol-5-ylethynyl)]
  • alkoxy eg, iso
  • A is more preferably an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, specifically, (1) (a) alkyl (eg, isopropyl, hexyl), and (b) mono- or di-alkylamino (eg, ethylamino, dimethylamino, diethylamino) 6- to 14-membered carbocyclic group optionally substituted by 1 to 3 (preferably 1 or 2) substituents selected from [eg, phenyl, indanyl (eg, 2-indanyl, 5- Indanyl)], or (2) (a) alkyl (eg, methyl, ethyl, isopropyl), and (b) alkylcarbonyl (eg, acetyl) 5- to 14-membered heterocyclic group optionally substituted with 1 to 3 (preferably 1 or 2) substituents selected from [eg, thienyl (eg, 2-thienyl), benzoimidazoly
  • A is more preferably (1) (a) alkyl (eg, isopropyl, hexyl), (b) mono- or di-alkylamino (eg ethylamino, dimethylamino, diethylamino), (c) (i) alkyl (eg, methyl) optionally substituted with 1 to 7 halogen atoms (eg, fluorine atom), (ii) Nitro, (iii) mono- or di-alkylamino (eg, dimethylamino), and (iv) alkoxy (eg, methoxy) Aryl (eg, phenyl) optionally substituted with 1 to 3 substituents selected from: (d) a non-aromatic heterocyclic group [eg, benzodioxanyl (eg, 1,4-benzo Dioxane-6-yl)] 6- to 14-membered carbocyclic group optionally substituted by 1 to 3 (preferably 1 or 2) substituents selected from:
  • A is more preferably an optionally substituted aryl, an optionally substituted biaryl, or an optionally substituted aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, isopropyl, tert-butyl), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) heterocyclic alkynyl [eg, thiazoleethynyl (eg, thiazol-5-ylethynyl)], (h) arylalkynyl (eg, phenylethynyl), (i) alkoxy (eg, is
  • A is more preferably an optionally substituted aryl, an optionally substituted biaryl, or an optionally substituted aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, isopropyl, tert-butyl), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) heterocyclic alkynyl [eg, thiazoleethynyl (eg, thiazol-5-ylethynyl)], (h) arylalkynyl (eg, phenylethynyl), (i) alkoxy (e
  • A is even more preferably an optionally substituted phenyl, specifically (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, methyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) heterocyclic alkynyl [eg, thiazolylethynyl (eg, thiazol-5-ylethynyl)], (h) arylalkynyl (eg, phenylethynyl), (i) al
  • B represents a divalent carbocyclic group that may be substituted, a biarylene that may be substituted, or a divalent heterocyclic group that may be substituted.
  • the “divalent carbocyclic group” of the “optionally substituted divalent carbocyclic group” represented by B is preferably a C 6-10 arylene or a divalent non-aromatic carbocyclic group, More preferably, phenylene (eg, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene), indan-diyl (eg, indan-2,5-diyl), naphthylene (eg, 1,5-phenylene) Naphthylene).
  • the “divalent carbocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted divalent carbocyclic group” is preferably (a) a halogen atom (eg, a chlorine atom), (b) alkoxy (eg, methoxy), (c) aryloxy (eg, phenoxy), and (d) arylalkoxyalkyl (eg, benzyloxymethyl) optionally substituted with alkyl (eg, isopropyl) C 6-10 arylene optionally substituted with 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1,2-phenylene), Indan-diyl (eg, indan-2,5-diyl), naphthylene (eg, 1,5-naphthylene)].
  • a halogen atom eg, a chlorine atom
  • alkoxy eg, methoxy
  • aryloxy eg, phenoxy
  • arylalkoxyalkyl eg
  • the “biarylene” of the “optionally substituted biarylene” represented by B is preferably biphenylylene, phenylpyridine-diyl, phenylpyrazole-diyl, phenylpyridazine-diyl, pyrazolylpyridazine-diyl.
  • the “biarylene” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted biarylene” represented by B is preferably “biarylene”, more preferably biphenylylene (eg, 4,4′-biphenylylene, 2,4′-biphenylylene), phenylpyridine- Diyl, phenylpyrazole-diyl, phenylpyridazine-diyl, pyrazolylpyridazine-diyl.
  • biaslene more preferably biphenylylene (eg, 4,4′-biphenylylene, 2,4′-biphenylylene), phenylpyridine- Diyl, phenylpyrazole-diyl, phenylpyridazine-diyl, pyrazolylpyridazine-diyl.
  • the “divalent heterocyclic group” of the “optionally substituted divalent heterocyclic group” represented by B is preferably thiophene-diyl, oxadiazole-diyl, pyridine-diyl, pyridazine-diyl, Benzofuran-diyl, indole-diyl, benzimidazole-diyl, dihydroindole-diyl, quinoline-diyl.
  • the “divalent heterocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “divalent heterocyclic group” of the “optionally substituted divalent heterocyclic group” represented by B is preferably thiophene-diyl, oxadiazole-diyl, pyridine-diyl. Pyridazine-diyl, benzofuran-diyl, indole-diyl, benzimidazole-diyl, dihydroindole-diyl, quinoline-diyl, pyrrole-diyl.
  • the “divalent heterocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted divalent heterocyclic group” is preferably a divalent heterocyclic group, more preferably thiophene-diyl (eg, thiophene-2,5-diyl), oxadi Azole-diyl (eg, [1,2,4] oxadiazole-3,5-diyl), pyridine-diyl (eg, pyridine-2,5-diyl), pyridazine-diyl (eg, pyridazine-3,6) -Diyl), benzofuran-diyl (eg, benzofuran-2,5-diyl, benzofuran-2,6-diyl), indole-diyl (eg, indole-2,6-diyl), benzimidazole-diyl (eg, benzo Imidazole-2,5-diyl), dihydroindole-
  • the “optionally substituted divalent heterocyclic group” is preferably a divalent heterocyclic group, more preferably thiophene-diyl (eg, thiophene-2,5- Diyl), oxadiazole-diyl (eg, [1,2,4] oxadiazole-3,5-diyl), pyridine-diyl (eg, pyridine-2,5-diyl), pyridazine-diyl (eg, Pyridazine-3,6-diyl), benzofuran-diyl (eg, benzofuran-2,5-diyl, benzofuran-2,6-diyl), indole-diyl (eg, indole-2,6-diyl), benzimidazole- Diyl (eg, benzimidazol-2,5-diyl), dihydroindole-diyl (
  • “2 of the optionally substituted divalent carbocyclic group”, “optionally substituted biarylene”, and “optionally substituted divalent heterocyclic group” represented by B are “2”. Either of the two bonds of “valent carbocyclic group”, “biarylene” and “divalent heterocyclic group” may be bonded to X.
  • “divalent heterocyclic group” of the “optionally substituted divalent heterocyclic group” represented by B “benzofuran-2,5-diyl”
  • B is preferably a divalent carbocyclic group that may be substituted, a biarylene that may be substituted, or a divalent heterocyclic group that may be substituted.
  • a halogen atom eg, chlorine atom
  • alkoxy eg, methoxy
  • aryloxy eg, phenoxy
  • arylalkoxyalkyl optionally substituted with alkyl (eg, isopropyl) (eg, benzyloxymethyl)
  • a divalent carbocyclic group which may be substituted by 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1,2-phenylene) , Indan-diyl (eg, indan-2,5-diyl), naphthylene (eg, 1,5-naphthylene)], (2) Biarylene [eg, biphenylylene (eg, 4,4′-bi
  • B is preferably a divalent carbocyclic group that may be substituted, a biarylene that may be substituted, or a divalent heterocyclic group that may be substituted.
  • Is (1) (a) a halogen atom (eg, chlorine atom), (b) alkoxy (eg, methoxy), (c) aryloxy (eg, phenoxy), and (d) arylalkoxyalkyl optionally substituted with alkyl (eg, isopropyl) (eg, benzyloxymethyl)
  • a divalent carbocyclic group optionally substituted by 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene), indan-diyl (eg, indan-2,5-diyl), naphthylene (eg, 1,5-naphthylene)], (2) Biarylene [eg, biphenylylene (e
  • B is more preferably an optionally substituted divalent 6 to 10-membered carbocyclic group or an optionally substituted divalent 5 to 14-membered heterocyclic group.
  • a halogen atom eg, chlorine atom
  • alkoxy eg, methoxy
  • aryloxy eg, phenoxy
  • arylalkoxyalkyl optionally substituted with alkyl (eg, isopropyl) (eg, benzyloxymethyl)
  • a divalent 6 to 10-membered carbocyclic group which may be substituted with 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1 , 3-phenylene, 1,2-phenylene), indan-diyl (eg, indan-2,5-diyl), naphthylene (eg, 1,5-naphthylene)], or (2) divalent 5- to 14-membered Heter
  • B is more preferably an optionally substituted divalent 6 to 10 membered carbocyclic group or an optionally substituted divalent 5 to 14 membered heterocyclic group,
  • a halogen atom eg, chlorine atom
  • alkoxy eg, methoxy
  • aryloxy eg, phenoxy
  • arylalkoxyalkyl optionally substituted with alkyl (eg, isopropyl) (eg, benzyloxymethyl)
  • a divalent 6 to 10-membered carbocyclic group which may be substituted with 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1 , 3-phenylene, 1,2-phenylene), indan-diyl (eg, indan-2,5-diyl), naphthylene (eg, 1,5-naphthylene)], or (2) divalent 5- to 14-membere
  • B is more preferably an optionally substituted arylene, specifically C 6-14 arylene [eg, phenylene (eg, 1,4-phenylene)].
  • B is more preferably an optionally substituted arylene or an optionally substituted divalent aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, chlorine atom), (b) alkoxy (eg, methoxy), and (c) aryloxy (eg, phenoxy) C 6-10 arylene optionally substituted with 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1,3-phenylene)] Or (2) a divalent aromatic heterocyclic group [eg, oxadiazole-diyl (eg, [1,2,4] oxadiazole-3,5-diyl), pyridazine-diyl (eg, pyridazine- 3,6-diyl), thiophene-diyl (eg, thiophene-2,5-diyl)].
