WO2011102514A1 - Composé cyclique aromatique - Google Patents

Composé cyclique aromatique Download PDF

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WO2011102514A1
WO2011102514A1 PCT/JP2011/053740 JP2011053740W WO2011102514A1 WO 2011102514 A1 WO2011102514 A1 WO 2011102514A1 JP 2011053740 W JP2011053740 W JP 2011053740W WO 2011102514 A1 WO2011102514 A1 WO 2011102514A1
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group
optionally substituted
compound
substituted
ring
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泰輔 俵石
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武田薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention has a long-chain fatty acid elongation enzyme 6 (Elongation of long chain fatty acid family member 6; hereinafter abbreviated as “Elovl6”) inhibitory action, and is a fragrance useful for the prevention and treatment of diabetes and the like. It relates to a ring compound.
  • Elovl6 long-chain fatty acid elongation enzyme 6
  • fatty acids are ingested by biosynthesis or diet by fatty acid synthase (FASN, fatty acid synthase) in the cytoplasmic fraction, and a part thereof undergoes chain length extension reaction to become long chain fatty acids.
  • FSN fatty acid synthase
  • the chain-lengthening reaction of long-chain fatty acids is a long-chain fatty acid that becomes a substrate with malonyl-CoA by the Elovl family of enzyme groups consisting of seven subtypes of Elovl (Elongation of long fatty acids) 1-7 It is considered that the first-stage condensation reaction with -CoA is catalyzed, and through a further three-stage enzymatic reaction, a long-chain fatty acid-CoA reaction product with two added carbon chains is obtained (Non-patent Document) 1).
  • Elovl6 was identified as an Elovl family molecule that is particularly highly expressed in the liver of SREBP-1a (sterol regulatory element binding protein-1a) transgenic mice (Non-patent Documents 2 and 3). Elovl6 is known to localize in the endoplasmic reticulum and catalyze the condensation reaction with malonyl-CoA using fatty acid-CoA with a carbon chain number of 12 to 16 (C12 to C16) as a substrate. It is known that it is induced, decreases physiologically by fasting, and increases by refeeding.
  • SREBP-1a sterol regulatory element binding protein-1a
  • Elovl6 genetically deficient in Elovl6 have been reported to be highly resistant to the induction of hyperinsulinemia, hyperglycemia and hyperleptinemia due to dietary or genetic load (non-patented Reference 4).
  • Elovl6 genetic deficiency or decreased gene expression increases C16 fatty acids, especially palmitoleate (C16: 1n7, palmitoleate), C18 fatty acids stearic acid (C18: 0, stearate), oleic acid (C18: 1n9, oleate) These fatty acid composition changes are thought to function to improve insulin resistance, glucose tolerance, and leptin resistance.
  • Non-patent Document 5 There is also a report confirming that palmitoleic acid is one of the humoral factors that act on anti-inflammatory and insulin sensitivity enhancement. Therefore, a compound having an Elovl6 inhibitory action is useful for the prevention and treatment of diabetes and the like.
  • Patent Document 1 (WO2009 / 13165) describes a compound of formula (I) as an LCE (Elovl6) inhibitor.
  • R 1 and R 2 each independently represent a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, or R 1 and R 2 together Forming a nitrogen-containing heterocycle with the nitrogen atom to which they are attached,
  • the alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or nitrogen-containing heterocycle is hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cyclo Alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6
  • any hydrogen atom in formula (II-1) to formula (II-4) may be substituted with C 1-6 alkyl, halo C 1-6 alkyl or C 3-8 cycloalkyl
  • Z is a hydrogen atom, hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino (wherein the amino is optionally substituted by C 1-6 alkyl, aryl or heteroaryl ), Carbamoyl (the carbamoyl may be 1 to 2 substituted with C 1-6 alkyl, aryl or heteroaryl), sulfanyl (the sulfanyl (the sulfany
  • Patent Document 2 discloses an LCE (Elovl6) inhibitor as a compound of formula (I)
  • R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted.
  • R 2 represents optionally substituted phenyl or optionally substituted heteroaryl, wherein the phenyl or heteroaryl is halogen, C 1-6 alkyl, haloC Optionally substituted with a substituent selected from the group consisting of 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyloxy, phenyl and nitrogen-containing heteroaryl
  • Q represents N or CH
  • M 1 and M 2 each independently represent a hydrogen atom
  • Patent Document 3 reports the following compounds as beta-3 adenoreceptor agonists.
  • Patent Document 4 (WO2005 / 000797) describes a method for producing the following compound.
  • R 1 is hydrogen, — (CH 2 ) p -heterocyclyl or a hydrocarbon group, wherein the latter two groups are halogen, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -haloalkyl, (C 1 -C 6 ) -alkoxy, substituted with one or more groups selected from the group consisting of cyano and nitro, or unsubstituted;
  • R 2 is hydrogen, (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, (C 1 -C 6 ) -alkoxy, (C 2- C 6 ) -alkenyloxy, wherein the latter five groups are one or more selected from the group consisting of halogen, (C 1 -C 4 ) -alkoxy and (C 1 -C 4 ) -alkylthio Sub
  • Patent Document 5 (US6251827) describes the following compounds.
  • R 1 is a hydrogen, heterocyclyl or hydrocarbon group, the latter two groups optionally being halogen, cyano, nitro, amino, hydroxy, carboxy, CHO, CONH 2 , SO 2 NH 2 and Z a —R a Substituted with one or more identical or different groups selected from the group consisting of: R 2 is hydrogen, hydroxy, (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, (C 1 -C 6 ) -alkoxy, (C 2 -C 6 ) -alkenyloxy, the latter five groups optionally being halogen, hydroxy, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy and (C 1 -C 4 )- Substituted with one or more identical or different groups selected from the group consisting of: R 2 is hydrogen,
  • Valence unit; Z b and Z c are each independently a direct bond, or O, S, CO, CS, C (O) O, C (O) S, SO, SO 2 , NR d , SO 2 NR d or C (O )
  • R d is hydrogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -haloalkyl;
  • n is an integer of 0 to 4; and
  • m is an integer of 0 to 5 when X is CH, or an integer of 0 to 4 when X is N, or a compound thereof Salts such as the following compounds:
  • Patent Document 6 (US370917) and Patent Document 7 (US3828054) describe compounds useful as gout therapeutic agents, for example, the following compounds.
  • R is lower alkyl containing 1-4 carbon atoms, cycloalkyl containing 5-6 ring carbon atoms, cycloalkylalkyl (wherein the cycloalkyl contains 5-6 ring carbon atoms) ), Alkenyl, alkynyl, halo lower alkyl containing 1-2 carbon atoms, polyhalo lower alkyl containing 1-3 carbon atoms, aryl, aralkyl, dialkylsulfamoyl substituted aryl or 5-6 membered heterocycle
  • R 1 is hydrogen, lower alkyl of 1-4 carbon atoms, or cycloalkyl of 5-6 ring carbon atoms
  • R 2 is lower alkyl of 1-6 carbon atoms or 5-6
  • Cycloalkyl of the ring carbon atom of X is a halo, lower alkyl, nitro, trihalomethyl, cyano or carboxy, or a hydrogen atom containing 3-4 carbon atoms between the points
  • Patent Document 8 Japanese Patent Laid-Open No. 63-057570 describes the following compounds useful as agricultural and horticultural fungicides.
  • X represents a halogen atom excluding a chlorine atom, a methylthio group, a lower alkoxy group
  • Y represents a hydrogen atom or a chlorine atom
  • Z represents a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a nitro group or a methylsulfonyl group
  • n represents an integer of 1 to 3.
  • a salt thereof for example, the following compounds.
  • Patent Document 9 Japanese Patent Laid-Open No. 62-161761 describes the following compounds useful as agricultural and horticultural fungicides.
  • X and Y represent the same or different hydrogen atom or chlorine atom
  • R represents a hydrogen atom, a lower alkyl group or an allyl group
  • Z represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a methoxy group, a methylthio group, a methylsulfonyl group, a trifluoromethyl group, a phenyl group, a phenoxy group, or a COOR ′ group (R ′ represents a methyl group or an ethyl group).
  • n represents an integer from 1 to 3.
  • X, Y, and R are simultaneously a hydrogen atom and Z is a methyl group is excluded.
  • a salt thereof for example, the following compounds.
  • Patent Document 10 Japanese Patent Laid-Open No. 59-140450 describes compounds such as the following, which are useful as phenolic cyan couplers for silver halide photographic materials.
  • Ring A includes a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkoxy group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and a substituted A 5- or 6-membered aromatic ring which may be further substituted with 1 to 4 substituents selected from optionally amino groups;
  • Ring B is 1 to 4 substituents selected from a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted hydroxy group.
  • a 6-membered aromatic ring which may be further substituted;
  • X 1 represents a bond or NR 4 (R 4 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group);
  • X 2 is CO or SO 2 ;
  • X 3 represents N or CR 5 (R 5 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group or does not exist);
  • R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted monocyclic heterocyclic group, a substituted hydroxy group, or an optionally substituted amino group;
  • R 2 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-10 cycloalkyl group;
  • R 3 represents an optionally substituted C 1 1- A 6 alkyl group, or an optionally substituted C 3-10 cycloalkyl group, R 2 and R 3 together with the adjacent X 3 may form an optional
  • Ring A is further substituted with 1 to 4 substituents selected from a halogen atom, a C 1-6 alkyl group which may be substituted with 1 to 5 halogen atoms, and a cyano group, respectively.
  • a salt thereof according to the above [1], which is a benzene ring or a pyridine ring
  • Ring B may be further substituted with 1 to 4 substituents selected from a halogen atom and a C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms
  • [4] The compound or salt thereof according to any one of [1] to [3] above, wherein X 1 is a bond or NH; [5] The compound or a salt thereof according to any one of the above [1] to [4], wherein X 2 is CO; [6] The compound or a salt thereof according to any one of [1] to [5] above, wherein
  • Ring A is further substituted with 1 to 4 substituents selected from a halogen atom, a C 1-6 alkyl group which may be substituted with 1 to 5 halogen atoms and a cyano group, respectively.
