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WO2014061693A1 - Novel non-aromatic carbocyclic or non-aromatic heterocyclic derivative - Google Patents

Novel non-aromatic carbocyclic or non-aromatic heterocyclic derivative Download PDF

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WO2014061693A1
WO2014061693A1 PCT/JP2013/078047 JP2013078047W WO2014061693A1 WO 2014061693 A1 WO2014061693 A1 WO 2014061693A1 JP 2013078047 W JP2013078047 W JP 2013078047W WO 2014061693 A1 WO2014061693 A1 WO 2014061693A1
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substituted
unsubstituted
ring
compound
group
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PCT/JP2013/078047
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Japanese (ja)
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松村　明
功嗣 増田
健太郎 旭
理史 岩津
巨樹 大藪
義一 佐々木
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塩野義製薬株式会社
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    • 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
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    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having an inhibitory action on acetyl CoA carboxylase 2 (hereinafter referred to as ACC2).
  • Acetyl CoA carboxylase (hereinafter referred to as ACC) is an enzyme that carboxylates acetyl-CoA to convert it to malonyl-CoA, and is involved in fatty acid metabolism.
  • ACC1 acetyl-CoA carboxylase 1
  • ACC2 is mainly expressed in the heart and skeletal muscle, and malonyl-CoA produced by ACC2 inhibits the oxidation of fatty acids by inhibiting carnitine palmitoyltransferase I (CPT-I).
  • ACC2-deficient mice continuous fatty acid oxidation occurs due to a decrease in the amount of malonyl-CoA in the heart and skeletal muscle, and a decrease in body weight is observed regardless of an increase in the amount of food. Furthermore, it has been reported that ACC2-deficient mice have acquired resistance to diabetes and obesity induced by administration of a high fat / high carbohydrate diet. From the above findings, it is suggested that ACC2 is involved in diseases such as diabetes and obesity, and the inhibitor becomes an antidiabetic drug or an antiobesity drug. On the other hand, since an ACC1-deficient mouse is lethal in the fetal stage, a selective inhibitor that inhibits ACC2 without inhibiting ACC1 is desired.
  • Patent Documents 1 to 4 describe ACC2 inhibitors.
  • Patent Document 1 discloses the following formula: Are described.
  • Non-Patent Documents 1 to 5 describe thiazole phenyl ether derivatives that specifically inhibit ACC2.
  • Non-Patent Document 7 describes biphenyl derivatives or 3-phenyl-pyridine derivatives having inhibitory activity against ACC1 and ACC2.
  • Non-Patent Document 8 describes the following compounds as compounds having ACC2 inhibitory activity and having favorable pharmacokinetic parameters.
  • Patent Documents 5 to 12 and Non-Patent Document 6 describe compounds having a non-aromatic ring structure.
  • Patent Document 5 discloses the following formula: Are described.
  • Patent Literature 11 includes the following formula: Are described.
  • An object of the present invention is to provide a novel compound having ACC2 inhibitory activity. Moreover, the pharmaceutical composition containing the said compound is provided.
  • the present invention relates to the following.
  • Substituent group ⁇ is Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or Unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted
  • Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring
  • Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
  • Ring B is a substituted or unsubstituted 6-membered 6-member
  • ring B is a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 4-membered non-aromatic heterocyclic ring Or a pharmaceutically acceptable salt thereof.
  • R 15 is independently hydrogen, substituted or unsubstituted alkyl, halogen or hydroxy, and the methylene group on the ring corresponding to ring B may be substituted.
  • U is —O—, —CR 4 R 5 — or —O—CR 4 R 5 — (where the left bond is bonded to ring A and the right bond is bonded to ring B) Or a pharmaceutically acceptable salt thereof.
  • the ring C is a substituted or unsubstituted 5-membered aromatic heterocycle, and is located at the 3rd or 4th position when the position number of the atom on the ring C bonded to T or the ring B is the 1st position
  • the atom on ring C The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (14), wherein the group represented by
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring, Or a pharmaceutically acceptable compound thereof according to any one of (1) to (14), wherein the group represented by is bonded to ring C at the meta position or para position to T or ring B salt.
  • the group represented by is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group ⁇ , unsubstituted 6-membered heteroaryl, substituent group ⁇ A 6-membered heteroaryl substituted with one or more groups (In the formula, ring E is a 5-membered aromatic heterocycle, ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle, and ring E and ring F are condensed to be bicyclic. The ring E and / or the ring F may be substituted with one or more groups selected from the substituent group ⁇ .) (1) The compound according to any of (19) or a pharmaceutically acceptable salt thereof.
  • R 12 is each independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or carboxy.
  • R 12 The compound described in the above or a pharmaceutically acceptable salt thereof.
  • Ring B is a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or 4-membered unsubstituted non-aromatic heterocyclic ring, p is 0 or 1; q is 0 or 1, r is 0, R 13 is substituted or unsubstituted alkyl; R 14 is substituted or unsubstituted alkylcarbonyl;
  • a pharmaceutical composition comprising the compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R 16 is hydrogen.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (27) or a pharmaceutically acceptable salt thereof.
  • Substituent group ⁇ is Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or Unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted
  • Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring
  • Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
  • Ring B is a substituted or unsubstituted 6-membered 6-member
  • Ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic ring, and is in the 3rd or 4th position when the position number of the atom on ring C bonded to T or ring B is the 1st position
  • the atom on ring C located is of the formula: The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (13 ′), to which a group represented by the formula: (15 ′) The compound according to any one of the above (1 ′) to (14 ′) or a pharmaceutically acceptable salt thereof, wherein ring C is substituted or unsubstituted isoxazole or thiazole.
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring, Or a pharmaceutically acceptable salt thereof, wherein the group represented by is bonded to ring C at the meta position or para position relative to T or ring B Acceptable salt.
  • ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and the atom of ring B bonded to U or ring A
  • the group represented by (1) is an aryl substituted with one or more groups selected from the substituent group ⁇ or a heteroaryl substituted with one or more groups selected from the substituent group ⁇ ;
  • the group represented by is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group ⁇ , unsubstituted 6-membered heteroaryl, substituent group ⁇ A 6-membered heteroaryl substituted with one or more groups (In the formula, ring E is a 5-membered aromatic heterocycle, ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle, and ring E and ring F are condensed to be bicyclic.
  • the ring E and / or the ring F may be substituted with one or more groups selected from the substituent group ⁇ .
  • R 12 is each independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or carboxy.
  • the compound of the above (21 ′) or a pharmaceutically acceptable salt thereof is each independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or carboxy.
  • Ring B is a substituted or unsubstituted 4- to 6-membered cycloalkane or a substituted or unsubstituted 4- to 6-membered saturated heterocyclic ring
  • Ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic group
  • q is 0,
  • a compound of formula (I) is represented by formula (II):
  • (28 ′) A pharmaceutical composition comprising the compound according to any one of (1 ′) to (27 ′) above or a pharmaceutically acceptable salt thereof.
  • (29 ′) The pharmaceutical composition according to the above (28 ′), which is used for treatment or prevention of a disease involving ACC2.
  • (30 ′) A method for treating or preventing a disease involving ACC2, which comprises administering the compound according to any one of (1 ′) to (27 ′) or a pharmaceutically acceptable salt thereof.
  • the compound according to the present invention has ACC2 inhibitory activity.
  • the pharmaceutical composition containing the compound according to the present invention is used for diseases involving ACC2, such as metabolic syndrome, obesity, Diabetes, insulin resistance, impaired glucose tolerance, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis Sclerosis, heart failure, myocardial infarction, infection, tumor, etc. (Journal of Cellular Biochemistry, 2006, 99, 1476-1488, EXPERT OPINION ON THERAPEUTIC Targets, 2005, 9, 267-281, International Therapeutic and / or prophylactic agents of Japanese Patent Application Publication No.
  • WO 2005/108370 Japanese Application Publication No. 2009-196966, Japanese Application Publication No. 2010-081894, Japanese Application Publication No. 2009-502785, especially diabetes Or / and therapeutic agent for obesity It is useful as a beauty / or prophylactic agent.
  • aryl refers to a monocyclic or polycyclic aromatic carbocyclic group having 6 to 14 carbon atoms, and a monocyclic or polycyclic aromatic carbocyclic group to which a 3- to 8-membered ring is further added. Or the group which condensed two is meant.
  • the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
  • the ring condensed with a monocyclic or polycyclic aromatic carbocyclic group include a non-aromatic carbocyclic ring and a monocyclic non-aromatic heterocyclic ring.
  • the bond is assumed to come from a monocyclic or polycyclic aromatic carbocyclic group.
  • the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.
  • the substituent on the aryl is a monocyclic or polycyclic aromatic carbocyclic group or a 3-8 membered ring fused to these monocyclic or polycyclic aromatic carbocyclic groups. Any of them may be substituted.
  • Substituted aryl includes aryl substituted with oxo.
  • “Oxo-substituted aryl” refers to two hydrogen atoms on a carbon atom on a 3- to 8-membered ring fused to a monocyclic or polycyclic aromatic carbocyclic group constituting aryl. It means a group substituted with a group.
  • aryl substituted with oxo the following formula: The group shown by can be mentioned.
  • Preferable embodiments of “aryl” in ring A include phenyl, naphthyl and the like.
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
  • a 5- or 6-membered heteroaryl is particularly preferable.
  • examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
  • polycyclic aromatic heterocyclic group a heteroaryl fused with a 5-membered or 6-membered ring is particularly preferable.
  • any ring may have a bond.
  • the ring condensed with a monocyclic or polycyclic aromatic heterocyclic group include a non-aromatic carbocyclic ring and a monocyclic non-aromatic heterocyclic ring.
  • the bond is assumed to come from a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • the following groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.
  • the substituents on the heteroaryl can be monocyclic or polycyclic aromatic heterocyclic groups or condensed to these monocyclic or polycyclic aromatic heterocyclic groups 3-8. Any of the member rings may be substituted.
  • Substituted heteroaryl also includes heteroaryl substituted with oxo.
  • “Oxo-substituted heteroaryl” refers to two hydrogen atoms on a carbon atom on a 3-8 membered ring fused to a monocyclic or polycyclic aromatic heterocyclic group comprising the heteroaryl. Means a group substituted with a ⁇ O group.
  • heteroaryl substituted with oxo the following formula: The group shown by can be mentioned.
  • heteroaryl in ring A include pyridyl, pyrimidine, benzothiazolyl, benzoxazolyl, benzoisothiazole, indazole, oxazol pyridyl and the like.
  • Non-aromatic carbocycle means a monocyclic or polycyclic ring having only aromaticity and composed only of carbon atoms. For example, it means a cycloalkane, a cycloalkene, a polycyclic carbocyclic ring formed by condensing or bridging them, and a polycyclic carbocyclic ring in which they are bonded by forming a spiro bond.
  • the “non-aromatic carbocycle” includes the following “cycloalkane” and “cycloalkene”.
  • “Cycloalkane” means a cyclic saturated hydrocarbon ring having 3 to 8 carbon atoms, and examples thereof include cyclohexane, cyclopentane, cyclobutane, and cyclopropane. In particular, cyclohexane and cyclobutane are preferable, and cyclobutane is more preferable.
  • “Cycloalkene” means a cyclic unsaturated aliphatic hydrocarbon ring having 3 to 8 carbon atoms, and examples thereof include cyclohexene and cyclopentene.
  • the cyclic unsaturated aliphatic hydrocarbon ring having 3 to 8 carbon atoms is preferably a cyclic unsaturated aliphatic carbon ring having 3 to 8 carbon atoms having 1 to 3 double bonds between carbon atoms on the ring.
  • a hydrogen ring is meant, and specific examples include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene and the like.
  • cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
  • “Monocyclic non-aromatic heterocycle” means a 3- to 8-membered non-aromatic heterocycle having 1 to 4 heteroatoms arbitrarily selected from O, S and N in the ring; For example, aziridine, thiirane, azetidine, 1,2-diazetidine, 1,3-diazetidine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, thiolane, 1,2-oxathiolane, tetrahydrofuran, 1,3-dioxolane, piperidine , Piperazine, morpholine, 1,4-oxathiane and the like.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups.
  • Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable, and cycloalkyl having 3 carbon atoms is more preferable.
  • Examples of the 3- to 8-membered ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cycloalkane, cycloalkene, and monocyclic non-aromatic heterocycle.
  • the bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
  • the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.
  • cycloalkyl In the case of a substituted cycloalkyl, the substituent on the cycloalkyl is either a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms or a 3 to 8 membered ring fused to a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. May be substituted.
  • cycloalkyl includes a group which forms a bridge or a spiro ring as described below.
  • “Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means.
  • the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms is preferably a cyclic unsaturated aliphatic carbon group having 3 to 8 carbon atoms having 1 to 3 double bonds between carbon atoms in the ring.
  • a hydrogen group is meant, and specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
  • cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
  • Examples of the ring condensed with the C 3-8 cyclic unsaturated aliphatic hydrocarbon group include aromatic carbocycles (eg, benzene, naphthalene, etc.), cycloalkanes, cycloalkenes, heterocycles (aromatic heterocycles (pyridine, Pyrimidine, pyrrole, imidazole, etc.) and monocyclic non-aromatic heterocycles.
  • the bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms.
  • the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.
  • the substituent on the cycloalkenyl is 3 to 8 condensed with a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms or a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. Any of the member rings may be substituted.
  • non-aromatic heterocyclic group means a monocyclic non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and those monocyclic It means a group (polycyclic non-aromatic heterocyclic group) in which one or two 3- to 8-membered rings are condensed to a non-aromatic heterocyclic group.
  • “Monocyclic non-aromatic heterocyclic group” refers to a monocyclic 3- to 8-membered non-aromatic heterocycle having 1 to 4 heteroatoms arbitrarily selected from O, S and N in the ring.
  • Cyclic groups are preferred, specifically, dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazinoyl, morpholinoyl, dimorpholinyl, Pyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl, oxetanyl, thiazolidinyl, tetrahydropyridyl, dihydroti Zoriru, dihydro be
  • the ring condensed with a monocyclic non-aromatic heterocyclic group having at least one hetero atom selected from O, S and N in the ring includes a carbocycle (aromatic carbocycle (eg, benzene, Naphthalene, etc.), cycloalkanes (eg, cyclohexane, cyclopentane, etc.), cycloalkenes (eg, cyclohexene, cyclopentene rings, etc.), heterocycles (aromatic heterocycles (pyridine, pyrimidine, pyrrole, imidazole, etc.)), monocyclic Non-aromatic heterocycle (for example, piperidine, piperazine, morpholine ring)).
  • aromatic carbocycle eg, benzene, Naphthalene, etc.
  • cycloalkanes eg, cyclohexane, cyclopentane, etc.
  • cycloalkenes eg
  • polycyclic non-aromatic heterocyclic group examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • the bond exits from the non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. It shall be.
  • the following groups are also included in the non-aromatic heterocyclic group. These groups may be substituted at any substitutable position.
  • the substituent on the non-aromatic heterocyclic group is a monocyclic non-aromatic having one or more hetero atoms arbitrarily selected from O, S and N in the ring It may be substituted with any of 3 to 8 membered rings fused to the aromatic heterocyclic group or these monocyclic non-aromatic heterocyclic groups.
  • the “non-aromatic heterocyclic group” also includes a group that forms a bridge or a spiro ring as described below.
  • cycloalkyl When the above “cycloalkyl”, “cycloalkenyl”, “aryl” and “non-aromatic heterocyclic group” have a substituent, “cycloalkane”, “cycloalkene” defined as a condensed ring thereof,
  • the “monocyclic non-aromatic heterocycle”, “aromatic carbocycle”, “aromatic heterocycle”, “carbocycle” and “heterocycle” may have a substituent, and “cycloalkane” “ “Cycloalkene” and “monocyclic non-aromatic heterocycle” may be substituted with oxo.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Cycloalkyloxy means a group in which the above “cycloalkyl” is bonded to an oxygen atom.
  • cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
  • Cycloalkenyloxy means a group in which “cycloalkenyl” is bonded to an oxygen atom. Examples include cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclohexadienyloxy, and the like.
  • Aryloxy means a group in which the above “aryl” is bonded to an oxygen atom.
  • aryl For example, phenyloxy, naphthyloxy and the like can be mentioned.
  • Heteroaryloxy means a group in which the above “heteroaryl” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • Non-aromatic heterocyclic oxy means a group in which the above “non-aromatic heterocyclic group” is bonded to an oxygen atom.
  • non-aromatic heterocyclic oxy examples include piperidinyloxy, tetrahydrofuryloxy and the like.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, tert-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl and the like.
  • alkylsulfanyl include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and tert-butylsulfanyl.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenylsulfanyl include vinylsulfanyl, allylsulfanyl, 1-propenylsulfanyl, 2-butenylsulfanyl, 2-pentenylsulfanyl, 2-hexenylsulfanyl, 2-heptenylsulfanyl, 2-octenylsulfanyl and the like. It is done.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • Alkynylsulfanyl includes, for example, ethynylsulfanyl, 1-propynylsulfanyl, 2-propynylsulfanyl, 2-butynylsulfanyl, 2-pentynylsulfanyl, 2-hexynylsulfanyl, 2-heptynylsulfanyl, 2-octynyl Nylsulfanyl etc. are mentioned.
  • Cycloalkylsulfanyl means a group in which the above “cycloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • Cycloalkenylsulfanyl means a group in which the above “cycloalkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropenylsulfanyl, cyclobutenylsulfanyl, cyclohexenylsulfanyl, cyclopentenylsulfanyl, cycloheptenylsulfanyl, cyclohexadienylsulfanyl and the like.
  • Arylsulfanyl means a group in which the above “aryl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • Heteroarylsulfanyl means a group in which the above “heteroaryl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which the above “non-aromatic heterocyclic group” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic heterocyclic group for example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • Cycloalkylsulfinyl means a group in which the above “cycloalkyl” is bonded to a sulfinyl group. Examples include cyclopropylsulfinyl, cyclohexylsulfinyl, cyclohexenylsulfinyl and the like.
  • Cycloalkenylsulfinyl means a group in which the above “cycloalkenyl” is bonded to a sulfinyl group. Examples include cyclopropenylsulfinyl, cyclobutenylsulfinyl, cyclohexenylsulfinyl, cyclopentenylsulfinyl, cycloheptenylsulfinyl, cyclohexadienylsulfinyl and the like.
  • Arylsulfinyl means a group in which the above “aryl” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
  • Heteroarylsulfinyl means a group in which the above “heteroaryl” is bonded to a sulfinyl group.
  • pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfinyl means a group in which the above “non-aromatic heterocyclic group” is bonded to a sulfinyl group.
  • non-aromatic heterocyclic group for example, piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
  • aminosulfinyl means a group in which an amino group is bonded to a sulfinyl group.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • Cycloalkylsulfonyl means a group in which the above “cycloalkyl” is bonded to a sulfonyl group.
  • cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • Cycloalkenylsulfonyl means a group in which the above “cycloalkenyl” is bonded to a sulfonyl group.
  • Arylsulfonyl means a group in which the above “aryl” is bonded to a sulfonyl group.
  • aryl a group in which the above “aryl” is bonded to a sulfonyl group.
  • phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Heteroarylsulfonyl means a group in which the above “heteroaryl” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which the “non-aromatic heterocyclic group” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • Alkylsulfonyloxy means a group in which the above “alkylsulfonyl” is bonded to an oxygen atom.
  • methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, tert-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyloxy” include methylsulfonyloxy and ethylsulfonyloxy.
  • Alkenylsulfonyloxy means a group in which the above “alkenylsulfonyl” is bonded to an oxygen atom.
  • alkenylsulfonyloxy ethylenylsulfonyloxy, propenylsulfonyloxy and the like can be mentioned.
  • Alkynylsulfonyloxy means a group in which the above “alkynylsulfonyl” is bonded to an oxygen atom.
  • alkynylsulfonyloxy ethynylsulfonyloxy, propynylsulfonyloxy and the like can be mentioned.
  • Cycloalkylsulfonyloxy means a group in which the above “cycloalkylsulfonyl” is bonded to an oxygen atom. Examples include cyclopropylsulfonyloxy, cyclohexylsulfonyloxy, cyclohexenylsulfonyloxy and the like.
  • Cycloalkenylsulfonyloxy means a group in which the above “cycloalkenylsulfonyl” is bonded to an oxygen atom.
  • Arylsulfonyloxy means a group in which the above “arylsulfonyl” is bonded to an oxygen atom.
  • arylsulfonyloxy phenylsulfonyloxy, naphthylsulfonyloxy and the like can be mentioned.
  • Heteroarylsulfonyloxy means a group in which the above “heteroarylsulfonyl” is bonded to an oxygen atom.
  • pyridylsulfonyloxy, oxazolylsulfonyloxy and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyloxy means a group in which the above “non-aromatic heterocyclic group sulfonyl” is bonded to an oxygen atom.
  • non-aromatic heterocyclic group sulfonyl is bonded to an oxygen atom.
  • piperidinylsulfonyloxy, tetrahydrofurylsulfonyloxy and the like can be mentioned.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group.
  • alkylcarbonyl include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
  • Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenylcarbonyl include ethylenylcarbonyl, propenylcarbonyl and the like.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group.
  • alkynylcarbonyl include ethynylcarbonyl, propynylcarbonyl and the like.
  • Cycloalkylcarbonyl means a group in which the above “cycloalkyl” is bonded to a carbonyl group.
  • Examples of “cycloalkylcarbonyl” include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
  • Cycloalkenylcarbonyl means a group in which the above “cycloalkenyl” is bonded to a carbonyl group.
  • Examples of “cycloalkenylcarbonyl” include cyclohexenylcarbonyl and the like.
  • Arylcarbonyl means a group in which the above “aryl” is bonded to a carbonyl group.