  • a halogen atom eg, chlorine atom
  • B is more preferably an optionally substituted arylene or an optionally substituted divalent aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, chlorine atom), (b) alkoxy (eg, methoxy), and (c) aryloxy (eg, phenoxy) C 6-10 arylene optionally substituted with 1 to 3 (preferably 1) substituents selected from [eg, phenylene (eg, 1,4-phenylene, 1,3-phenylene)] Or (2) a divalent aromatic heterocyclic group [eg, oxadiazole-diyl (eg, [1,2,4] oxadiazole-3,5-diyl), pyridazine-diyl (eg, pyridazine- 3,6-diyl), thiophene-diyl (eg, thiophene-2,5-diyl), pyridine-diyl (eg,
  • B is more preferably an optionally substituted phenylene or an optionally substituted benzofuranylene, specifically, (1) (a) a halogen atom (eg, chlorine atom), (b) alkoxy (eg, methoxy), (c) aryloxy (eg, phenoxy), and (d) arylalkoxyalkyl optionally substituted with alkyl (eg, isopropyl) (eg, benzyloxymethyl) Phenylene (eg, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene) optionally substituted with 1 to 3 (preferably 1) substituents selected from 2) Benzofuranylene [eg, benzofuran-2,5-diyl, benzofuran-2,6-diyl, especially
  • a halogen atom eg, chlorine atom
  • alkoxy eg, methoxy
  • aryloxy eg, phenoxy
  • arylalkoxyalkyl optionally
  • C is an optionally substituted carbocyclic group, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted alkyl, a substituted Or an optionally substituted cycloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic alkenyl.
  • the “carbocyclic group” of the “optionally substituted carbocyclic group” represented by C is preferably a 6- to 10-membered carbocyclic group, more preferably phenyl, indenyl (eg, 2-indenyl). ), Indanyl (eg, 2-indanyl), naphthyl (eg, 1-naphthyl, 2-naphthyl), fluorenyl (eg, 2-fluorenyl, 9-fluorenyl), azulenyl (eg, azulen-1-yl).
  • the “carbocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted carbocyclic group” is preferably (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, (g) alkyl (eg, methyl, isopropyl), (h) alkoxy (eg, methoxy), and (i) aryl (eg, phenyl) 6- to 10-membered carbocyclic group optionally substituted with 1 to 3 substituents selected from [eg, phenyl, indanyl (eg, 2-indanyl), naphthyl (eg, 1-naphthyl, 2- Naphthyl), fluorenyl (eg, 2-fluorenyl, 9-fluorenyl), azulenyl (eg, azulen-1-yl)] It is.
  • a halogen atom
  • the biaryl of the “optionally substituted biaryl” represented by C is preferably C 12-18 biaryl, more preferably biphenylyl (eg, 4-biphenylyl, 2-biphenylyl, etc.) and the like.
  • the “biaryl” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted biaryl” is preferably C 12-18 biaryl [eg, biphenylyl (eg, 4-biphenylyl, 2-biphenylyl)].
  • the “arylalkyl” of the “optionally substituted arylalkyl” represented by C is preferably C 6-10 aryl-C 1-6 alkyl, more preferably benzyl, naphthylethyl (eg, 2 -(2-naphthyl) ethyl).
  • the “arylalkyl” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted arylalkyl” is preferably C 6-10 aryl optionally substituted with 1 to 3 (preferably 1 or 2) halogen atoms (eg, chlorine atom).
  • -C 1-6 alkyl eg, benzyl, naphthylethyl (eg, 2- (2-naphthyl) ethyl)].
  • the “arylalkenyl” of the “optionally substituted arylalkenyl” represented by C is preferably C 6-10 aryl-C 2-6 alkenyl, more preferably naphthyl vinyl (eg, 2- ( 2-naphthyl) vinyl).
  • the “arylalkenyl” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted arylalkenyl” is preferably C 6-10 aryl-C 2-6 alkenyl, more preferably naphthyl vinyl (eg, 2- (2-naphthyl) vinyl). .
  • Alkyl of “optionally substituted alkyl” represented by C is preferably C 1-12 alkyl, more preferably methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, Octyl and dodecyl.
  • the “alkyl” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the following substituent group B. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • [Substituent group B] (1) a halogen atom, (2) hydroxy, (3) Carboxy, (4) Cyano, (5) Nitro, (6) amino, (7) alkoxy, (8) aryloxy, (9) Aromatic heterocyclic oxy, (10) mono- or di-alkylamino, (11) cycloalkyl, (12) cycloalkoxy, (13) (i) a halogen atom, and (ii) an aryl optionally substituted with 1 to 3 selected from alkyl optionally substituted with 1 to 7 halogen atoms, (14) a non-aromatic heterocyclic group, and (15) An aromatic heterocyclic group optionally substituted with 1 to 3 alkyls.
  • the “optionally substituted alkyl” is preferably (a) hydroxy, (b) alkoxy (eg butoxy), (c) aryl optionally substituted by 1 to 3 halogen atoms (eg, chlorine atom) [eg, phenyl, naphthyl (eg, 2-naphthyl)], and (d) Cycloalkyl (eg, cyclopropyl, cyclohexyl) C 1-12 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl) optionally substituted with 1 to 3 (preferably 1) substituents selected from , Dodecyl) It is.
  • halogen atoms eg, chlorine atom
  • Cycloalkyl eg, cyclopropyl, cyclohexyl
  • C 1-12 alkyl eg, methyl,
  • alkenyl of “optionally substituted alkenyl” represented by C is preferably C 2-12 alkenyl, more preferably vinyl, butadienyl (eg, 1,3-butadienyl), heptatrienyl (eg, Hepta-1,3,5-trien-1-yl).
  • the “alkenyl” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include the substituent group B described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted alkenyl” is preferably (a) aryl [eg, naphthyl (eg, 2-naphthyl)], and (b) Aromatic heterocyclic group [eg, furanyl (eg, 2-furanyl)] C 2-12 alkenyl (eg, vinyl, 1,3-butadienyl, hepta-1,3,5-triene) optionally substituted with 1 to 3 (preferably 1) substituents selected from -1-Ile) It is.
  • aryl eg, naphthyl (eg, 2-naphthyl)
  • Aromatic heterocyclic group eg, furanyl (eg, 2-furanyl)] C 2-12 alkenyl (eg, vinyl, 1,3-butadienyl, hepta-1,3,5-triene) optionally substituted with 1 to 3 (preferably 1) substituents selected from -1-Ile) It is.
  • Cycloalkyl of “optionally substituted cycloalkyl” represented by C is preferably C 3-10 cycloalkyl, more preferably cyclopentyl or cyclohexyl.
  • the “cycloalkyl” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted cycloalkyl” is preferably C 3-10 cycloalkyl (eg, cyclopentyl, cyclohexyl).
  • Cycloalkylalkyl of “optionally substituted cycloalkylalkyl” represented by C is preferably C 3-6 cycloalkyl-C 1-6 alkyl, more preferably cyclohexylethyl (eg, 2-cyclohexylethyl), cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl.
  • the “cycloalkylalkyl” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted cycloalkylalkyl” is preferably cycloalkylalkyl, more preferably C 3-6 cycloalkyl-C 1-6 alkyl [preferably cyclohexylethyl (eg, 2-ethyl Cyclohexylethyl), cyclopropylpropyl (eg, 3-cyclopropylpropyl), cyclopropylbutyl (eg, 4-cyclopropylbutyl), cyclopropylpentyl (eg, 5-cyclopropylpentyl)].
  • cyclohexylethyl eg, 2-ethyl Cyclohexylethyl
  • cyclopropylpropyl eg, 3-cyclopropylpropyl
  • cyclopropylbutyl eg, 4-cyclopropylbutyl
  • cyclopropylpentyl eg, 5-cyclopropylpenty
  • the “heterocyclic group” of the “optionally substituted heterocyclic group” represented by C is preferably thienyl (eg, 2-thienyl), isoxazolyl (eg, 4-isoxazolyl), quinolyl (eg, 6- Quinolyl), dibenzothiophenyl (eg, dibenzothiophen-2-yl), pyridyl, azocanyl (eg, 1-azocanyl).
  • the “heterocyclic group” may have one or more (preferably 1 to 3, more preferably 1 or 2) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted heterocyclic group” is preferably (a) a halogen atom (eg, a chlorine atom), and (b) Alkyl (eg, methyl)
  • the “aromatic heterocyclic alkenyl” of the “optionally substituted aromatic heterocyclic alkenyl” represented by C is preferably an aromatic heterocyclic-C 2-6 alkenyl, more preferably furylbutadiene. Enyl (eg, 4- (2-furyl) buta-1,3-dien-1-yl).
  • the “aromatic heterocyclic alkenyl” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include the substituent group A described above. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “optionally substituted aromatic heterocyclic alkenyl” is preferably an aromatic heterocyclic alkenyl, more preferably an aromatic heterocyclic-C 2-6 alkenyl [preferably furylbutadienyl ( Example, 4- (2-furyl) buta-1,3-dien-1-yl)].
  • C is preferably an optionally substituted carbocyclic group, biaryl, optionally substituted arylalkyl, arylalkenyl, optionally substituted alkyl, optionally substituted alkenyl, cycloalkyl, cyclo
  • An alkylalkyl, an optionally substituted aromatic heterocyclic group, an aromatic heterocyclic alkenyl or a 3 to 14-membered monocyclic non-aromatic heterocyclic group specifically, (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, (g) alkyl (eg, methyl, isopropyl), (h) alkoxy (eg, methoxy), and (i) aryl (eg, phenyl) A carbocyclic group optionally substituted with 1 to 3 substituents selected from [eg, phenyl
  • C is preferably an optionally substituted carbocyclic group, biaryl, an optionally substituted arylalkyl, an arylalkenyl, an optionally substituted alkyl, an optionally substituted alkenyl.