  • Ring B is a benzene ring which may be further substituted with 1 to 4 substituents selected from a halogen atom and a C 1-6 alkyl group which may be substituted with 1 to 5 halogen atoms
  • X 1 is a bond or NH
  • X 2 is CO
  • X 3 is N or CR 5 (R 5 represents a hydrogen atom or does not exist)
  • R 1 is (1) a halogen atom, (2) a cyano group, (3) a C 1-6 alkyl group which may be substituted with 1 to 5 halogen atoms, (4) a monocyclic heterocyclic group optionally substituted with 1 to 5 C 1-6 alkyl groups, (5) a C 1-6 alkoxy group which may be substituted with 1 to 5 halogen atoms, (6) an amino group optionally substituted with one or two substituents selected from (a) a C 1-6 alkyl group and (b) a C 3-10 cycl
  • Compound (I) has an Elovl6 inhibitory action and is useful as a prophylactic / therapeutic agent for diabetes and the like. Detailed Description of the Invention
  • halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, 1,1-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 2-6 alkenyl group examples include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- It means methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like.
  • C 2-6 alkynyl group means ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl unless otherwise specified. , 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • C 3-10 cycloalkyl group in the present specification means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, unless otherwise specified. Of these, a C 3-6 cycloalkyl group is preferable.
  • C 3-10 cycloalkenyl group in the present specification includes, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Is mentioned.
  • C 4-10 cycloalkadienyl group in the present specification includes, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-1 -Il and the like.
  • C 6-14 aryl group is, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like, unless otherwise specified. Is mentioned.
  • the C 6-14 aryl may be partially saturated, and examples of the partially saturated C 6-14 aryl include tetrahydronaphthyl and the like.
  • C 7-16 aralkyl group in the present specification includes, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3- Examples include phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like.
  • Examples of the “C 8-16 arylalkenyl group” in the present specification include styryl and the like.
  • C 1-3 alkylenedioxy group in the present specification means methylenedioxy, ethylenedioxy, trimethylenedioxy and the like, unless otherwise specified.
  • C 1-6 alkoxy group in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like unless otherwise specified.
  • C 1-6 alkoxy-carbonyl group in the present specification means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
  • C 1-6 alkyl-carbonyl group in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like, unless otherwise specified.
  • Ring A includes a halogen atom, a cyano group, a nitro group, an optionally substituted C 1-6 alkoxy group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and a substituted A 5- or 6-membered aromatic ring which may be further substituted with 1 to 4 substituents selected from the optionally selected amino groups.
  • substituted (I ′) is bonded to each other.
  • substituent (I ′) is bonded to each other.
  • examples of the “5- or 6-membered aromatic ring” represented by ring A include benzene or a 5- or 6-membered aromatic heterocyclic ring.
  • the 5- or 6-membered aromatic heterocycle includes, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • a 5- or 6-membered aromatic heterocyclic ring containing 4 is mentioned.
  • the 5-membered aromatic heterocycle include, for example, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (eg, 1,2,4-oxadi Azole, 1,3,4-oxadiazole), thiadiazole (eg, 1,2,4-thiadiazole, 1,3,4-thiadiazole), triazole (eg, 1,2,3-triazole, 1,3, 4-triazole) and the like.
  • 6-membered aromatic heterocycle examples include, for example, pyridine, pyrimidine, pyridazine, pyrazine, triazine (eg, 1,2,3-triazine, 1,2,4-triazine, 1,3,5 -Triazine etc.).
  • the “5- or 6-membered aromatic ring” of the “optionally substituted 5- or 6-membered aromatic ring” represented by ring A is preferably (1) benzene, or (2) a 6-membered aromatic heterocycle, More preferred is benzene or pyridine.
  • the “5- or 6-membered aromatic ring” represented by ring A is substituted with a halogen atom, a cyano group, a nitro group, or a substituted group.
  • substituents selected from an optionally substituted C 1-6 alkoxy group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted amino group May further be included.
  • the “C 1-6 alkoxy group” as the substituent of ring A may have a substituent (eg, 1 to 5, preferably 1 to 3) at a substitutable position.
  • a substituent eg, 1 to 5, preferably 1 to 3
  • substituents include [Substituent group ⁇ ] described later.
  • each substituent may be the same or different.
  • [Substituent group ⁇ ] (1) C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) C 6- optionally substituted with 1 to 3 substituents selected from halogen atoms. 14 aryl groups (eg, phenyl, naphthyl);
  • a cyclic group eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl); (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a non-aromatic group optionally substituted with 1 to 3 substituents selected from halogen atoms
  • a heterocyclic group eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl);
  • a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl); (9) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (10) a thiocarbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (11) a sulfamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
  • a C 2-6 alkenyloxy group eg, ethenyloxy
  • C 6-14 aryloxy group eg, phenyloxy, naphthyloxy
  • C 1-6 alkyl-carbonyloxy group eg, acetyloxy, tert-butylcarbonyloxy
  • a C 6-14 aryl-carbonyl group eg, benzoyl
  • a non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, Pyrrolidinylcarbonyl, morpholinylcarbonyl, 1,1-dioxidethiomorpholinylcarbonyl); (20) a mercapto group; (21) a C 1-6 alkylthio group optionally substituted with 1 to 3 halogen atoms (eg, methylthio, ethylthio); (22) C 7-13 aralkylthio group (eg, benzylthio); (23) C 6-14 arylthio group (eg, phenylthio, naphthylthio); (24) a cyano group; (25) a nitro group; (26) a halogen atom; (27) a C 1-3 alkylenedioxy group;
  • C 1-6 alkyl groups optionally substituted with 1
  • Aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms eg, pyrazolylcarbonyl, pyrazinylcarbonyl) , Isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl
  • (30) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (d) an aromatic complex which may be substituted with 1 to 3 substituents selected from halogen atoms.
  • a ring oxy group eg, thienyloxy, furyloxy, pyridyloxy, pyrazolyloxy, imidazolyloxy, tetrazolyloxy, oxazolyloxy, thiazolyloxy, oxadiazolyloxy, thiadiazolyloxy;
  • (31) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a non-aromatic group optionally substituted with 1 to 3 substituents selected from halogen atoms Heterocyclic oxy group (eg, tetrahydrofuryloxy, morpholinyloxy, thiomorpholinyloxy, piperidinyloxy, pyrrolidinyloxy, piperazinyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy); etc. .
  • halogen atoms Heterocyclic oxy group (eg, tetrahydrofuryloxy, morpholinyloxy, thiomorpholinyloxy, piperidinyloxy, pyrrolidinyloxy, piperazinyloxy
  • hydrocarbon group of the “optionally substituted hydrocarbon group” as the substituent of ring A examples include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 4-10 cycloalkadienyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 8-16 arylalkenyl group, etc. It is done.
  • C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkadienyl group may each form a condensed ring group with a benzene ring, and such a condensed ring group Examples thereof include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • the C 1-10 alkyl group, C 2-10 alkenyl group and C 2-10 alkynyl group exemplified as the “hydrocarbon group” above may be substituted at a substitutable position (eg 1 to 5, preferably 1 to 3).
  • a substitutable position eg 1 to 5, preferably 1 to 3
  • substituents include the same as those in the above [Substituent group ⁇ ].
  • each substituent may be the same or different.
  • the C 8-16 arylalkenyl group may have a substituent (for example, 1 to 5, preferably 1 to 3) at a substitutable position.
  • substituents include [Substituent group ⁇ ] described later. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted hydrocarbon group” as the substituent for ring A is preferably a C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms.
  • heterogroup of the “optionally substituted heterocyclic group” as the substituent of ring A examples include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • aromatic heterocyclic group is, for example, a 4- to 7-membered (preferably 5- or 5-membered) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring-constituting atoms. 6-membered) monocyclic aromatic heterocyclic group and condensed aromatic heterocyclic group.
  • Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group, and a 5- or 6-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms, And a group derived from a ring condensed with 1 to 2 rings selected from a 5-membered aromatic heterocyclic ring containing one sulfur atom or oxygen atom and a benzene ring.
  • “aromatic heterocyclic group” for example, Furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl) 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (Eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl
  • Quinolyl eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl
  • isoquinolyl eg, 3-isoquinolyl
  • quinazolyl eg, 2-quinazolyl, 4-quinazolyl
  • quinoxalyl eg, 2-quinoxalyl
  • benzofuranyl eg, 2-benzofuranyl, 3-benzofuranyl
  • benzothienyl eg, 2-benzothienyl, 3-benzothienyl
  • benzoxazolyl eg, 2-benzoxazolyl
  • Benzisoxazolyl eg, 7-benzisoxazolyl
  • benzothiazolyl eg, 2-benzothiazolyl
  • benzimidazolyl eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5- Yl
  • benzotriazolyl eg
  • non-aromatic heterocyclic group is, for example, a 3- to 8-membered (preferably 5-membered) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms.
  • a 6-membered) monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group examples include a ring corresponding to the 3- to 8-membered monocyclic non-aromatic heterocyclic group, and 1 to 2 selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • non-aromatic heterocyclic group for example, Aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2 -Piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleneiminyl (eg, , Hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidin-2-
  • Dihydroindolyl eg, 2,3-dihydro-1H-indol-1-yl
  • dihydroisoindolyl eg, 1,3-dihydro-2H-isoindol-2-yl
  • dihydrobenzofuranyl eg, 2,3-dihydrobenzofuran-5-yl
  • dihydrobenzodioxinyl eg, 2,3-dihydro-1,4-benzodioxinyl
  • dihydrobenzodioxepinyl eg, 3,4- Dihydro-2H-1,5-benzodioxepinyl
  • tetrahydrobenzofuranyl eg, 4,5,6,7-tetrahydrobenzofuran-3-yl
  • chromenyl eg, 4H-chromen-2-yl, 2H-chromen-3-yl
  • dihydroquinolinyl eg, 1,2-d
  • heterocyclic group may have a substituent (for example, 1 to 5, preferably 1 to 3) at a substitutable position.
  • substituent include the same ones as in the above [Substituent group ⁇ ].
  • an oxo group is further included as a substituent.
  • each substituent may be the same or different.
  • the “optionally substituted heterocyclic group” as the substituent of ring A includes a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 C 1-6 alkyl groups. preferable.
  • Examples of the “optionally substituted amino group” as the substituent for ring A include (1-a) an optionally substituted hydrocarbon group, (2-a) an optionally substituted heterocyclic group, (3-a) An amino group which may be substituted with one or two substituents selected from an acyl group and the like. When there are two substituents, the substituents may be the same or different.
  • acyl group in (3-a) include, for example, the formula: —COR A1 , —CO—OR A1 , —SO 3 R A1 , —SO 2 R A1 , —SOR A1 , —CO—NR A2 R B2 , —SO 2 —NR A2 R B2 , —CS—NR A2 R B2 [wherein R A1 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; , R A2 and R B2 independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R A2 and R B2 together with an adjacent nitrogen atom And a nitrogen-containing heterocyclic ring which may be substituted may be formed].