  • arylcarbonyl include phenylcarbonyl, naphthylcarbonyl and the like.
  • Heteroarylcarbonyl means a group in which the above “heteroaryl” is bonded to a carbonyl group.
  • Examples of “heteroarylcarbonyl” include pyridylcarbonyl, oxazolylcarbonyl and the like.
  • Non-aromatic heterocyclic carbonyl means a group in which the above “non-aromatic heterocyclic group” is bonded to a carbonyl group.
  • Examples of the “non-aromatic heterocyclic carbonyl” include piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • alkylcarbonyloxy include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
  • Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Cycloalkylcarbonyloxy means a group in which the above “cycloalkylcarbonyl” is bonded to an oxygen atom.
  • Examples of “cycloalkylcarbonyloxy” include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy, cyclohexenylcarbonyloxy and the like.
  • Cycloalkenylcarbonyloxy means a group in which the above “cycloalkenylcarbonyl” is bonded to an oxygen atom.
  • Examples of “cycloalkenylcarbonyloxy” include cyclohexenylcarbonyloxy and the like.
  • Arylcarbonyloxy means a group in which the above “arylcarbonyl” is bonded to an oxygen atom.
  • Examples of “arylcarbonyloxy” include phenylcarbonyloxy, naphthylcarbonyloxy and the like.
  • Heteroarylcarbonyloxy means a group in which the above “heteroarylcarbonyl” is bonded to an oxygen atom.
  • Examples of “heteroarylcarbonyloxy” include pyridylcarbonyloxy, oxazolylcarbonyloxy and the like.
  • Non-aromatic heterocyclic carbonyloxy means a group in which the above “non-aromatic heterocyclic carbonyl” is bonded to an oxygen atom.
  • Examples of “non-aromatic heterocyclic carbonyloxy” include piperidinylcarbonyloxy, tetrahydrofurylcarbonyloxy and the like.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group.
  • alkyloxycarbonyl include, for example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl , Hexyloxycarbonyl and the like.
  • Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group.
  • alkenyloxycarbonyl include ethylenyloxycarbonyl, propenyloxycarbonyl and the like.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group.
  • alkynyloxycarbonyl include ethynyloxycarbonyl, propynyloxycarbonyl and the like.
  • Cycloalkyloxycarbonyl means a group in which the above “cycloalkyloxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Cycloalkenyloxycarbonyl means a group in which the above “cycloalkenyloxy” is bonded to a carbonyl group. For example, cyclopropenyloxycarbonyl, cyclohexenyloxycarbonyl, etc. are mentioned.
  • Aryloxycarbonyl means a group in which the above “aryloxy” is bonded to a carbonyl group.
  • aryloxycarbonyl phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • Heteroaryloxycarbonyl means a group in which the above “heteroaryloxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxycarbonyl means a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Halogen includes fluorine atom, chlorine atom, bromine atom and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • non-aromatic carbocycle in ring B means a monocyclic or polycyclic ring having only aromaticity and composed only of carbon atoms.
  • it means a cycloalkane, a cycloalkene, a polycyclic carbocyclic ring formed by condensing or bridging them, and a polycyclic carbocyclic ring in which they are bonded by forming a spiro bond.
  • a monocyclic cycloalkane a monocyclic cycloalkene, a ring fused with 2-3 cycloalkane rings, a ring fused with 2-3 cycloalkene rings, a cycloalkane and a cycloalkene 2 to 3 condensed rings, cycloalkane and cycloalkane spiro ring, cycloalkene and cycloalkene spiro ring, cycloalkane and cycloalkene spiro ring, bridged cycloalkane, bridged Including cycloalkene.
  • non-aromatic carbocycle examples include the following formulas: Is also exemplified as a non-aromatic carbocycle.
  • a monocyclic cycloalkane is preferable.
  • a 4- to 6-membered cycloalkane is preferable, and cyclobutane is more preferable.
  • non-aromatic heterocycle in ring B means a monocyclic non-aromatic heterocycle or a polycyclic heterocycle in which none of the constituent rings has an aromatic attribute.
  • a ring a ring obtained by condensing two or three monocyclic non-aromatic heterocycles, a ring obtained by condensing a monocyclic non-aromatic heterocycle and cycloalkane or / and cycloalkene, or a spiro ring composed of non-aromatic heterocycles
  • non-aromatic heterocycle examples include the following formulas: Is also exemplified as a non-aromatic heterocyclic ring.
  • the “non-aromatic heterocycle” in ring B is preferably a monocyclic non-aromatic heterocycle or a bicyclic non-aromatic heterocycle in which a monocyclic non-aromatic heterocycle and a cycloalkane are condensed.
  • the monocyclic non-aromatic ring is preferably a 4- to 6-membered non-aromatic heterocyclic ring, more preferably a 4-membered non-aromatic heterocyclic ring, and further preferably azetidine.
  • a bicyclic non-aromatic heterocycle in which a monocyclic non-aromatic heterocycle and a cycloalkane are condensed includes the following formula:
  • a ring represented by is preferred.
  • the “6-membered aromatic carbocycle” in ring C means benzene.
  • the “5-membered aromatic heterocycle” in ring C means a 5-membered aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • Examples thereof include pyrrole, imidazole, pyrazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene.
  • Particularly preferred are isoxazole, thiazole, oxadiazole and the like.
  • the “6-membered aromatic heterocycle” in ring C means a 5-membered aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like can be mentioned.
  • substituents include the following substituents.
  • the hydrogen atom on the nitrogen atom may be substituted with 1 to 2 groups selected from the following substituents.
  • a hydrogen atom on a carbon atom at an arbitrary position may be substituted with one or more groups selected from the following substituents.
  • One or more groups selected from the following substituents may be substituted for a hydrogen atom on an atom at any position on the ring.
  • Alkylcarbonylsulfanyl means a group in which the above “alkylcarbonyl” is bonded to a sulfur atom.
  • alkylcarbonylsulfanyl include, for example, methylcarbonylsulfanyl, ethylcarbonylsulfanyl, propylcarbonylsulfanyl, isopropylcarbonylsulfanyl, tert-butylcarbonylsulfanyl, isobutylcarbonylsulfanyl, sec-butylcarbonylsulfanyl and the like.
  • Haloalkyl means a group in which one or more arbitrary hydrogen atoms of the above “alkyl” are substituted with the above “halogen”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
  • Haloalkylcarbonyl means a group in which the above “haloalkyl” is bonded to a carbonyl group.
  • monofluoromethylcarbonyl difluoromethylcarbonyl, monofluoroethylcarbonyl, monofluoropropylcarbonyl, 2,2,3,3,3-pentafluoropropylcarbonyl, monochloromethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, 2 2,2-trifluoroethyl, 2,2,2-trichloroethylcarbonyl, 1,2-dibromoethylcarbonyl, 1,1,1-trifluoropropan-2-ylcarbonyl and the like.
  • Haloalkenyl means a group in which one or more arbitrary hydrogen atoms of the above “alkenyl” are substituted with the above “halogen”.
  • Hydroalkyl means a group in which one or more arbitrary hydrogen atoms of the above “alkyl” are substituted with hydroxy.
  • Trialkylsilyl means a group in which the above three “alkyls” are bonded to a silicon atom.
  • the three alkyls may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl and the like can be mentioned.
  • Trialkylsilyloxy means a group in which the above “trialkylsilyl” is bonded to an oxygen atom.
  • trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, triisopropylsilyloxy and the like can be mentioned.
  • Cyanoalkyl means a group in which one or more arbitrary hydrogen atoms of the above “alkyl” are substituted with cyano. For example, cyanomethyl and the like can be mentioned.
  • Cyanoalkyloxy means a group in which the above “cyanoalkyl” is bonded to an oxygen atom. For example, cyanomethyloxy and the like can be mentioned.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
  • Carbamoylalkylcarbonyl means the above “alkylcarbonyl” substituted with carbamoyl. Examples include carbamoylmethylcarbonyl, carbamoylethylcarbonyl, and the like.
  • “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned. Preferable embodiments of “monoalkylamino” include methylamino and ethylamino.
  • Dialkylamino means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like. Preferred embodiments of “dialkylamino” include dimethylamino and diethylamino.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • Preferable embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Preferred embodiments of “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkyloxycarbonylamino” means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • Preferable embodiments of “monoalkyloxycarbonylamino” include methyloxycarbonylamino and ethyloxycarbonylamino.
  • Dialkyloxycarbonylamino means a group in which the above “alkyloxycarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyloxycarbonyl groups may be the same or different.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
  • Preferable embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned. Preferred embodiments of “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
  • “Monoalkylcarbamoylalkyloxy” means the above “alkyloxy” substituted with one or more of the above “monoalkylcarbamoyl”. For example, methylcarbamoylmethyloxy and the like can be mentioned.
  • “Mono (hydroxyalkyl) carbamoyl” means a group in which any hydrogen atom of the alkyl group of the above “monoalkylcarbamoyl” is replaced with hydroxy. Examples thereof include hydroxymethylcarbamoyl and hydroxyethylcarbamoyl.
  • Dialkylcarbamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • Alkyloxycarbonylalkyl means the above “alkyl” substituted with one or more of the above “alkyloxycarbonyl”.
  • “Monoalkyloxycarbonylalkylcarbamoyl” means a group in which the above “alkyloxycarbonylalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • methyloxycarbonylmethylcarbamoyl, ethyloxycarcarbonylmethylcarbamoyl and the like can be mentioned.
  • Dialkyloxycarbonylalkylcarbamoyl means a group in which the above “alkyloxycarbonylalkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • Carboxyalkyl means the above “alkyl” substituted with one or more “carboxy”.
  • Carboxyalkylcarbamoyl means a group in which one or more of the above “carboxyalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, carboxymethylcarbamoyl etc. are mentioned.
  • Dialkylaminoalkyl means the above “alkyl” substituted with one or more “dialkylamino”. Examples thereof include dimethylaminomethyl and dimethylaminoethyl.
  • “Mono (dialkylaminoalkyl) carbamoyl” means a group in which the above “dialkylaminoalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include dimethylaminomethylcarbamoyl, dimethylaminoethylcarbamoyl and the like.
  • Dia (dialkylaminoalkyl) carbamoyl means a group in which the above “dialkylaminoalkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • di (methyloxycarbonylmethyl) carbamoyl, di (ethyloxycarbcarbonylmethyl) carbamoyl and the like can be mentioned.
  • Cycloalkylcarbamoyl means a group in which one or more of the above “cycloalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, cyclopropylcarbamoyl etc. are mentioned.
  • Non-aromatic heterocyclic carbamoyl means a group in which one or more of the above “non-aromatic heterocyclic groups” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • groups represented by the following formulas can be mentioned.
  • “Monoalkyloxycarbamoyl” means a group in which the above “alkyloxy” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. For example, methyloxycarbamoyl etc. are mentioned.
  • Dialkyloxycarbamoyl means a group in which the above “alkyloxy” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Examples thereof include di (methyloxy) carbamoyl.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoylmoyl, etc. are mentioned.
  • Dialkylsulfamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • Arylalkyl means the above “alkyl” substituted with one or more of the above “aryl”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc. Preferable embodiments of “arylalkyl” include benzyl, phenethyl and benzhydryl.
  • Cycloalkylalkyl means the above “alkyl” substituted with one or more of the above “cycloalkyl”. “Cycloalkylalkyl” also includes “cycloalkylalkyl” in which the alkyl moiety is further substituted with the above “aryl”. For example, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • Cycloalkenylalkyl means the above “alkyl” substituted with one or more of the above “cycloalkenyl”. “Cycloalkenylalkyl” also includes “cycloalkenylalkyl” in which the alkyl moiety is further substituted with the above “aryl”. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • Heteroarylalkyl means the above “alkyl” substituted with one or more of the above “heteroaryl”. “Heteroarylalkyl” also includes “heteroarylalkyl” in which the alkyl moiety is further substituted with the above “aryl” and / or “cycloalkyl”.
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • non-aromatic heterocyclic alkyl means the above “alkyl” substituted with one or more of the above “non-aromatic heterocyclic group”.
  • the “non-aromatic heterocyclic alkyl” also includes “non-aromatic heterocyclic alkyl” in which the alkyl moiety is further substituted with the above “aryl”, “cycloalkyl” and / or “heteroaryl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkylcarbamoyl means a group in which one or more of the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • groups represented by the following formulas can be exemplified.
  • Arylalkyloxy means the above “alkyloxy” substituted with one or more of the above “aryl”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Cycloalkylalkyloxy means the above “alkyloxy” substituted with one or more of the above “cycloalkyl”. “Cycloalkylalkyloxy” also includes “cycloalkylalkyloxy” in which the alkyl moiety is further substituted with the above “aryl”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • Cycloalkenylalkyloxy means the above “alkyloxy” substituted with one or more of the above “cycloalkenyl”. “Cycloalkenylalkyloxy” also includes “cycloalkenylalkyloxy” in which the alkyl moiety is further substituted with the above “aryl”, “cycloalkyl”, or both. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • Heteroarylalkyloxy means the above “alkyloxy” substituted with one or more “heteroaryl”. “Heteroarylalkyloxy” also includes “heteroarylalkyloxy” in which the alkyl moiety is further substituted with the above “aryl” and / or “cycloalkyl”.
  • Non-aromatic heterocyclic alkyloxy means the above “alkyloxy” substituted with one or more of the above “non-aromatic heterocyclic groups”. “Non-aromatic heterocyclic alkyloxy” also includes “non-aromatic heterocyclic alkyloxy” in which the alkyl moiety is further substituted with the above-mentioned “aryl”, “cycloalkyl” and / or “heteroaryl”. . For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • Arylalkyloxycarbonyl means the above “alkyloxycarbonyl” substituted with one or more of the above “aryl”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Cycloalkylalkyloxycarbonyl means the above “alkyloxycarbonyl” substituted with one or more “cycloalkyl”. “Cycloalkylalkyloxycarbonyl” also includes “cycloalkylalkyloxycarbonyl” in which the alkyl moiety is further substituted with the above “aryl”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • Cycloalkenylalkyloxycarbonyl means the above “alkyloxycarbonyl” substituted by one or more of the above “cycloalkenyl”.
  • Heteroarylalkyloxycarbonyl means the above “alkyloxycarbonyl” substituted with one or more “heteroaryl”. “Heteroarylalkyloxycarbonyl” also includes “heteroarylalkyloxycarbonyl” in which the alkyl moiety is further substituted with the above “aryl”, “cycloalkyl” and / or “cycloalkenyl”.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means the above “alkyloxycarbonyl” substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the “non-aromatic heterocyclic alkyloxycarbonyl” is a “non-aromatic heterocyclic ring” in which the alkyl part is further substituted with the above “aryl”, “cycloalkyl”, “cycloalkynyl” and / or “heteroaryl”.
  • alkyloxycarbonyl for example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • Arylalkylamino means a group in which the above “arylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Cycloalkylalkylamino means a group in which the above “cycloalkylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • Cycloalkenylalkylamino means a group in which the above “cycloalkenylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Heteroarylalkylamino means a group in which the above “heteroarylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • pyridylmethylamino furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above-mentioned “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • Alkyloxyalkyl means the above “alkyl” substituted with 1 or 2 of the above “alkyloxy”. For example, methyloxymethyl, methyloxyethyl, ethyloxymethyl and the like can be mentioned.
  • Arylalkyloxyalkyl means the above “alkyloxyalkyl” substituted with one or more of the above “aryl”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Cycloalkylalkyloxyalkyl means the above “alkyloxyalkyl” substituted by one or more of the above “cycloalkyl”. “Cycloalkylalkyloxyalkyl” also includes “cycloalkylalkyloxyalkyl” in which the alkyl moiety to which cycloalkyl is bonded is further substituted with the above “aryl”. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • Cycloalkenylalkyloxyalkyl means the above “alkyloxyalkyl” substituted with one or more of the above “cycloalkenyl”. “Cycloalkenylalkyloxyalkyl” also includes “cycloalkenylalkyloxyalkyl” in which the alkyl moiety to which cycloalkenyl is bonded is further substituted with the above “aryl”, “cycloalkyl”, or both. For example, the group shown below Etc.
  • Heteroarylalkyloxyalkyl means the above “alkyloxyalkyl” substituted with one or more of the above “heteroaryl”.
  • heteroarylalkyloxyalkyl is a “heteroarylalkyloxyalkyl” in which the alkyl moiety to which the aromatic heterocycle is bonded is further substituted with the above “aryl”, “cycloalkyl” and / or “cycloalkenyl”. Is also included.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means the above “alkyloxyalkyl” substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is further substituted with the above “aryl”, “cycloalkyl”, “cycloalkenyl” and / or “heteroaryl”.
  • non-aromatic heterocyclic alkyloxyalkyl For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • Alkyloxyalkyloxy means a group in which the above “alkyloxyalkyl” is bonded to an oxygen atom.
  • the group represented by is substituted with one or more groups selected from unsubstituted aryl, aryl substituted with one or more groups selected from substituent group ⁇ , unsubstituted heteroaryl, or substituent group ⁇ Heteroaryl.
  • it is aryl substituted with one or more groups selected from substituent group ⁇ or heteroaryl substituted with one or more groups selected from substituent group ⁇ .
  • it is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group ⁇ , unsubstituted 6-membered heteroaryl, substituent group ⁇ 6-membered heteroaryl substituted with one or more groups or formula: It is group shown by these.
  • Substituent group ⁇ is Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, Substituted or unsubstituted heteroaryloxy, substituted or unsubstitute
  • Substituent group ⁇ includes substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl
  • the group consisting of oxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy and cyano is preferred.
  • substituent group ⁇ halogen, cyano, alkyl, hydroxyalkyl, cyanoalkyl, arylalkenyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, cycloalkylalkyloxy, halocycloalkylalkyloxy, arylalkyl Oxy, cycloalkyl, halocycloalkyl, alkylcycloalkyl, alkylaryl, haloaryl, cyanoaryl, heteroaryl, haloheteroaryl, non-aromatic heterocyclic group, alkylamino, arylamino, arylcarbonylamino, haloalkylsulfonyloxy, alkyl
  • the group consisting of carbamoyl, alkylsulfonyl, alkylcarbonyl, alkyloxycarbonyl and oxo is preferred.
  • Ring E is a 5-membered aromatic heterocyclic ring
  • ring F is a 6-membered aromatic carbocyclic ring or 6-membered aromatic heterocyclic ring
  • ring E and ring F are condensed to form It forms a cyclic aromatic heterocycle.
  • Ring E and / or ring F may be substituted with one or more groups selected from substituent group ⁇ .
  • ring E and / or ring F are substituted with substituted or unsubstituted alkyloxy and / or halogen. More preferably, ring E is substituted with substituted or unsubstituted alkyloxy or halogen.
  • Is a “6-membered aryl substituted with one or more groups selected from substituent group ⁇ ”, specifically, the group represented by the formula: Is preferred.
  • X 1 is independently —C (H) ⁇ or —C (R 12 ) ⁇ .
  • R 17 represents substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted Aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy.
  • R 17 is preferably substituted or unsubstituted alkyloxy.
  • R 12 is each independently a group selected from the substituent group ⁇ , and is independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted. Carbamoyl, substituted or unsubstituted sulfamoyl or carboxy is preferred. R 12 is preferably halogen (for example, fluorine atom, chlorine atom, etc.).
  • Is a “6-membered aryl substituted with one or more groups selected from the substituent group ⁇ ”, another embodiment includes a group represented by the formula: Is preferred.
  • X 1 is independently —C (H) ⁇ or —C (R 12 ) ⁇ .
  • R 17 represents substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted Aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy.
  • R 17 is preferably substituted or unsubstituted alkyloxy.
  • R 12 is each independently a group selected from the substituent group ⁇ , and is independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted. Carbamoyl, substituted or unsubstituted sulfamoyl or carboxy is preferred.
  • R 12 ′ is preferably a halogen (eg, fluorine atom, chlorine atom).
  • R 1a , R 1b , R 1c , R 1d , and R 1e are each independently hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylcarbony
  • R 1a is preferably substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 1b and R 1c are each independently preferably hydrogen or halogen (for example, a fluorine atom, a chlorine atom, etc.).
  • Ring B in formula (I) is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • Ring B is preferably a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 4-membered non-aromatic heterocyclic ring, more preferably a substituted or unsubstituted 4-membered non-aromatic ring.
  • Group carbocycle more preferably substituted or unsubstituted cyclobutane. .
  • Each R 15 is independently hydrogen, substituted or unsubstituted alkyl, halogen or hydroxy, preferably hydrogen.
  • the methylene group on the ring corresponding to ring B may be substituted.
  • the substituent include a ring selected from the substituent group ⁇ . Preferred is halogen, substituted or unsubstituted alkyl.
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring, or a substituted or unsubstituted 6-membered aromatic heterocyclic ring. Preferably, it is a substituted or unsubstituted 5-membered aromatic heterocyclic ring.
  • benzene is preferable.
  • isoxazole, thiazole or oxadiazole is preferable, and isoxazole is particularly preferable.
  • U is -CR 4 R 5 -, - CR 4 R 5 -O -, - CR 4 R 5 -S -, - CR 4 R 5 -NR 6 -, - O -, - S -, - NR 6 -, —O—CR 4 R 5 —, —S—CR 4 R 5 — or —NR 6 —CR 4 R 5 —, wherein the left bond is bonded to ring A and the right bond is a ring Bind to B.
  • Preferred is —O—, —CR 4 R 5 — or —O—CR 4 R 5 —, and more preferred is —O—.
  • T is -CR 7 R 8 -, - CR 7 R 8 -O -, - CR 7 R 8 -S -, - CR 7 R 8 -NR 9 -, - O -, - S -, - NR 9 -, —C ( ⁇ O) — or —SO 2 —, wherein the left bond is bonded to ring B and the right bond is bonded to ring C.