  • Cycloalkyl, cycloalkylalkyl, an optionally substituted aromatic heterocyclic group, an aromatic heterocyclic alkenyl or a 3 to 14-membered monocyclic non-aromatic heterocyclic group specifically, (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, (g) alkyl (eg, methyl, isopropyl), (h) alkoxy (eg, methoxy), and (i) aryl (eg, phenyl)
  • a carbocyclic group optionally substituted with 1 to 3 substituents selected from [e
  • C is more preferably an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) alkyl (eg, methyl, isopropyl), and (c) alkoxy (eg, methoxy) C 6-14 aryl optionally substituted with 1 to 3 substituents selected from [eg phenyl], or (2) 1 to 3 (preferably 1 or 2) halogen atoms ( Eg, a 5- or 6-membered aromatic heterocyclic group optionally substituted with a chlorine atom [eg, thienyl (eg, 2-thienyl)] It is.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • alkyl eg, methyl, isopropyl
  • alkoxy eg, methoxy
  • C 6-14 aryl optionally substituted with 1
  • C is more preferably an optionally substituted aryl, an optionally substituted aromatic heterocyclic group, or an optionally substituted alkyl, specifically, (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) alkyl (eg, methyl, isopropyl), and (c) alkoxy (eg, methoxy) C 6-14 aryl optionally substituted with 1 to 3 substituents selected from [eg phenyl], (2) 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 (preferably 1 or 2) halogen atoms (eg, chlorine atom) [eg, thienyl (eg, 2) -Thienyl)], or (3) alkyl (eg, hexyl) It is.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • alkyl eg, methyl, isopropyl
  • C is more preferably an optionally substituted phenyl, biphenylyl, an optionally substituted naphthyl, an optionally substituted alkyl, a cycloalkylalkyl or an optionally substituted quinolyl, specifically Is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, (g) alkyl (eg, methyl, isopropyl), (h) alkoxy (eg, methoxy), and (i) phenyl optionally substituted with 1 to 3 substituents selected from aryl, (2) biphenylyl (eg, 4-biphenylyl, 2-biphenylyl), (3) naphthyl (eg, 1-naphthyl, 2-naphthyl) optionally substituted by 1 to 3 halogen atoms (eg
  • C is more preferably an optionally substituted aryl, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, a substituted An optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aromatic heterocyclic group, or an optionally substituted A non-aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, (g) aryl (eg, phenyl), and (h) alkyl (eg, methyl, isopropyl) C 6-10 aryl optionally substituted with 1 to 3 substituents selected from [eg, phenyl, naphthyl (e
  • C is more preferably an optionally substituted aryl, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, a substituted An optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aromatic heterocyclic group, or an optionally substituted A non-aromatic heterocyclic group, specifically, (1) (a) a halogen atom (eg, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, (g) aryl (eg, phenyl), and (h) alkyl (eg, methyl, isopropyl) C 6-10 aryl optionally substituted with 1 to 3 substituents selected from [eg, phenyl, naphthyl (e
  • C is even more preferably an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted quinolyl.
  • a halogen atom eg, chlorine atom, bromine atom
  • hydroxy e.g., hydroxy
  • carboxy e.g., benzyl
  • cyano e
  • Nitro e
  • aryl eg, phenyl Phenyl optionally substituted with 1 to 3 substituents selected from (2) naphthyl (eg, 1-naphthyl, 2-naphthyl) optionally substituted with 1 to 3 halogen atoms (eg, chlorine atom), (3) (a) hydroxy, (b) alkoxy (eg butoxy), (c) aryl (eg, phenyl, naphthyl) optionally substituted with 1 to 3 halogen atom
  • C is even more preferably an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or a substituted Quinolyl, which may be (1) (a) a halogen atom (eg, chlorine atom, bromine atom), (b) hydroxy, (c) carboxy, (d) cyano, (e) Nitro, (f) amino, and (g) aryl (eg, phenyl) Phenyl optionally substituted with 1 to 3 substituents selected from (2) naphthyl (eg, 1-naphthyl, 2-naphthyl) optionally substituted with 1 to 3 halogen atoms (eg, chlorine atom), (3) (a) hydroxy, (b) alkoxy (eg butoxy), (c) aryl (eg, phenyl, naphthyl) optionally substituted by 1 to 3 halogen
  • X is Optionally substituted alkylene, Optionally substituted alkenylene, Optionally substituted alkynylene, Optionally substituted * — (CH 2 ) m —O— (CH 2 ) n — **, Optionally substituted * — (CH 2 ) m —S (O) p — (CH 2 ) n — **, Optionally substituted * — (CH 2 ) m —N (R 1 ) — (CH 2 ) n — **, Optionally substituted * — (CH 2 ) m —CO— (CH 2 ) n — **, Optionally substituted * — (CH 2 ) q —CO—N (R 1 ) — (CH 2 ) r — **, Optionally substituted * — (CH 2 ) q —CO—N (R 1 ) — (CH 2 ) r — **, Optionally substituted * — (CH 2 ) q —N (R 1 )
  • alkylene is preferably C 1-6 alkylene (eg, methylene, ethylene, trimethylene).
  • alkenylene is preferably C 2-6 alkenylene, more preferably vinylene.
  • alkynylene is preferably C 2-6 alkynylene, more preferably ethynylene.
  • n is preferably 0 or 1.
  • q is preferably 0 or 1.
  • r is preferably 0 or 1.
  • p is preferably 0, 1 or 2.
  • the “* — (CH 2 ) m —O— (CH 2 ) n — **” is preferably —O—, * —CH 2 —O — **, —CH 2 —O—CH 2 —, Or * — (CH 2 ) 2 —O — **.
  • the “* — (CH 2 ) m —O— (CH 2 ) n — **” is preferably —O—, * —CH 2 —O — **, —CH 2 —O. —CH 2 —, * — (CH 2 ) 2 —O — **, or * —O—CH 2 — **.
  • the “*-(CH 2 ) m —S (O) p — (CH 2 ) n — **” is preferably —S—, —CH 2 —S—CH 2 —, —CH 2 —SO—. CH 2 —, or —CH 2 —SO 2 —CH 2 —.
  • the “*-(CH 2 ) m —N (R 1 ) — (CH 2 ) n — **” is preferably —NH—, —CH 2 —NH—CH 2 — or —CH 2 —N ( CH 3 ) —CH 2 —.
  • the “*-(CH 2 ) m —CO— (CH 2 ) n — **” is preferably —CO—.
  • the “* — (CH 2 ) q —CO—N (R 1 ) — (CH 2 ) r — **” is preferably * —CH 2 —CO—NH—CH 2 — **.
  • the “* — (CH 2 ) q —N (R 1 ) —CO— (CH 2 ) r — **” is preferably * —CH 2 —NH—CO—CH 2 — **.
  • the “* — (CH 2 ) q —SO 2 —N (R 1 ) — (CH 2 ) r — **” is preferably * —CH 2 —SO 2 —NH—CH 2 — **. .
  • the “*-(CH 2 ) q —N (R 1 ) —SO 2 — (CH 2 ) r — **” is preferably * —CH 2 —NH—SO 2 —CH 2 — **. .
  • X is preferably an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted * — (CH 2 ) m —O— (CH 2 ).
  • X is preferably an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted * — (CH 2 ) m —O.
  • X is more preferably an optionally substituted * — (CH 2 ) m —O— (CH 2 ) n — **, or an optionally substituted * — (CH 2 ) m —S (O P- (CH 2 ) n -** (wherein, m and n each independently represents an integer of 1 to 4, p represents 0 or 2, * represents a bonding position with A) , ** represents a bonding position with B.) (preferably —CH 2 —O—CH 2 — or —CH 2 —S—CH 2 —), specifically, (1) (a) aryl (eg, phenyl), and (b) aromatic heterocyclic group [eg, thiazolyl (eg, 2-thiazolyl)] * — (CH 2 ) m —O— (CH 2 ) n — ** (eg, —CH 2 —) which may be substituted with 1 to 3 (preferably 1) substituents selected from O—CH 2 —), or (2) *
  • aryl eg, phenyl
  • aromatic heterocyclic group [eg, thiazolyl (eg, 2-thiazolyl)] * — (CH 2 ) m —O— (CH 2 ) n — ** (preferably — may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from CH 2 —O—
  • X is even more preferably * — (CH 2 ) m —O— (CH 2 ) n — ** or optionally substituted * — (CH 2 ) m —S (O ) P- (CH 2 ) n -** (wherein, m and n each independently represents 0 or an integer of 1 to 4, p represents 0 or 2, and * represents a bonding position with A) , ** represents a bonding position with B.) (Preferably —O—, —CH 2 —O—CH 2 — or —CH 2 —S—CH 2 —), specifically, (1) (a) aryl (eg, phenyl), and (b) aromatic heterocyclic group [eg, thiazolyl, (eg, 2-thiazolyl)] * — (CH 2 ) m —O— (CH 2 ) n — ** (eg, —CH 2 —) which may be substituted with 1 to 3 (preferably 1) substituents selected from O—
  • X is even more preferably * — (CH 2 ) m —O— (CH 2 ) n — **, optionally substituted * — (CH 2 ).
  • X is more preferably * — (CH 2 ) m —O— (CH 2 ) n — **, or * — (CH 2 ) m —S (O) p — (CH 2 ).
  • n -** (wherein m and n each independently represents an integer of 1 to 4, p represents 0 or 2, * represents a bonding position with A, and ** represents a bonding position with B.
  • X is even more preferably —CH 2 —O—CH 2 — or —CH 2 —S—CH 2 —.
  • Z is * -CONHSO 2 -**, * -SO 2 NHCO-**, * -N (R 2 ) CONHSO 2 -**, * -SO 2 NHCON (R 2 )-**, * -CONHSO 2 N (R 2 )-**, * -N (R 2 ) SO 2 NHCO-**, * -COCONHSO 2 -**, * -SO 2 NHCOCO-**, * -N (R 2 ) COCONHSO 2- ** or * -SO 2 NHCOCON (R 2 )-** (wherein R 2 represents a hydrogen atom or lower alkyl, * represents a bonding position with B, ** represents a bonding position with C) Is shown.)
  • the “lower alkyl” represented by R 2 is preferably C 1-6 alkyl.
  • R 2 is preferably a hydrogen atom or C 1-6 alkyl (eg, butyl), more preferably a hydrogen atom.
  • Z is preferably * -CONHSO 2 -**, * -SO 2 NHCO-**, * -N (R 2 ) CONHSO 2 -**, * -CONHSO 2 N (R 2 )-**, or * —CONCONHSO 2 — ** (wherein R 2 represents a hydrogen atom or lower alkyl, * represents a bonding position with B, and ** represents a bonding position with C), specifically Is (1) * -CONHSO 2 -**, (2) * -SO 2 NHCO-**, (3) * -NHCONHSO 2 -**, (4) *-CONHSO 2 N (R 2 )-** (where R 2 is a hydrogen atom or lower alkyl (eg, butyl)), or (5) *-CONCONHSO 2 -** (In the above (1) to (5), * indicates the bonding position with B, and ** indicates the bonding position with C.) It is.
  • Z is preferably * -CONHSO 2 -**, * -SO 2 NHCO-**, * -NHCONHSO 2 -**, * -SO 2 NHCONH-**, * -CONHSO 2 NH-**, * -NHSO 2 NHCO-**, * -CONCONSO 2 -**, * -SO 2 NHCOCO-**, * -NHCOCONHSO 2 -** or * -SO 2 NHCOCONH-**.