  • the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R A2 and R B2 together with the adjacent nitrogen atom is, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom.
  • nitrogen-containing heterocycle in the “optionally substituted nitrogen-containing heterocycle” formed by R A2 and R B2 together with the adjacent nitrogen atom is, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom.
  • Examples thereof include a 3- to 8-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • the nitrogen-containing heterocycle include azetidine, aziridine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like.
  • the nitrogen-containing heterocycle may have 1 to 2 substituents at substitutable positions. Examples of such a substituent include those similar to the above [Substituent group ⁇ ] and oxo groups. When there are two or more substituents, each substituent may be the same or different.
  • acyl group examples include formyl group, carboxy group, carbamoyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, C 3-8 cycloalkyl-carbonyl group, C 6 -14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, C 6-14 aryloxy-carbonyl group, C 7-16 aralkyloxy-carbonyl group, mono- or di-C 1-6 alkyl-carbamoyl group, Mono- or di-C 6-14 aryl-carbamoyl group, mono- or di-C 3-8 cycloalkyl-carbamoyl group, mono- or di-C 7-16 aralkyl-carbamoyl group, C 1-6 alkylsulfonyl group , C 6-14 arylsulfonyl group, nitrogen-containing heterocyclic - carbonyl group, C 1-6 alkyl
  • the “optionally substituted amino group” as the substituent for ring A is preferably an amino group which may be substituted with one or two C 1-6 alkyl groups.
  • Ring A is preferably a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), 1 to 5 selected from a C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms, and a cyano group.
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • 1 to 5 selected from a C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms, and a cyano group.
  • a 6-membered aromatic hydrocarbon eg, benzene
  • a 6-membered aromatic heterocycle eg, pyridine
  • substituents more preferably 6-membered aromatic hydrocarbon (eg, benzene) or 6-membered optionally substituted by 1 to 4 substituents selected from a halogen atom (eg, chlorine atom, bromine atom) and a cyano group
  • An aromatic heterocyclic ring eg, pyridine).
  • Ring B is 1 to 4 substituents selected from a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted hydroxy group. Furthermore, the 6-membered aromatic ring which may be substituted is shown.
  • substituted aromatic ring B (In this specification, it may be abbreviated as “substituent (I ′ ′′)”) is bonded to each other at the para position.
  • substituent (I ′ ′′) is bonded to each other at the para position.
  • examples of the “6-membered aromatic ring” represented by ring B include benzene or a 6-membered aromatic heterocycle.
  • Examples of the “6-membered aromatic heterocyclic ring” include those having a 6-membered ring among the “5- or 6-membered aromatic heterocyclic ring” as the “5- or 6-membered aromatic ring” represented by the ring A. It is done.
  • the “6-membered aromatic ring” represented by ring B may be substituted with a halogen atom, a cyano group or a substituted position. It may further have 1 to 4 substituents selected from a hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted hydroxy group.
  • the “optionally substituted hydrocarbon group” as the substituent of ring B is a C 1-6 alkyl group (eg, optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom)).
  • a methyl group is preferred.
  • the “optionally substituted heterocyclic group” as the substituent of ring B includes a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 C 1-6 alkyl groups. preferable.
  • Examples of the “optionally substituted hydroxy group” as the substituent of ring B include (1-b) an optionally substituted hydrocarbon group, (2-b) an optionally substituted heterocyclic group, (3-b) a hydroxy group which may be substituted with a substituent selected from an acyl group and the like.
  • the “optionally substituted hydrocarbon group” in the above (1-b) and the “optionally substituted heterocyclic group” in the above (2-b) are each represented by “ Examples thereof include the same as the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group”.
  • Examples of the “acyl group” in (3-b) include the same “acyl group” in (3-a).
  • the “optionally substituted hydroxy group” as the substituent of ring B is a C 1-6 alkoxy group, C 1-6 alkyl-carbonyloxy group which may be substituted with 1 to 3 halogen atoms. And a C 6-14 aryloxy group is preferred.
  • Ring B is preferably selected from a halogen atom (eg, fluorine atom) and a C 1-6 alkyl group (eg, methyl group, trifluoromethyl group) optionally substituted with 1 to 5 halogen atoms.
  • a halogen atom eg, fluorine atom
  • a C 1-6 alkyl group eg, methyl group, trifluoromethyl group
  • a 6-membered aromatic ring eg, benzene which may be further substituted with 1 to 4 substituents.
  • X 1 represents a bond or NR 4 (R 4 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group).
  • the “C 1-6 alkyl group” represented by R 4 may have a substituent (eg, 1 to 5, preferably 1 to 3) at a substitutable position. Examples of such a substituent include the same as those in the above [Substituent group ⁇ ]. When there are two or more substituents, each substituent may be the same or different.
  • X 1 is preferably a bond or NH, more preferably a bond.
  • X 2 represents CO or SO 2 .
  • X 2 is preferably CO.
  • X 3 represents N or CR 5 (R 5 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group or does not exist).
  • X 3 is preferably N or CR 5 (R 5 represents a hydrogen atom or is absent).
  • R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted monocyclic heterocyclic group, a substituted hydroxy group, or an optionally substituted amino group.
  • a C 1-6 alkyl group eg, methyl group, ethyl group, tert-butyl group
  • 1 to 5 halogen atoms eg, fluorine atom, chlorine atom
  • a C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms
  • a C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms
  • a C 1-6 alkoxy group optionally substituted with 1 to 5 halogen atoms
  • a phenyl group which may be substituted with 1 to 5 substituents selected from halogen atoms is preferred
  • a C 1-6 alkyl group eg, methyl group, ethyl group, tert-butyl group
  • 1 to 5 halogen atoms eg, fluorine atom, chlorine atom
  • R 1 1 or 2 substituents selected from (a) a C 1-6 alkyl group (eg, methyl group, isopropyl group) and (b) a C 3-8 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl group)
  • a C 1-6 alkyl group eg, methyl group, isopropyl group
  • a C 3-8 cycloalkyl-carbonyl group eg, cyclopropylcarbonyl group
  • An optionally substituted amino group is preferred.
  • the “optionally substituted heterocyclic group” as the substituent of ring A can be Among the “heterocyclic groups”, monocyclic ones can be mentioned.
  • the “monocyclic heterocyclic group” may have a substituent (for example, 1 to 5, preferably 1 to 3) at a substitutable position. Examples of such a substituent include the same ones as in the above [Substituent group ⁇ ].
  • an oxo group is further included as a substituent.
  • each substituent may be the same or different.
  • the “optionally substituted monocyclic heterocyclic group” represented by R 1 is a 5- or 6-membered optionally substituted with 1 to 5 C 1-6 alkyl groups (eg, methyl group).
  • C 1-6 alkyl groups eg, methyl group
  • the “substituted hydroxy group” represented by R 1 includes (1-c) an optionally substituted hydrocarbon group, (2-c) an optionally substituted heterocyclic group, (3-c) Examples thereof include a hydroxy group substituted with a substituent selected from an acyl group and the like.
  • acyl group examples include the same “acyl group” in (3-a).
  • the “substituted hydroxy group” represented by R 1 is a C 1-6 alkoxy group (eg, methoxy group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom, chlorine atom). Ethoxy groups) are preferred.
  • R 1 is preferably (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) a C 1-6 alkyl group (eg, methyl group, ethyl group, tert-butyl group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (4) a monocyclic heterocyclic group (eg, pyrazolyl group) optionally substituted with 1 to 5 C 1-6 alkyl groups (eg, methyl group), (5) a C 1-6 alkoxy group (eg, methoxy group, ethoxy group) optionally substituted by 1 to 5 halogen atoms (eg, fluorine atom), (6) 1 or 2 substituents selected from (a) C 1-6 alkyl group (eg, methyl group, isopropyl group) and (b) C 3-10 cycloalkylcarbonyl (eg, cyclopropylcarbonyl
  • R 2 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-10 cycloalkyl group
  • R 3 represents an optionally substituted C 1 1- A 6 alkyl group, or an optionally substituted C 3-10 cycloalkyl group, R 2 and R 3 together with the adjacent X 3 may form an optionally substituted 3- to 8-membered ring.
  • the “C 3-10 cycloalkyl group” represented by R 2 or R 3 may have a substituent (eg, 1 to 5, preferably 1 to 3) at a substitutable position.
  • a substituent eg, 1 to 5, preferably 1 to 3
  • substituents include those similar to the above [Substituent group ⁇ ] and oxo groups.
  • each substituent may be the same or different.
  • the "3 to 8-membered nitrogen-containing heterocyclic ring" R 2 and R 3 form together with X 3 adjacent, for example, at least in addition to carbon atoms as ring atoms 1
  • Examples thereof include a 3- to 8-membered nitrogen-containing heterocycle containing 1 nitrogen atom and further containing 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • nitrogen-containing heterocycle examples include azetidine, aziridine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine, homopiperidine, homopiperazine, homomorpholine, thiohomomorpholine, azocane Etc.
  • the “3- to 8-membered non-aromatic ring” formed by R 2 and R 3 together with the adjacent X 3 includes 3- to 8-membered non-aromatic cyclic hydrocarbon and 3 to 8 membered non-aromatic heterocycle is mentioned.
  • Examples of the “3- to 8-membered non-aromatic cyclic hydrocarbon” include C 3-8 cycloalkane, C 3-8 cycloalkene, C 4-8 cycloalkadiene and the like.
  • C 3-8 cycloalkane examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.1] octane and the like. Of these, C 3-6 cycloalkane is preferred.
  • C 3-8 cycloalkene examples include cyclopentene, cyclohexene and the like.
  • C 4-8 cycloalkadiene examples include 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene, and the like.
  • Examples of the “3- to 8-membered non-aromatic heterocycle” include, for example, a 3- to 8-membered ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom ( Preferred is a 5- or 6-membered non-aromatic heterocyclic ring.
  • Examples of the “3- to 8-membered non-aromatic heterocycle” include, for example, aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, oxazoline, thiazoline, imidazoline, dioxol, Dioxolane, dihydrooxadiazole, 2-thioxo-1,3-oxazolidine, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, 1-oxidetetrahydrothiopyran, 1,1-dioxidetetrahydrothiopyran, tetrahydrofuran, pyrazolidine, pyrazoline , Tetrahydropyrimidine, dihydrotriazole, tetrahydrotriazole, homopiperidine, homopiperazine
  • the “3- to 8-membered ring” may have a substituent (for example, 1 to 5, preferably 1 to 3) at a substitutable position.