  • Preferred is —CR 7 R 8 — or —O—.
  • L is —CR 10 R 11 — or —C ( ⁇ O) —.
  • R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl or cyano. Preferred is hydrogen or halogen, and more preferred is hydrogen.
  • R 6 and R 9 are each independently hydrogen or substituted or unsubstituted alkyl, preferably hydrogen.
  • P is 0 or 1. Preferably it is 0.
  • Q is 0 or 1. Preferably it is 0.
  • R is 0 or 1. Preferably it is 0.
  • R 13 is methyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and cyano.
  • R 13 is preferably methyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, more preferably methyl.
  • R 14 is methylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, methyloxy and substituted or unsubstituted carbamoyl.
  • R 14 is preferably methylcarbonyl optionally substituted with one or more substituents selected from the group consisting of: halogen and hydroxy, and more preferably methylcarbonyl.
  • R 16 is hydrogen or substituted or unsubstituted alkyl, preferably hydrogen.
  • ring C when ring C is a substituted or unsubstituted 5-membered aromatic heterocycle, the position number of the atom on ring C bonded to T or ring B is the 1-position To the atom on ring C located in the 3- or 4-position of Or a pharmaceutically acceptable salt thereof is preferred.
  • a ring C that is a substituted or unsubstituted 5-membered aromatic heterocycle is represented by the following formula: The following formula: Or the following formula: Or a pharmaceutically acceptable salt thereof is preferred.
  • Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring
  • the position number of the atom on Ring B bonded to U or Ring A is A compound or a pharmaceutically acceptable salt thereof in which T or ring C is bonded to an atom on ring B located at the 4-position when it is located at the 1-position.
  • Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring A compound in which p is 0, q is 0, and ring C is bonded to a nitrogen atom on ring B
  • Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
  • Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubsti
  • Diseases involving ACC2 include metabolic syndrome, obesity, diabetes, insulin resistance, impaired glucose tolerance, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, dyslipidemia Disease, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, heart failure, myocardial infarction, infection, tumor and the like.
  • the compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers etc.), racemates or mixtures thereof.
  • the carbon atom to which R 13 is bonded is an asymmetric carbon, and R and S forms exist.
  • racemates and optically active forms are present. Any body).
  • the compound of formula (I) is represented by formula (II): The compound shown by these is preferable.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base.
  • a suitable catalyst such as Pd / C
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium). , Barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline) , Quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, propion) Acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid Oxalic acid, maleic
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention Various solvates and crystal polymorphs are also included.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • Examples of the protective group used for the prodrug include CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 — CF 3 CH 2 SO 3 —, p—CH 3 —O—PhSO 3 —, PhSO 3 —, and p—CH 3 PhSO 3 —.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the synthetic route shown in the following production methods A to L.
  • Formula (I) according to the present invention is represented by the following formula (Ia): (Wherein X 4 is —S—, —NR 6 — or —O—, n is 0 or 1, m is 0 or 1, and other symbols are as defined above.) For example, it can be produced by the synthesis route shown in the following production method A.
  • a compound represented by formula (Ia3) is reacted with a compound represented by formula (Ia2) to produce a compound represented by formula (Ia3).
  • the condensing agent include DEAD and DIAD, and 1 to 5 equivalents can be used with respect to the compound represented by the formula (Ia1).
  • the activator methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be used.
  • the base examples include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Potassium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal acetate (eg, sodium acetate, potassium acetate, cesium acetate) Etc.), metal phosphate (sodium phosphate, potassium phosphate, etc.), metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU, pyridine, 2,6-lutidine, etc.), pyridine, alkyllithium (N-BuLi, sec-BuLi, tert BuLi), the Grignard reagent, and the like.
  • a metal carbonate eg, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction temperature is 0 ° C. to heating under reflux.
  • the reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.
  • Reaction solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) Halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, Ethyl acetate, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water, and
  • Process 2 the compound represented by the formula (Ia3) is reacted with a reducing agent to produce the compound represented by the formula (Ia4).
  • the reducing agent include lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, and 1 to 10 equivalents can be used with respect to the compound represented by the formula (Ia3).
  • the reaction temperature is 0 ° C. to heating under reflux.
  • the reaction time is 0.2 to 48 hours, preferably 0.5 to 24 hours.
  • the reaction solvent the solvent described in Step 1 can be used.
  • methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane, or the like may be used alone or in combination.
  • Process 3 the compound represented by the formula (Ia4) is reacted with an oxidizing agent to produce the compound represented by the formula (Ia5).
  • the oxidizing agent include metal salts and metal oxides such as Dess-Martin, periodinane, IBX (2-iodoxybenzoic acid), chromium, manganese, and silver, and an organic oxidizing agent. Up to 10 molar equivalents can be used.
  • the reaction temperature is 0 ° C. to heating under reflux, preferably 20 ° C. to heating under reflux.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • the reaction solvent the solvent described in Step 1 can be used.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • This oxidation reaction step can also be performed under conditions such as Swern oxidation and TEMPO oxidation.
  • Process 4 the compound represented by the formula (Ia5) is reacted with hydroxylamine hydrochloride in the presence of a base to produce a compound represented by the formula (Ia6).
  • the base described in Step 1 can be used.
  • metal acetate eg, sodium acetate, potassium acetate, cesium acetate, etc.
  • metal carbonate eg, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.
  • organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction temperature is 0 ° C. to heating under reflux.
  • the temperature is preferably 0 ° C to 30 ° C.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • the solvent described in Step 1 can be used.
  • methanol, ethanol, propanol, isopropanol, butanol, water and the like can be mentioned, and these may be used alone or in combination.
  • Process 5 the compound represented by the formula (Ia6) is reacted with NCS, and then the compound represented by the formula (Ia7) is reacted to produce the compound represented by the formula (Ia8). It can be carried out in the presence of a base.
  • the base the base described in Step 1 can be used.
  • Preferable examples include triethylamine, DIEA, and the like, and 1 to 10 equivalents can be used with respect to the compound represented by the formula (Ia6).
  • the reaction temperature is 0 ° C. to solvent reflux.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the solvent described in Step 1 can be used.
  • tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane and the like can be mentioned, and these can be used alone or in combination.
  • Step 6 a compound represented by the formula (Ia8) is reacted with a deprotecting agent to obtain a compound represented by the formula (Ia9).
  • the deprotecting agent include hydrazine, methyl hydrazine and the like, and 1 to 20 equivalents can be used with respect to the compound represented by the formula (Ia8).
  • the reaction temperature is 20 ° C. to a temperature under reflux of the solvent, optionally under microwave irradiation.
  • the reaction time is 0.1 hour to 120 hours, preferably 1 hour to 80 hours.
  • the solvent described in Step 1 can be used.
  • tetrahydrofuran, dioxane, methanol, ethanol, chloroform, dichloromethane, water and the like can be mentioned, and these may be used alone or in combination.
  • Step 7 the compound represented by the formula (Ia) is produced from the compound represented by the formula (Ia9).
  • Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used.
  • condensing agents include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 equivalents can be used with respect to the compound represented by the formula (Ia8).
  • the base the base described in Step 1 can be used.
  • 1 to 10 equivalents of pyridine, triethylamine, DIEA, sodium carbonate, sodium hydrogen carbonate and the like may be used with respect to the compound represented by the formula (Ia9).
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent the solvent described in Step 1 can be used.
  • methanol, tetrahydrofuran, toluene, DMF, dioxane, dichloromethane, water and the like can be mentioned, and these may be used alone or in combination.
  • the compound represented by the formula (I) according to the present invention is represented by the formula (Ib): (In the formula, each symbol is as defined above.) Can be produced by the production method B shown below. Manufacturing method B (Wherein Y 3 is a protecting group such as Boc and benzyl, Y 4 is halogen, —O—Tf, —O—Ms, —O—Ts, etc., and other symbols are as defined above.) )
  • Process 1 the compound represented by the formula (Ib1) is reacted with a reducing agent to produce the compound represented by the formula (Ib2).
  • This step can be performed in the same manner as in step 2 of production method A.
  • Process 2 the compound represented by the formula (Ib2) is reacted with an oxidizing agent to produce the compound represented by the formula (Ib3).
  • This step can be performed in the same manner as in step 3 of production method A.
  • Process 3 the compound represented by the formula (Ib3) is reacted with hydroxylamine hydrochloride in the presence of a base to produce the compound represented by the formula (Ib4).
  • This step can be performed in the same manner as in step 1 of production method A.
  • Process 4 the compound represented by the formula (Ib4) is reacted with NCS and then the compound represented by the formula (Ib5) is reacted to produce the compound represented by the formula (Ib6). It can be carried out in the presence of a base. This step can be performed in the same manner as in step 5 of production method A.
  • Process 5 a compound represented by the formula (Ib6) is reacted with a deprotecting agent to obtain a compound represented by the formula (Ib7).
  • This step can be performed in the same manner as in step 6 of production method A.
  • Step 6 the compound represented by the formula (Ib8) is produced from the compound represented by the formula (Ib7).
  • Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used.
  • This step can be performed in the same manner as in step 7 of production method A.
  • Step 7 the compound represented by the formula (Ib8) is deprotected to produce the compound represented by the formula (Ib9).
  • the deprotection reaction of the protecting group is known and can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 4th Edition (Peter G. M. Wuts, Theodora W. Greene, Wiley, 2006).
  • the reaction solvent the solvents described in Step 1 can be used alone or in combination.
  • Process 8 the compound represented by the formula (Ib9) is reacted with the compound represented by the formula (Ib10) to obtain a compound represented by the formula (Ib).
  • the reaction can be performed in the presence of a base, a metal catalyst, and a ligand.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri -Tert-butylphosphine) palladium, bis (cyclopentadienyl) zirconium chloride hydride, and the like, and 0.001-0.5 equivalents can be used with respect to the compound represented by the formula (Ib10).
  • Examples of the ligand include triphenylphosphine, Xantphos, BINAP, X-phos and the like, and 0.001 to 1 equivalent can be used.
  • the base the base described in Step 1 of production method A can be used.
  • triethylamine, diisopropylethylamine, DBU, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, etc. 1 to 10 equivalents may be used with respect to the compound represented by the formula (Ib10).
  • the reaction is carried out at a temperature from 0 ° C.
  • reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used. Preferred examples include tetrahydrofuran, dimethoxyethane, toluene, DMF, DMA, NMP, DMSO, dioxane, water, and the like, which may be used alone or in combination.
  • the compound represented by the formula (I) according to the present invention is represented by the formula (Ic): Wherein ring F is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring, and X 2 represents —S—, —O— or —NR 18 —. And R 18 is a hydrogen or a substituent selected from the substituent group ⁇ , and other symbols are as defined above.), It is produced by the production method C shown below. You can also.
  • the compound represented by the formula (Ic1) is reacted with the compound represented by the formula (Ic2) to produce a compound represented by the formula (Ic3). It can be produced by a method using a dehydrating agent after condensing an amino group and a carboxylic acid using a condensing agent to amidate.
  • a condensing agent dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3 , 5, -triazin-2-yl) -4-methylmorpholinium chloride, HATU and the like can be used in an amount of 1 to 5 equivalents with respect to the compound represented by the formula (Ic1).
  • Examples of the dehydrating agent include a method using DIAD or DEAD together with triphenylphosphine, and a method performed under acidic conditions (eg, p-tosylic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid, etc.).
  • the reaction solvent the solvent described in Production Method A, Step 1 can be used.
  • tetrahydrofuran, toluene or the like may be used.
  • the reaction temperature is 0 ° C. to solvent reflux.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • Process 2 the compound represented by the formula (Ic3) is reacted with the borohydride compound and then treated with an oxidizing agent to produce the compound represented by the formula (Ic4).
  • Boron hydride compounds include borane / tetrahydrofuran complex, borane / dimethyl sulfide complex, catecholborane, 9-borabicyclo [3.3.1] nonane, and the like. Molar equivalents can be used.
  • the oxidizing agent include hydrogen peroxide and sodium perborate, and 1 to 15 molar equivalents can be used with respect to the compound represented by the formula (Ic3).
  • the reaction temperature is 0 ° C. to heating under reflux.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • the reaction solvent the solvent described in Production Method A, Step 1 can be used. Preferred examples include tetrahydrofuran, dimethoxyethane, dioxane and the like, which may be used alone or in combination.
  • Process 3 the compound represented by the formula (Ic4) is reacted with an oxidizing agent to produce the compound represented by the formula (Ic5).
  • This step can be performed in the same manner as in step 3 of production method A.
  • Process 4 the compound represented by the formula (Ic5) is reacted with hydroxylamine hydrochloride to produce the compound represented by the formula (Ic6). It can be carried out in the presence of a base. This step can be performed in the same manner as in step 4 of production method A.
  • Process 5 the compound represented by the formula (Ic6) is reacted with NCS and then the compound represented by the formula (Ic7) is reacted to produce the compound represented by the formula (Ic8). It can be carried out in the presence of a base. This step can be performed in the same manner as in step 5 of production method A.
  • Step 6 the compound represented by the formula (Ic8) is reacted with a deprotecting agent to obtain the compound represented by the formula (Ic9).
  • This step can be performed in the same manner as in step 6 of production method A.
  • Step 7 the compound represented by the formula (Ic) is produced from the compound represented by the formula (Ic9).
  • Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used.
  • This step can be performed in the same manner as in step 7 of production method A.
  • the compound represented by formula (I) according to the present invention is represented by formula (Id): (Wherein each symbol has the same meaning as described above) can also be produced by the production method D shown below. Manufacturing method D (In the formula, Y 5 and Y 6 are amino-protecting groups, or one of them may be hydrogen, and Y 5 and Y 6 may form a ring as an amino-protecting group. It is the same meaning as above.)
  • Process 1 the compound represented by the formula (Ia5) is reacted with dimethyl (1-diazo-2-oxopropyl) phosphonate to produce the compound represented by the formula (Id1). It can be carried out in the presence of a base. As the base, potassium carbonate or the like can be used. The reaction temperature is 0 ° C. to heating under reflux. The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours. Examples of the reaction solvent include methanol, ethanol, water and the like, and these can be used alone or in combination.
  • Process 2 After reacting the compound represented by the formula (Id2) (described in the synthesis method in known literature; Bioorganic & Medicinal Chemistry, 1996, Vol. 4, 209-225) with NCS, the compound represented by the formula (Id1) is reacted. And a step for producing a compound represented by the formula (Id3). It can be carried out in the presence of a base. This step can be performed in the same manner as in step 5 of production method A.
  • Process 3 the compound represented by the formula (Id3) is reacted with a deprotecting agent to obtain the compound represented by the formula (Id4).
  • This step can be performed in the same manner as in step 7 of production method B.
  • Process 4 the compound represented by the formula (Id) is produced from the compound represented by the formula (Id4).
  • Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used.
  • This step can be performed in the same manner as in step 7 of production method A.
  • the compound (I) according to the present invention is represented by the formula (Ie): (Wherein X 3 represents —S—, —NR 9 — or —O—, and each symbol has the same meaning as described above). You can also. Manufacturing method E (In the formula, each symbol is as defined above.)
  • Process 1 a compound represented by formula (Ie1) is reacted with a compound represented by (Ie2) to produce a compound represented by formula (Ie3).
  • This step can be performed in the same manner as in step 8 of production method B.
  • Process 2 In this step, a compound represented by the formula (Ie) is reacted with a compound represented by the formula (Ie4) to produce a compound represented by the formula (Ie).
  • This step can be performed in the same manner as in step 1 of production method A.
  • the compound represented by formula (I) according to the present invention is represented by formula (If): Can also be produced by the production method F shown below. Manufacturing method F (In the formula, k is 0 or 1, and other symbols are as defined above.)
  • Process 1 the compound represented by the formula (If1) is reacted with the compound represented by the formula (If2) to produce a compound represented by the formula (If3).
  • This step can be performed in the same manner as in step 1 of production method A.
  • Process 2 In this step, a compound represented by the formula (If3) is reacted with a deprotecting agent to obtain a compound represented by the formula (If4).
  • This step can be performed in the same manner as in step 7 of production method B.
  • Process 3 the compound represented by the formula (If4) is reacted with thiophosgene in the presence of a base and then treated with ammonia to produce the compound represented by the formula (If5).
  • the base the base described in Step 1 of Production Method A can be used.
  • 1 to 10 equivalents of pyridine, triethylamine, DIEA or the like may be used with respect to the compound represented by the formula (If4).
  • the reaction temperature is 0 ° C. to heating under reflux.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • the solvents described in Step 1 of Production Method A can be used alone or in combination.
  • Process 4 the compound represented by the formula (If6) is reacted with diols (ethylene glycol, propane-1,3-diol, etc.) and trimethylsilyl bromide to produce the compound represented by the formula (If7).
  • the reaction temperature is 0 ° C to 30 ° C.
  • the reaction time is 0.2 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent the solvents described in Step 1 of Production Method A can be used alone or in combination.
  • acetonitrile may be used.
  • Process 5 the compound represented by the formula (If7) is reacted with phthalimide potassium salt to produce the compound represented by the formula (If8).
  • the reaction temperature is 0 ° C. to heating under reflux.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • the solvents described in Step 1 of Production Method A can be used alone or in combination.
  • Step 6 a compound represented by the formula (If8) is reacted with a deprotecting agent to obtain a compound represented by the formula (If9).
  • the deprotection reaction of the protecting group is known and can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 4th Edition (Peter G. M. Wuts, Theodora W. Greene, Wiley, 2006).
  • the reaction solvent the solvents described in Step 1 of Production Method A can be used alone or in combination.
  • TMS-O-Tf, 2,6-lutidine can also be used as a deprotecting agent.
  • the reaction temperature is ⁇ 78 ° C. to 30 ° C., preferably ⁇ 30 ° C. to 0 ° C.
  • the reaction time is 0.2 to 6 hours, preferably 1 to 3 hours.
  • dichloromethane or the like can be used.
  • Step 7 a compound represented by the formula (If9) is reacted with a brominating agent to obtain a compound represented by the formula (If10).
  • a brominating agent NBS, bromine, 5,5-dibromohexahydropyrimidine-2,4,6-trione and the like can be used.
  • the reaction temperature is ⁇ 78 ° C. to heating under reflux, preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.2 hours to 12 hours.
  • the reaction solvents described in Step 1 of Production Method A can be used alone or in combination.
  • Process 8 In this step, the compound represented by the formula (If10) is reacted with the compound represented by the formula (If5) to obtain a compound represented by the formula (If11).
  • the reaction temperature is 0 ° C. to solvent reflux.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used.
  • ethanol, DMF, etc. are mentioned, What is necessary is just to use individually or in mixture.
  • Step 9 a compound represented by the formula (If11) is reacted with a deprotecting agent to obtain a compound represented by the formula (If12).
  • This step can be performed in the same manner as in step 6 of production method A.
  • Step 10 the compound represented by the formula (If) is produced from the compound represented by the formula (If12).
  • Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used.
  • This step can be performed in the same manner as in step 7 of production method A.
  • the compound represented by formula (I) below Formula (Ig): (Wherein each symbol has the same meaning as described above).
  • the compound represented by the formula (Ig) can be produced by the following production method G. Manufacturing method G (Wherein X 3 is —O—, —S— or —NR 9 —, and other symbols are as defined above.)
  • Process 1 the compound represented by the formula (Ig) is reacted with the compound represented by the formula (Ig2) to produce the compound represented by the formula (Ig).
  • This step can be performed in the same manner as in step 1 of production method A.
  • the compound represented by the formula (Ih) can be produced by the following production method H. Manufacturing method H (Wherein Y 7 is halogen (preferably bromine or iodine), and other symbols are as defined above.)
  • Process 1 the compound represented by the formula (Ih1) is reacted with the compound represented by the formula (Ih2) to produce a compound represented by the formula (Ih3). It can be carried out in the presence of a base.
  • a base alkyl lithium, Grignard reagent and the like can be used.
  • the reaction temperature is -78 ° C to 30 ° C, preferably -78 ° C to 0 ° C.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used.
  • tetrahydrofuran, diethyl ether, etc. are mentioned, What is necessary is just to use individually or in mixture.
  • Process 2 the compound represented by the formula (Ih3) is reacted with a reducing agent to produce the compound represented by the formula (Ih). It can be performed under acidic conditions.
  • the reducing agent include triethylsilane.
  • the acid include trifluoroacetic acid.
  • the reaction temperature is ⁇ 78 ° C. to heating under reflux, preferably 0 ° C. to heating under reflux.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used. Preferred are halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.), which may be used alone or in combination.
  • This step can also be produced by a reduction reaction with a transition metal catalyst such as palladium or platinum catalyst in a hydrogen atmosphere.
  • the compound represented by the formula (Ii) can be produced by the following production method I.
  • Step 1 the compound represented by formula (Ii1) is reacted with the compound represented by (Ih2) to produce a compound represented by formula (Ii). It can be carried out in the presence of a base.
  • a base alkyl lithium, Grignard reagent and the like can be used.
  • the reaction temperature is -78 ° C to 30 ° C, preferably -78 ° C to 0 ° C.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used.
  • tetrahydrofuran, diethyl ether and the like can be mentioned, and they may be used alone or in combination.
  • Manufacturing method J (In the formula, each symbol is as defined above.)
  • Process 1 a compound represented by formula (Ij) is reacted with a compound represented by formula (Ij2) using a condensing agent to produce a compound represented by formula (Ij).
  • the condensing agent the condensing agent described in Step 7 of production method A can be used.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used.
  • Process 1 the compound represented by the formula (Ik1) is activated with a metal and then reacted with the compound represented by the formula (Ih2) to produce the compound represented by the formula (Ik).
  • the reaction can be performed in the presence of a ligand and a transition metal catalyst. Examples of the metal include zinc and magnesium.