  • Z is more preferably * -CONHSO 2 -**, * -SO 2 NHCO-**, * -N (R 2 ) CONHSO 2 -**, * -CONHSO 2 N (R 2 )-**, * -CONCONHSO 2 -**, or * -N (R 2 ) COCONHSO 2 -** (wherein R 2 represents a hydrogen atom or lower alkyl, * represents a bonding position with B, and ** Represents a bonding position with C), specifically, (1) * -CONHSO 2 -**, (2) * -SO 2 NHCO-**, (3) * -NHCONHSO 2 -**, (4) * -CONHSO 2 N (R 2 )-** (R 2 is a hydrogen atom or lower alkyl (eg, butyl)), (5) * -CONCONHSO 2 -** or (6) *-NHCONCONHSO 2 -** (In the above (1) to (6), * indicates the bonding position with B,
  • Z is more preferably * -CONHSO 2 -**, * -NHCONHSO 2 -**, * -CONHSO 2 NH-**, * -CONCONHSO 2 -**, or * -NHCONCONHSO 2 -**.
  • Z is more preferably * -CONHSO 2 -**, * -SO 2 NHCO-**, * -N (R 2 ) CONHSO 2 -**, * -CONHSO 2 N (R 2 )-**, * -CONCONSO 2 -**, or * -N (R 2 ) CONONSO 2 -** (wherein R 2 represents a hydrogen atom or lower alkyl, and * represents the position of bonding to B) ** indicates the bonding position with C.), specifically, * -CONHSO 2 -**, * -SO 2 NHCO-**, * -CONHSO 2 N (R 2 )-* *, * -NHCONHSO 2 -**, * -CONCONHSO 2 -**, or * -NHCOCONHSO 2 -** (R 2 is a hydrogen atom or butyl).
  • Z is more preferably * -CONHSO 2 -**, * -N (R 2 ) CONHSO 2 -**, * -CONHSO 2 N (R 2 )-**, *- COCONHSO 2 -** or * -N (R 2 ) COCONHSO 2 -** (wherein R 2 represents a hydrogen atom or an optionally substituted lower alkyl, * represents a bonding position with Y, * * Indicates a bonding position with C.), specifically, * -CONHSO 2 -**, * -NHCONHSO 2 -**, * -CONHSO 2 NH-**, * -CONHSO 2 N ( Bu)-**, * -SO 2 NHCO-**, * -COCONHSO 2 -**, or * -NHCOCONHSO 2 -** (wherein, * indicates the bonding position with B, ** is C and Indicates the bonding position of The
  • Z is even more preferably * -CONHSO 2 -** (wherein * represents a bonding position with B and ** represents a bonding position with C).
  • the compound represented by formula (I) is preferably A is an optionally substituted carbocyclic group, an optionally substituted biaryl, or an optionally substituted heterocyclic group; B is a divalent carbocyclic group that may be substituted, a biarylene that may be substituted, or a divalent heterocyclic group that may be substituted; C is an optionally substituted carbocyclic group, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted alkyl, a substituted An optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic alkenyl, X is an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted * — (CH 2 )
  • the compound represented by formula (I) is preferably A is an optionally substituted carbocyclic group, an optionally substituted biaryl, or an optionally substituted heterocyclic group; B is a divalent carbocyclic group that may be substituted, a biarylene that may be substituted, or a divalent heterocyclic group that may be substituted; C is an optionally substituted carbocyclic group, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted alkyl, a substituted An optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic alkenyl, X is an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted * — (CH
  • the compound represented by the formula (I) is more preferably A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; B is arylene which may be substituted; C is an optionally substituted aryl or an optionally substituted aromatic heterocyclic group; X is * —C (R 1 ) ⁇ N—O — ** (wherein R 1 represents a hydrogen atom or lower alkyl, * represents a bonding position with A, and ** represents a bonding position with B) ) A compound in which Z is * -CONHSO 2 -** (wherein * represents a bonding position with B and ** represents a bonding position with C), specifically, A is (1) (a) alkyl (eg, isopropyl, hexyl), and (b) mono- or di-alkylamino (eg, ethylamino, dimethylamino, diethylamino) 6- to 14-membered carbocyclic group optionally substituted by 1 to 3
  • the compound represented by formula (I) is more preferably A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; B is arylene which may be substituted; C is an optionally substituted aryl, an optionally substituted aromatic heterocyclic group, or an optionally substituted alkyl; X is * —C (R 1 ) ⁇ N—O — ** (wherein R 1 represents a hydrogen atom or lower alkyl, * represents a bonding position with A, and ** represents a bonding position with B) ) A compound in which Z is * -CONHSO 2 -** (wherein * represents a bonding position with B and ** represents a bonding position with C), specifically, A is (1) (a) alkyl (eg, isopropyl, hexyl), (b) mono- or di-alkylamino (eg ethylamino, dimethylamino, diethylamino), (c) (i) alkyl (
  • the compound represented by formula (I) is more preferably A is an optionally substituted aryl, an optionally substituted biaryl, or an optionally substituted aromatic heterocyclic group; B is an optionally substituted arylene or an optionally substituted divalent aromatic heterocyclic group; C is an optionally substituted aryl, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted alkyl, an optionally substituted A good alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aromatic heterocyclic group, or an optionally substituted non-aromatic heterocyclic group, X may be substituted * — (CH 2 ) m —O— (CH 2 ) n — **, or may be substituted * — (CH 2 ) m —S (O) p — ( CH 2 ) n
  • the compound represented by formula (I) is more preferably A is an optionally substituted aryl, an optionally substituted biaryl, or an optionally substituted aromatic heterocyclic group; B is an optionally substituted arylene or an optionally substituted divalent aromatic heterocyclic group; C is an optionally substituted aryl, an optionally substituted biaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted alkyl, an optionally substituted A good alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aromatic heterocyclic group, or an optionally substituted non-aromatic heterocyclic group, X is optionally substituted * — (CH 2 ) m —O— (CH 2 ) n — **, optionally substituted * — (CH 2 ) m —S (O) p — (CH 2 ) n
  • the compound represented by formula (I) is more preferably A is an optionally substituted phenyl, B is phenylene which may be substituted, or benzofuranylene which may be substituted; C is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted quinolyl; X may be substituted * — (CH 2 ) m —O— (CH 2 ) n — ** or may be substituted * — (CH 2 ) m —S (O) p — (CH 2 ) n -** (wherein, m and n each independently represents 0 or an integer of 1 to 4, p represents 0 or 2, * represents a bonding position with A, and ** represents B) (Preferably —O—, —CH 2 —O—CH 2 — or —CH 2 —S—CH 2 —), Z is
  • A is (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, methyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, ethynyl), (g) heterocyclic alkynyl [eg, thiazoly
  • the compound represented by formula (I) is more preferably A is an optionally substituted phenyl, B is phenylene which may be substituted, or benzofuranylene which may be substituted; C is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted quinolyl; X is optionally substituted * — (CH 2 ) m —O— (CH 2 ) n — **, optionally substituted * — (CH 2 ) m —S (O) p — (CH 2 ) n -**, or optionally substituted *-(CH 2 ) m -N (R 1 )-(CH 2 ) n -** (wherein m and n are each independently 0 or An integer of 1 to 4, p represents 0 or 2, R 1 represents a hydrogen atom or lower alkyl, * represents
  • Z is * -CONHSO 2 -**, * -N (R 2 ) CONHSO 2 -**, * -CONHSO 2 N (R 2 )-**, * -CONHSO 2 -**, or * -N ( R 2 ) COCONHSO 2 -** (wherein R 2 represents a hydrogen atom or an optionally substituted lower alkyl, * represents a bonding position with Y, and ** represents a bonding position with C).
  • A is (1) (a) a halogen atom (eg, chlorine atom), (b) Nitro, (c) alkyl (eg, isopropyl, tert-butyl), (d) alkenyl (eg, 2-methyl-1-propenyl, 4-methyl-1-pentenyl, 5-methyl-1-hexenyl), (e) arylalkenyl [eg, phenyl vinyl (eg, 2-phenyl vinyl)], (f) alkynyl (eg, 1-propynyl), (g) heterocyclic alkynyl [eg, thiazoleethynyl (eg, thiazol-5-ylethynyl)], (h
  • the compound represented by the formula (I) is particularly preferably (1) N- [4- (biphenyl-4-ylmethylsulfanylmethyl) benzoyl] octane-1-sulfonamide,
  • the compound represented by formula (I) is particularly preferably (1) (1) N- [4- (3′-methoxybiphenyl-4-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide,
  • Compound (I) of the present invention may form a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt in this specification may be any salt as long as it is a pharmaceutically non-toxic salt.
  • compound (I) has a basic group, it can form an acid addition salt.
  • an acid for forming such an acid addition salt it can form a salt with a basic moiety, and can be a pharmaceutical. There is no particular limitation as long as the acid is acceptable.
  • acids examples include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and toluenesulfonic acid.
  • an acidic group such as a carboxy group, for example, an alkali metal salt (for example, sodium salt, potassium salt), an alkaline earth metal salt (for example, calcium salt, magnesium salt), an organic base Salts (eg, triethylamine salts, dicyclohexylamine salts, pyridine salts, etc.) can be formed.
  • an alkali metal salt for example, sodium salt, potassium salt
  • an alkaline earth metal salt for example, calcium salt, magnesium salt
  • an organic base Salts eg, triethylamine salts, dicyclohexylamine salts, pyridine salts, etc.
  • Production method 1 is a method for producing a compound (Ia) in which, in the general formula (I), Z is * -CONHSO 2 -** (wherein * and ** are as defined above). is there.
  • Production method 1 is a method for producing compound (Ia) by subjecting compound (1) to an amidation reaction. This reaction is carried out using a method known per se, for example, a method of directly condensing compound (1) and compound (2) or a method of reacting a reactive derivative of compound (1) with compound (2). Done.
  • the method of directly condensing the compound (1) and the compound (2) is performed in the presence of a condensing agent in a solvent that does not adversely influence the reaction.
  • 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.
  • 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).
  • 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 (1).
  • 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 condensation accelerator, organic base and alkali metal carbonate used is usually 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.
  • examples of the reactive derivative of compound (1) 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 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.
  • 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.
  • compound (1) and substituted phosphoric acid or chlorocarbonate are converted to a base (eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N , N-dimethylaniline, etc .; alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) to make a reactive derivative, and further react with compound (2).
  • a base eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N , N-dimethylaniline, etc .
  • alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.
  • 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.
  • Compound (1) used in this production method can be produced according to the method described in production methods 8 to 13 or a method analogous thereto. It can also be obtained as a commercial product.
  • Compound (2) used in this production method can be obtained as a commercial product, or can be produced according to a method known per se or a method analogous thereto.
  • Production method 2 is a method for producing compound (Ib) in which, in general formula (I), Z is * -SO 2 NHCO-** (wherein * and ** are as defined above). It is.
  • Compound (Ib) can be produced by subjecting compound (3) and compound (4) to a reaction similar to the amidation reaction described in Production Method 1.