  • a substituent for example, 1 to 5, preferably 1 to 3
  • substituents include the same ones as in the above [Substituent group ⁇ ].
  • an oxo group is further included as a substituent.
  • each substituent may be the same or different.
  • R 2 is preferably a hydrogen atom or a C 1-6 alkyl group (eg, methyl group), R 3 is preferably 1 selected from (1) (a) a hydroxy group and (b) an amino group (eg, dimethylamino group) optionally substituted by 1 or 2 C 1-6 alkyl groups.
  • a C 1-6 alkyl group eg, methyl group, ethyl group, n-propyl group, isopropyl group
  • a C 3-10 cycloalkyl group eg, , A cyclopropyl group
  • R 2 and R 3 are formed together with adjacent X 3 , (1) an oxo group, (2) a hydroxy group and (3) an optionally substituted C 1 1 to 3 hydroxy group
  • a 3- to 8-membered nitrogen-containing heterocyclic ring eg, azetidine, pyrrolidine, morpholine, thiomorpholine
  • 5 optionally substituted with 1 to 3 substituents selected from a -6 alkyl group (eg, methyl group)
  • a 6-membered aromatic ring for example, benzene
  • R 2 is a hydrogen atom or a C 1-6 alkyl group (eg, a methyl group)
  • R 3 is (1) a C 1-6 alkyl group (eg, methyl group, ethyl group, n-propyl group, isopropyl group) optionally substituted with 1 to 3 hydroxy groups, or (2) C 3 A 3-10 cycloalkyl group (eg, a cyclopropyl group), or R 2 and R 3 are formed together with adjacent X 3 , (1) a hydroxy group and (2) a C 1-6 alkyl group optionally substituted with 1 to 3 hydroxy groups (eg, A 3- to 8-membered nitrogen-containing heterocyclic ring (eg, azetidine, pyrrolidine, morpholine, thiomorpholine) or a 5- or 6-membered aromatic ring (eg, optionally substituted with 1 to 3 substituents selected from methyl group)
  • Example: benzene benzene
  • Ring A is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms (eg, methyl group, trifluoromethyl group) And a 6-membered aromatic hydrocarbon (eg, benzene) or a 6-membered aromatic heterocycle (eg, pyridine), each of which may be further substituted with 1 to 4 substituents selected from a cyano group; Ring 1 to 4 selected from a halogen atom (eg, fluorine atom) and a C 1-6 alkyl group (eg, methyl group, trifluoromethyl group) optionally substituted with 1 to 5 halogen atoms.
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms
  • 1 to 5 halogen atoms eg, methyl
  • a 6-membered aromatic ring (eg, benzene) optionally further substituted with one substituent;
  • X 1 is a bond or NH;
  • X 2 is CO;
  • X 3 is N or CR 5 (R 5 represents a hydrogen atom or is absent);
  • R 1 is (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) a C 1-6 alkyl group (eg, methyl group, ethyl group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (4) a monocyclic heterocyclic group (eg, pyrazolyl group) optionally substituted with 1 to 5 C 1-6 alkyl groups (eg, methyl group), (5) a C 1-6 alkoxy group (eg, methoxy group, ethoxy group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), or
  • Ring A is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms (eg, methyl group, trifluoromethyl group) And a 6-membered aromatic hydrocarbon (eg, benzene) or a 6-membered aromatic heterocycle (eg, pyridine), each of which may be further substituted with 1 to 4 substituents selected from a cyano group; Ring 1 to 4 selected from a halogen atom (eg, fluorine atom) and a C 1-6 alkyl group (eg, methyl group, trifluoromethyl group) optionally substituted with 1 to 5 halogen atoms.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms
  • 1 to 5 halogen atoms eg,
  • a 6-membered aromatic ring (eg, benzene) optionally further substituted with one substituent;
  • X 1 is a bond or NH (preferably a bond);
  • X 2 is CO;
  • X 3 is N or CR 5 (R 5 represents a hydrogen atom or is absent);
  • R 1 is (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) a C 1-6 alkyl group (eg, methyl group, ethyl group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (4) a monocyclic heterocyclic group (eg, pyrazolyl group) optionally substituted with 1 to 5 C 1-6 alkyl groups (eg, methyl group), (5) a C 1-6 alkoxy group (eg, methoxy group, ethoxy group) optionally substituted by 1 to 5 halogen atoms (eg, fluor
  • a 3- to 8-membered nitrogen-containing heterocyclic ring eg, azetidine, pyrrolidine, morpholine, thiomorpholine
  • 6 alkyl groups eg, methyl group
  • 6-membered aromatic ring eg, benzene
  • Ring A is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms (eg, methyl group, trifluoromethyl group) And a 6-membered aromatic hydrocarbon (eg, benzene) or a 6-membered aromatic heterocycle (eg, pyridine), each of which may be further substituted with 1 to 4 substituents selected from a cyano group; Ring 1 to 4 selected from a halogen atom (eg, fluorine atom) and a C 1-6 alkyl group (eg, methyl group, trifluoromethyl group) optionally substituted with 1 to 5 halogen atoms.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • C 1-6 alkyl group optionally substituted with 1 to 5 halogen atoms
  • 1 to 5 halogen atoms eg,
  • a 6-membered aromatic ring (eg, benzene) optionally further substituted with one substituent;
  • X 1 is a bond or NH (preferably a bond);
  • X 2 is CO;
  • X 3 is N or CR 5 (R 5 represents a hydrogen atom or is absent);
  • R 1 is (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) a C 1-6 alkyl group (eg, methyl group, ethyl group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (4) a monocyclic heterocyclic group (eg, pyrazolyl group) optionally substituted with 1 to 5 C 1-6 alkyl groups (eg, methyl group), (5) a C 1-6 alkoxy group (eg, methoxy group, ethoxy group) optionally substituted with 1 to 5 halogen atoms (eg, fluor
  • a 3- to 8-membered nitrogen-containing heterocyclic ring eg, azetidine, pyrrolidine, morpholine, thiomorpholine
  • 6 alkyl groups eg, methyl group
  • 6-membered aromatic ring eg, benzene
  • Ring A is a 6-membered aromatic hydrocarbon (eg, benzene) which may be further substituted with 1 to 4 substituents selected from a halogen atom (eg, chlorine atom, bromine atom) and a cyano group, respectively. Or a 6-membered aromatic heterocycle (eg, pyridine); Ring 1 to 4 selected from a halogen atom (eg, fluorine atom) and a C 1-6 alkyl group (eg, methyl group, trifluoromethyl group) optionally substituted with 1 to 5 halogen atoms.
  • a halogen atom eg, chlorine atom, bromine atom
  • a cyano group e.g, a 6-membered aromatic heterocycle
  • Ring 1 to 4 selected from a halogen atom (eg, fluorine atom) and a C 1-6 alkyl group (eg, methyl group, trifluoromethyl group) optionally substituted with 1 to 5 halogen atoms
  • a 6-membered aromatic ring (eg, benzene) optionally further substituted with one substituent;
  • X 1 is a bond or NH (preferably a bond);
  • X 2 is CO;
  • X 3 is N or CR 5 (R 5 represents a hydrogen atom or is absent);
  • R 1 is (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) a C 1-6 alkyl group (eg, methyl group, ethyl group) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (4) a monocyclic heterocyclic group (eg, pyrazolyl group) optionally substituted with 1 to 5 C 1-6 alkyl groups (eg, methyl group), (5) a C 1-6 alkoxy group (eg, methoxy group, ethoxy group) optionally substituted with 1 to 5 halogen atoms (eg, fluor
  • examples of such a salt include a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic, acidic Examples include salts with amino acids.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid and the like.
  • Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Compound (I) may be a solvate (for example, an anhydride) or a solvate (for example, a hydrate). Further, the compound (I) may be labeled with an isotope (eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I). Further, a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • an isotope eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I.
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) Etc., each can be obtained as a single item.
  • the compound (I) may be a crystal, and it is included in the compound (I) regardless of whether the crystal form is single or a crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). Means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the prodrug of the compound (I) is a compound that is converted to the compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, the compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).
  • the prodrug of compound (I) is a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated.
  • the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • Compound (I) can be produced by a method known per se, for example, the following methods A to E, L, or a method analogous thereto.
  • the raw material compound may be used as a salt, and as such a salt, those exemplified as the salt of the compound represented by the formula (I) are used.
  • the compound obtained in each step can be used in the next reaction as it is in the reaction solution or after obtaining as a crude product, but can also be isolated from the reaction mixture according to a conventional method, recrystallization, distillation, It can be easily purified by separation means such as chromatography.
  • compound (I-1) can be produced by subjecting compound (II) to a condensation reaction. This reaction is carried out using a method known per se, for example, a method of directly condensing compound (II) and compound (III) or a method of reacting a reactive derivative of compound (III) with compound (II). Is called.
  • the reactive derivative of compound (III) for example, acid halide (for example, acid chloride, acid bromide), imidazolide, mixed acid anhydride (for example, methyl carbonate, ethyl carbonate, isobutyl carbonate, benzenesulfonic acid, Mixed acid anhydride with 2-methyl-6-nitrobenzoic acid, etc.).
  • acid halide for example, acid chloride, acid bromide
  • imidazolide for example, mixed acid anhydride (for example, methyl carbonate, ethyl carbonate, isobutyl carbonate, benzenesulfonic acid, Mixed acid anhydride with 2-methyl-6-nitrobenzoic acid, etc.).
  • mixed acid anhydride for example, methyl carbonate, ethyl carbonate, isobutyl carbonate, benzenesulfonic acid, Mixed acid anhydride with 2-methyl-6-nitrobenzoic acid, etc.
  • the method of directly condensing compound (II) and compound (III) is performed in the presence of a condensing agent in a solvent that does not adversely influence the reaction.
  • condensing agent examples include carbodiimide-based condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide and hydrochloride thereof; diethyl cyanophosphate, diphenyl azidophosphate
  • phosphoric acid condensation reagents such as 2-methyl-6-nitrobenzoic anhydride, N, N′-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, etc.
  • a condensing agent is mentioned.
  • solvents examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene And the like; ethers such as tetrahydrofuran, dioxane, diethyl ether; acetonitrile, ethyl acetate and the like. These solvents may be mixed and used at an appropriate ratio.
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene And the like
  • ethers such as tetrahydrofuran, dioxane, diethyl ether
  • acetonitrile ethyl acetate and the like.
  • the amount of compound (III) to be used is generally 0.5 to 10 mol, preferably 0.8 to 3 mol, per 1 mol of compound (II).