  • Transition metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis ( And tri-tert-butylphosphine) palladium, bis (cyclopentadienyl), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride, and the like.
  • 0.001 to 0.5 equivalent can be used.
  • Examples of the ligand include triphenylphosphine, Xantphos, BINAP, X-phos and the like, and 0.001 to 1 equivalent can be used.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used.
  • tetrahydrofuran, toluene, etc. are mentioned, and they may be used alone or in combination.
  • the compound represented by the formula (I-1) can be produced by the production method L shown below. Manufacturing method L (In the formula, each symbol is as defined above.)
  • Process 1 the compound represented by the formula (Il1) is reacted with an oxidizing agent to produce the compound represented by the formula (Il).
  • the compound represented by the formula (Il1) can be produced by the production method G described above.
  • the oxidizing agent include mCPBA, and 2 to 10 equivalents can be used.
  • the reaction solvent the solvent described in Step 1 of Production Method A can be used.
  • halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.) can be used.
  • the compound according to the present invention has ACC2 inhibitory activity. Furthermore, since the compound according to the present invention has higher selectivity for ACC2 than ACC1, it can be a pharmaceutical with reduced side effects. In addition, since the compound according to the present invention has low cardiovascular risk, MBI risk and the like, it can be a pharmaceutical with reduced side effects.
  • the pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diseases involving ACC2.
  • a disease involving ACC2 means a disease caused by malonyl-CoA produced by ACC2, specifically, metabolic syndrome, obesity, diabetes, insulin resistance, impaired glucose tolerance, diabetic peripheral neuropathy , Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, heart failure, myocardial infarction, infection, tumor, etc. It is done.
  • the pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for these diseases.
  • the compound of the present invention has not only an ACC2 inhibitory action but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • Good pharmacokinetics such as high bioavailability and moderate clearance.
  • e Not mutagenic.
  • High solubility for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • parenteral administration any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • Retention time or “RT” in each reference example and example or table represents a retention time in LC / MS: liquid chromatography / mass spectrometry, and was measured under the following conditions.
  • Measurement condition 1 ACQUITY UPLC® BEH C18 (1.7 ⁇ m id 2.1 ⁇ 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
  • Mobile phase [A] was 0.1% formic acid-containing aqueous solution, [B] was 0.1% formic acid-containing acetonitrile solution
  • Gradient Linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes Thereafter, 100% solvent [B] was maintained for 0.5 minutes.
  • Measurement condition 2 Column: Shim-pack XR-ODS (2.2 ⁇ m, id 50 ⁇ 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
  • Measurement condition 3 Column: ACQUITY UPLC (R) BEH C18 Flow rate: 0.55 mL / min UV detection wavelength: 254 nm
  • Step 1 Synthesis of Compound 2 Under a nitrogen atmosphere, 4-ethoxyphenol (4.0 g, 29.0 mmol) was dissolved in chloroform (40 mL), and sulfuryl chloride (2.47 mL, 30.4 mmol) was added dropwise under ice cooling. Stir at room temperature for 14 hours. The reaction mixture was slowly poured into 10% aqueous sodium hydrogen sulfite and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 2 (4.31 g, yield 86%) as a pale yellow liquid.
  • Step 2 Synthesis of Compound 4
  • Compound 2 (862 mg, 4.99 mmol), Compound 3 (300 mg, 2.08 mmol) and triphenylphosphine (655 mg, 2.50 mmol) were dissolved in THF (15 mL), and DIAD (486 ⁇ L, 2 .50 mmol) was added, and the mixture was stirred for 30 minutes at room temperature, and then stirred for 40 minutes under reflux with heating.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 4 (460 mg, yield 74%) as a colorless liquid.
  • Step 3 Synthesis of Compound 5
  • Compound 4 (459 mg, 1.54 mmol) was dissolved in THF (15 mL) under a nitrogen atmosphere, and 1 mol / L diisobutylaluminum hydride in hexane (3.38 mL, 3 mL) was cooled at 0 ° C. .38 mmol) was added dropwise and stirred at 0 ° C. for 30 minutes. Water was added, followed by a saturated aqueous Rochelle salt solution, and the mixture was stirred at room temperature for 1.5 hours. Then, it extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate.
  • Step 4 Synthesis of Compound 6
  • Compound 5 (376 mg, 1.47 mmol) was dissolved in dichloromethane (15 mL), Dess-Martin periodinane (870 mg, 2.05 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
  • a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate.
  • Step 5 Synthesis of Compound 7
  • Compound 6 200 mg, 0.785 mmol was dissolved in ethanol (10 mL), sodium acetate (193 mg, 2.36 mmol) was added, and hydroxylamine hydrochloride (136 mg) was cooled at 0 ° C. 1.96 mmol) was added little by little and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 7 (208 mg, yield 98%) as a crude product of a diastereo mixture.
  • Step 6 Synthesis of Compound 9
  • Compound 7 (207 mg, 0.767 mmol) was dissolved in DMF (2 mL), NCS (133 mg, 0.998 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours.
  • a DMF (1 mL) solution of compound 8 (183 mg, 0.921 mmol, synthesis method described in US2006 / 0178400) and triethylamine (160 ⁇ L, 1.15 mmol) was added dropwise at room temperature, and then at room temperature. Stir overnight.
  • 0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate.
  • Step 7 Synthesis of Compound I-001
  • Compound 9 (131 mg, 0.281 mmol) was dissolved in a mixed solvent of ethanol (3 mL) and chloroform (0.5 mL), and hydrazine monohydrate (0.136 mL, 2.81 mmol) was dissolved. And stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain amine as a crude product.
  • Example 002 Synthesis of Compound I-002 Step 1 Synthesis of Compound 11 Compound 11 was obtained as a diastereomeric mixture by using Compound 10 instead of Compound 6 of Step 5 of Example 001.
  • Step 2 Synthesis of Compound 12
  • Compound 12 was obtained by using Compound 11 instead of Compound 7 of Step 6 of Example 001.
  • Step 3 Synthesis of Compound 13 Compound 13 was obtained by using Compound 12 instead of Compound 9 of Step 7 of Example 001.
  • Step 4 Synthesis of Compound 14
  • Compound 13 (401 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature until the reaction was complete.
  • the solvent of the reaction mixture was distilled off under reduced pressure, dichloromethane was added to the resulting residue, and the solvent was distilled off under reduced pressure three times.
  • This residue was dissolved in methanol, a 2 mol / mL hydrochloric acid methanol solution was added, and then the solvent was distilled off under reduced pressure to obtain Compound 14 (359 mg) as a crude product.
  • Measurement condition 2, RT 0.40min, M + H 210.30
  • Step 5 Synthesis of Compound 16
  • compound 14 35 mg, 0.142 mmol
  • compound 15 (24.2 mg, 0.142 mmol, described in US2011 / 0263562 as a synthesis method) were dissolved in DMF (1 mL) at 0 ° C.
  • N, N-diisopropylethylamine 87 ⁇ L, 0.499 mmol
  • Water and 10% aqueous citric acid solution were added to adjust the pH to about 5, and the mixture was extracted 3 times with ethyl acetate.
  • the organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain Compound 16 as a crude product.
  • Step 6 Synthesis of Compound I-002
  • the crude product of Compound 16 was dissolved in DMF (1 mL), and potassium carbonate (29.5 mg, 0.214 mmol) and (bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) were added. In addition, the mixture was stirred at 60 ° C. for 3 hours. Thereafter, potassium carbonate (29.5 mg, 0.214 mmol) and (bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) were added, and the mixture was stirred at 60 ° C. for 1 hour. (Bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours.
  • Step 1 Synthesis of Compound 18
  • Compound 17 (805 mg, 7.18 mmol) was dissolved in DMF (7 mL) under a nitrogen atmosphere, and HATU (3.55 g, 9.33 mmol) was added under cooling at 0 ° C., followed by triethylamine ( 1.29 mL, 9.33 mmol) was added dropwise.
  • the obtained reaction mixture was suspended in DMF (14 mL) of 4-aminoresorcinol hydrochloride (2.32 g, 14.36 mmol) and triethylamine (1.49 mL, 10.8 mmol) under cooling at 0 ° C. in a nitrogen atmosphere. The solution was added dropwise to the suspension and stirred at 0 ° C. for 1 hour.
  • reaction mixture was stirred at room temperature, and further triphenylphosphine (2.83 g, 10.8 mmol) and DIAD (2.09 mL, 10.8 mmol) were added successively and stirred at room temperature for 30 minutes.
  • the obtained reaction mixture was evaporated under reduced pressure, water was added to the resulting residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).
  • Step 3 Synthesis of Compound 20
  • a THF solution (9.53 mL, 8) of a 0.9 mol / L borane THF complex was added to a THF (10 mL) solution of Compound 19 (365 mg, 1.43 mmol) under cooling at 0 ° C. in a nitrogen atmosphere. .58 mmol) was added dropwise and stirred at room temperature for 30 minutes.
  • 0.9 mol / L borane THF complex in THF (4.77 mL, 4.29 mmol) was added dropwise under cooling at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
  • Step 4 Synthesis of Compound 21
  • Compound 20 (222 mg, 0.812 mmol) was dissolved in dichloromethane (8 mL), Dess-Martin periodinane (517 mg, 1.22 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After adding ethyl acetate, the mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 21 (62 mg, 28% yield) and its steric form. The cis isomer (77 mg, yield 35%) was obtained.
  • Step 5 Synthesis of Compound 22 Hydroxylamine hydrochloride (24 mg, 0.34 mmol) in a suspension of Compound 21 (62 mg, 0.23 mmol) and sodium acetate (56 mg, 0.69 mmol) in ethanol (4 mL) under ice-cooling at 0 ° C. ) was added little by little and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 22 as a crude product.
  • Step 6 Synthesis of Compound 23 Under nitrogen atmosphere, the crude product Compound 22 obtained in Step 5 was dissolved in DMF (2 mL), NCS (30.5 mg, 0.23 mmol) was added, and the mixture was stirred at room temperature for 2 hours. . To the obtained reaction mixture, a DMF (1 mL) solution of compound 8 (59.2 mg, 0.297 mmol) and triethylamine (63 ⁇ L, 0.457 mmol) was added, and the mixture was stirred at room temperature for 6 hours. 0.1 mol / L hydrochloric acid was added to the reaction mixture, followed by extraction three times with ethyl acetate.
  • the solvent was distilled off under reduced pressure to obtain the target amine as a crude product.
  • the obtained amine and pyridine (27 ⁇ L, 0.331 mmol) were dissolved in dichloromethane (2 mL), acetic anhydride (9.4 ⁇ L, 0.099 mmol) was added, and the mixture was stirred at room temperature for 30 minutes.
  • 0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate.
  • Step 1 Synthesis of Compound 24
  • Compound 24 was obtained by using p-ethoxyphenol in place of Compound 2 in Step 2 of Example 001.
  • Step 2 Synthesis of Compound 25
  • Compound 25 was obtained by using Compound 24 instead of Compound 4 of Step 3 of Example 001.
  • Step 3 Synthesis of Compound 26
  • Compound 26 was obtained by using Compound 25 instead of Compound 5 of Step 4 of Example 001.
  • Step 4 Synthesis of Compound 27
  • Compound 26 150 mg, 0.681 mmol
  • potassium carbonate 188 mg, 1.36 mmol
  • dimethyl (1-diazo-2-oxopropyl) phosphonate 144 mg, 0 749 mmol
  • 0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate.
  • Step 5 Synthesis of Compound 29
  • Compound 28 (110 mg, 0.583 mmol, synthesis method described in known literature; Bioorganic & Medicinal Chemistry, 1996, Vol. 4, 209-225) was dissolved in DMF (2 mL) and NCS (91 mg, 0.680 mmol) was added and stirred at room temperature for 1 hour.
  • NCS 25.9 mg, 0.194 mmol was added and stirred at room temperature for 1 hour.
  • a DMF (2 mL) solution of compound 27 105 mg, 0.485 mmol
  • triethylamine (135 mg, 0.971 mmol
  • Step 6 Synthesis of Compound 30
  • Compound 29 (79 mg, 0.196 mmol) was dissolved in dioxane (1 mL), 4 mol / L hydrochloric acid in dioxane (1 mL) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • the solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting residue, and the solvent was distilled off under reduced pressure. Ethyl acetate was added once more, and the solvent was distilled off under reduced pressure.
  • Methanol was added to the residue, and distillation under reduced pressure was repeated twice to obtain Compound 30 (66 mg, yield 100%) as a powder.
  • Step 7 Synthesis of Compound I-004 Under a nitrogen atmosphere, dichloromethane (1 mL) was added to Compound 30 (26 mg, 0.077 mmol) and pyridine (31 ⁇ L, 0.384 mmol), and then acetic anhydride (8.7 ⁇ L, 0.092 mmol). ) And stirred at room temperature for 30 minutes. 0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate.
  • Step 1 Synthesis of Compound 31
  • Compound 30 (cis / trans mixture 200 mg, 0.908 mmol) was dissolved in dichloromethane (2 mL), Dess Martin periodinane (404 mg, 0.953 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. .
  • Sodium thiosulfate was added and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate.
  • Step 3 Synthesis of Compound 33
  • Compound 33 was obtained by using Compound 32 instead of Compound 9 of Step 7 of Example 001.
  • Step 4 Synthesis of Compound 34
  • Compound 33 (172 mg, 0.502 mmol) was dissolved in THF (1.5 mL), and lithium borohydride (55 mg, 2.51 mmol), methanol (0.10 mL, 2. 5 mmol) was added and stirred at room temperature for 3 hours.
  • a saturated aqueous ammonium chloride solution was added under ice cooling, and the mixture was extracted 10 times with chloroform / methanol (10: 1). The organic layers were combined and dried over magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 34 (120 mg, 100% yield) as a colorless liquid.
  • Step 5 Synthesis of Compound I-005 Using p-ethoxyphenol in place of Compound 2 in Step 2 of Example 001 and Compound 34 in place of Compound 3, the reaction was carried out at a reaction temperature of 50 ° C. 5 was obtained.
  • Step 1 Synthesis of Compound 37
  • DMF 10 mL
  • triethylamine 6.67 mL, 48.1 mmol
  • Acetyl chloride (1.72 mL, 24.1 mmol) was added to the solution and stirred at room temperature for 3 hours.
  • the solvent was distilled off under reduced pressure at 60 ° C., 2 mol / L hydrochloric acid (30 mL) was added, and sodium chloride was added to saturate.
  • the aqueous layer was extracted with chloroform-methanol (97: 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound 39
  • Compound 38 (1.50 g, 7.53 mmol) was added to THF (30 mL), azetidin-3-ol hydrochloride (0.991 g, 9.04 mmol), (2-biphenyl) dicyclohexylphosphine (0. 330 g, 0.942 mmol) was added.
  • tris (dibenzylideneacetone) dipalladium 0.90 g, 0.753 mmol
  • Step 3 Synthesis of Compound I-006
  • Compound 39 (100 mg, 0.523 mmol) was dissolved in THF (2 mL) and cooled on ice. Triethylamine (0.087 mL, 0.627 mmol) and methanesulfonyl chloride (0.049 mL, 0.627 mmol) were added to the reaction mixture, and the mixture was stirred at 0 ° C. for 15 minutes. This was designated as Solution A.
  • Compound 37 (94.0 mg, 0.523 mmol) was dissolved in DMF (1 mL) and cooled on ice. 60% sodium hydride (23.0 mg, 0.575 mmol) was added to the solution and stirred for 3 minutes.
  • Step 1 Synthesis of Compound 42
  • Compound 41 700 mg, 2.79 mmol
  • p-ethoxyphenol 443 mg, 3.20 mmol
  • DMF 6 mL
  • cesium carbonate (1997 mg, 6.13 mmol)
  • 90 ° C. For 4.5 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate.
  • Step 2 Synthesis of Compound 43 To Compound 42 (690 mg) containing p-ethoxyphenol obtained in Step 1, 4 mol / L hydrochloric acid in ethyl acetate (4 mL) was added and stirred at room temperature for 15 hours. Hexane was added to the reaction mixture, and the precipitated solid was filtered and washed with hexane to obtain Compound 43 (453 mg, 84% yield (2 steps)) as a colorless solid.
  • Step 4 Synthesis of Compound 46
  • Compound 45 (2.61 g, 12.48 mmol, synthesis method described in Eur. J. Org. Chem. 2011, 7097-7106) was dissolved in DMF (13 mL), and potassium phthalimide (2. 54 g, 13.73 mmol) was added, and the mixture was stirred at 100 ° C. for 7 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate.
  • Step 5 Synthesis of Compound 47
  • Compound 46 500 mg containing 8% phthalimide obtained in Step 4 and 2,6-lutidine (3.81 mL, 32.7 mmol) were dissolved in dichloromethane (5 mL) and cooled to 0 ° C.
  • Trimethylsilyl triflate (3.94 mL, 21.79 mmol) was added and stirred at 0 ° C. for 2 hours.
  • Water (15 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour, and extracted three times with ethyl acetate. The organic layers were combined, washed with 1 mol / L hydrochloric acid, and dried over magnesium sulfate.
  • Step 7 Synthesis of Compound 49
  • Compound 48 (67 mg, 0.226 mmol) was dissolved in DMF (0.7 mL), compound 44 (51.9 mg, 0.206 mmol) was added, and the mixture was stirred at 50 ° C. for 22 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 49 (45 mg, yield 49%) as an orange liquid.
  • Step 8 Synthesis of Compound I-007
  • Compound I-007 was obtained by substituting Compound 49 for Compound 9 in Step 7 of Example 001.
  • Preparation Example 1 Preparation of Recombinant Human ACC2 A cDNA encoding the human ACC2 protein (27 amino acid residues to 2458 amino acid residues from the N terminus) was cloned from a human kidney cDNA library (Clontech) and His- After the tag sequence was introduced, it was inserted into pFastBac1 (Invitrogen). According to the protocol of the Bac-to-Bac baculovirus expression system (Invitrogen), a recombinant baculovirus was prepared and then infected with Sf-9 cells to express the human ACC2 protein. The collected cells were crushed, filtered, and subjected to Ni affinity chromatography and anion exchange chromatography. The fraction containing human ACC2 protein was collected to obtain recombinant human ACC2.
  • Preparation Example 2 Preparation of Recombinant Human ACC1 A cDNA encoding the human ACC1 protein (1 to 2346 amino acid residues from the N terminus) was cloned from a human liver cDNA library (BioChain) and a myc tag at the 3 ′ end. And His-tag sequence were introduced, and then inserted into pIEXBAC3 (Novagen). According to the protocol of FlashBACGOLD (Oxford Expression Technologies), a recombinant baculovirus was prepared and then infected with Sf-9 cells to express the human ACC1 protein. The collected cells were crushed, filtered, and subjected to Ni affinity chromatography and anion exchange chromatography. Fractions containing human ACC1 protein were collected to obtain recombinant human ACC1.
  • Test Example 1 Measurement of human ACC1 and ACC2 inhibitory activity Recombinant human ACC1 and recombinant human ACC2 obtained by the above preparation examples were mixed with assay buffer (50 mM HEPES-KOH (pH 7.4), 10 mM magnesium chloride, 6 to 10 Preincubation was carried out for 1 hour in mM potassium citrate, 4 mM reduced glutathione, 1.5 mg / ml bovine serum albumin).
  • assay buffer 50 mM HEPES-KOH (pH 7.4)
  • 10 mM magnesium chloride 6 to 10 Preincubation was carried out for 1 hour in mM potassium citrate, 4 mM reduced glutathione, 1.5 mg / ml bovine serum albumin.
  • MALDI-TOF MS matrix-assisted laser desorption / ionization-time-of-flight mass spectrometer
  • Deprotonated ions of substrate acetyl CoA (AcCoA) and reaction product malonyl CoA (MalCoA) are detected, and the respective signal intensity is used to convert to malonyl CoA or succinyl CoA Intensity of [MalCoA-H] ⁇ / (Intensity of [MalCoA-H] — + Intensity of [AcCoA-H] — ) was calculated.
  • the 50% inhibition concentration (IC50 value) was calculated from the inhibition rate of the enzyme reaction at each compound concentration.
  • the potassium citrate concentration in the assay buffer, the potassium bicarbonate concentration in the substrate solution, and the incubation time were adjusted within the above concentrations or reaction times for each lot of enzyme used.
  • the compound of the present invention exhibits strong ACC2 inhibitory activity. Therefore, it can be used for prevention and / or treatment of diseases involving ACC2.
  • Test Example 2 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction.
  • NADPH a coenzyme
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
  • Intravenous administration is performed from the tail vein using a syringe with a needle.
  • the bioavailability (BA) of the compound of the present invention is calculated from the AUC of the group.
  • Test Example 4 Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
  • the compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
  • Test Example 5 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (under the metabolic activation conditions, 498 ⁇ L of the test bacterial solution and S9 mix 90 ⁇ L of the mixture) and incubate with shaking at 37 ° C.
  • Test Example 7 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process
  • hERG human ether-a-go-related gene
  • the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL), JP-2. Solution (add 500 mL of water to 500 mL of phosphate buffer at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (add JP-2 solution to 1.08 g of TCA to make 100 mL) Is added in 200 ⁇ L aliquots. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Lactose 15mg Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
  • the compound of the present invention has an ACC2 inhibitory action and is useful for treatment or prevention of diseases involving ACC2.