  • Compound (3) and compound (4) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Z is * —CONHSO 2 N (R 2 ) — ** (wherein R 2 , * and ** are as defined above) (I -C).
  • Compound (Ic) can be produced by subjecting compound (1) and compound (5) to a reaction similar to the amidation reaction described in Production Method 1.
  • Compound (5) used in this production method can be obtained as a commercially available product, or can be produced according to a method known per se or a method analogous thereto.
  • L 1 and L 2 each independently represent hydroxy, halogen atoms (for example, fluorine atom, chlorine atom, bromine atom) , Iodine atom), imidazolyl, succinimideoxy, alkanesulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.) or arylsulfonyloxy (eg, benzenesulfonyloxy, tolylsulfonyloxy, etc.) And the like.
  • alkanesulfonyloxy eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • arylsulfonyloxy eg, benzenesulfony
  • Z is * —N (R 2 ) CONHSO 2 — ** (wherein R 2 , * and ** are as defined above).
  • This production method is a method known per se, for example, after reacting compound (6) and compound (7) in a solvent that does not affect the reaction, the resulting compound and compound (2) are reacted. The reaction is carried out in a solvent that does not affect the reaction.
  • this reaction is carried out by using an organic base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene; sodium carbonate
  • a base such as an alkali metal carbonate such as sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or cesium carbonate.
  • the compound (7) include N, N′-carbonyldiimidazole, diphosgene, triphosgene and the like.
  • 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 compound (2) 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.
  • Compound (2), compound (6) and compound (7) used in this production method can be obtained as commercial products, or can be produced according to a method known per se or a method analogous thereto.
  • Z is * —N (R 2 ) CONHSO 2 — ** (wherein R 2 , * and ** are as defined above).
  • This production method is carried out by a method known per se, for example, by reacting compound (6) and compound (8) in a solvent that does not affect the reaction.
  • this reaction is carried out by using an organic base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene; sodium carbonate
  • a base such as an alkali metal carbonate such as sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or cesium carbonate.
  • solvents that do not adversely affect the reaction include acetone, dioxane, acetonitrile, chloroform, benzene, toluene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N′-dimethylformamide, pyridine, water, and the like. And the like.
  • the amount of compound (8) 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.
  • Compound (6) and compound (8) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Process 4-C produces compound (Ie) in which general formula (I) is such that Z is * -NHCONHSO 2 -** (wherein * and ** are as defined above).
  • This production method is produced by heating an acid azide obtained by reacting compound (1) with diphenylphosphoric acid azide (DPPA) in the presence of a base such as triethylamine in a solvent that does not affect the reaction. This is carried out by reacting the isocyanate compound with the compound (2).
  • DPPA diphenylphosphoric acid azide
  • solvents that do not adversely affect the reaction include acetone, dioxane, acetonitrile, chloroform, benzene, toluene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N′-dimethylformamide, pyridine, and mixtures thereof.
  • Etc. The amount of DPPA to be used is generally 1-5 mol, preferably 1-3 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 in the step of reacting compound (1) with DPPA to obtain isocyanate, the reaction temperature is usually from ⁇ 30 to 110 ° C. Yes, the reaction time is from 30 minutes to 20 hours. In the step of reacting the isocyanate compound with compound (2), the reaction temperature is usually ⁇ 30 to 50 ° C., and the reaction time is 30 minutes to 20 hours.
  • Production method 5 is a compound in which Z is * —N (R 2 ) SO 2 NHCO — ** (wherein R 2 , * and ** are as defined above) in general formula (I). If)).
  • Compound (If) can be produced by subjecting compound (4) and compound (9) to a reaction similar to the amidation reaction described in Production Method 1.
  • Compound (9) and compound (4) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Z is * —SO 2 NHCON (R 2 ) — ** (wherein R 2 , * and ** are as defined above).
  • -G Compound (Ig) is produced by reacting compound (10) with compound (7) and then subjecting the resulting compound and compound (3) to a reaction similar to the reaction described in Production Method 4. be able to.
  • Compound (3), compound (7) and compound (10) used in this production method can be obtained as commercial products, or can be produced according to a method known per se or a method analogous thereto.
  • R 3 represents lower alkyl
  • L 3 represents a leaving group such as hydroxy or a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom)
  • Z represents * -CONHSO 2 -** or * -CONHSO 2 N (R 2 )-** (wherein R 2 , * and ** are as defined above).
  • Compound (15) is reacted with Compound (11) and ethyl N-hydroxyacetimidate in a solvent that does not affect the reaction in the presence of a base such as calcium tert-butoxide to obtain Compound (12). Then, it is reacted with compound (13) and perchloric acid to obtain compound (14), which can be produced by hydrolyzing the ester of compound (14) by a method known per se.
  • Compound (Ih) wherein Z is * -CONHSO 2 -** or * -CONHSO 2 N (R 2 )-** (wherein R 2 , * and ** are as defined above) Can be produced from compound (15) by reacting according to production method 1 or production method 3. Further, the ester of compound (12) is hydrolyzed by a method known per se to obtain compound (16), and then reacted according to production method 1 and production method 3, whereby Z is * -CONHSO 2 -** or *- CONNHSO 2 N (R 2 )-** (wherein R 2 , * and ** are as defined above) is obtained as compound (17), and compound (17) is obtained from compound (12). It can manufacture by making it react according to the method of obtaining a compound (14). Compound (11) and compound (13) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • a leaving group such as oxy, alkanesulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.) or arylsulfonyloxy (eg, benzenesulfonyloxy, tolylsulfonyloxy, etc.) is shown.
  • alkanesulfonyloxy eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • arylsulfonyloxy eg, benzenesulfonyloxy, tolylsulfonyloxy, etc.
  • X of the compound (1) is * — (CH 2 ) m —O— (CH 2 ) n — ** (wherein m, n, * and ** are as defined above).
  • Compound (25) can be produced by reacting compound (22) with compound (23) to obtain compound (24), and hydrolyzing the ester of compound (24) by a method known per se. it can.
  • the reaction between compound (22) and compound (23) is Mitsunobu reaction (“Reagents for Organic Synthesis” by Fieser & Fieser, Vol. 6, 645), etc. It is carried out by subjecting to a dehydration reaction as exemplified.
  • the reaction is usually carried out by using azo compounds and phosphines in the presence of a solvent.
  • the azo compounds include diC 1-6 alkyl azodicarboxylate (eg, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate), azodicarboxamide (eg, 1,1′-azobis (N , N′-dimethylformamide, 1,1 ′-(azodicarbonyl) dipiperidine, etc.)
  • phosphines include triarylphosphine (for example, triphenylphosphine), triC 1-8 alkylphosphine ( For example, tri-n-butylphosphine, tri-n-hexylphosphine, tri-n-octylphosphine, etc.) are used, and the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • dioxane acetonitrile, teto Hydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethyl sulfoxide, and mixtures thereof.
  • the amount of compound (23) used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of compound (22).
  • the amounts of azo compounds and phosphines used are respectively The amount is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (22).
  • the reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, the reaction temperature is usually ⁇ 30 to 50 ° C., and the reaction time is 30 minutes to 20 hours.
  • the reaction of compound (22) and compound (23) is carried out in the presence of a base in a solvent that does not affect the reaction when L 4 is a leaving group.
  • the base used in the reaction is not particularly limited, and alkali metal carbonates (for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.), metal hydride compounds (for example, sodium hydride) , Potassium hydride, calcium hydride, etc.), inorganic bases such as silver oxide; and alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), amines (eg, triethylamine, diisopropylethylamine, etc.) ) Organic bases.
  • alkali metal carbonates for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.
  • metal hydride compounds for example, sodium hydride
  • Potassium hydride calcium hydride, etc.
  • inorganic bases such as silver oxide
  • alkali metal alcoholates eg, sodium methoxide, sodium ethoxid
  • the amount of compound (23) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (22), and the amount of base used is compound (22) or (23) The amount is usually 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol.
  • a catalyst can also be used in a solvent in the presence of a base.
  • Suitable solvents are toluene and benzene
  • catalysts include, for example, quaternary ammonium salts such as tetramethylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, tetraethylammonium chloride, tetraethylammonium fluoride, benzyltrimethylammonium bromide; And tris [2- (2-methoxyethoxy) ethyl] amine.
  • Preferred is tetraethylammonium fluoride or tris [2- (2-methoxyethoxy) ethyl] amine.
  • the amount of the catalyst to be used is generally 0.1-1 mol, preferably 0.1-0.5 mol, per 1 mol of compound (22).
  • 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.
  • Compound (22) and compound (23) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Production Method 8-B is a method for producing compound (25).
  • Compound (25) can be produced by reacting compound (26) and compound (27) to obtain compound (24), and hydrolyzing the ester of compound (24) by a method known per se. it can.
  • This production method is carried out by subjecting to the same reaction as described in Production Method 8-A.
  • Compound (26) and compound (27) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • D represents a substituted boron atom or a compound (19) when the compound (19) is an organic boronic acid or an organic boronic acid ester.
  • D represents a substituted tin atom.
  • Examples of the substituted boron atom represented by D include dihydroxyboryl, 4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl and the like.
  • Examples of the substituted tin atom represented by D include trimethyltin and tributyltin.
  • Production method 8-C is a method for producing compound (30) in which X of compound (1) is —O—.
  • Compound (30) is obtained by subjecting compound (28) and compound (19) to a coupling reaction using an organometallic catalyst to obtain compound (29) by a method known per se. It can be produced by hydrolyzing the ester.
  • This production method is carried out in a solvent that does not affect the reaction, if necessary, in the presence of a base. Moreover, you may perform this manufacturing method in presence of a phosphine ligand as needed.
  • 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.
  • Specific examples of solvents that do not adversely influence the reaction include acetone, dioxane, acetonitrile, benzene, toluene, xylene, hexane, heptane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, N, N′-dimethylformamide, N—
  • Examples include methyl pyrrolidone, dimethyl sulfoxide, methanol, ethanol, tert-butyl alcohol, water, and mixtures thereof.
  • the amount of compound (19) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (28).
  • the amount of the organometallic catalyst to be used is generally 0.001 to 1 mol, preferably 0.01 to 0.5 mol, per 1 mol of compound (28).
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (28).
  • 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.
  • the amount of the phosphine ligand to be used is generally 0.001-1 mol, preferably 0.01-0.5 mol, per 1 mol of compound (28).
  • 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.
  • Compound (19) and compound (28) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • X is * — (CH 2 ) m —O— (CH 2 ) n — ** (wherein m, n, * and ** are as defined above).