  • the amount of the condensing agent to be used is generally 0.5 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (II).
  • an appropriate condensing accelerator for example, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzoic acid
  • triazole N-hydroxysuccinimide, N-hydroxyphthalimide, 4-dimethylaminopyridine, etc.
  • the reaction efficiency can be improved.
  • a phosphoric acid-based condensing reagent or 2-methyl-6-nitrobenzoic anhydride is used as the condensing agent, the reaction efficiency is usually increased by adding an organic amine base such as triethylamine or N, N-diisopropylethylamine. Can be improved.
  • the amount of the condensation accelerator or organic amine base used is usually 0.05 to 10 mol, preferably 0.05 to 5 mol, per 1 mol of compound (II).
  • the reaction temperature is usually ⁇ 30 ° C. to 100 ° C.
  • the reaction time is usually 0.5 to 100 hours.
  • compound (III) is reacted with a halogenating agent (eg, thionyl chloride, phosphoryl chloride, oxalyl chloride, etc.) in a solvent that does not adversely affect the reaction, and Bases (eg, amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; sodium bicarbonate And inorganic bases such as sodium carbonate and potassium carbonate) and the compound (II).
  • a halogenating agent eg, thionyl chloride, phosphoryl chloride, oxalyl chloride, etc.
  • Bases eg, amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diaza
  • solvents that does not adversely influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether, acetonitrile, ethyl acetate, Water etc. are mentioned. These solvents may be mixed and used at an appropriate ratio.
  • the amount of compound (III) to be used is generally 0.5 to 10 mol, preferably 0.8 to 3 mol, per 1 mol of compound (II).
  • the amount of the halogenating agent to be used is generally 1-50 mol, preferably 1-10 mol, per 1 mol of compound (III).
  • the amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (II).
  • the reaction can be promoted by adding N, N-dimethylformamide.
  • the amount of N, N-dimethylformamide to be used is usually 0.001 to 0.5 mol with respect to 1 mol of compound (III).
  • the reaction temperature is usually ⁇ 30 ° C. to 100 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • compound (III) When a mixed acid anhydride is used as the reactive derivative of compound (III), compound (III) and chlorocarbonate (for example, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) are used in a solvent that does not adversely influence the reaction.
  • chlorocarbonate for example, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate
  • solvents that does not adversely influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether, acetonitrile, ethyl acetate, Water etc. are mentioned. These solvents may be mixed and used at an appropriate ratio.
  • the amount of compound (III) to be used is generally 0.5 to 10 mol, preferably 0.8 to 3 mol, per 1 mol of compound (II).
  • the amount of chlorocarbonate, acid anhydride and sulfonyl halide to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (III).
  • the amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (III).
  • the reaction temperature is usually ⁇ 30 ° C. to 100 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • compound (III) When imidazolide is used as a reactive derivative of compound (III), compound (III) is reacted with N, N′-carbonyldiimidazole in a solvent that does not adversely influence the reaction, and further a base (for example, triethylamine, N , N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene; sodium bicarbonate, sodium carbonate, potassium carbonate, etc. In the presence of an inorganic base).
  • a base for example, triethylamine, N , N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene; sodium bicarbonate, sodium carbonate, potassium carbonate, etc.
  • a base for example
  • solvents that does not adversely influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, ethyl acetate and the like. Is mentioned. These solvents may be mixed and used at an appropriate ratio.
  • the amount of compound (III) to be used is generally 0.5 to 10 mol, preferably 0.8 to 3 mol, per 1 mol of compound (II).
  • the amount of N, N′-carbonyldiimidazole to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (III).
  • the amount of the base to be used is generally 1 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (II).
  • the reaction temperature is usually ⁇ 30 ° C. to 100 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • Compound (II) can be produced, for example, according to Method F described later or a method analogous thereto.
  • Compound (III) can be produced according to a known method.
  • compound (I-2) can be produced by reacting compound (II) with compound (IV). This reaction is performed in a solvent that does not adversely influence the reaction. This reaction may be carried out in the presence of 1 to 5 mol of a base with respect to 1 mol of compound (II), if necessary.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • Amines such as aminopyridine
  • inorganic bases such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium hydride, sodium hydride and the like.
  • Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene Ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, acetone, pyridine, ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the amount of compound (IV) to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (II).
  • the reaction temperature is usually ⁇ 30 ° C. to 120 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • Compound (IV) can be produced according to a method known per se.
  • L 1 and L 2 each independently represent a leaving group, and other symbols are as defined above.
  • the leaving group represented by L 1 or L 2 include a hydroxy group, a halogen atom, an imidazolyl group, a succinimidooxy group, —OSO 2 R 6 (R 6 is a C 1-4 alkyl group (preferably Represents methyl), a C 6-10 aryl group (preferably tolyl) which may be substituted with a C 1-4 alkyl group, and the like.
  • Examples of the compound (VI) include N, N′-carbonyldiimidazole, diphosgene, triphosgene and the like.
  • compound (I-3) can be produced by sequentially reacting compound (V) and compound (II) with compound (V).
  • This reaction is carried out by a method known per se, for example, by reacting compound (V) and compound (VI) in a solvent that does not adversely influence the reaction, and then reacting the resulting compound with compound (II).
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • This reaction may be carried out in the presence of 1 to 5 mol of a base with respect to 1 mol of compound (V), if necessary.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • Amines such as aminopyridine
  • inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydride, sodium hydride and the like.
  • solvents examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene Ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, ethyl acetate, pyridine and the like. These solvents may be mixed and used at an appropriate ratio.
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene Ethers such as tetrahydrofuran, dioxane and diethyl ether
  • acetonitrile ethyl acetate, pyridine and the like.
  • the amount of compound (VI) to be used is generally 0.5 to 10 mol, preferably 0.5 to 2 mol, per 1 mol of compound (V).
  • the amount of compound (II) to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (V).
  • the reaction temperature is usually ⁇ 10 ° C. to 100 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • the compound (V) and the compound (VI) can be produced according to a method known per se.
  • compound (I-4) can be produced by reacting compound (II) with compound (VII). This reaction is performed in a solvent that does not adversely influence the reaction. If necessary, this reaction may be carried out in the presence of 1 to 5 mol of a base with respect to 1 mol of compound (II).
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • examples include amines such as aminopyridine; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydride, sodium hydride, and the like.
  • Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene And the like; ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, pyridine, ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene And the like
  • ethers such as tetrahydrofuran, dioxane and diethyl ether
  • acetonitrile pyridine, eth
  • the amount of compound (VII) to be used is generally 0.5 to 10 mol, preferably 0.5 to 5 mol, per 1 mol of compound (II).
  • the reaction temperature is usually ⁇ 30 ° C. to 150 ° C.
  • the reaction time is usually 0.5 to 100 hours.
  • Compound (VII) can be produced according to a method known per se.
  • compound (I-5) can be produced by reacting compound (II) with compound (VIII). This reaction is performed in a solvent that does not adversely influence the reaction. If necessary, this reaction may be carried out in the presence of 1 to 5 mol of a base with respect to 1 mol of compound (II).
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • examples include amines such as aminopyridine; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydride, sodium hydride, and the like.
  • Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene And the like; ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, pyridine, ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene And the like
  • ethers such as tetrahydrofuran, dioxane and diethyl ether
  • acetonitrile pyridine, eth
  • the amount of compound (VIII) to be used is generally 0.5 to 10 mol, preferably 0.5 to 5 mol, per 1 mol of compound (II).
  • the reaction temperature is usually ⁇ 30 ° C. to 150 ° C.
  • the reaction time is usually 0.5 to 100 hours.
  • Compound (VIII) can be produced according to a method known per se.
  • Compound (II) used as a raw material compound in the methods A to E is produced, for example, by the following method F. [F method]
  • compound (II) can be produced by reacting compound (IX) with ammonia. This reaction is performed in a solvent that does not adversely influence the reaction.
  • the amount of ammonia used is usually an excess amount relative to 1 mol of compound (IX).
  • the amount is 10 to 100 mol with respect to 1 mol of compound (IX).
  • solvents that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform and dichloromethane, acetone, acetonitrile, ethyl acetate, and water. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 80 to 100 ° C., preferably ⁇ 10 to 60 ° C.
  • the reaction time is usually 0.01 to 30 hours.
  • the compound represented by the formula (IX) is produced, for example, by the following method G1 or G2. [G1 method]
  • L 3 represents a leaving group, and other symbols are as defined above.
  • Examples of the leaving group represented by L 3 include a halogen atom. Of these, a bromine atom and an iodine atom are preferable.
  • compound (X-2) can be produced by subjecting compound (X-1) and phenylmethanethiol to a coupling reaction.
  • This reaction is performed in the presence of a base in a solvent that does not adversely influence the reaction, and may be performed in the presence of an organometallic catalyst or a metal catalyst and a phosphine ligand, if necessary. In addition, you may mix and use these catalysts in a suitable ratio.
  • Organometallic catalysts include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), [1,1 '-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane adduct and the like.
  • metal catalyst examples include copper (I) iodide, copper (I) chloride, copper (II) bromide, copper (II) oxide, copper powder, and zinc powder.
  • phosphine ligand examples include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), triphenylphosphine, tris (2-methylphenyl) phosphine, bis (diphenylphosphino) ferrocene, And 5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • examples include amines such as aminopyridine; inorganic bases such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and the like.
  • solvents examples include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; methanol, ethanol, 2-propanol Alcohols such as tert-butanol and ethylene glycol; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • aliphatic hydrocarbons such as hexane and heptane
  • the reaction is preferably performed in an inert gas.
  • the inert gas include argon.
  • the amount of phenylmethanethiol to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (X-1).
  • the amount of the organic metal catalyst or metal catalyst used is usually 0.001 to 5 mol, preferably 0.01 to 1 mol, per 1 mol of compound (X-1).
  • the amount of the base to be used is generally 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (X-1).
  • the amount of the phosphine ligand to be used is generally 0.001 to 10 mol, preferably 0.01 to 3 mol, per 1 mol of compound (X-1).
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 180 ° C.
  • the reaction time is usually 0.05 to 50 hours.
  • Compound (X-1) can be produced, for example, according to Method H, Method I described later, or a method analogous thereto.
  • compound (IX) can be produced by subjecting compound (X-2) to a reaction with chlorine gas or N-chlorosuccinimide. This reaction is performed in a solvent that does not adversely influence the reaction.
  • the amount of chlorine gas used is usually a large excess with respect to 1 mol of compound (X-2).
  • the amount of N-chlorosuccinimide to be used is generally 1 to 20 mol per 1 mol of compound (X-2).