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Abstract

The purpose of the present invention is to provide a novel compound that has an ACC2 inhibitory activity. Also provided is a medicinal composition containing the compound. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In formula (I): the group represented by formula (chemical formula 2) is an unsubstituted aryl, etc.; substituent group α is substituted or unsubstituted alkyl, etc.; ring B is a substituted or unsubstituted non-aromatic carbocycle, etc.; ring C is a substituted or unsubstituted 6-membered aromatic carbocycle, etc.; U is -CR4R5-, etc.; T is -CR7R8-, etc.; L is -CR10R11-, etc.; p is 0 or 1; q is 0 or 1; r is 0 or 1; R4, R5, R7, R8, R10 and R11 are independently hydrogen, etc.; R6 and R9 are independently hydrogen or substituted or unsubstituted alkyl; R13 is substituted or unsubstituted alkyl; R14 is substituted or unsubstituted alkylcarbonyl, etc.; and R16 is hydrogen or substituted or unsubstituted alkyl.

Description

新規非芳香族炭素環又は非芳香族複素環誘導体Novel non-aromatic carbocyclic or non-aromatic heterocyclic derivatives
　本発明は、アセチルＣｏＡカルボキシラーゼ２（以下、ＡＣＣ２という）阻害作用を有する化合物に関する。 The present invention relates to a compound having an inhibitory action on acetyl CoA carboxylase 2 (hereinafter referred to as ACC2).
　アセチルＣｏＡカルボキシラーゼ（以下、ＡＣＣという）は、アセチル－ＣｏＡをカルボキシル化してマロニル－ＣｏＡに変換する酵素であり、脂肪酸の代謝に関与する。ＡＣＣには、アセチル－ＣｏＡカルボキシラーゼ１（以下、ＡＣＣ１という）及びＡＣＣ２の２つのアイソフォームが存在する。
　ＡＣＣ２は、おもに心臓や骨格筋で発現しており、ＡＣＣ２によって産生されるマロニル－ＣｏＡはカルニチンパルミトイルトランスフェラーゼＩ（ＣＰＴ－Ｉ）を阻害することにより脂肪酸の酸化を阻害する。
　ＡＣＣ２欠損マウスにおいて、心臓や骨格筋におけるマロニル－ＣｏＡ量の低下により、継続的な脂肪酸の酸化が起こっており、食餌量の増加にかかわらず、体重の減少が見られる。さらに、ＡＣＣ２欠損マウスは高脂肪／高炭水化物の餌の投与によって誘発される糖尿病や肥満に対して耐性を獲得していることも報告されている。
　以上の知見から、ＡＣＣ２は糖尿病や肥満症などの疾患に関与しており、その阻害剤は抗糖尿病薬や抗肥満薬となることが示唆される。
　一方、ＡＣＣ１欠損マウスは胎児期において致死的であることから、ＡＣＣ１を阻害することなくＡＣＣ２を阻害する選択的な阻害剤が望まれている。 Acetyl CoA carboxylase (hereinafter referred to as ACC) is an enzyme that carboxylates acetyl-CoA to convert it to malonyl-CoA, and is involved in fatty acid metabolism. There are two isoforms of ACC: acetyl-CoA carboxylase 1 (hereinafter referred to as ACC1) and ACC2.
ACC2 is mainly expressed in the heart and skeletal muscle, and malonyl-CoA produced by ACC2 inhibits the oxidation of fatty acids by inhibiting carnitine palmitoyltransferase I (CPT-I).
In ACC2-deficient mice, continuous fatty acid oxidation occurs due to a decrease in the amount of malonyl-CoA in the heart and skeletal muscle, and a decrease in body weight is observed regardless of an increase in the amount of food. Furthermore, it has been reported that ACC2-deficient mice have acquired resistance to diabetes and obesity induced by administration of a high fat / high carbohydrate diet.
From the above findings, it is suggested that ACC2 is involved in diseases such as diabetes and obesity, and the inhibitor becomes an antidiabetic drug or an antiobesity drug.
On the other hand, since an ACC1-deficient mouse is lethal in the fetal stage, a selective inhibitor that inhibits ACC2 without inhibiting ACC1 is desired.
　特許文献１～特許文献４にはＡＣＣ２阻害剤が記載されている。 Patent Documents 1 to 4 describe ACC2 inhibitors.
　例えば、特許文献１には、以下の式：
Figure JPOXMLDOC01-appb-C000017
で示される化合物が記載されている。 For example, Patent Document 1 discloses the following formula:
Figure JPOXMLDOC01-appb-C000017
Are described.
　非特許文献１～５には、ＡＣＣ２を特異的に阻害するチアゾールフェニルエーテル誘導体が記載されている。非特許文献７には、ＡＣＣ１及びＡＣＣ２に対し阻害活性を有するビフェニル誘導体あるいは３－フェニル－ピリジン誘導体が記載されている。非特許文献８には、以下の化合物がＡＣＣ２阻害活性を有し、かつ、好ましい薬物動態パラメーターを有する化合物として記載されている。
Figure JPOXMLDOC01-appb-C000018
 Non-Patent Documents 1 to 5 describe thiazole phenyl ether derivatives that specifically inhibit ACC2. Non-Patent Document 7 describes biphenyl derivatives or 3-phenyl-pyridine derivatives having inhibitory activity against ACC1 and ACC2. Non-Patent Document 8 describes the following compounds as compounds having ACC2 inhibitory activity and having favorable pharmacokinetic parameters.
Figure JPOXMLDOC01-appb-C000018
　特許文献５～１２及び非特許文献６には、非芳香族環構造を有する化合物が記載されている。 Patent Documents 5 to 12 and Non-Patent Document 6 describe compounds having a non-aromatic ring structure.
　例えば、特許文献５には、以下の式：
Figure JPOXMLDOC01-appb-C000019
で示される化合物が記載されている。 For example, Patent Document 5 discloses the following formula:
Figure JPOXMLDOC01-appb-C000019
Are described.
　例えば、特許文献１１には、以下の式：：
Figure JPOXMLDOC01-appb-C000020
で示される化合物が記載されている。 For example, Patent Literature 11 includes the following formula:
Figure JPOXMLDOC01-appb-C000020
Are described.
　しかし、本発明については、上記先行技術には記載も示唆もされていない。 However, the present invention is neither described nor suggested in the above prior art.
国際公開公報ＷＯ２０１２／００１１０７号International Publication No. WO2012 / 001107 国際公開公報ＷＯ２００７／０９５６０２号International Publication No. WO2007 / 095602 国際公開公報ＷＯ２０１２／０９０２１９号International Publication No. WO2012 / 090219 国際公開公報ＷＯ２０１３／１３６３８５号International Publication No. WO2013 / 136385 国際公開公報ＷＯ２０１２／０３５０１１号International Publication No. WO2012 / 035011 国際公開公報ＷＯ２０１１／０８０２１１号International Publication No. WO2011 / 080211 国際公開公報ＷＯ２０１１／０５１４５５号International Publication No. WO2011 / 051455 国際公開公報ＷＯ２００８／１２８７１１号International Publication No. WO2008 / 128711 国際公開公報ＷＯ２００８／１４６７５３号International Publication No. WO2008 / 146653 国際公開公報ＷＯ２００５／１０３０１３号International Publication No. WO2005 / 103013 国際公開公報ＷＯ９９／１９３０１号International Publication No. WO99 / 19301 米国出願公開公報２００５／０１５４０２４号US Application Publication No. 2005/0154024
　本発明の目的は、ＡＣＣ２阻害活性を有する新規化合物を提供することにある。また、上記化合物を含有する医薬組成物を提供する。 An object of the present invention is to provide a novel compound having ACC2 inhibitory activity. Moreover, the pharmaceutical composition containing the said compound is provided.
　本発明は、以下に関する。 The present invention relates to the following.
　（１）式（I）：
Figure JPOXMLDOC01-appb-C000021
（式中、
式：
Figure JPOXMLDOC01-appb-C000022
で示される基は非置換のアリール、置換基群αより選択される１以上の基で置換されたアリール、非置換のヘテロアリール、又は置換基群αより選択される１以上の基で置換されたヘテロアリールであり、
置換基群αは、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のシクロアルキルスルファニル、置換若しくは非置換のシクロアルケニルスルファニル、置換若しくは非置換のアリールスルファニル、置換若しくは非置換のヘテロアリールスルファニル、置換若しくは非置換の非芳香族複素環スルファニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のシクロアルキルスルフィニル、置換若しくは非置換のシクロアルケニルスルフィニル、置換若しくは非置換のアリールスルフィニル、置換若しくは非置換のヘテロアリールスルフィニル、置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアミノスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換の非芳香族複素環スルホニル、置換若しくは非置換のアルキルスルホニルオキシ、置換若しくは非置換のアルケニルスルホニルオキシ、置換若しくは非置換のアルキニルスルホニルオキシ、置換若しくは非置換のシクロアルキルスルホニルオキシ、置換若しくは非置換のシクロアルケニルスルホニルオキシ、置換若しくは非置換のアリールスルホニルオキシ、置換若しくは非置換のヘテロアリールスルホニルオキシ、置換若しくは非置換の非芳香族複素環スルホニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアルケニルカルボニルオキシ、置換若しくは非置換のアルキニルカルボニルオキシ、置換若しくは非置換のシクロアルキルカルボニルオキシ、置換若しくは非置換のシクロアルケニルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、置換若しくは非置換のヘテロアリールカルボニルオキシ、置換若しくは非置換の非芳香族複素環カルボニルオキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル、ハロゲン、ヒドロキシ、メルカプト、シアノ、アジド、置換若しくは非置換のアミジノ、グアニジノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル及びカルボキシからなる群であり、
環Ｂは置換若しくは非置換の非芳香族炭素環又は置換若しくは非置換の非芳香族複素環であり、
環Ｃは置換若しくは非置換の６員の芳香族炭素環、置換若しくは非置換の５員の芳香族複素環又は置換若しくは非置換の６員の芳香族複素環であり、
Ｕは－ＣＲ４Ｒ５－、－ＣＲ４Ｒ５－Ｏ－、－ＣＲ４Ｒ５－Ｓ－、－ＣＲ４Ｒ５－ＮＲ６－、－Ｏ－、－Ｓ－、－ＮＲ６－、－Ｏ－ＣＲ４Ｒ５－、－Ｓ－ＣＲ４Ｒ５－又は－ＮＲ６－ＣＲ４Ｒ５－（ここで、左の結合手は環Ａに結合し、右の結合手は環Ｂに結合する。）であり、
Ｔは－ＣＲ７Ｒ８－、－ＣＲ７Ｒ８－Ｏ－、－ＣＲ７Ｒ８－Ｓ－、－ＣＲ７Ｒ８－ＮＲ９－、－Ｏ－、－Ｓ－、－ＮＲ９－、－Ｃ（＝Ｏ）－又は－ＳＯ２－（ここで、左の結合手は環Ｂに結合し、右の結合手は環Ｃに結合する。）であり、
Ｌは－ＣＲ１０Ｒ１１－又は－Ｃ（＝Ｏ）－であり、
ｐは０又は１であり、
ｑは０又は１であり、
ｒは０又は１であり、
Ｒ４、Ｒ５、Ｒ７、Ｒ８、Ｒ１０及びＲ１１はそれぞれ独立して水素、ヒドロキシ、ハロゲン、置換若しくは非置換のアルキル又はシアノであり、
Ｒ６及びＲ９はそれぞれ独立して水素又は置換若しくは非置換のアルキルであり、
Ｒ１３は置換若しくは非置換のアルキルであり、
Ｒ１４は置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル又は置換若しくは非置換のカルバモイルであり、
Ｒ１６は水素又は置換若しくは非置換のアルキルである。
但し、以下の化合物を除く。
（i）環Ｂが置換若しくは非置換の５員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０であり、環Ｃが環Ｂ上の窒素原子に結合している化合物、
（ii）環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０である化合物、
（iii）環Ｂが置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが１であり、Ｔが環Ｂ上の窒素原子に結合している化合物。）
で示される化合物又はその製薬上許容される塩。 (1) Formula (I):
Figure JPOXMLDOC01-appb-C000021
(Where
formula:
Figure JPOXMLDOC01-appb-C000022
The group represented by is substituted with one or more groups selected from unsubstituted aryl, aryl substituted with one or more groups selected from substituent group α, unsubstituted heteroaryl, or substituent group α. Heteroaryl,
Substituent group α is
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or Unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenyl The Fanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted cycloalkylsulfanyl, substituted or unsubstituted cycloalkenylsulfanyl, substituted or unsubstituted arylsulfanyl, substituted or unsubstituted heteroarylsulfanyl, substituted or unsubstituted Non-aromatic heterocyclic sulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted Or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted Is unsubstituted aminosulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy, substituted or unsubstituted Alkynylsulfonyloxy, substituted or unsubstituted cycloalkylsulfonyloxy, substituted or unsubstituted cycloalkenylsulfonyloxy, substituted or unsubstituted arylsulfonyl Oxy, substituted or unsubstituted heteroarylsulfonyloxy, substituted or unsubstituted non-aromatic heterocyclic sulfonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted Or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted nonaromatic heterocyclic carbonyl, substituted or unsubstituted Alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted cycloalkylcarbonyloxy, substituted or unsubstituted Unsubstituted cycloalkenylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, substituted or unsubstituted heteroarylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Heteroaryloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, halogen, hydroxy, mercapto, cyano, azide, substituted or unsubstituted amino Bruno, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, a group consisting of a substituted or unsubstituted sulfamoyl, and carboxy,
Ring B is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
U is -CR 4 R 5 -, - CR 4 R 5 -O -, - CR 4 R 5 -S -, - CR 4 R 5 -NR 6 -, - O -, - S -, - NR 6 -, -O-CR 4 R 5 -, - S-CR 4 R 5 - or -NR 6 -CR 4 R 5 - (wherein the left bond is attached to the ring a, the right bond is to the ring B Combined)
T is -CR 7 R 8 -, - CR 7 R 8 -O -, - CR 7 R 8 -S -, - CR 7 R 8 -NR 9 -, - O -, - S -, - NR 9 -, -C (= O)-or -SO 2- (where the left bond is bonded to ring B and the right bond is bonded to ring C);
L is —CR 10 R 11 — or —C (═O) —,
p is 0 or 1;
q is 0 or 1;
r is 0 or 1,
R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl or cyano,
R 6 and R 9 are each independently hydrogen or substituted or unsubstituted alkyl;
R 13 is substituted or unsubstituted alkyl;
R 14 represents substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted Arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl Substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Substituted heteroaryloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl or substituted or unsubstituted carbamoyl,
R 16 is hydrogen or substituted or unsubstituted alkyl.
However, the following compounds are excluded.
(I) Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring A compound in which p is 0, q is 0, and ring C is bonded to a nitrogen atom on ring B;
(Ii) Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
(Iii) Ring B is a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring Wherein p is 0, q is 1 and T is bonded to a nitrogen atom on ring B. )
Or a pharmaceutically acceptable salt thereof.
　（２）ｒが０である、（１）記載の化合物又はその製薬上許容される塩。 (2) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein r is 0.
　（３）Ｒ１４が置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアリールカルボニル又は置換若しくは非置換のヘテロアリールカルボニルである、（１）又は（２）記載の化合物又はその製薬上許容される塩。 (3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R 14 is substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, or substituted or unsubstituted heteroarylcarbonyl. salt.
　（４）環Ｂが置換若しくは非置換の４員の非芳香族炭素環又は置換若しくは非置換の４員の非芳香族複素環である、（１）～（３）のいずれかに記載の化合物又はその製薬上許容される塩。 (4) The compound according to any one of (1) to (3), wherein ring B is a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 4-membered non-aromatic heterocyclic ring Or a pharmaceutically acceptable salt thereof.
　（５）環Ｂが置換若しくは非置換の４員の非芳香族炭素環である、（４）記載の化合物又はその製薬上許容される塩。 (5) The compound according to (4) or a pharmaceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted 4-membered non-aromatic carbocycle.
　（６）式：
Figure JPOXMLDOC01-appb-C000023
で示される基が、式：
Figure JPOXMLDOC01-appb-C000024
（式中、Ｒ１５はそれぞれ独立して水素、置換若しくは非置換のアルキル、ハロゲン又はヒドロキシであり、環Ｂに相当する環上のメチレン基は置換されていてもよい。）で示される基である、（１）～（３）のいずれかに記載の化合物又はその製薬上許容される塩。 (6) Formula:
Figure JPOXMLDOC01-appb-C000023
The group represented by the formula:
Figure JPOXMLDOC01-appb-C000024
Wherein R 15 is independently hydrogen, substituted or unsubstituted alkyl, halogen or hydroxy, and the methylene group on the ring corresponding to ring B may be substituted. A compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof.
　（７）Ｒ１５が水素であり、環Ｂに相当する環上のメチレン基が非置換である、（６）記載の化合物又はその製薬上許容される塩。 (7) The compound according to (6) or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen and the methylene group on the ring corresponding to ring B is unsubstituted.
　（８）式：
Figure JPOXMLDOC01-appb-C000025
で示される基が、式：
Figure JPOXMLDOC01-appb-C000026
で示される基である、（１）～（３）のいずれかに記載の化合物又はその製薬上許容される塩。 (8) Formula:
Figure JPOXMLDOC01-appb-C000025
The group represented by the formula:
Figure JPOXMLDOC01-appb-C000026
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), which is a group represented by:
　（９）ｑが１である、（１）～（８）のいずれかに記載の化合物又はその製薬上許容される塩。 (9) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein q is 1.
　（１０）Ｔが－Ｏ－又は－ＣＲ７Ｒ８－である、（９）記載の化合物又はその製薬上許容される塩。 (10) The compound according to (9) or a pharmaceutically acceptable salt thereof, wherein T is —O— or —CR 7 R 8 —.
　（１１）ｐが０である、（９）又は（１０）記載の化合物又はその製薬上許容される塩。 (11) The compound or a pharmaceutically acceptable salt thereof according to (9) or (10), wherein p is 0.
　（１２）ｐが１である、（１）～（８）のいずれかに記載の化合物又はその製薬上許容される塩。 (12) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein p is 1.
　（１３）Ｕが－Ｏ－、－ＣＲ４Ｒ５－又は－Ｏ－ＣＲ４Ｒ５－である（ここで、左の結合手は環Ａに結合し、右の結合手は環Ｂに結合する。）、（１２）記載の化合物又はその製薬上許容される塩。 (13) U is —O—, —CR 4 R 5 — or —O—CR 4 R 5 — (where the left bond is bonded to ring A and the right bond is bonded to ring B) Or a pharmaceutically acceptable salt thereof.
　（１４）ｑが０である、（１２）又は（１３）のいずれかに記載の化合物又はその製薬上許容される塩。 (14) The compound or a pharmaceutically acceptable salt thereof according to any one of (12) and (13), wherein q is 0.
　（１５）環Ｃが置換若しくは非置換の５員の芳香族複素環であり、Ｔ又は環Ｂと結合する環Ｃ上の原子の位置番号を１位とした場合の３位又は４位に位置する環Ｃ上の原子に、式：
Figure JPOXMLDOC01-appb-C000027
で示される基が結合している、（１）～（１４）のいずれかに記載の化合物又はその製薬上許容される塩。 (15) The ring C is a substituted or unsubstituted 5-membered aromatic heterocycle, and is located at the 3rd or 4th position when the position number of the atom on the ring C bonded to T or the ring B is the 1st position The atom on ring C
Figure JPOXMLDOC01-appb-C000027
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (14), wherein the group represented by
　（１６）環Ｃが置換若しくは非置換のイソオキサゾール又は置換若しくは非置換のチアゾールである、（１５）記載の化合物又はその製薬上許容される塩。 (16) The compound according to (15) or a pharmaceutically acceptable salt thereof, wherein ring C is substituted or unsubstituted isoxazole or substituted or unsubstituted thiazole.
　（１７）環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、
Figure JPOXMLDOC01-appb-C000028
で示される基が、Ｔ又は環Ｂに対してメタ位又はパラ位の位置で環Ｃと結合している、（１）～（１４）のいずれかに記載の化合物又はその製薬上許容される塩。 (17) Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
Figure JPOXMLDOC01-appb-C000028
Or a pharmaceutically acceptable compound thereof according to any one of (1) to (14), wherein the group represented by is bonded to ring C at the meta position or para position to T or ring B salt.
　（１８）環Ｃが置換若しくは非置換のベンゼンである、（１７）記載の化合物又はその製薬上許容される塩。 (18) The compound according to (17) or a pharmaceutically acceptable salt thereof, wherein ring C is substituted or unsubstituted benzene.
　（１９）環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、Ｕ又は環Ａと結合する環Ｂ上の原子の位置番号を１位とした場合の４位に位置する環Ｂ上の原子にＴ又は環Ｃが結合している、（１７）又は（１８）記載の化合物又はその製薬上許容される塩。 (19) The position of an atom on ring B in which ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring and is bonded to U or ring A The compound or a pharmaceutically acceptable salt thereof according to (17) or (18), wherein T or ring C is bonded to an atom on ring B located at the 4-position when the number is 1-position.
　（２０）式：
Figure JPOXMLDOC01-appb-C000029
で示される基が置換基群αより選択される１以上の基で置換されたアリール又は置換基群αより選択される１以上の基で置換されたヘテロアリールである、（１）～（１９）のいずれかに記載の化合物又はその製薬上許容される塩。 (20) Formula:
Figure JPOXMLDOC01-appb-C000029
(1) to (19), wherein the group represented by is aryl substituted with one or more groups selected from substituent group α or heteroaryl substituted with one or more groups selected from substituent group α ) Or a pharmaceutically acceptable salt thereof.