  • (3), (6) and (9) are produced. Further, a compound in which X is * — (CH 2 ) m —O— (CH 2 ) n — ** (wherein m, n, * and ** are as defined above). 1), Compound (3), Compound (6), and Compound (9) are used in the same reaction as in Production Methods 1 to 6, whereby X is * — (CH 2 ) m —O— (CH 2 ).
  • X of compound (1) is * — (CH 2 ) m —S— (CH 2 ) n — ** (wherein * and ** are as defined above).
  • This is a method for producing a certain compound (33).
  • Compound (33) can be produced by reacting compound (31) with compound (27) to obtain compound (32), and hydrolyzing the ester of compound (32) by a method known per se. it can.
  • This production method is carried out by subjecting to the same reaction as described in Production Method 8-A.
  • Compound (27) and compound (31) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Production Method 9-B is a method for producing compound (33) as in Production Method 9-A. This production method is carried out by subjecting to the same reaction as described in the production method 9-A. Further, X of the compound (1) is * — (CH 2 ) m —S (O) p — (CH 2 ) n — ** (wherein m, n, p, * and ** are the same as above)
  • the compound (36) which is significant) can be produced by oxidizing the compound (32) by a method known per se to obtain the compound (35) and hydrolyzing the ester of the compound (35). it can.
  • Compound (22) and compound (34) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • X is * — (CH 2 ) m —S (O) p — (CH 2 ) n — ** (where m, n, p, * and ** are The compounds (1), (3), (6) and (9) are produced. Further, these X are * — (CH 2 ) m —S (O) p — (CH 2 ) n — ** (wherein m, n, p, * and ** are as defined above).
  • Q represents a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom).
  • Production method 10 is a method for producing compound (41) in which X of compound (1) is methylene and compound (43) in which X is —CO—.
  • Compound (39) is produced by lithiation of compound (38) with n-butyllithium or the like and reaction with compound (37).
  • Compound (40) is produced by reacting compound (39) with triethylsilane, and compound (41) is produced by hydrolyzing the obtained ester of compound (40) by a method known per se.
  • the Compound (43) is produced by oxidizing the hydroxy group of compound (39) by a method known per se and hydrolyzing the ester of compound (42) obtained by a method known per se.
  • Compound (37) and compound (38) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • compound (1), compound (3), compound (6) and compound (9) wherein X is methylene, or compound (1), compound (3) wherein X is —CO— Compound (6) and compound (9) are produced. Further, by using the compound (1), the compound (3), the compound (6), and the compound (9) in which X is methylene or X is —CO—, the same reaction as in production methods 1 to 6 is performed. , X is methylene or X is —CO—, compound (Ia), compound (Ib), compound (Ic), compound (Id), compound (Ie), compound (I -F) and compound (Ig) can be prepared.
  • Production method 11 is a method for producing compound (47) in which X of compound (1) is vinylene and compound (48) in which X is ethylene.
  • Compound (47) is produced by subjecting compound (37) and an organic phosphorus reagent such as compound (44) to a carbon increase reaction to produce compound (45).
  • the ester can be produced by hydrolysis by a method known per se.
  • Compound (48) is produced by subjecting compound (45) to a hydrogenation reaction to produce compound (46), and hydrolyzing the resulting ester of compound (46) by a method known per se. Can be manufactured.
  • the carbon increase reaction for obtaining the compound (45) is carried out in the presence of a base in a solvent that does not affect the reaction. Examples of the base used in the reaction 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. .
  • Specific solvents that do not adversely influence the reaction include acetone, dioxane, acetonitrile, benzene, toluene, xylene, hexane, heptane, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, N, N′-dimethyl.
  • Examples include formamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, tert-butyl alcohol, water, and mixtures thereof.
  • the amount of compound (44) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (37).
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (37).
  • 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 hydrogenation reaction to obtain the compound (46) is hydrogenated using a metal catalyst such as palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, Raney nickel in a solvent that does not affect the reaction. Is done.
  • Compound (37) and compound (44) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Production method 12 is a method for producing compound (51) in which X of compound (1) is ethynylene.
  • Compound (51) is obtained by subjecting Compound (18) and Compound (49) to a coupling reaction using an organometallic catalyst to obtain Compound (50) by a method known per se. It can be produced by hydrolyzing the ester.
  • This production method is carried out by subjecting to the same reaction as described in Production Method 8-C.
  • Compound (18) and compound (49) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • compound (1), compound (3), compound (6) and compound (9), wherein X is ethynylene are produced.
  • A, X, R 3 and L 4 are as defined above, and B is a nitrogen-containing heterocyclic group.
  • Production method 13-A is a method for producing a compound (55) in which X is bonded to a nitrogen atom in B.
  • Production Method 13-B is a method for producing a compound (59) in which X is bonded to a nitrogen atom in A.
  • Production method 13 is carried out by subjecting the reaction to the same reaction as described in production method 8.
  • compound (1), compound (3), compound (6) and compound (9) in which X is bound to the nitrogen atom in A or the nitrogen atom in B are produced.
  • Production method 14 is a method for producing a compound (Ii) in which, in the general formula (I), Z is * -CONCONHSO 2 -** (wherein * and ** are as defined above). is there.
  • Compound (Ii) can be produced by subjecting compound (60) and compound (2) to a reaction similar to the amidation reaction described in Production Method 1.
  • the compound (60) used in this production method can be produced according to the following method.
  • Compound (60) is obtained by lithiation with alkyllithium such as n-BuLi in a solvent that does not affect the reaction of compound (61), and then reacted with diethyl oxalate to obtain compound (62), which is known per se This can be produced by hydrolyzing the ester of compound (62).
  • Compound (61) used in this production method can be obtained as a commercially available product, or can be produced according to a method known per se or a method analogous thereto.
  • Production method 15 is a method for producing compound (Ij) in which, in general formula (I), Z is * —SO 2 NHCOCO-** (wherein * and ** are as defined above). It is.
  • Compound (Ij) can be produced by subjecting compound (3) and compound (63) to a reaction similar to the amidation reaction described in Production Method 1.
  • Compound (3) and compound (63) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • Z is * —N (R 2 ) COCONHSO 2 — ** (wherein R 2 , * and ** are as defined above).
  • -K Compound (Ik) can be produced by subjecting compound (64) and compound (2) to a reaction similar to the amidation reaction described in Production Method 1.
  • Compound (64) used in this production method can be produced according to the following method.
  • Compound (64) is a method known per se by reacting compound (6) with ethyl chloroglyoxylate in the presence of a base such as triethylamine in a solvent that does not affect the reaction, to give compound (65).
  • a base such as triethylamine
  • the ester of compound (65) can be hydrolyzed.
  • Compound (6) used in this production method can be obtained as a commercial product, or can be produced according to a method known per se or a method analogous thereto.
  • Z is * -SO 2 NHCOCON (R 2 )-** (wherein R 2 , * and ** are as defined above).
  • -L Compound (Il) can be produced by subjecting compound (3) and compound (66) to a reaction similar to the amidation reaction described in Production Method 1.
  • Compound (3) and compound (66) used in this production method can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.
  • M represents an alkali metal such as sodium or potassium.
  • Production method 18 is a method for producing compound (1-ab) which is an alkali metal salt from compound (1-a).
  • Compound (1-ab) can be produced by reacting compound (1-a) with a base.
  • the base used in the reaction include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and potassium hydrogen carbonate; metal hydrides such as potassium hydride and sodium hydride, and alcoholates such as sodium methoxide. Etc.
  • solvents that do not affect the reaction include acetone, acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, N, N′-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, tert-butyl alcohol, water, Examples thereof include a mixture thereof.
  • the amount of the base to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (1-a).
  • 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.
  • Compound (I) obtained by the above production method 1-18 can be isolated by a conventional method, and if necessary, purified by a conventional method such as recrystallization, preparative thin layer chromatography, column chromatography, etc. can do.
  • 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 pharmaceutical composition containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be formulated with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier examples include excipients (eg, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (For example, magnesium stearate, talc, etc.), disintegrating agents (for example, carboxymethyl cellulose, talc, etc.) and the like can be mentioned.
  • excipients eg, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.
  • binders eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.
  • lubricants For example, magnesium stearate, talc, etc.
  • disintegrating agents for example, carboxymethyl
  • the mixture is subjected to per se known means, for example, for oral administration such as capsules, tablets, fine granules, granules, dry syrups, or for parenteral administration such as injections and suppositories. It can be a formulation.
  • the dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms, and other factors. For example, for patients with diabetes, diabetic complications or hyperlipidemia, When orally administered to adults, give 1 to 500 mg at a time, about 1 to 3 times daily.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has protein tyrosine phosphatase-1B (PTP-1B; ProteinProTyrosine Phosphatase-1B) inhibitory activity, and is a mammal (human, horse, cow, dog, Cats, rats, mice, hamsters, etc.) have excellent blood glucose lowering effect, blood lipid lowering effect, insulin resistance improving action, antihyperglycemic agent, antihyperlipidemic agent, insulin resistance improving agent , Antidiabetic agent, diabetic complication agent, glucose intolerance improving agent, anti-arteriosclerosis agent, anti-obesity agent, anti-inflammatory agent, prevention / treatment agent of PTP-1B-mediated diseases and prevention / metabolic syndrome It is useful as a therapeutic agent.
  • PTP-1B protein tyrosine phosphatase-1B
  • PTP-1B proteinProTyrosine Phosphatase-1B
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof contains hyperglycemia, hyperlipidemia, diabetes, diabetic complications, diseases caused by insulin resistance, diseases caused by impaired glucose tolerance, It is useful as a prophylactic and therapeutic agent for arteriosclerosis, obesity, inflammation, diseases mediated by PTP-1B and metabolic syndrome.
  • the resulting yellow powder was purified by column chromatography.
  • the obtained crude product was dissolved in AcOEt (10 mL) with heating, diethyl ether (Et 2 O) (40 mL) was added, and the mixture was stirred at room temperature for 4 hours. The precipitate was collected by filtration to give a pink powder (242 mg) of the title compound.
  • the obtained brown oil was dissolved in AcOEt (8 mL) with heating, Et 2 O (30 mL) was added, and the mixture was stirred at room temperature for 1 hr, and the precipitate was collected by filtration.
  • the obtained light brown powder 250 mg was dissolved in AcOEt (3.5 mL) with heating, Et 2 O (30 mL) and n-hexane (5 mL) were added, and the mixture was stirred for 1 hour under ice cooling. The precipitate was collected by filtration to give a pale brown powder (140 mg) of the title compound.
  • the solvent was distilled off under reduced pressure, the resulting residue was purified by column chromatography, and the solvent of the target fraction was distilled off under reduced pressure.