  • solvents that does not adversely influence the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; organic acids such as acetic acid and formic acid, acetonitrile, water, and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 50 to 100 ° C.
  • the reaction time is usually 0.01 to 30 hours.
  • compound (X-4) can be produced by subjecting compound (X-3) to a reduction reaction.
  • This reaction can be carried out, for example, by using a metal catalyst such as palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, iron powder (optionally added calcium chloride), zinc powder, etc. and hydrogen
  • a metal catalyst such as palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, iron powder (optionally added calcium chloride), zinc powder, etc. and hydrogen
  • the reaction is carried out in the presence of a source in a solvent that does not adversely influence the reaction.
  • the amount of the metal catalyst to be used is generally 0.001 to 10 mol, preferably 0.01 to 5 mol, per 1 mol of compound (X-3).
  • Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt, phosphoric acid, hydrazine and the like.
  • the amount of hydrogen gas used is usually a large excess with respect to 1 mol of compound (X-3).
  • the amount of formic acid, formic acid amine salt, phosphoric acid and hydrazine to be used is generally 1-1000 mol per 1 mol of compound (X-3).
  • Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol and tert-butanol; aromatic carbonization such as benzene, toluene and xylene Hydrogens; aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane; dichloromethane, chloroform, 1,2-dichloroethane Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ethyl acetate, acetic acid
  • the reaction temperature is usually 0 to 120 ° C., preferably 10 to 80 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • Compound (X-3) can be produced, for example, according to Method J, Method K described later, or a method analogous thereto.
  • Step 2 the compound (X-4) is first subjected to a diazotization reaction with sodium nitrite in the presence of hydrochloric acid, and then reacted with sodium hydrogen sulfite in the presence of copper (II) sulfate.
  • IX can be produced. This reaction is performed in an aqueous solution.
  • the amount of hydrochloric acid used is usually a large excess relative to 1 mol of compound (X-4).
  • the amount of sodium nitrite to be used is generally 1 to 10 mol per 1 mol of compound (X-4).
  • the amount of copper (II) sulfate used is usually 0.01 to 5 mol per 1 mol of compound (X-4).
  • the amount of sodium hydrogen sulfite to be used is generally 1 to 20 mol per 1 mol of compound (X-4).
  • the reaction temperature is usually ⁇ 30 ° C. to 100 ° C.
  • the reaction time is usually 0.1 to 30 hours.
  • compound (X-1a) can be produced by reacting compound (XI) with compound (XII). This reaction is performed in a solvent that does not adversely influence the reaction. This reaction may be carried out in the presence of 1 to 5 mol of a base with respect to 1 mol of compound (XI), if necessary.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • examples include amines such as aminopyridine; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydride, sodium hydride, and the like.
  • Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene And the like; ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, pyridine, ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene And the like
  • ethers such as tetrahydrofuran, dioxane and diethyl ether
  • acetonitrile pyridine, eth
  • the amount of compound (XII) to be used is generally 0.5 to 10 mol per 1 mol of compound (XI).
  • the reaction temperature is usually ⁇ 30 ° C. to 120 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • Compound (XI) and compound (XII) can be produced according to a method known per se.
  • L 4 represents a leaving group, and other symbols are as defined above.
  • Examples of the leaving group represented by L 4 include a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like.
  • a halogen atom a bromine atom and an iodine atom are preferable.
  • compound (XIII-2) can be produced by reacting compound (XIII-1) with compound (XIV). This reaction is performed in the presence of 1 to 5 mol of a base in 1 mol of compound (XIII-1) in a solvent that does not adversely influence the reaction.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4-dimethyl.
  • examples include amines such as aminopyridine; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydride, sodium hydride, and the like.
  • Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene And the like; ethers such as tetrahydrofuran, dioxane and diethyl ether; acetonitrile, pyridine, ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio.
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene And the like
  • ethers such as tetrahydrofuran, dioxane and diethyl ether
  • acetonitrile pyridine, eth
  • the amount of compound (XIV) to be used is generally 0.5 to 10 mol per 1 mol of compound (XIII-1).
  • the reaction temperature is usually from 0 ° C to 120 ° C.
  • the reaction time is usually 0.1 to 100 hours.
  • Compound (XIII-1) and compound (XIV) can be produced according to a method known per se.
  • compound (X-1b) can be produced by subjecting compound (XIII-2) to an oxidation reaction. This reaction is performed in the presence of an oxidizing agent in a solvent that does not adversely influence the reaction.
  • oxidizing agent examples include 3-chloroperbenzoic acid, Oxone (trade name), hydrogen peroxide, peracetic acid and the like.
  • the amount of the oxidizing agent used is usually 2 to 10 mol per 1 mol of compound (XIII-2).
  • solvents that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and 1,2-dimethoxyethane; alcohols such as methanol and tert-butanol; halogenated hydrocarbons such as chloroform and dichloromethane; acetone, ethyl acetate, acetic acid, water and the like. These solvents may be mixed and used at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • aliphatic hydrocarbons such as hexane and heptane
  • the reaction temperature is usually ⁇ 30 to 120 ° C., preferably ⁇ 10 to 50 ° C.
  • the reaction time is usually 0.1 to 50 hours.
  • Compound (X-3a), which is compound (X-3) used as a raw material compound in Method G2 and X 3 is N, is produced, for example, by Method J below. [J method]
  • compound (X-3a) can be produced by reacting compound (XV) with compound (XII). This reaction is carried out in the same manner as the reaction described in Method H above.
  • Compound (XV) can be produced according to a method known per se.
  • L 5 represents a leaving group, and other symbols are as defined above.
  • Examples of the leaving group represented by L 5 include a halogen atom or a trifluoromethanesulfonyloxy group.
  • a halogen atom a bromine atom and an iodine atom are preferable.
  • compound (XVI-3) can be produced by reacting compound (XVI-1) with compound (XIV). This reaction is carried out in the same manner as the reaction described in Step 1 of Method I above.
  • Compound (XVI-1) can be produced according to a method known per se.
  • compound (XVI-3) can be produced by subjecting compound (XVI-2) and compound (XVII) to a coupling reaction. This reaction is performed in the same manner as the reaction described in Step 1 of Method G1.
  • Compound (XVI-2) and compound (XVII) can be produced according to a method known per se.
  • Step 3 compound (X-3b) can be produced by subjecting compound (XVI-3) to an oxidation reaction. This reaction is carried out in the same manner as the reaction described in Step 2 of Method I above.
  • the compound (I-6) in which X 3 is N and the compound (I-7) in which X 3 is CR 5 can also be produced, for example, by the following Method L. [L method]
  • compound (XVIII-1) can be produced by reacting compound (XI) with ammonia. This reaction is performed in the same manner as the reaction described in Method F above.
  • Step 2 compound (XVIII-2) can be produced by subjecting compound (XVIII-1) to a condensation reaction. This reaction is carried out in the same manner as described in the above methods A to E.
  • Step 3 compound (XVIII-3) can be produced by subjecting compound (XVIII-2) and phenylmethanethiol to a coupling reaction. This reaction is performed in the same manner as the reaction described in Step 1 of Method G1.
  • compound (XVIII-3) can be produced by subjecting compound (XVIII-3) to reaction with chlorine gas or N-chlorosuccinimide. This reaction is carried out in the same manner as the reaction described in Step 2 of Method G1.
  • compound (I-6) can be produced by reacting compound (XVIII-4) with compound (XII). This reaction is carried out in the same manner as the reaction described in Method H above.
  • Step 6 compound (XVIII-5) can be produced by subjecting compound (XVIII-2) and compound (XVII) to a coupling reaction. This reaction is performed in the same manner as the reaction described in Step 1 of Method G1.
  • Step 7 compound (I-7) can be produced by subjecting compound (XVIII-5) to an oxidation reaction. This reaction is carried out in the same manner as the reaction described in Step 2 of Method I above.
  • the raw material compound when the raw material compound has an amino group, a carboxy group, a hydroxy group or the like as a substituent, these groups may be protected with a protecting group that is generally used in peptide chemistry or the like. .
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • amino-protecting groups include formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl).
  • Benzoyl group C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) ) And the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • Examples of the protecting group for the carboxy group include a C 1-6 alkyl group, a C 7-10 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C
  • Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkyl-acetal) and the like.
  • Examples of the protecting group for the mercapto group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a C 1-6 alkyl-carbonyl group, a benzoyl group, a C 7- 10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, Benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl group, C 1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl) and the like. These groups may be substituted with 1 to 3 substituents selected
  • the compound (I) obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material for the next step without isolation.
  • Compound (I) and prodrugs thereof have low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), and have side effects
  • toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity
  • it can be used as a preventive or therapeutic agent for various diseases described below or a diagnostic agent for mammals (eg, humans, cows, horses, dogs, cats, monkeys, mice, rats).
  • the compound of the present invention has an excellent long-chain fatty acid elongation enzyme 6 (Elovl6) inhibitory action.
  • the compound of the present invention has a higher inhibitory effect on Elovl6 than an inhibitory effect on other Elovl subtypes such as Elovl3. That is, the compound of the present invention has a highly selective inhibitory action on Elovl6.
  • the compound of the present invention can be used as an Elovl6 inhibitor.
  • Elovl6 inhibitor increases palmitoleic acid (C16: 1n7, palmitoleate) among C16 fatty acids in total fatty acids in the liver, and is a C18 fatty acid, stearic acid (C18: 0, stearate), oleic acid (C18: 1n9). , oleate) (reducing the elongation index, which is the ratio of oleic acid as the numerator and palmitoleic acid as the denominator).
  • the compound of the present invention has a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, an insulin sensitivity enhancing action, a leptin resistance improving action and the like.
  • the compound of the present invention can be used as a prophylactic or therapeutic agent for diseases related to Elovl6.
  • diseases related to Elovl6 include diseases caused by lifestyle habits and genetic background.
  • obesity eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes
  • postprandial hyperglycemia hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, high LDL cholesterol blood) Syndrome, low HDL cholesterolemia, postprandial hyperlipidemia)
  • metabolic syndrome accordinging to the diagnostic criteria in Japanese reported in 2005 by the Japanese Society of Obesity, etc., metabolic syndrome is an abdominal circumference of 85 cm for men and 90 cm for women
  • fasting blood glucose level glucose level (glucose concentration in venous plasma) is 110 mg / dl or
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
  • 75 gOGTT 75 g oral glucose tolerance test
  • glucose level in venous plasma is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
  • a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
  • diabetes is a diabetes-like symptom (polyuria, heavy drinking, overeating, overwork, weight loss, foggy vision, growth disorder), and anytime blood glucose level (glucose concentration in venous plasma) It is a state in which 200 mg / dl or more, fasting blood glucose level (glucose concentration in venous plasma) is 126 mg / dl or more, and 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl or more. .