　（２１）式：
Figure JPOXMLDOC01-appb-C000030
で示される基が非置換の６員のアリール、置換基群αより選択される１以上の基で置換された６員のアリール、非置換の６員のヘテロアリール、置換基群αより選択される１以上の基で置換された６員のヘテロアリール又は式：
Figure JPOXMLDOC01-appb-C000031
（式中、環Ｅは５員の芳香族複素環であり、環Ｆは６員の芳香族炭素環又は６員の芳香族複素環であり、環Ｅと環Ｆは縮合して二環性の芳香族複素環を形成している。環Ｅ及び／又は環Ｆは置換基群αより選択される１以上の基で置換されていてもよい。）で示される基である、（１）～（１９）のいずれかに記載の化合物又はその製薬上許容される塩。 (21) Formula:
Figure JPOXMLDOC01-appb-C000030
The group represented by is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group α, unsubstituted 6-membered heteroaryl, substituent group α A 6-membered heteroaryl substituted with one or more groups
Figure JPOXMLDOC01-appb-C000031
(In the formula, ring E is a 5-membered aromatic heterocycle, ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle, and ring E and ring F are condensed to be bicyclic. The ring E and / or the ring F may be substituted with one or more groups selected from the substituent group α.) (1) The compound according to any of (19) or a pharmaceutically acceptable salt thereof.
　（２２）式：
Figure JPOXMLDOC01-appb-C000032
で示される基が式：
Figure JPOXMLDOC01-appb-C000033
（式中、Ｘ１はそれぞれ独立して－Ｃ（Ｈ）＝又は－Ｃ（Ｒ１２）＝であり、Ｒ１７は置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ又は置換若しくは非置換の非芳香族複素環オキシであり、
Ｒ１２はそれぞれ独立して置換基群αより選択される基である。）で示される基である、（１）～（１９）のいずれかに記載の化合物又はその製薬上許容される塩。 (22) Formula:
Figure JPOXMLDOC01-appb-C000032
A group represented by the formula:
Figure JPOXMLDOC01-appb-C000033
Wherein X 1 is independently —C (H) ═ or —C (R 12 ) ═, and R 17 is substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or substituted or unsubstituted non-aromatic heterocycle Is oxy,
R 12 is a group independently selected from the substituent group α. The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (19),
　（２３）Ｒ１２がそれぞれ独立して置換若しくは非置換のアルキル、ハロゲン、ヒドロキシ、スルファニル、シアノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又はカルボキシである、（２２）記載の化合物又はその製薬上許容される塩。 (23) R 12 is each independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or carboxy. (22) The compound described in the above or a pharmaceutically acceptable salt thereof.
　（２４）式：
Figure JPOXMLDOC01-appb-C000034
で示される基が、
Figure JPOXMLDOC01-appb-C000035

（式中、環上の炭素原子は置換基群αより選択される１以上の基で置換されていてもよい。）で示される基である（１）～（１９）のいずれかに記載の化合物又はその製薬上許容される塩。 (24) Formula:
Figure JPOXMLDOC01-appb-C000034
A group represented by
Figure JPOXMLDOC01-appb-C000035

(Wherein the carbon atom on the ring may be substituted with one or more groups selected from substituent group α), according to any one of (1) to (19) A compound or a pharmaceutically acceptable salt thereof.
　（２５）式：
Figure JPOXMLDOC01-appb-C000036
で示される基が、式：
Figure JPOXMLDOC01-appb-C000037
（式中、式中、各記号は上記（２２）と同意義）で示される基であり、
環Ｂは置換若しくは非置換の４員の非芳香族炭素環又は置換若しくは４員の非置換の非芳香族複素環であり、
ｐが０又は１であり、
ｑが０又は１であり、
ｒが０であり、
Ｒ１３が置換若しくは非置換のアルキルであり、
Ｒ１４が置換若しくは非置換のアルキルカルボニルであり、
Ｒ１６が水素である、（１）記載の化合物又はその又はその製薬上許容される塩を含有する医薬組成物。 (25) Formula:
Figure JPOXMLDOC01-appb-C000036
The group represented by the formula:
Figure JPOXMLDOC01-appb-C000037
(Wherein each symbol is as defined in (22) above),
Ring B is a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or 4-membered unsubstituted non-aromatic heterocyclic ring,
p is 0 or 1;
q is 0 or 1,
r is 0,
R 13 is substituted or unsubstituted alkyl;
R 14 is substituted or unsubstituted alkylcarbonyl;
A pharmaceutical composition comprising the compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R 16 is hydrogen.
　（２６）式：
Figure JPOXMLDOC01-appb-C000038
で示される基が、式：
Figure JPOXMLDOC01-appb-C000039
（式中、各記号は上記（２１）と同意義）で示される基であり、
Ｕが－Ｏ－、－ＣＲ４Ｒ５－又は－Ｏ－ＣＲ４Ｒ５－（ここで、左の結合手は環Ａに結合し、右の結合手は環Ｂに結合する。）であり、
Ｔが－Ｏ－又は－ＣＲ７Ｒ８－であり、
ｐが０又は１であり、
ｑが０又は１であり、
ｒが０であり、
Ｒ１３が置換若しくは非置換のアルキルであり、
Ｒ１４が置換若しくは非置換のアルキルカルボニルであり、
Ｒ１６が水素である、（１）記載の化合物又はその又はその製薬上許容される塩を含有する医薬組成物。
　（２７）式（I）で示される化合物が、式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000040
で示される化合物である、（１）～（２６）のいずれかに記載の化合物又はその製薬上許容される塩。 (26) Formula:
Figure JPOXMLDOC01-appb-C000038
The group represented by the formula:
Figure JPOXMLDOC01-appb-C000039
(Wherein each symbol has the same meaning as (21) above),
U is —O—, —CR 4 R 5 — or —O—CR 4 R 5 — (where the left bond is bonded to ring A and the right bond is bonded to ring B). ,
T is —O— or —CR 7 R 8 —,
p is 0 or 1;
q is 0 or 1,
r is 0,
R 13 is substituted or unsubstituted alkyl;
R 14 is substituted or unsubstituted alkylcarbonyl;
A pharmaceutical composition comprising the compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R 16 is hydrogen.
(27) The compound represented by formula (I) is represented by formula (II):
Figure JPOXMLDOC01-appb-C000040
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (26), wherein
　（２８）（１）～（２７）のいずれかに記載の化合物又はその又はその製薬上許容される塩を含有する医薬組成物。 (28) A pharmaceutical composition comprising the compound according to any one of (1) to (27) or a pharmaceutically acceptable salt thereof.
　（２９）ＡＣＣ２が関与する疾患の治療又は予防に用いる、（２８）記載の医薬組成物。 (29) The pharmaceutical composition according to (28), which is used for treatment or prevention of diseases involving ACC2.
　（３０）上記（１）～（２７）のいずれかに記載の化合物、又はその製薬上許容される塩を投与することを特徴とする、ＡＣＣ２の関与する疾患の治療又は予防方法。 (30) A method for treating or preventing a disease involving ACC2, comprising administering the compound according to any one of (1) to (27) above or a pharmaceutically acceptable salt thereof.
　（３１）ＡＣＣ２の関与する疾患の治療剤又は予防剤を製造するための、上記（１）～（２７）のいずれかに記載の化合物、又はその製薬上許容される塩の使用。 (31) Use of the compound according to any one of (1) to (27) above or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving ACC2.
　（３２）ＡＣＣ２の関与する疾患を治療又は予防するための、上記（１）～（２７）のいずれかに記載の化合物、又はその製薬上許容される塩。
（１’）
式（I）：
Figure JPOXMLDOC01-appb-C000041
（式中、
式：
Figure JPOXMLDOC01-appb-C000042
で示される基は非置換のアリール、置換基群αより選択される１以上の基で置換されたアリール、非置換のヘテロアリール、又は置換基群αより選択される１以上の基で置換されたヘテロアリールであり、
置換基群αは、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のシクロアルキルスルファニル、置換若しくは非置換のシクロアルケニルスルファニル、置換若しくは非置換のアリールスルファニル、置換若しくは非置換のヘテロアリールスルファニル、置換若しくは非置換の非芳香族複素環スルファニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のシクロアルキルスルフィニル、置換若しくは非置換のシクロアルケニルスルフィニル、置換若しくは非置換のアリールスルフィニル、置換若しくは非置換のヘテロアリールスルフィニル、置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアミノスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換の非芳香族複素環スルホニル、置換若しくは非置換のアルキルスルホニルオキシ、置換若しくは非置換のアルケニルスルホニルオキシ、置換若しくは非置換のアルキニルスルホニルオキシ、置換若しくは非置換のシクロアルキルスルホニルオキシ、置換若しくは非置換のシクロアルケニルスルホニルオキシ、置換若しくは非置換のアリールスルホニルオキシ、置換若しくは非置換のヘテロアリールスルホニルオキシ、置換若しくは非置換の非芳香族複素環スルホニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアルケニルカルボニルオキシ、置換若しくは非置換のアルキニルカルボニルオキシ、置換若しくは非置換のシクロアルキルカルボニルオキシ、置換若しくは非置換のシクロアルケニルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、置換若しくは非置換のヘテロアリールカルボニルオキシ、置換若しくは非置換の非芳香族複素環カルボニルオキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル、ハロゲン、ヒドロキシ、メルカプト、シアノ、アジド、置換若しくは非置換のアミジノ、グアニジノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル及びカルボキシからなる群であり、
環Ｂは置換若しくは非置換の非芳香族炭素環又は置換若しくは非置換の非芳香族複素環であり、
環Ｃは置換若しくは非置換の６員の芳香族炭素環、置換若しくは非置換の５員の芳香族複素環又は置換若しくは非置換の６員の芳香族複素環であり、
Ｕは－ＣＲ４Ｒ５－、－ＣＲ４Ｒ５－Ｏ－、－ＣＲ４Ｒ５－Ｓ－、－ＣＲ４Ｒ５－ＮＲ６－、－Ｏ－、－Ｓ－、－ＮＲ６－、－Ｏ－ＣＲ４Ｒ５－、－Ｓ－ＣＲ４Ｒ５－又は－ＮＲ６－ＣＲ４Ｒ５－（ここで、左の結合手は環Ａに結合し、右の結合手は環Ｂに結合する。）であり、
Ｔは－ＣＲ７Ｒ８－、－ＣＲ７Ｒ８－Ｏ－、－ＣＲ７Ｒ８－Ｓ－、－ＣＲ７Ｒ８－ＮＲ９－、－Ｏ－、－Ｓ－、－ＮＲ９－、－Ｃ（＝Ｏ）－又は－ＳＯ２－（ここで、左の結合手は環Ｂに結合し、右の結合手は環Ｃに結合する。）であり、
Ｌは－ＣＲ１０Ｒ１１－又は－Ｃ（＝Ｏ）－であり、
ｐは０又は１であり、
ｑは０又は１であり、
ｒは０又は１であり、
Ｒ４、Ｒ５、Ｒ７、Ｒ８、Ｒ１０及びＲ１１はそれぞれ独立して水素、ヒドロキシ、ハロゲン、置換若しくは非置換のアルキル又はシアノであり、
Ｒ６及びＲ９はそれぞれ独立して水素又は置換若しくは非置換のアルキルであり、
Ｒ１３はハロゲン、ヒドロキシ及びシアノからなる群から選択される１以上の置換基で置換されていてもよいメチルであり、
Ｒ１４はハロゲン、ヒドロキシ、シアノ、メチルオキシ及び置換若しくは非置換のカルバモイルからなる群から選択される１以上の置換基で置換されていてもよいメチルカルボニルであり、
Ｒ１６は水素又は置換若しくは非置換のアルキルである。
但し、以下の化合物を除く。
（i）環Ｂが置換若しくは非置換の５員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０であり、環Ｃが環Ｂ上の窒素原子に結合している化合物、
（ii）環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０である化合物、
（iii）環Ｂが置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが１であり、Ｔが環Ｂ上の窒素原子に結合している化合物。）
で示される化合物又はその製薬上許容される塩。
（２’）ｒが０である、上記（１’）記載の化合物又はその製薬上許容される塩。
（３’）環Ｂが置換若しくは非置換の４員の非芳香族炭素環又は置換若しくは非置換の４員の非芳香族複素環である、上記（１’）又は（２’）記載の化合物又はその製薬上許容される塩。
（４’）環Ｂが置換若しくは非置換の４員の非芳香族炭素環である、（３’）記載の化合物又はその製薬上許容される塩。
（５’）
式：
Figure JPOXMLDOC01-appb-C000043
で示される基が、式：
Figure JPOXMLDOC01-appb-C000044
（式中、Ｒ１５はそれぞれ独立して水素、置換若しくは非置換のアルキル、ハロゲン又はヒドロキシであり、環Ｂに相当する環上のメチレン基は置換されていてもよい。）で示される基である、上記（１’）又は（２’）記載の化合物又はその製薬上許容される塩。
（６’）Ｒ１５が水素であり、環Ｂに相当する環上のメチレン基が非置換である、上記（５’）記載の化合物又はその製薬上許容される塩。
（７’）式：
Figure JPOXMLDOC01-appb-C000045
で示される基が、式：
Figure JPOXMLDOC01-appb-C000046
で示される基である、上記（１’）又は（２’）記載の化合物又はその製薬上許容される塩。
（８’）ｑが１である、上記（１’）～（７’）のいずれかに記載の化合物又はその製薬上許容される塩。
（９’）Ｔが－Ｏ－又は－ＣＲ７Ｒ８－である、上記（８’）記載の化合物又はその製薬上許容される塩。
（１０’）ｐが０である、上記（８’）又は（９’）記載の化合物又はその製薬上許容される塩。
（１１’）ｐが１である、上記（１’）～（７’）のいずれかに記載の化合物又はその製薬上許容される塩。
（１２’）Ｕが－Ｏ－、－ＣＲ４Ｒ５－又は－Ｏ－ＣＲ４Ｒ５－である、上記（１１’）記載の化合物又はその製薬上許容される塩。
（１３’）ｑが０である、上記（１１’）又は（１２’）記載の化合物又はその製薬上許容される塩。
（１４’）環Ｃが置換若しくは非置換の５員の芳香族複素環であり、Ｔ又は環Ｂと結合する環Ｃ上の原子の位置番号を１位とした場合の３位又は４位に位置する環Ｃ上の原子に、式：
Figure JPOXMLDOC01-appb-C000047
で示される基が結合している、上記（１’）～（１３’）のいずれかに記載の化合物又はその製薬上許容される塩。
（１５’）環Ｃが置換若しくは非置換のイソオキサゾール又はチアゾールである、上記（１’）～（１４’）のいずれかに記載の化合物又はその製薬上許容される塩。
（１６’）環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、
Figure JPOXMLDOC01-appb-C000048
で示される基が、Ｔ又は環Ｂに対してメタ位又はパラ位の位置で環Ｃと結合している、上記（１’）～（１３’）のいずれかに記載の化合物又はその製薬上許容される塩。
（１７’）環Ｃが置換若しくは非置換のベンゼンである、上記（１６’）記載の化合物又はその製薬上許容される塩。
（１８’）環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、Ｕ又は環Ａと結合する環Ｂ上の原子の位置番号を１位とした場合の４位に位置する環Ｂ上の原子にＴ又は環Ｃが結合している、上記（１６’）又は（１７’）記載の化合物又はその製薬上許容される塩。
（１９’）
式：
Figure JPOXMLDOC01-appb-C000049
で示される基が置換基群αより選択される１以上の基で置換されたアリール又は置換基群αより選択される１以上の基で置換されたヘテロアリールである、上記（１’）～（１８’）のいずれかに記載の化合物又はその製薬上許容される塩。
（２０’）
式：
Figure JPOXMLDOC01-appb-C000050
で示される基が非置換の６員のアリール、置換基群αより選択される１以上の基で置換された６員のアリール、非置換の６員のヘテロアリール、置換基群αより選択される１以上の基で置換された６員のヘテロアリール又は式：
Figure JPOXMLDOC01-appb-C000051
（式中、環Ｅは５員の芳香族複素環であり、環Ｆは６員の芳香族炭素環又は６員の芳香族複素環であり、環Ｅと環Ｆは縮合して二環性の芳香族複素環を形成している。環Ｅ及び／又は環Ｆは置換基群αより選択される１以上の基で置換されていてもよい。）で示される基である、上記（１’）～（１８’）のいずれかに記載の化合物又はその製薬上許容される塩。
（２１’）
式：
Figure JPOXMLDOC01-appb-C000052
で示される基が式：
Figure JPOXMLDOC01-appb-C000053
（式中、Ｘ１はそれぞれ独立して－Ｃ（Ｈ）＝又は－Ｃ（Ｒ１２）＝であり、Ｒ１７は置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ又は置換若しくは非置換の非芳香族複素環オキシであり、
Ｒ１２はそれぞれ独立して置換基群αより選択される基である。）で示される基である、上記（１’）～（１８’）のいずれかに記載の化合物又はその製薬上許容される塩。
（２２’）Ｒ１２がそれぞれ独立して置換若しくは非置換のアルキル、ハロゲン、ヒドロキシ、スルファニル、シアノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又はカルボキシである、上記（２１’）記載の化合物又はその製薬上許容される塩。
（２３’）
式：
Figure JPOXMLDOC01-appb-C000054
で示される基が、
Figure JPOXMLDOC01-appb-C000055
（式中、環上の炭素原子は置換基群αより選択される１以上の基で置換されていてもよい。）で示される基である上記（１’）～（１８’）のいずれかに記載の化合物又はその製薬上許容される塩。
（２４’）環Ｂが置換若しくは非置換の４～６員のシクロアルカン又は置換若しくは非置換の４～６員の飽和複素環であり、
環Ｃが置換若しくは非置換の５員の芳香族複素環式基であり、
ｑが０であり、
ｒが０である、上記（１’）記載の化合物又はその製薬上許容される塩。
（２５’）環Ｂが置換若しくは非置換のシクロブタン又は置換若しくは非置換のアゼチジンである、上記（２４’）記載の化合物又はその製薬上許容される塩。
（２６’）環Ｃが置換若しくは非置換のイソオキサゾール、置換若しくは非置換のチアゾール又は置換若しくは非置換のオキサジアゾールである、上記（２４’）又は（２５’）記載の化合物又はその製薬上許容される塩。
（２７’）式（I）で示される化合物が、式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000056
で示される化合物である、上記（１’）～（２６’）のいずれかに記載の化合物又はその製薬上許容される塩。
（２８’）上記（１’）～（２７’）のいずれかに記載の化合物又はその又はその製薬上許容される塩を含有する医薬組成物。
（２９’）ＡＣＣ２が関与する疾患の治療又は予防に用いる、上記（２８’）記載の医薬組成物。
（３０’）上記（１’）～（２７’）のいずれかに記載の化合物、又はその製薬上許容される塩を投与することを特徴とする、ＡＣＣ２の関与する疾患の治療又は予防方法。
（３１’）ＡＣＣ２の関与する疾患を治療又は予防するための、上記（１’）～（２７’）のいずれかに記載の化合物、又はその製薬上許容される塩。
（３２’）ＡＣＣ２の関与する疾患の治療剤又は予防剤を製造するための、上記（１’）～（２７’）のいずれかに記載の化合物、又はその製薬上許容される塩の使用。 (32) The compound according to any one of (1) to (27) or a pharmaceutically acceptable salt thereof for treating or preventing a disease involving ACC2.
(1 ')
Formula (I):
Figure JPOXMLDOC01-appb-C000041
(Where
formula:
Figure JPOXMLDOC01-appb-C000042
The group represented by is substituted with one or more groups selected from unsubstituted aryl, aryl substituted with one or more groups selected from substituent group α, unsubstituted heteroaryl, or substituent group α. Heteroaryl,
Substituent group α is
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or Unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenyl The Fanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted cycloalkylsulfanyl, substituted or unsubstituted cycloalkenylsulfanyl, substituted or unsubstituted arylsulfanyl, substituted or unsubstituted heteroarylsulfanyl, substituted or unsubstituted Non-aromatic heterocyclic sulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted Or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted Is unsubstituted aminosulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy, substituted or unsubstituted Alkynylsulfonyloxy, substituted or unsubstituted cycloalkylsulfonyloxy, substituted or unsubstituted cycloalkenylsulfonyloxy, substituted or unsubstituted arylsulfonyl Oxy, substituted or unsubstituted heteroarylsulfonyloxy, substituted or unsubstituted non-aromatic heterocyclic sulfonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted Or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted nonaromatic heterocyclic carbonyl, substituted or unsubstituted Alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted cycloalkylcarbonyloxy, substituted or unsubstituted Unsubstituted cycloalkenylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, substituted or unsubstituted heteroarylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Heteroaryloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, halogen, hydroxy, mercapto, cyano, azide, substituted or unsubstituted amino Bruno, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, a group consisting of a substituted or unsubstituted sulfamoyl, and carboxy,
Ring B is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
U is -CR 4 R 5 -, - CR 4 R 5 -O -, - CR 4 R 5 -S -, - CR 4 R 5 -NR 6 -, - O -, - S -, - NR 6 -, -O-CR 4 R 5 -, - S-CR 4 R 5 - or -NR 6 -CR 4 R 5 - (wherein the left bond is attached to the ring a, the right bond is to the ring B Combined)
T is -CR 7 R 8 -, - CR 7 R 8 -O -, - CR 7 R 8 -S -, - CR 7 R 8 -NR 9 -, - O -, - S -, - NR 9 -, -C (= O)-or -SO 2- (where the left bond is bonded to ring B and the right bond is bonded to ring C);
L is —CR 10 R 11 — or —C (═O) —,
p is 0 or 1;
q is 0 or 1;
r is 0 or 1,
R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl or cyano,
R 6 and R 9 are each independently hydrogen or substituted or unsubstituted alkyl;
R 13 is methyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and cyano,
R 14 is methylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, methyloxy and substituted or unsubstituted carbamoyl;
R 16 is hydrogen or substituted or unsubstituted alkyl.
However, the following compounds are excluded.