  • the obtained colorless oil was dissolved in acetone (130 mL), water (130 mL), ammonium acetate (AcONH 4 ) (6.17 g) and NaIO 4 (17.1 g) were added, and the mixture was stirred at 20 ° C. for 15 hr. . AcOEt and water were added to the reaction solution, and the two layers were separated. The organic layer was washed with saturated brine and dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography, and the solvent of the target fraction was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography, and the solvent of the target fraction was distilled off under reduced pressure.
  • the obtained colorless oil (200 mg) was dissolved in Et 2 O (3 mL), n-hexane (25 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hr.
  • the precipitate was collected by filtration to give the title compound as a white powder (120 mg).
  • the obtained residue was purified by column chromatography, the solvent of the target fraction was evaporated under reduced pressure, n-hexane was added to the obtained residue, and the mixture was collected by filtration to give the title compound as a white powder (310 mg). It was.
  • the obtained residue was purified by column chromatography, and the solvent of the target fraction was distilled off under reduced pressure to obtain a white powder.
  • the obtained powder was dissolved in AcOEt (1 mL) with heating, and n-hexane (3 mL) was added under ice cooling, followed by stirring at the same temperature for 1 hour. The precipitate was collected by filtration to give the title compound as a white powder (55 mg).
  • the obtained powder (850 mg) was suspended in MeOH (10 mL), 5.0 M NaOH aqueous solution (1.7 mL) was added, and the mixture was stirred at 40 ° C. for 30 min.
  • the reaction solution was washed with AcOEt, acidified with 6.0 M hydrochloric acid, and extracted with AcOEt.
  • the organic layer was washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure to give 4- (biphenyl-4-ylmethyl) benzoic acid as a white powder (416 mg).
  • Example 46 (2) The compound (500 mg) obtained in Example 46 (1) was dissolved in DMF (5 mL), CDI (281 mg) was added, and the mixture was stirred at room temperature for 1 hour. The compound obtained in (1) (424 mg) and DBU (0.26 mL) were added, and the mixture was stirred at room temperature for 14 hours and then stirred at 50 ° C. for 1 hour. After allowing to cool, 10% aqueous citric acid solution (30 mL) and AcOEt (30 mL) were added to the reaction mixture, the organic layer was separated, the aqueous layer was extracted with AcOEt (30 mL), the organic layers were combined, After sequentially washing with saturated brine and drying (Na 2 SO 4 ), the solvent was distilled off under reduced pressure.
  • Trifluoroacetic acid (5.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 4 hours. Saturated multistory water was added to the reaction liquid, extracted twice with CHCl 3 , 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 N, N-dibutylsulfamoylamine (2.63 g).
  • Example 46 (2) The compound (478 mg) obtained in (1) of Example 46 was dissolved in DMF (5 mL), CDI (365 mg) was added, and the mixture was stirred at room temperature for 0.5 hour and then obtained in (1). The obtained compound (625 mg) and DBU (0.671 mL) were added, and the mixture was stirred at 80 ° C. for 3 hr. A 5% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted twice with AcOEt. The organic layer was washed successively with water and saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure.
  • Example 52 N- [4- (4-Isopropylbenzyloxymethyl) phenyl] -N '-(octane-1-sulfonyl) urea diphenylphosphoric acid azide (DPPA) (550 mg) was dissolved in toluene (5 mL) and 4- (4-Isopropylbenzyloxymethyl) benzoic acid (569 mg) and Et 3 N (0.31 mL) were added, and the mixture was stirred at 100 ° C. for 15 min.
  • DPPA diphenylphosphoric acid azide
  • Example 101 N- [4- (2,4-Dichlorobenzyloxymethyl) benzoyl] dodecane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1677, 1338, 1157 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.81-0.88 (3H, m), 1.18-1.28 (16H, m), 1.33-1.43 (2H, m), 1.64-1.74 (2H , m), 3.47-3.54 (2H, m), 4.62 (2H, s), 4.69 (2H, s), 7.44-7.52 (3H, m), 7.55-7.59 (1H, m), 7.61-7.63 (1H , m), 7.90-7.94 (2H, m), 12.01-12.08 (1H, br).
  • Example 104 2- [4- (Biphenyl-4-ylmethoxymethyl) benzoylsulfamoyl] benzoic acid IR ⁇ (ATR) cm -1 ; 1724, 1687 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 4.60 (2H, s), 4.63 (2H, s), 7.33-7.40 (1H, m), 7.42-7.52 (6H, m), 7.63-7.80 (7H, m), 7.88-7.95 (2H, m), 8.10-8.17 (1H, m), 11.50-14.50 (2H, br).
  • Example 105 N- [4- (Biphenyl-4-ylmethoxymethyl) benzoyl] octane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1675 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.80-0.86 (3H, m), 1.15-1.31 (8H, m), 1.34-1.45 (2H, m), 1.65-1.75 (2H , m), 3.46-3.55 (2H, m), 4.62 (2H, s), 4.65 (2H, s), 7.33-7.39 (1H, m), 7.43-7.55 (6H, m), 7.65-7.70 (4H , m), 7.91-7.97 (2H, m), 12.05 (1H, s).
  • Example 109 N- [4- (Benzhydryloxymethyl) benzoyl] octane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1668 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.79-0.86 (3H, m), 1.15-1.30 (8H, m), 1.32-1.44 (2H, m), 1.65-1.75 (2H , m), 3.46-3.55 (2H, m), 4.56 (2H, s), 5.58 (1H, s), 7.22-7.28 (2H, m), 7.31-7.38 (4H, m), 7.38-7.46 (4H , m), 7.46-7.53 (2H, m), 7.87-7.95 (2H, m), 12.04 (1H, s).
  • Example 135 N- [4- (9H-carbazol-9-ylmethyl) benzoyl] octane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 3261, 1689 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.77-0.82 (3H, m), 1.14-1.24 (8H, m), 1.29-1.38 (2H, m), 1.59-1.68 (2H , m), 3.42-3.48 (2H, m), 5.75 (2H, s), 7.19-7.25 (4H, m), 7.39-7.44 (2H, m), 7.57-7.61 (2H, m), 7.79-7.83 (2H, m), 8.16-8.20 (2H, m), 11.88-11.97 (1H, br).
  • Example 160 N- [4- (3-Biphenyl-4-ylpropyl) benzoyl] octane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1689 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.78-0.86 (3H, m), 1.15-1.29 (8H, m), 1.31-1.44 (2H, m), 1.62-1.73 (2H , m), 1.85-1.98 (2H, m), 2.58-2.75 (4H, m), 3.46-3.55 (2H, m), 7.25-7.38 (5H, m), 7.40-7.46 (2H, m), 7.53 -7.66 (4H, m), 7.82-7.90 (2H, m), 11.95 (1H, s).
  • Example 161 N- [4- (2-Pyrazol-1-ylthiazol-5-ylmethylsulfanylmethyl) benzoyl] octane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1608 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.79-0.89 (3H, m), 1.16-1.30 (8H, m), 1.31-1.47 (2H, m), 1.62-1.77 (2H , m), 3.46-3.56 (2H, m), 3.83 (2H, s), 3.92 (2H, s), 6.60-6.66 (1H, m), 7.40-7.51 (3H, m), 7.84-7.95 (3H , m), 8.45-8.52 (1H, m), 11.96-12.09 (1H, br).
  • Example 163 N- [4- (4- [1,3,4] thiadiazol-2-ylbenzylsulfanylmethyl) benzoyl] octane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1616 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.78-0.89 (3H, m), 1.16-1.29 (8H, m), 1.30-1.40 (2H, m), 1.50-1.70 (2H , m), 3.16-3.27 (2H, m), 3.68-3.77 (4H, m), 7.28-7.35 (2H, m), 7.44-7.51 (2H, m), 7.84-7.92 (2H, m), 7.94 -8.03 (2H, m), 9.62 (1H, s), 11.90-12.11 (1H, br).
  • Example 186 4- (Biphenyl-4-ylmethylsulfanylmethyl) -N '-(hexylaminosulfonyl) benzamide IR ⁇ (ATR) cm -1 ; 1687, 1604 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.77-0.84 (3H, m), 1.12-1.29 (6H, m), 1.39-1.49 (2H, m), 2.87-2.95 (2H , m), 3.71 (2H, s), 3.76 (2H, s), 7.32-7.40 (3H, m), 7.40-7.49 (4H, m), 7.58-7.68 (4H, m), 7.74-7.80 (1H , m), 7.85-7.91 (2H, m), 11.72 (1H, s).
  • Example 195 N- ⁇ [4- (biphenyl-4-ylmethyl) methylamino] methyl ⁇ benzoyl) hexane-1-sulfonamide
  • the above compound is a reductive alkylation of methyl 4- (aminomethyl) benzoate hydrochloride and 4-phenylbenzaldehyde, Subsequently, after methylating with methyl iodide, it manufactured by the method similar to Example 33.
  • Example 196 N- [4- (5-Phenylpyridin-2-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1680 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.78-0.87 (3H, m), 1.18-1.28 (4H, m), 1.32-1.44 (2H, m), 1.60-1.73 (2H , m), 3.45-3.53 (2H, m), 3.78 (2H, s), 3.73 (2H, s), 7.38-7.54 (3H, m), 7.66-7.74 (2H, m), 7.83-7.92 (2H , m), 7.97-8.07 (1H, m), 8.75-8.81 (1H, m), 11.90-12.10 (1H, br).
  • Example 202 N- [4- (3'-Methoxybiphenyl-4-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1685 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.81-0.87 (3H, m), 1.21-1.28 (4H, m), 1.35-1.44 (2H, m), 1.65-1.72 (2H , m), 3.47-3.54 (2H, m), 3.71 (2H, s), 3.77 (2H, s), 3.82 (3H, s), 6.90-6.96 (1H, m), 7.15-7.19 (1H, m ), 7.19-7.23 (1H, m), 7.33-7.39 (3H, m), 7.42-7.46 (2H, m), 7.59-7.63 (2H, m), 7.87-7.91 (2H, m), 11.96-12.05 (1H, br).
  • Example 210 N- [4- (3'-Nitrobiphenyl-4-ylmethylsulfanylmethyl) -benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1680 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.80-0.89 (3H, m), 1.20-1.30 (4H, m), 1.33-1.45 (2H, m), 1.63-1.74 (2H , m), 3.45-3.55 (2H, m), 3.74 (2H, s), 3.88 (2H, s), 7.40-7.49 (4H, m), 7.71-7.80 (3H, m), 7.85-7.93 (2H , m), 8.12-8.16 (1H, m), 8.18-8.25 (1H, m), 8.43 (1H, s), 11.70-12.70 (1H, br).