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, or a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. It is the state which shows.
  • glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose).
  • the IFG is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
  • the compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
  • the compound of the present invention is also used for secondary prevention and progression suppression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).
  • cardiovascular events such as myocardial infarction
  • the compound of the present invention is used as a prophylactic / therapeutic agent for fatty liver (eg, non-alcoholic fatty liver (NAFLD)), steatohepatitis (eg, non-alcoholic steatohepatitis (NASH)), or an agent for improving these pathological conditions.
  • fatty liver eg, non-alcoholic fatty liver (NAFLD)
  • steatohepatitis eg, non-alcoholic steatohepatitis (NASH)
  • an agent for improving these pathological conditions can do.
  • the medicament containing the compound of the present invention can be used alone or mixed with a pharmacologically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia).
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills powders, granules, capsules (including soft capsules and microcapsules), troches Agent, syrup, solution, emulsion, suspension, controlled release formulation (eg, immediate release formulation, sustained release formulation, sustained release microcapsule), aerosol, film agent (eg, orally disintegrating film, Oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch, sitting Suppositories (eg, rectal suppositories) Vaginal suppositories), pellets,
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials, for example, excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, Examples include solubilizers, suspending agents, isotonic agents, buffers, and soothing agents.
  • additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used as necessary in the formulation.
  • excipients examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • lubricant examples include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose (L-HPC).
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, and corn oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • isotonic agent examples include glucose, D-sorbitol, sodium chloride, glycerin, and D-mannitol.
  • buffer solutions of phosphate, acetate, carbonate, citrate and the like examples include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Examples of the antioxidant include sulfite and ascorbic acid.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2), water-insoluble lake dyes (eg, And water-soluble edible tar pigments) and natural pigments (eg, ⁇ -carotene, chlorophyll, bengara).
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2
  • water-insoluble lake dyes eg, And water-soluble edible tar pigments
  • natural pigments eg, ⁇ -carotene, chlorophyll, bengara
  • sweetener examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • adsorbent examples include porous starch, calcium silicate (trade name: FLORITE RE), magnesium aluminate metasilicate (trade name: neucillin), and light anhydrous silicic acid (trade name: silicia).
  • wetting agent examples include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • the content of the compound of the present invention in the pharmaceutical composition is, for example, about 0.1 to 100% by weight of the whole pharmaceutical composition.
  • the dose of the compound of the present invention is appropriately selected depending on the administration subject, administration route, disease and the like.
  • the daily dose is about 0.1 to about 500 mg, preferably about 1 to about 100 mg, more preferably about 5 To about 100 mg, which can be administered in 1 to several divided doses per day.
  • the compound of the present invention is used for the purpose of, for example, enhancing the action of the compound of the present invention (therapeutic effect of diabetes, obesity, hyperlipidemia, arteriosclerosis, etc.), reducing the amount of the compound of the present invention used, etc.
  • concomitant drugs examples include “diabetes therapeutics”, “diabetic complications”, “anti-obesity drugs”, “hypertension drugs”, “hyperlipidemic drugs”, “anti-arteriosclerosis” Drugs, “antithrombotic drugs”, “arthritis therapeutic drugs”, “anti-anxiety drugs”, “antidepressant drugs”, “psycho-neural drugs”, “sleep-inducing drugs” and the like.
  • These concomitant drugs may be low molecular weight compounds, or may be polymer proteins, polypeptides, antibodies or vaccines.
  • insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation
  • insulin resistance improving agent eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate)
  • Metaglidasen AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034 , GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 0997 94
  • ⁇ -glucosidase inhibitors eg,
  • diabetic complication therapeutic agents include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its increase drug (Eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-phenol) Nasyl thiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor .
  • anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonist, histamine H3 receptor Body, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban), ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylating enzyme Inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin 4 receptor agonist, 11 ⁇ -hydroxysteroid dehydrogenase inhibitor (eg, AZD-4017), pancreatic lipase inhibitor (eg, , Orlistat, cetilistat), ⁇ 3 agonists (eg, phentermine, si
  • FGF21 preparations eg, extracted from bovine, porcine pancreas
  • Animal FGF21 preparations Animal FGF21 preparations
  • human FGF21 preparations synthesized by genetic engineering using Escherichia coli and yeast
  • fragments or derivatives of FGF21 antifeedants (eg, P-57) and the like.
  • hypotensive agent examples include, for example, angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan , Irbesartan, tasosartan, olmesartan, olmesartan, medoxomil, azilsartan, azilsartan, medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, sinyldipine, etc.), ⁇ -blockers (eg, metoprolol, atelolol, atelolol) Carvedilol, pindol, pind
  • diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflux.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflux.
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetazolamide, etc.
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide, etc.
  • Azosemide is
  • an HMG-CoA reductase inhibitor eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (eg, sodium salt, calcium salt)
  • Squalene synthase inhibitors eg, compounds described in pamphlet of WO97 / 10224, for example, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro- 5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (Eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin
  • anti-arteriosclerotic agents include acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitors (eg, K-604), LpPLA2 inhibitors (eg, dalapradiv, rilapradib etc.), FLAP inhibitors (eg, AM103, AM803), 5LO inhibitors (eg, VIA-2291), sPLA2 inhibitors (eg, A-002), apoAI mimetic peptides (eg, D4F), HDL preparations (eg, CSL-111), etc.
  • ACAT acylcoenzyme A cholesterol acyltransferase
  • LpPLA2 inhibitors eg, dalapradiv, rilapradib etc.
  • FLAP inhibitors eg, AM103, AM803
  • 5LO inhibitors eg, VIA-2291
  • sPLA2 inhibitors eg, A-002
  • apoAI mimetic peptides eg, D
  • antithrombotic agents include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban) (aragatroban), dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504 compounds), thrombolytic drugs (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase (pamiteplase)), platelet aggregation inhibitors (eg , Ticlopidine hydrochloride, clopidogrel, prasugre
  • Examples of the “arthritis therapeutic agent” include ibuprofen and the like.
  • Examples of the above-mentioned ⁇ anti-anxiety drugs '' include alprazolam, etizolam, oxazolam, tandospirone, cloxazolam, clothiazepam, dipotassium chlorazepate, chlordiazepoxide, diazepam, fludiazepam, flutazolam, flutopazepam, prazepam, brozepampampazemaze, prazepam , Ethyl loflazepate, lorazepam and the like.
  • antidepressant examples include tricyclic antidepressants (eg, imipramine, trimipramine, clomipramine, amitriptyline, nortriptyline, amoxapine, lofepramine, dosrepin, desipramine), tetracyclic antidepressants (eg, maprotiline, Mianserin, seriprine), selective serotonin uptake inhibitors (eg, fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram), serotonin and noradrenaline uptake inhibitors (eg, milnacipran, duloxetine, venlafaxine), trazodone, mirtazapine , Moclobecdo and the like.
  • tricyclic antidepressants eg, imipramine, trimipramine, clomipramine, amitriptyline, nortriptyline, amoxapine, lofepramine, dosrepin, des
  • mental nerve agent examples include, for example, typical antipsychotic drugs (eg, clocapramine, chlorpromazine, phenobarbital, sultopride, thioprid, thioridazine, fluropamide, mosapramine, moperon, oxypertin, carpipramine, spiperone, sulpiride, zotepine, timiperone, Nemonapride, haloperidol, pimozide, prochlorperazine, propericazine, bromperidol, perphenazine, fluphenazine maleate, mizoribine, levomepromazine), atypical antipsychotics (eg, perospirone, olanzapine, quetiapine, risperidone, clozapine, Aripiprazole, ziprasidone, blonanserin, lurasidone) and the like.
  • typical antipsychotic drugs eg
  • the “sleep inducer” include, for example, ramelteon, GABA hypnotic (eg, brotizolam, estazolam, flurazepam, nitrazepam, triazolam, flunitrazepam, lormetazepam, rilmazafone, quazepam, zopiclone, eszopicone, zolpidem, zolepidin, Non-GABA hypnotics (eg, eprivaserin, purvanserin, diphenhydramine, trazodone, doxepin) and the like.
  • GABA hypnotic eg, brotizolam, estazolam, flurazepam, nitrazepam, triazolam, flunitrazepam, lormetazepam, rilmazafone, quazepam, zopiclone, eszopicone, zolpidem,
  • the administration time of the aforementioned concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such dosage forms include 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) formulating the compound of the present invention and the concomitant drug separately.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • Root temperature in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C., but is not particularly limited.
  • the mixing ratio of the liquid indicates a volume ratio.
  • % Indicates weight percent unless otherwise specified. However, the yield indicates mol / mol%.
  • the proton NMR spectrum which cannot be confirmed by broad such as OH or NH proton is not described in the data.
  • Silica gel column chromatography was performed using MERCK silica gel 60 (0.063-0.200 mm) or Fuji Silysia Chemical Co., Ltd. Chromatorex (trade name) NH (described as basic silica gel column chromatography).
  • Mass spectra were measured using Waters ZMD, Waters ZQ2000 or Agilent Agilent G6100 series.
  • ionization method an electron impact ionization method (Electron Spray Ionization: ESI) or an atmospheric pressure chemical ionization method (APCI) was used, and ESI was used unless otherwise specified.
  • ESI Electrode Spray Ionization: ESI
  • APCI atmospheric pressure chemical ionization method
  • the melting point was measured using a Yanagimoto micro melting point measuring apparatus or a Buchi micro melting point measuring apparatus (B-545), and was described without correction.
  • the melting point may vary depending on the measurement equipment, measurement conditions, and the like.
  • the crystal in the present specification may be a crystal having a value different from the melting point described in the present specification as long as it is within a normal error range.
  • 1 H-NMR spectrum uses tetramethylsilane as an internal standard, Varian Gemini-200 (200 MHz) type, Mercury-300 (300 MHz) type spectrum meter, Bruker AVANCE AV300 (300 MHz) or JNM-AL400 type (400 MHz) nuclear magnetic field. It measured using the resonance apparatus JEOL DATUM (JEOL datum).