(I) Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring A compound in which p is 0, q is 0, and ring C is bonded to a nitrogen atom on ring B;
(Ii) Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
(Iii) Ring B is a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring Wherein p is 0, q is 1 and T is bonded to a nitrogen atom on ring B. )
Or a pharmaceutically acceptable salt thereof.
(2 ′) The compound or a pharmaceutically acceptable salt thereof according to the above (1 ′), wherein r is 0.
(3 ′) The compound according to (1 ′) or (2 ′) above, wherein ring B is a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 4-membered non-aromatic heterocyclic ring Or a pharmaceutically acceptable salt thereof.
(4 ′) The compound according to (3 ′) or a pharmaceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted 4-membered non-aromatic carbocycle.
(5 ')
formula:
Figure JPOXMLDOC01-appb-C000043
The group represented by the formula:
Figure JPOXMLDOC01-appb-C000044
Wherein R 15 is independently hydrogen, substituted or unsubstituted alkyl, halogen or hydroxy, and the methylene group on the ring corresponding to ring B may be substituted. A compound according to the above (1 ′) or (2 ′) or a pharmaceutically acceptable salt thereof.
(6 ′) The compound according to the above (5 ′) or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen and the methylene group on the ring corresponding to ring B is unsubstituted.
(7 ') Formula:
Figure JPOXMLDOC01-appb-C000045
The group represented by the formula:
Figure JPOXMLDOC01-appb-C000046
Or a pharmaceutically acceptable salt thereof, which is a group represented by the above formula (1 ′) or (2 ′).
(8 ′) The compound according to any one of the above (1 ′) to (7 ′) or a pharmaceutically acceptable salt thereof, wherein q is 1.
(9 ′) The compound according to the above (8 ′) or a pharmaceutically acceptable salt thereof, wherein T is —O— or —CR 7 R 8 —.
(10 ′) The compound according to (8 ′) or (9 ′) or a pharmaceutically acceptable salt thereof, wherein p is 0.
(11 ′) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (7 ′), wherein p is 1.
(12 ′) The compound according to the above (11 ′) or a pharmaceutically acceptable salt thereof, wherein U is —O—, —CR 4 R 5 — or —O—CR 4 R 5 —.
(13 ′) The compound according to the above (11 ′) or (12 ′) or a pharmaceutically acceptable salt thereof, wherein q is 0.
(14 ′) Ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic ring, and is in the 3rd or 4th position when the position number of the atom on ring C bonded to T or ring B is the 1st position The atom on ring C located is of the formula:
Figure JPOXMLDOC01-appb-C000047
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (13 ′), to which a group represented by the formula:
(15 ′) The compound according to any one of the above (1 ′) to (14 ′) or a pharmaceutically acceptable salt thereof, wherein ring C is substituted or unsubstituted isoxazole or thiazole.
(16 ′) Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
Figure JPOXMLDOC01-appb-C000048
Or a pharmaceutically acceptable salt thereof, wherein the group represented by is bonded to ring C at the meta position or para position relative to T or ring B Acceptable salt.
(17 ′) The compound according to (16 ′) above or a pharmaceutically acceptable salt thereof, wherein ring C is substituted or unsubstituted benzene.
(18 ′) ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and the atom of ring B bonded to U or ring A The compound according to the above (16 ′) or (17 ′) or a pharmaceutically acceptable salt thereof, wherein T or ring C is bonded to the atom on ring B located at the 4-position when the position number is 1-position. salt.
(19 ')
formula:
Figure JPOXMLDOC01-appb-C000049
The group represented by (1) is an aryl substituted with one or more groups selected from the substituent group α or a heteroaryl substituted with one or more groups selected from the substituent group α; The compound according to any one of (18 ') or a pharmaceutically acceptable salt thereof.
(20 ')
formula:
Figure JPOXMLDOC01-appb-C000050
The group represented by is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group α, unsubstituted 6-membered heteroaryl, substituent group α A 6-membered heteroaryl substituted with one or more groups
Figure JPOXMLDOC01-appb-C000051
(In the formula, ring E is a 5-membered aromatic heterocycle, ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle, and ring E and ring F are condensed to be bicyclic. The ring E and / or the ring F may be substituted with one or more groups selected from the substituent group α.) (1) The compound according to any one of ') to (18') or a pharmaceutically acceptable salt thereof.
(21 ')
formula:
Figure JPOXMLDOC01-appb-C000052
A group represented by the formula:
Figure JPOXMLDOC01-appb-C000053
Wherein X 1 is independently —C (H) ═ or —C (R 12 ) ═, and R 17 is substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or substituted or unsubstituted non-aromatic heterocycle Is oxy,
R 12 is a group independently selected from the substituent group α. Or a pharmaceutically acceptable salt thereof. The compound according to any one of (1 ′) to (18 ′) above, which is a group represented by
(22 ′) R 12 is each independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or carboxy. The compound of the above (21 ′) or a pharmaceutically acceptable salt thereof.
(23 ')
formula:
Figure JPOXMLDOC01-appb-C000054
A group represented by
Figure JPOXMLDOC01-appb-C000055
(Wherein the carbon atom on the ring may be substituted with one or more groups selected from substituent group α) any one of the above (1 ′) to (18 ′) Or a pharmaceutically acceptable salt thereof.
(24 ′) Ring B is a substituted or unsubstituted 4- to 6-membered cycloalkane or a substituted or unsubstituted 4- to 6-membered saturated heterocyclic ring,
Ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic group,
q is 0,
The compound of the above (1 ′) or a pharmaceutically acceptable salt thereof, wherein r is 0.
(25 ′) The compound according to (24 ′) above or a pharmaceutically acceptable salt thereof, wherein ring B is substituted or unsubstituted cyclobutane or substituted or unsubstituted azetidine.
(26 ′) The compound according to (24 ′) or (25 ′) above, wherein the ring C is substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, or substituted or unsubstituted oxadiazole, or a pharmaceutical thereof Acceptable salt.
(27 ′) a compound of formula (I) is represented by formula (II):
Figure JPOXMLDOC01-appb-C000056
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (26 ′), which is a compound represented by the formula:
(28 ′) A pharmaceutical composition comprising the compound according to any one of (1 ′) to (27 ′) above or a pharmaceutically acceptable salt thereof.
(29 ′) The pharmaceutical composition according to the above (28 ′), which is used for treatment or prevention of a disease involving ACC2.
(30 ′) A method for treating or preventing a disease involving ACC2, which comprises administering the compound according to any one of (1 ′) to (27 ′) or a pharmaceutically acceptable salt thereof.
(31 ′) The compound according to any one of the above (1 ′) to (27 ′) or a pharmaceutically acceptable salt thereof for treating or preventing a disease involving ACC2.
(32 ′) Use of the compound according to any one of (1 ′) to (27 ′) above or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving ACC2.
　本発明に係る化合物は、ＡＣＣ２阻害活性を有する。本発明に係る化合物を含有する医薬組成物は、ＡＣＣ２が関与する疾患、たとえばメタボリックシンドローム、肥満症、
糖尿病、インスリン抵抗性、耐糖能異常、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、脂質異常症、高血圧症、心血管疾患、動脈硬化症、アテローム性動脈硬化症、心不全、心筋梗塞、感染症、腫瘍等（Ｊｏｕｒｎａｌ　ｏｆ　Ｃｅｌｌｕｌａｒ　Ｂｉｏｃｈｅｍｉｓｔｒｙ、２００６年、第９９巻、１４７６-１４８８頁、ＥＸＰＥＲＴ　ＯＰＩＮＩＯＮ　ＯＮ　ＴＨＥＲＡＰＥＵＴＩＣ　Ｔａｒｇｅｔｓ、２００５年、第９巻、２６７－２８１頁、国際公開公報ＷＯ２００５／１０８３７０号、日本国出願公開公報２００９－１９６９６６号、日本国出願公開公報２０１０－０８１８９４号、日本国出願国内公表公報２００９－５０２７８５号）の治療剤及び／又は予防剤、特に、糖尿病又は／及び肥満症の治療剤及び／又は予防剤として有用である。 The compound according to the present invention has ACC2 inhibitory activity. The pharmaceutical composition containing the compound according to the present invention is used for diseases involving ACC2, such as metabolic syndrome, obesity,
Diabetes, insulin resistance, impaired glucose tolerance, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis Sclerosis, heart failure, myocardial infarction, infection, tumor, etc. (Journal of Cellular Biochemistry, 2006, 99, 1476-1488, EXPERT OPINION ON THERAPEUTIC Targets, 2005, 9, 267-281, International Therapeutic and / or prophylactic agents of Japanese Patent Application Publication No. WO 2005/108370, Japanese Application Publication No. 2009-196966, Japanese Application Publication No. 2010-081894, Japanese Application Publication No. 2009-502785, especially diabetes Or / and therapeutic agent for obesity It is useful as a beauty / or prophylactic agent.
　以下に本明細書において用いられる各用語の意味を説明する。各用語は特に断りのない限り、単独で用いられる場合も、又は他の用語と組み合わせて用いられる場合も、同一の意味で用いられる。 The meaning of each term used in this specification is explained below. Unless otherwise noted, each term is used in the same meaning whether used alone or in combination with other terms.
　「アリール」とは、炭素数６～１４の単環又は多環の芳香族炭素環式基、及びこれらの単環又は多環の芳香族炭素環式基にさらに３～８員の環が１又は２個縮合した基を意味する。単環又は多環の芳香族炭素環式基としては、例えば、フェニル、ナフチル、アントリル、フェナントリルが挙げられる。特にフェニルが好ましい。
　単環又は多環の芳香族炭素環式基に縮合する環としては、非芳香族炭素環、単環の非芳香族複素環が挙げられる。なお、結合手は、単環又は多環の芳香族炭素環式基から出ているものとする。
　例えば、以下の基もアリールとして例示され、アリールに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。置換のアリールの場合、アリール上の置換基は、単環又は多環の芳香族炭素環式基又はこれらの単環又は多環の芳香族炭素環式基に縮合する３～８員の環のいずれに置換していてもよい。
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000058
 The term “aryl” refers to a monocyclic or polycyclic aromatic carbocyclic group having 6 to 14 carbon atoms, and a monocyclic or polycyclic aromatic carbocyclic group to which a 3- to 8-membered ring is further added. Or the group which condensed two is meant. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
Examples of the ring condensed with a monocyclic or polycyclic aromatic carbocyclic group include a non-aromatic carbocyclic ring and a monocyclic non-aromatic heterocyclic ring. The bond is assumed to come from a monocyclic or polycyclic aromatic carbocyclic group.
For example, the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position. In the case of substituted aryl, the substituent on the aryl is a monocyclic or polycyclic aromatic carbocyclic group or a 3-8 membered ring fused to these monocyclic or polycyclic aromatic carbocyclic groups. Any of them may be substituted.
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000058
　置換のアリールにはオキソで置換されたアリールも含まれる。「オキソで置換されたアリール」とは、アリールを構成する単環又は多環の芳香族炭素環式基に縮合する３～８員の環上の炭素原子上の２個の水素原子が＝Ｏ基で置換されている基を意味する。「オキソで置換されたアリール」として以下の式：
Figure JPOXMLDOC01-appb-C000059
で示される基を挙げることができる。
　環Ａにおける「アリール」の好ましい態様としては、フェニル、ナフチル等が挙げられる。 Substituted aryl includes aryl substituted with oxo. “Oxo-substituted aryl” refers to two hydrogen atoms on a carbon atom on a 3- to 8-membered ring fused to a monocyclic or polycyclic aromatic carbocyclic group constituting aryl. It means a group substituted with a group. As "aryl substituted with oxo" the following formula:
Figure JPOXMLDOC01-appb-C000059
The group shown by can be mentioned.
Preferable embodiments of “aryl” in ring A include phenyl, naphthyl and the like.
　「ヘテロアリール」とは、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する単環又は多環の芳香族へテロ環式基、及びこれらの単環又は多環の芳香族へテロ環式基にさらに３～８員の環が１又は２個縮合した基を意味する。
　「単環の芳香族ヘテロ環式基」としては、特に５員又は６員のヘテロアリールが好ましく、例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリル、チエニル等が挙げられる。
　「多環の芳香族ヘテロ環式基」としては、特に５員又は６員の環が縮合したヘテロアリールが好ましく、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等の２環の芳香族へテロ環式基；カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチニル、フェノキサジニル、ジベンゾフリル等の３環の芳香族へテロ環式基等が挙げられる。多環の芳香族へテロ環式基である場合、結合手をいずれの環に有していてもよい。
　単環又は多環の芳香族へテロ環式基に縮合する環としては、例えば、非芳香族炭素環、単環の非芳香族複素環が挙げられる。なお、結合手は、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する単環又は多環の芳香族へテロ環式基から出ているものとする。
　例えば、以下の基もヘテロアリールとして例示され、ヘテロアリールに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。置換のヘテロアリールの場合、ヘテロアリール上の置換基は、単環又は多環の芳香族へテロ環式基又はこれらの単環又は多環の芳香族へテロ環式基に縮合する３～８員の環のいずれに置換していてもよい。
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000061
 “Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
As the “monocyclic aromatic heterocyclic group”, a 5- or 6-membered heteroaryl is particularly preferable. For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, Examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
As the “polycyclic aromatic heterocyclic group”, a heteroaryl fused with a 5-membered or 6-membered ring is particularly preferable. Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, a Lysinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, cycloalkenyl, phenoxazinyl, heterocyclic groups such as the aromatic tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.
Examples of the ring condensed with a monocyclic or polycyclic aromatic heterocyclic group include a non-aromatic carbocyclic ring and a monocyclic non-aromatic heterocyclic ring. The bond is assumed to come from a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
For example, the following groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position. In the case of substituted heteroaryl, the substituents on the heteroaryl can be monocyclic or polycyclic aromatic heterocyclic groups or condensed to these monocyclic or polycyclic aromatic heterocyclic groups 3-8. Any of the member rings may be substituted.
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000061
　置換のヘテロアリールにはオキソで置換されたヘテロアリールも含まれる。「オキソで置換されたヘテロアリール」とは、ヘテロアリールを構成する単環又は多環の芳香族へテロ環式基に縮合する３～８員の環上の炭素原子上の２個の水素原子が＝Ｏ基で置換されている基を意味する。「オキソで置換されたヘテロアリール」として以下の式：
Figure JPOXMLDOC01-appb-C000062
で示される基を挙げることができる。
　環Ａにおける「ヘテロアリール」の好ましい態様としては、ピリジル、ピリミジン、ベンゾチアゾリル、ベンゾオキサゾリル、ベンゾイソチアゾール、インダゾール、オキサゾルピリジル等が挙げられる。 Substituted heteroaryl also includes heteroaryl substituted with oxo. “Oxo-substituted heteroaryl” refers to two hydrogen atoms on a carbon atom on a 3-8 membered ring fused to a monocyclic or polycyclic aromatic heterocyclic group comprising the heteroaryl. Means a group substituted with a ═O group. As "heteroaryl substituted with oxo" the following formula:
Figure JPOXMLDOC01-appb-C000062
The group shown by can be mentioned.
Preferable embodiments of “heteroaryl” in ring A include pyridyl, pyrimidine, benzothiazolyl, benzoxazolyl, benzoisothiazole, indazole, oxazol pyridyl and the like.
　「非芳香族炭素環」とは、炭素原子のみにより構成された芳香族性を有さない単環または多環の環を意味する。例えば、シクロアルカン、シクロアルケン、それらが縮合または架橋して形成された多環の炭素環、それらがスピロ結合を形成して結合した多環の炭素環を意味する。具体的には、単環のシクロアルカン、単環のシクロアルケン、２－３個のシクロアルカンが縮合した環、２－３個のシクロアルケンが縮合した環、シクロアルカンとシクロアルケンと合わせて２－３個が縮合した環、シクロアルカンとシクロアルカンとのスピロ環、シクロアルケンとシクロアルケンとのスピロ環、シクロアルカンとシクロアルケンとのスピロ環、架橋しているシクロアルカン、架橋しているシクロアルケン等を包含する。「非芳香族炭素環」には、以下の「シクロアルカン」及び「シクロアルケン」を包含する。 “Non-aromatic carbocycle” means a monocyclic or polycyclic ring having only aromaticity and composed only of carbon atoms. For example, it means a cycloalkane, a cycloalkene, a polycyclic carbocyclic ring formed by condensing or bridging them, and a polycyclic carbocyclic ring in which they are bonded by forming a spiro bond. Specifically, a monocyclic cycloalkane, a monocyclic cycloalkene, a ring condensed with 2-3 cycloalkanes, a ring condensed with 2-3 cycloalkenes, a combination of cycloalkane and cycloalkene, and 2 -3 condensed rings, cycloalkane and cycloalkane spiro ring, cycloalkene and cycloalkene spiro ring, cycloalkane and cycloalkene spiro ring, bridged cycloalkane, bridged cycloalkane Includes alkenes and the like. The “non-aromatic carbocycle” includes the following “cycloalkane” and “cycloalkene”.
　「シクロアルカン」とは、炭素数３～８の環状飽和炭化水素環を意味し、例えば、シクロヘキサン、シクロペンタン、シクロブタン、シクロプロパン等が挙げられる。特に、シクロヘキサン、シクロブタンが好ましく、シクロブタンがより好ましい。 “Cycloalkane” means a cyclic saturated hydrocarbon ring having 3 to 8 carbon atoms, and examples thereof include cyclohexane, cyclopentane, cyclobutane, and cyclopropane. In particular, cyclohexane and cyclobutane are preferable, and cyclobutane is more preferable.
　「シクロアルケン」とは、炭素数３～８個の環状不飽和脂肪族炭化水素環を意味し、例えば、シクロヘキセン、シクロペンテン等が挙げられる。炭素数３～８個の環状不飽和脂肪族炭化水素環としては、好ましくは環上の炭素原子間において１～３個の二重結合を有する炭素数３～８個の環状不飽和脂肪族炭化水素環を意味し、具体的には、シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロヘキサジエン等が挙げられる。特に、炭素数３～６のシクロアルケニル、炭素数５又は６のシクロアルケニルが好ましい。 “Cycloalkene” means a cyclic unsaturated aliphatic hydrocarbon ring having 3 to 8 carbon atoms, and examples thereof include cyclohexene and cyclopentene. The cyclic unsaturated aliphatic hydrocarbon ring having 3 to 8 carbon atoms is preferably a cyclic unsaturated aliphatic carbon ring having 3 to 8 carbon atoms having 1 to 3 double bonds between carbon atoms on the ring. A hydrogen ring is meant, and specific examples include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene and the like. In particular, cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
　「単環の非芳香族複素環」とは、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１～４個有する３～８員の非芳香族へテロ環を意味し、例えば、アジリジン、チイラン、アゼチジン、1,2-ジアゼチジン、1,3-ジアゼチジン、ピロリジン、ピロリン、イミダゾリン、イミダゾリジン、ピラゾリン、ピラゾリジン、チオラン、1,2-オキサチオラン、テトラヒドロフラン、1,3-ジオキソラン、ピペリジン、ピペラジン、モルホリン、1,4-オキサチアン等が挙げられる。 “Monocyclic non-aromatic heterocycle” means a 3- to 8-membered non-aromatic heterocycle having 1 to 4 heteroatoms arbitrarily selected from O, S and N in the ring; For example, aziridine, thiirane, azetidine, 1,2-diazetidine, 1,3-diazetidine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, thiolane, 1,2-oxathiolane, tetrahydrofuran, 1,3-dioxolane, piperidine , Piperazine, morpholine, 1,4-oxathiane and the like.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の炭化水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　「アルキル」の好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 “Alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
Preferred embodiments of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
　「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
　「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 “Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。これらはさらに任意の位置に二重結合を有していてもよい。
　「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
　「シクロアルキル」とは、炭素数３～８の環状飽和炭化水素基、及びこれらの環状飽和炭化水素基にさらに３～８員の環が１又は２個縮合した基を意味する。炭素数３～８の環状飽和炭化水素基としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロへプチル、シクロオクチルが挙げられる。特に、炭素数３～６のシクロアルキル、炭素数５又は６のシクロアルキルが好ましく、さらには炭素数の３のシクロアルキルが好ましい。
　炭素数３～８の環状飽和炭化水素基に縮合する３～８員の環としては、例えば、シクロアルカン、シクロアルケン、単環の非芳香族複素環が挙げられる。なお、結合手は、炭素数３～８の環状飽和炭化水素基から出ているものとする。
　例えば、以下の基もシクロアルキルに例示され、シクロアルキルに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。置換のシクロアルキルの場合、シクロアルキル上の置換基は、炭素数３～８の環状飽和炭化水素基又は炭素数３～８の環状飽和炭化水素基に縮合する３～８員の環のいずれに置換していてもよい。
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
　さらに、「シクロアルキル」は、以下のように架橋している基、又はスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000066
 “Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups. Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable, and cycloalkyl having 3 carbon atoms is more preferable.
Examples of the 3- to 8-membered ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cycloalkane, cycloalkene, and monocyclic non-aromatic heterocycle. The bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
For example, the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position. In the case of a substituted cycloalkyl, the substituent on the cycloalkyl is either a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms or a 3 to 8 membered ring fused to a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. May be substituted.