  • Example 214 N- (4- ⁇ 4- [3- (trifluoromethyl) isoxazol-5-yl] benzylsulfanylmethyl ⁇ benzoyl) hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1683 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.80-0.88 (3H, m), 1.20-1.30 (4H, m), 1.33-1.45 (2H, m), 1.64-1.75 (2H , m), 3.45-3.55 (2H, m), 3.76 (2H, s), 3.77 (2H, s), 7.40-7.46 (2H, m), 7.46-7.52 (2H, m), 7.70 (1H, s ), 7.85-7.95 (4H, m), 11.60-12.40 (1H, br).
  • Example 215 N- [4- (3'-Methoxybiphenyl-4-ylmethoxymethyl) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1682 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.81-0.88 (3H, m), 1.21-1.31 (4H, m), 1.35-1.45 (2H, m), 1.65-1.74 (2H , m), 3.48-3.54 (2H, m), 3.82 (3H, s), 4.61 (2H, s), 4.65 (2H, s), 6.91-6.97 (1H, m), 7.17-7.20 (1H, m ), 7.21-7.26 (1H, m), 7.36-7.40 (1H, m), 7.45-7.49 (2H, m), 7.49-7.54 (2H, m), 7.65-7.69 (2H, m), 7.91-7.97 (2H, m), 11.99-12
  • Example 216 N- [4- (3'-Methoxybiphenyl-3-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1685 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.81-0.87 (3H, m), 1.21-1.29 (4H, m), 1.34-1.44 (2H, m), 1.64-1.74 (2H , m), 3.47-3.54 (2H, m), 3.75 (2H, s), 3.78 (2H, s), 3.82 (3H, s), 6.91-6.97 (1H, m), 7.14-7.16 (1H, m ), 7.16-7.21 (1H, m), 7.25-7.30 (1H, m), 7.35-7.46 (4H, m), 7.51-7.57 (2H, m), 7.86-7.90 (2H, m), 11.95-12.03 (1H, br).
  • Example 218 N- [4- (3'-Dimethylaminobiphenyl-4-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1653 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.81-0.87 (3H, m), 1.21-1.29 (4H, m), 1.34-1.45 (2H, m), 1.64-1.75 (2H , m), 2.95 (6H, s), 3.46-3.52 (2H, m), 3.70 (2H, s), 3.76 (2H, s), 6.70-6.74 (1H, m), 6.87-6.92 (2H, m ), 7.21-7.27 (1H, m), 7.31-7.36 (2H, m), 7.42-7.46 (2H, m), 7.55-7.60 (2H, m), 7.87-7.92 (2H, m), 11.95-12.03 (1H, br).
  • Example 224 N- ⁇ 4- [4- (1,4-Benzodioxane-6-yl) benzyloxymethyl] benzoyl ⁇ hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1701 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.80-0.87 (3H, m), 1.21-1.30 (4H, m), 1.34-1.44 (2H, m), 1.65-1.74 (2H , m), 3.46-3.53 (2H, m), 4.27 (4H, s), 4.58 (2H, s), 4.63 (2H, s), 6.89-6.93 (1H, m), 7.10-7.15 (2H, m ), 7.37-7.43 (2H, m), 7.47-7.52 (2H, m), 7.55-7.60 (2H, m), 7.90-7.94 (2H, m), 11.98-12.07 (1H, br).
  • Example 225 (E) -N- [4- (3'-Dimethylaminobiphenyl-4-ylmethyleneaminooxy) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1684 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.80-0.91 (3H, m), 1.20-1.31 (4H, m), 1.33-1.46 (2H, m), 1.65-1.76 (2H , m), 2.98 (6H, s), 3.47-3.53 (2H, m), 6.74-6.83 (1H, m), 6.94-7.04 (2H, m), 7.25-7.32 (1H, m), 7.35-7.41 (2H, m), 7.75-7.81 (2H, m), 7.86-7.92 (2H, m), 7.97-8.03 (2H, m), 8.82 (1H, s), 11.86-12.00 (1H, br).
  • Example 226 N- [4- (3-Methoxybiphenyl-4-ylmethylsulfanylmethyl) benzoyl] hexane-1-sulfonamide IR ⁇ (ATR) cm -1 ; 1683 1 H-NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm); 0.80-0.88 (3H, m), 1.20-1.32 (4H, m), 1.34-1.46 (2H, m), 1.65-1.75 (2H , m), 3.46-3.55 (2H, m), 3.67 (2H, s), 3.80 (2H, s), 3.88 (3H, s), 7.15-7.24 (2H, m), 7.25-7.30 (1H, m ), 7.35-7.40 (1H, m), 7.43-7.50 (4H, m), 7.65-7.72 (2H, m), 7.86-7.93 (2H, m), 11.95-12.05 (1H, br).
  • Test Example 1 Measurement of PTP-1B Inhibitory Activity
  • PTP-1B inhibitory activity was measured using recombinant human PTP-1B as an enzyme and p-nitrophenyl phosphate (pNPP) as a substrate.
  • pNPP p-nitrophenyl phosphate
  • a 100% DMSO stock solution of the test compound was prepared and 2 ⁇ L was added to each well of a 96-well plate.
  • assay buffer 100 mM HEPES (pH 7.2), 1 mM EDTA, 1 mM DTT) (170 ⁇ L) and PTP-1B enzyme solution (10 ⁇ L) were added to each well and incubated at 37 ° C. for 10 minutes. Thereafter, 30 mM pNPP (20 ⁇ L) was added and incubated at 37 ° C.
  • Test Example 2 Pharmacological Action of Example Compound in db / db Mice (Test Method) Allocate 8-7-year-old male db / db mice to the control group and the 30 mg / kg / day administration group of the test compound as 6 to 7 animals per group so that the average values of body weight, plasma glucose and triglyceride are almost equal. It was. The test compound was suspended in 0.5% methylcellulose solution and orally administered daily for 4 weeks. In the control group, only 0.5% methylcellulose solution was orally administered.
  • glucose and triglycerides in plasma were measured using a commercially available measurement kit (glucose CII-Test Wako and triglyceride G-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.).
  • the rate of decrease in plasma glucose and triglycerides was determined from the following equation.
  • Decrease rate (%) [(average value of control group ⁇ average value of test compound administration group) / average value of control group] ⁇ 100 (result)
  • the compounds of Examples 122, 170, and 175 were 31.1%, 24.1%, and 29.1% plasma glucose, and triglyceride plasma, respectively, by repeated oral administration at 30 mg / kg / day for 4 weeks. 41.0%, 56.7% and 58.9%.
  • Test Example 3 Pharmacological Action of Example Compound in High Fat Diet Induced Obese Mice High-fat diet was given to 5-week-old male C57 / 6J mice for 4-6 weeks to create obese model mice. Before the start of the test, each group was assigned to the control group and the 30 mg / kg / day administration group of the test compound as 6 to 7 animals so that the average body weight and the average value of plasma triglyceride were approximately equal. The test compound was suspended in 0.5% methylcellulose solution and orally administered every day. In the control group, only 0.5% methylcellulose solution was orally administered.
  • Test Example 4 Blood Level after Oral Administration
  • Male test rats (7 weeks old) were forcibly orally administered 10 mg / kg of the test compound suspended in a 0.5% methylcellulose solution.
  • Blood was collected from the jugular vein using 1 mL syringes with heparin added at 0.25, 0.5, 1, 3, 5, 8 and 24 hours after administration.
  • the plasma drug concentration was measured using HPLC to determine the maximum blood concentration.
  • the compounds of Examples 46, 54, 83, 122, 138, 157, 170, 175 and 187-190 exhibited a maximum blood concentration of 1-20 ⁇ g / mL.
  • Test Example 5 Insulin Receptor Phosphorylation Test (In Vitro) (Test method) HepG2 cells are seeded at a cell density of 2 ⁇ 10 6 cells / 2 mL / well in a DMEM medium solution containing 10% fetal bovine serum in a 6-well plate, and cultured at 37 ° C. under 5% CO 2 conditions for 24 hours. did. Subsequently, it was replaced with fetal bovine serum free DMEM medium and starved for 6 hours. Each test compound was added and 1 nM insulin was added after 1 hour incubation.
  • Tris buffer pH 7.5
  • a sample collection buffer (20 mM Tris-HCl (pH 7.5), 5 mM EDTA-2Na, 10 mM Sodium fluoride, 10 mM Sodium pyrophosphate, 1 mM Sodium orthovanadate, 1 ⁇ g / mL p-Amidinophenyl methanol fluoride, 1 ⁇ g / mL Leupeptin, 1 ⁇ g / mL Antipain, 1 ⁇ g / mL Benzymidine).
  • the protein concentration was measured, mixed with the SDS treatment buffer so as to have the same protein concentration, and incubated at 100 ° C.
  • the present invention relates to an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance improving agent, a diabetes therapeutic agent, a diabetic complication therapeutic agent, a glucose intolerance improving agent, an antiarteriosclerosis agent, an antiobesity agent, an anti-obesity agent, It is useful as an inflammatory agent, a prophylactic / therapeutic agent for diseases mediated by PTP-1B and a prophylactic / therapeutic agent for metabolic syndrome. Moreover, since the pharmaceutical which contains this invention compound as an active ingredient has few side effects, it can become a highly safe therapeutic agent for diabetes.

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Abstract

Cette invention concerne un composé ayant une activité inhibitrice de PTP-1B qui est excellent à titre de médicament, ou un sel pharmaceutiquement acceptable de celui-ci. Un composé représenté par la formule générale (I) (chaque symbole dans la formule ayant la signification indiquée dans la description), ou un sel pharmaceutiquement acceptable de celui-ci est en outre décrit.
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CN113272276A (zh) * 2018-12-05 2021-08-17 中国医学科学院药物研究所 N-酰基磺酰胺盐类FBPase抑制剂、其制备方法、药物组合物及用途

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CN107098846B (zh) * 2016-02-26 2020-10-09 中国医学科学院药物研究所 N-酰基磺酰胺类FBPase抑制剂、其制备方法、药物组合物及用途
US20180244611A1 (en) * 2017-02-24 2018-08-30 AbbVie S.à.r.l. Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use
CN113272276A (zh) * 2018-12-05 2021-08-17 中国医学科学院药物研究所 N-酰基磺酰胺盐类FBPase抑制剂、其制备方法、药物组合物及用途
CN109608415A (zh) * 2019-01-21 2019-04-12 暨南大学 噻唑甲酰胺类化合物及其合成和应用
CN109608415B (zh) * 2019-01-21 2020-12-01 暨南大学 噻唑甲酰胺类化合物及其合成和应用

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