  • N-[(4-bromophenyl) sulfonyl] -4- (trifluoromethyl) benzamide 300 mg
  • propane-2-thiol 112 mg
  • N, N-diisopropylethylamine 286 mg
  • tris (dibenzylideneacetone) dipalladium (0) 33.7 mg
  • 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene 42.5 mg
  • N-[(4-Bromophenyl) sulfonyl] -4- (trifluoromethyl) benzamide 300 mg
  • butane-1-thiol 99.1 mg
  • N, N-diisopropylethylamine 286 mg
  • toluene 3. 7 mL
  • tris dibenzylideneacetone
  • dipalladium (0) 33.7 mg
  • 4,5-bis diphenylphosphino) -9,9-dimethylxanthene (42.5 mg)
  • N- ⁇ [4- (phenylsulfanyl) phenyl] sulfonyl ⁇ -4- (trifluoromethyl) benzamide 300 mg) in acetone (6.8 mL) in water with Oxone (trade name) (843 mg) in water (4.6 mL) The solution was added at room temperature. After the reaction mixture was stirred at room temperature for 1 hour, a solution of acetone (6.8 mL) and Oxone (843 mg) in water (2.3 mL) was further added at room temperature. The reaction mixture was stirred overnight, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate were added, and the mixture was stirred for 1 hr.
  • 6- (trifluoromethyl) nicotinic acid (470 mg), 4-[(2-methylpyrrolidin-1-yl) sulfonyl] benzenesulfonamide (750 mg), 2-methyl-6-nitrobenzoic anhydride (1.01 g ), 4-dimethylaminopyridine (300 mg), and triethylamine (760 mg) in acetonitrile (20 mL) were stirred at room temperature for 15 hours, and then the solvent was distilled off under reduced pressure. Aqueous ammonium chloride solution was added to the residue, and ethyl acetate was added. Extracted.
  • Elovl6 inhibitory activity of the compounds of the present invention was evaluated by the following method.
  • (1) Preparation of expression vector A vector for expressing human Elovl6 was prepared as follows. First, PCR was performed using the following primers 1 and 2 using pTriEx-3 (Novagen) as a template.
  • Primer 1 5′-CCTATTAATATAGTAATCAATTTACGGGGTCATTAG-3 ′ (SEQ ID NO: 1)
  • Primer 2 5'-CGCATGCCTTTCAGCAAAAAAACCCCCTCAAGACC-3 '(SEQ ID NO: 2)
  • the reaction was carried out using Pyrobest DNA Polymerase (Takara Bio) for 1 minute at 98 ° C., followed by 35 times of 98 ° C. for 10 seconds and 67 ° C. for 1 minute, followed by treatment at 72 ° C. for 5 minutes.
  • the 1.6 kbp PCR product was recovered by agarose gel electrophoresis.
  • This DNA fragment was inserted into pFastBac1 (Invitrogen) cleaved with Sna BI and Avr II (both Takara Bio) and blunt-ended using Blunting High (Toyobo), cloned into E. coli JM109 (Nippon Gene) and cloned into the expression vector pFastTriEx Was made.
  • Tag was introduced using synthetic DNA. Primer 3 and primer 4 were annealed to obtain a double-stranded DNA fragment HPA-F / HPA-R.
  • Primer 3 5'-TAAAATATACTATACTGTAAATTACATTTTATTTACAATCAAGGGAGTTAAC-3 '(SEQ ID NO: 3)
  • Primer 4 5'-CATGGGTTAACCCTCTTTGATTGTATAATAAAAATGTAATTTACAGTATAGTATTTATA-3 '(SEQ ID NO: 4)
  • primer 5 and primer 6, primer 7 and primer 8 were annealed to obtain FNCONHE-F / NCONHE-R and FNHENOT-F / NHENOT-R, respectively.
  • Primer 5 5′-CATGGACTACAAGGACGACGATGACAAGGGATCCG-3 ′ (SEQ ID NO: 5)
  • Primer 6 5′-CTAGCGGATCCCCTGTCATCATGTCGTCCTTGTAGTC-3 ′ (SEQ ID NO: 6)
  • Primer 7 5′-CTAGCGACTACAAGGACGACGATGACAAGTGGAGC-3 ′ (SEQ ID NO: 7)
  • Primer 8 5′-GGCCCGCTCACTTGTCCATCGTCGTCCTTGTTAGCG-3 ′ (SEQ ID NO: 8)
  • Three double-stranded DNA fragments HPA-F / HPA-R, FNCONHE-F / NCONHE-R and FNHENOT-F / NHENOT-R were cut with Pac I (New England Biolabs) and Not I (Takara Bio) The gene was inserted into pFastTriEx and cloned into E. coli JM109 to prepare an expression vector pFTF ( ⁇ ).
  • the human Elovl6 gene was obtained by PCR using P3xFLAG-CMV10-Elovl6 as a template with the following primer 9 and primer 10 using Pyrobest DNA Polymerase (Takara Bio).
  • Primer 9 5′-TATTATGGATCCCATGAACATGTCAGTGTTGAC-3 ′ (SEQ ID NO: 9)
  • Primer 10 5′-TATTATGCGGCCGCCTATTCAGCTTTTCGTTGTTTCCTC-3 ′ (SEQ ID NO: 10)
  • the obtained PCR product and pFTF ( ⁇ ) were digested with restriction enzymes BamH I and Not I and ligated to construct a FLAG-tagged vector pFTF ( ⁇ ) / FLAG-hElovl6.
  • Baculovirus was prepared from the expression plasmid pFTF ( ⁇ ) / FLAG-hElovl6 using a BacToBac baculovirus expression system (Invitrogen). Viral titer was measured by Real-Time PCR method using SYBR Green.
  • the p3xFLAG-CMV10-Elovl6 was obtained by PCR with the following primers 11 and 12 using human Marathon-Ready cDNA Library, liver (CLONTECH) as a template.
  • Primer 11 5′-ATTGCCGCCGCGATGAACAGTGCAGTGTTGAACTTT-3 ′ (SEQ ID NO: 11)
  • Primer 12 5′-CGGGATATCCTATTCAGCCTTTCGTTGTTTCCTC-3 ′ (SEQ ID NO: 12)
  • Elovl6 reaction measurement system by filter method 50 ⁇ L of a test compound diluted with an assay buffer is dispensed into 96-well plate (Corning) made of polypropylene, followed by 0.1 ⁇ g of microsomes diluted with a microsome buffer ((3) above) 50 ⁇ L of the recombinant protein-expressing insect cell membrane fraction obtained in step 1) was added. To this was added 50 ⁇ L of [ 14 C] malonyl CoA (PerkinElmer) and palmitoyl CoA (Sigma) diluted to 15 ⁇ mol / L with a substrate buffer to initiate the reaction. After reacting at 37 ° C.
  • Assay buffer 50 mmol / L K 2 PO 4 , 500 mmol / L NaCl, 0.01% ALBUMIN BOVINE Fatty Acid Free (BSA) (Sigma), 100 ⁇ mol / L DTT (Wako), pH 6.6
  • Microsome buffer 50 mmol / L K 2 PO 4 , 500 mmol / L NaCl, 0.01% BSA, 100 ⁇ mol / L DTT, 15 ⁇ mol / L Rotenone (Sigma), pH 6.6
  • Substrate buffer 50 mmol / L K 2 PO 4 , 500 mmol / L NaCl, 0.01% BSA, 100 ⁇ mol / L DTT, 1.5 mmol / L NADPH (oriental yeast), pH 6.6
  • the compound of the present invention has an excellent Elovl6 inhibitory action.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • the compound of the present invention has an Elovl6 inhibitory action and is useful as a preventive / therapeutic agent for diabetes and the like.
  • This application is based on Japanese Patent Application No. 2010-036099 filed in Japan, the contents of which are incorporated in full herein. While the invention has been presented or described with reference to preferred embodiments thereof, various changes in form and detail have been made herein without departing from the scope of the invention as encompassed by the appended claims. It will be appreciated by those skilled in the art. All patents, patent publications and other publications shown or referenced herein are incorporated by reference in their entirety.

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Abstract

L'invention porte sur un composé représenté par la formule (I) [dans laquelle chaque symbole est tel que défini dans la description], sur un sel de ce composé, ou sur un promédicament du composé ou du sel, qui présente une excellente activité inhibitrice sur l'élément 6-élongase de la famille des acides gras à longue chaîne, et qui est utile pour prévenir ou traiter le diabète et d'autres maladies.
PCT/JP2011/053740 2010-02-22 2011-02-21 Composé cyclique aromatique WO2011102514A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014123203A1 (fr) * 2013-02-06 2014-08-14 京都薬品工業株式会社 Agent thérapeutique destiné à traiter le diabète
US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN108794358A (zh) * 2017-04-27 2018-11-13 中国人民解放军第二军医大学 取代苯磺酰基类化合物及其制备药物的用途
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59140450A (ja) * 1982-12-28 1984-08-11 Konishiroku Photo Ind Co Ltd ハロゲン化銀写真感光材料
WO2009081789A1 (fr) * 2007-12-26 2009-07-02 Banyu Pharmaceutical Co., Ltd. Dérivé de noyau à six chaînons à substitution sulphonyle
WO2009131065A1 (fr) * 2008-04-24 2009-10-29 萬有製薬株式会社 Inhibiteur d'enzyme d'allongement d'acide gras à longue chaîne incluant un dérivé arylsulfonylé en tant que principe actif

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59140450A (ja) * 1982-12-28 1984-08-11 Konishiroku Photo Ind Co Ltd ハロゲン化銀写真感光材料
WO2009081789A1 (fr) * 2007-12-26 2009-07-02 Banyu Pharmaceutical Co., Ltd. Dérivé de noyau à six chaînons à substitution sulphonyle
WO2009131065A1 (fr) * 2008-04-24 2009-10-29 萬有製薬株式会社 Inhibiteur d'enzyme d'allongement d'acide gras à longue chaîne incluant un dérivé arylsulfonylé en tant que principe actif

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014123203A1 (fr) * 2013-02-06 2014-08-14 京都薬品工業株式会社 Agent thérapeutique destiné à traiter le diabète
US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10758534B2 (en) 2014-10-06 2020-09-01 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10258624B2 (en) 2014-10-06 2019-04-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11186566B2 (en) 2016-09-30 2021-11-30 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11453655B2 (en) 2016-12-09 2022-09-27 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
CN108794358A (zh) * 2017-04-27 2018-11-13 中国人民解放军第二军医大学 取代苯磺酰基类化合物及其制备药物的用途
CN108794358B (zh) * 2017-04-27 2022-08-12 中国人民解放军第二军医大学 取代苯磺酰基类化合物及其制备药物的用途
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11155533B2 (en) 2017-10-19 2021-10-26 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator

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