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
Furthermore, “cycloalkyl” includes a group which forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000066
　「シクロアルケニル」とは、炭素数３～８個の環状不飽和脂肪族炭化水素基、及びこれらの環状不飽和脂肪族炭化水素基にさらに３～８員の環が１又は２個縮合した基を意味する。炭素数３～８個の環状不飽和脂肪族炭化水素基としては、好ましくは環中の炭素原子間において１～３個の二重結合を有する炭素数３～８個の環状不飽和脂肪族炭化水素基を意味し、具体的には、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。特に、炭素数３～６のシクロアルケニル、炭素数５又は６のシクロアルケニルが好ましい。
　炭素数３～８の環状不飽和脂肪族炭化水素基に縮合する環としては、芳香族炭素環（例えば、ベンゼン、ナフタレン等）、シクロアルカン、シクロアルケン、複素環（芳香族複素環（ピリジン、ピリミジン、ピロール、イミダゾール等）、単環の非芳香族複素環が挙げられる。
　なお、結合手は、炭素数３～８の環状不飽和脂肪族炭化水素基から出ているものとする。
　例えば、以下の基もシクロアルケニルとして例示され、シクロアルケニルに含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。置換のシクロアルケニルの場合、シクロアルケニル上の置換基は、炭素数３～８の環状不飽和脂肪族炭化水素基又は炭素数３～８の環状不飽和脂肪族炭化水素基に縮合する３～８員の環のいずれに置換していてもよい。
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000070
 “Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means. The cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms is preferably a cyclic unsaturated aliphatic carbon group having 3 to 8 carbon atoms having 1 to 3 double bonds between carbon atoms in the ring. A hydrogen group is meant, and specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like. In particular, cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the C 3-8 cyclic unsaturated aliphatic hydrocarbon group include aromatic carbocycles (eg, benzene, naphthalene, etc.), cycloalkanes, cycloalkenes, heterocycles (aromatic heterocycles (pyridine, Pyrimidine, pyrrole, imidazole, etc.) and monocyclic non-aromatic heterocycles.
The bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms.
For example, the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position. In the case of substituted cycloalkenyl, the substituent on the cycloalkenyl is 3 to 8 condensed with a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms or a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. Any of the member rings may be substituted.
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000070
　「非芳香族複素環式基」とは、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する単環の非芳香族へテロ環式基、及びこれらの単環の非芳香族へテロ環式基にさらに３～８員の環が１又は２個縮合した基（多環の非芳香族へテロ環式基）を意味する。
　「単環の非芳香族複素環式基」としては、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１～４個有する単環の３～８員の非芳香族へテロ環式基が好ましく、具体的には、ジオキサニル、チイラニル、オキシラニル、オキサチオラニル、アゼチジニル、チアニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペリジノ、ピペラジニル、ピペラジノ、モルホリニル、モルホリノ、オキサジアジニル、ジヒドロピリジル、チオモルホリニル、チオモルホリノ、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、オキサゾリジル、チアゾリジル、オキセタニル、チアゾリジニル、テトラヒドロピリジル、ジヒドロチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル等が挙げられる。
　Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する単環の非芳香族へテロ環式基に縮合する環としては、炭素環（芳香族炭素環（例えば、ベンゼン、ナフタレン等）、シクロアルカン（例：シクロヘキサン、シクロペンタン等）、シクロアルケン（例：シクロヘキセン、シクロペンテン環）等）、複素環（芳香族複素環（ピリジン、ピリミジン、ピロール、イミダゾール等）、単環の非芳香族複素環（例えば、ピペリジン、ピペラジン、モルホリン環））が挙げられる。
　「多環の非芳香族複素環式基」として、具体的には、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。
　多環の非芳香族へテロ環式基である場合、結合手は、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する非芳香族へテロ環式基から出ているものとする。
　例えば、以下の基も非芳香族複素環式基に含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。置換の非芳香族複素環式基の場合、非芳香族複素環式基上の置換基は、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する単環の非芳香族へテロ環式基又はこれらの単環の非芳香族へテロ環式基に縮合する３～８員の環のいずれに置換していてもよい。
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000074
　「非芳香族複素環式基」は、以下のように架橋している基、又はスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000075
 The “non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and those monocyclic It means a group (polycyclic non-aromatic heterocyclic group) in which one or two 3- to 8-membered rings are condensed to a non-aromatic heterocyclic group.
“Monocyclic non-aromatic heterocyclic group” refers to a monocyclic 3- to 8-membered non-aromatic heterocycle having 1 to 4 heteroatoms arbitrarily selected from O, S and N in the ring. Cyclic groups are preferred, specifically, dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazinoyl, morpholinoyl, dimorpholinyl, Pyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl, oxetanyl, thiazolidinyl, tetrahydropyridyl, dihydroti Zoriru, dihydro benzoxazinyl, hexahydroazepinyl, tetrahydropyran diazepinium sulfonyl, tetrahydronaphthyl pyridazinyl, hexahydropyrimidinyl, dioxolanyl, Jiokisajiniru, aziridinyl, Jiokisoriniru, oxepanyl, thiolanyl, Chiiniru, triazinyl, and the like.
The ring condensed with a monocyclic non-aromatic heterocyclic group having at least one hetero atom selected from O, S and N in the ring includes a carbocycle (aromatic carbocycle (eg, benzene, Naphthalene, etc.), cycloalkanes (eg, cyclohexane, cyclopentane, etc.), cycloalkenes (eg, cyclohexene, cyclopentene rings, etc.), heterocycles (aromatic heterocycles (pyridine, pyrimidine, pyrrole, imidazole, etc.)), monocyclic Non-aromatic heterocycle (for example, piperidine, piperazine, morpholine ring)).
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
In the case of a polycyclic non-aromatic heterocyclic group, the bond exits from the non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. It shall be.
For example, the following groups are also included in the non-aromatic heterocyclic group. These groups may be substituted at any substitutable position. In the case of a substituted non-aromatic heterocyclic group, the substituent on the non-aromatic heterocyclic group is a monocyclic non-aromatic having one or more hetero atoms arbitrarily selected from O, S and N in the ring It may be substituted with any of 3 to 8 membered rings fused to the aromatic heterocyclic group or these monocyclic non-aromatic heterocyclic groups.
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000074
The “non-aromatic heterocyclic group” also includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000075
　上記「シクロアルキル」、「シクロアルケニル」、「アリール」及び「非芳香族複素環式基」が置換基を有する場合、これらの縮合している環として定義した「シクロアルカン」「シクロアルケン」、「単環の非芳香族複素環」、「芳香族炭素環」、「芳香族複素環」、「炭素環」及び「複素環」上に置換基を有してもよく、「シクロアルカン」「シクロアルケン」、「単環の非芳香族複素環」は、オキソで置換されていてもよい。 When the above “cycloalkyl”, “cycloalkenyl”, “aryl” and “non-aromatic heterocyclic group” have a substituent, “cycloalkane”, “cycloalkene” defined as a condensed ring thereof, The “monocyclic non-aromatic heterocycle”, “aromatic carbocycle”, “aromatic heterocycle”, “carbocycle” and “heterocycle” may have a substituent, and “cycloalkane” “ “Cycloalkene” and “monocyclic non-aromatic heterocycle” may be substituted with oxo.
　「アルキルオキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。例えば、メチルオキシ、エチルオキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｎ－ブチルオキシ、ｔｅｒｔ－ブチルオキシ、イソブチルオキシ、ｓｅｃ－ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、へキシルオキシ等が挙げられる。「アルキルオキシ」の好ましい態様として、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｔｅｒｔ－ブチルオキシが挙げられる。 “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
　「アルケニルオキシ」とは、上記「アルケニル」が酸素原子に結合した基を意味する。
例えば、ビニルオキシ、アリルオキシ、１－プロペニルオキシ、２－ブテニルオキシ、２－ペンテニルオキシ、２－ヘキセニルオキシ、２－ヘプテニルオキシ、２－オクテニルオキシ等が挙げられる。 “Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom.
Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
　「アルキニルオキシ」とは、上記「アルキニル」が酸素原子に結合した基を意味する。
例えば、エチニルオキシ、１－プロピニルオキシ、２－プロピニルオキシ、２－ブチニルオキシ、２－ペンチニルオキシ、２－ヘキシニルオキシ、２－ヘプチニルオキシ、２－オクチニルオキシ等が挙げられる。 “Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
　「シクロアルキルオキシ」とは、上記「シクロアルキル」が酸素原子に結合した基を意味する。例えば、シクロプロピルオキシ、シクロヘキシルオキシ、シクロへキセニルオキシ等が挙げられる。 “Cycloalkyloxy” means a group in which the above “cycloalkyl” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
　「シクロアルケニルオキシ」とは、「シクロアルケニル」が酸素原子に結合した基を意味する。例えば、シクロプロペニルオキシ、シクロブテニルオキシ、シクロペンテニルオキシ、シクロヘキセニルオキシ、シクロヘプテニルオキシ、シクロヘキサジエニルオキシ等が挙げられる。 “Cycloalkenyloxy” means a group in which “cycloalkenyl” is bonded to an oxygen atom. Examples include cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclohexadienyloxy, and the like.
　「アリールオキシ」とは、上記「アリール」が酸素原子に結合した基を意味する。例えば、フェニルオキシ、ナフチルオキシ等が挙げられる。 “Aryloxy” means a group in which the above “aryl” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
　「ヘテロアリールオキシ」とは、上記「ヘテロアリール」が酸素原子に結合した基を意味する。例えば、ピリジルオキシ、オキサゾリルオキシ等が挙げられる。 “Heteroaryloxy” means a group in which the above “heteroaryl” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
　「非芳香族複素環オキシ」とは、上記「非芳香族複素環式基」が酸素原子に結合した基を意味する。 “Non-aromatic heterocyclic oxy” means a group in which the above “non-aromatic heterocyclic group” is bonded to an oxygen atom.
　「非芳香族複素環オキシ」としては、例えば、ピペリジニルオキシ、テトラヒドロフリルオキシ等が挙げられる。 Examples of “non-aromatic heterocyclic oxy” include piperidinyloxy, tetrahydrofuryloxy and the like.
　「アルキルスルファニル」とは、上記「アルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル、ｎ－ブチルスルファニル、ｔｅｒｔ－ブチルスルファニル、イソブチルスルファニル、ｓｅｃ－ブチルスルファニル、ペンチルスルファニル、イソペンチルスルファニル、へキシルスルファニル等が挙げられる。「アルキルスルファニル」の好ましい態様として、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル、ｔｅｒｔ－ブチルスルファニルが挙げられる。 “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, tert-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl and the like. Preferred embodiments of “alkylsulfanyl” include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and tert-butylsulfanyl.
　「アルケニルスルファニル」とは、上記「アルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。「アルケニルスルファニル」としては、例えば、ビニルスルファニル、アリルスルファニル、１－プロペニルスルファニル、２－ブテニルスルファニル、２－ペンテニルスルファニル、２－ヘキセニルスルファニル、２－ヘプテニルスルファニル、２－オクテニルスルファニル等が挙げられる。 “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples of “alkenylsulfanyl” include vinylsulfanyl, allylsulfanyl, 1-propenylsulfanyl, 2-butenylsulfanyl, 2-pentenylsulfanyl, 2-hexenylsulfanyl, 2-heptenylsulfanyl, 2-octenylsulfanyl and the like. It is done.
　「アルキニルスルファニル」とは、上記「アルキニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。「アルキニルスルファニル」としては、例えば、エチニルスルファニル、１－プロピニルスルファニル、２－プロピニルスルファニル、２－ブチニルスルファニル、２－ペンチニルスルファニル、２－ヘキシニルスルファニル、２－ヘプチニルスルファニル、２－オクチニルスルファニル等が挙げられる。 “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. “Alkynylsulfanyl” includes, for example, ethynylsulfanyl, 1-propynylsulfanyl, 2-propynylsulfanyl, 2-butynylsulfanyl, 2-pentynylsulfanyl, 2-hexynylsulfanyl, 2-heptynylsulfanyl, 2-octynyl Nylsulfanyl etc. are mentioned.
　「シクロアルキルスルファニル」とは、上記「シクロアルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロピルスルファニル、シクロヘキシルスルファニル、シクロヘキセニルスルファニル等が挙げられる。 “Cycloalkylsulfanyl” means a group in which the above “cycloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
　「シクロアルケニルスルファニル」とは、上記「シクロアルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロペニルスルファニル、シクロブテニルスルファニル、シクロヘキセニルスルファニル、シクロペンテニルスルファニル、シクロヘプテニルスルファニル、シクロヘキサジエニルスルファニル等が挙げられる。 “Cycloalkenylsulfanyl” means a group in which the above “cycloalkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropenylsulfanyl, cyclobutenylsulfanyl, cyclohexenylsulfanyl, cyclopentenylsulfanyl, cycloheptenylsulfanyl, cyclohexadienylsulfanyl and the like.
　「アリールスルファニル」とは、上記「アリール」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、フェニルスルファニル、ナフチルスルファニル等が挙げられる。 “Arylsulfanyl” means a group in which the above “aryl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
　「ヘテロアリールスルファニル」とは、上記「ヘテロアリール」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピリジルスルファニル、オキサゾリルスルファニル等が挙げられる。 “Heteroarylsulfanyl” means a group in which the above “heteroaryl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
　「非芳香族複素環スルファニル」とは、上記「非芳香族複素環式基」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピペリジニルスルファニル、テトラヒドロフリルスルファニル等が挙げられる。 “Non-aromatic heterocyclic sulfanyl” means a group in which the above “non-aromatic heterocyclic group” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
　「アルキルスルフィニル」とは、上記「アルキル」がスルフィニル基に結合した基を意味する。例えば、メチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル等が挙げられる。 “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
　「アルケニルスルフィニル」とは、上記「アルケニル」がスルフィニル基に結合した基を意味する。例えば、エチレニルスルフィニル、プロペニルスルフィニル等が挙げられる。 “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
　「アルキニルスルフィニル」とは、上記「アルキニル」がスルフィニル基に結合した基を意味する。例えば、エチニルスルフィニル、プロピニルスルフィニル等が挙げられる。 “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
　「シクロアルキルスルフィニル」とは、上記「シクロアルキル」がスルフィニル基に結合した基を意味する。例えば、シクロプロピルスルフィニル、シクロヘキシルスルフィニル、シクロヘキセニルスルフィニル等が挙げられる。 “Cycloalkylsulfinyl” means a group in which the above “cycloalkyl” is bonded to a sulfinyl group. Examples include cyclopropylsulfinyl, cyclohexylsulfinyl, cyclohexenylsulfinyl and the like.
　「シクロアルケニルスルフィニル」とは、上記「シクロアルケニル」がスルフィニル基に結合した基を意味する。例えば、シクロプロペニルスルフィニル、シクロブテニルスルフィニル、シクロヘキセニルスルフィニル、シクロペンテニルスルフィニル、シクロヘプテニルスルフィニル、シクロヘキサジエニルスルフィニル等が挙げられる。 “Cycloalkenylsulfinyl” means a group in which the above “cycloalkenyl” is bonded to a sulfinyl group. Examples include cyclopropenylsulfinyl, cyclobutenylsulfinyl, cyclohexenylsulfinyl, cyclopentenylsulfinyl, cycloheptenylsulfinyl, cyclohexadienylsulfinyl and the like.
　「アリールスルフィニル」とは、上記「アリール」がスルフィニル基に結合した基を意味する。例えば、フェニルスルフィニル、ナフチルスルフィニル等が挙げられる。 “Arylsulfinyl” means a group in which the above “aryl” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
　「ヘテロアリールスルフィニル」とは、上記「ヘテロアリール」がスルフィニル基に結合した基を意味する。例えば、ピリジルスルフィニル、オキサゾリルスルフィニル等が挙げられる。 “Heteroarylsulfinyl” means a group in which the above “heteroaryl” is bonded to a sulfinyl group. For example, pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
　「非芳香族複素環スルフィニル」とは、上記「非芳香族複素環式基」がスルフィニル基に結合した基を意味する。例えば、ピペリジニルスルフィニル、テトラヒドロフリルスルフィニル等が挙げられる。 “Non-aromatic heterocyclic sulfinyl” means a group in which the above “non-aromatic heterocyclic group” is bonded to a sulfinyl group. For example, piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
　「アミノスルフィニル」とは、アミノ基がスルフィニル基に結合した基を意味する。 “Aminosulfinyl” means a group in which an amino group is bonded to a sulfinyl group.
　「アルキルスルホニル」とは、上記「アルキル」がスルホニル基に結合した基を意味する。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ｔｅｒｔ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル等が挙げられる。
　「アルキルスルホニル」の好ましい態様として、メチルスルホニル、エチルスルホニルが挙げられる。 “Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
　「アルケニルスルホニル」とは、上記「アルケニル」がスルホニル基に結合した基を意味する。例えば、エチレニルスルホニル、プロペニルスルホニル等が挙げられる。 “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
　「アルキニルスルホニル」とは、上記「アルキニル」がスルホニル基に結合した基を意味する。例えば、エチニルスルホニル、プロピニルスルホニル等が挙げられる。 “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
　「シクロアルキルスルホニル」とは、上記「シクロアルキル」がスルホニル基に結合した基を意味する。例えば、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル等が挙げられる。 “Cycloalkylsulfonyl” means a group in which the above “cycloalkyl” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
　「シクロアルケニルスルホニル」とは、上記「シクロアルケニル」がスルホニル基に結合した基を意味する。 “Cycloalkenylsulfonyl” means a group in which the above “cycloalkenyl” is bonded to a sulfonyl group.
　「アリールスルホニル」とは、上記「アリール」がスルホニル基に結合した基を意味する。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。 “Arylsulfonyl” means a group in which the above “aryl” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
　「ヘテロアリールスルホニル」とは、上記「ヘテロアリール」がスルホニル基に結合した基を意味する。例えば、ピリジルスルホニル、オキサゾリルスルホニル等が挙げられる。 “Heteroarylsulfonyl” means a group in which the above “heteroaryl” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
　「非芳香族複素環スルホニル」とは、上記「非芳香族複素環式基」がスルホニル基に結合した基を意味する。例えば、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。 “Non-aromatic heterocyclic sulfonyl” means a group in which the “non-aromatic heterocyclic group” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
　「アルキルスルホニルオキシ」とは、上記「アルキルスルホニル」が酸素原子に結合した基を意味する。例えば、メチルスルホニルオキシ、エチルスルホニルオキシ、プロピルスルホニルオキシ、イソプロピルスルホニルオキシ、ｔｅｒｔ－ブチルスルホニルオキシ、イソブチルスルホニルオキシ、ｓｅｃ－ブチルスルホニルオキシ等が挙げられる。
　「アルキルスルホニルオキシ」の好ましい態様として、メチルスルホニルオキシ、エチルスルホニルオキシが挙げられる。 “Alkylsulfonyloxy” means a group in which the above “alkylsulfonyl” is bonded to an oxygen atom. For example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, tert-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy and the like can be mentioned.
Preferable embodiments of “alkylsulfonyloxy” include methylsulfonyloxy and ethylsulfonyloxy.
　「アルケニルスルホニルオキシ」とは、上記「アルケニルスルホニル」が酸素原子に結合した基を意味する。例えば、エチレニルスルホニルオキシ、プロペニルスルホニルオキシ等が挙げられる。 “Alkenylsulfonyloxy” means a group in which the above “alkenylsulfonyl” is bonded to an oxygen atom. For example, ethylenylsulfonyloxy, propenylsulfonyloxy and the like can be mentioned.
　「アルキニルスルホニルオキシ」とは、上記「アルキニルスルホニル」が酸素原子に結合した基を意味する。例えば、エチニルスルホニルオキシ、プロピニルスルホニルオキシ等が挙げられる。 “Alkynylsulfonyloxy” means a group in which the above “alkynylsulfonyl” is bonded to an oxygen atom. For example, ethynylsulfonyloxy, propynylsulfonyloxy and the like can be mentioned.
　「シクロアルキルスルホニルオキシ」とは、上記「シクロアルキルスルホニル」が酸素原子に結合した基を意味する。例えば、シクロプロピルスルホニルオキシ、シクロヘキシルスルホニルオキシ、シクロヘキセニルスルホニルオキシ等が挙げられる。 “Cycloalkylsulfonyloxy” means a group in which the above “cycloalkylsulfonyl” is bonded to an oxygen atom. Examples include cyclopropylsulfonyloxy, cyclohexylsulfonyloxy, cyclohexenylsulfonyloxy and the like.
　「シクロアルケニルスルホニルオキシ」とは、上記「シクロアルケニルスルホニル」が酸素原子に結合した基を意味する。 “Cycloalkenylsulfonyloxy” means a group in which the above “cycloalkenylsulfonyl” is bonded to an oxygen atom.
　「アリールスルホニルオキシ」とは、上記「アリールスルホニル」が酸素原子に結合した基を意味する。例えば、フェニルスルホニルオキシ、ナフチルスルホニルオキシ等が挙げられる。 “Arylsulfonyloxy” means a group in which the above “arylsulfonyl” is bonded to an oxygen atom. For example, phenylsulfonyloxy, naphthylsulfonyloxy and the like can be mentioned.
　「ヘテロアリールスルホニルオキシ」とは、上記「ヘテロアリールスルホニル」が酸素原子に結合した基を意味する。例えば、ピリジルスルホニルオキシ、オキサゾリルスルホニルオキシ等が挙げられる。 “Heteroarylsulfonyloxy” means a group in which the above “heteroarylsulfonyl” is bonded to an oxygen atom. For example, pyridylsulfonyloxy, oxazolylsulfonyloxy and the like can be mentioned.
　「非芳香族複素環スルホニルオキシ」とは、上記「非芳香族複素環式基スルホニル」が酸素原子に結合した基を意味する。例えば、ピペリジニルスルホニルオキシ、テトラヒドロフリルスルホニルオキシ等が挙げられる。 “Non-aromatic heterocyclic sulfonyloxy” means a group in which the above “non-aromatic heterocyclic group sulfonyl” is bonded to an oxygen atom. For example, piperidinylsulfonyloxy, tetrahydrofurylsulfonyloxy and the like can be mentioned.
　「アルキルカルボニル」とは、上記「アルキル」がカルボニル基に結合した基を意味する。「アルキルカルボニル」としては、例えば、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ｔｅｒｔ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ペンチルカルボニル、イソペンチルカルボニル、へキシルカルボニル等が挙げられる。「アルキルカルボニル」の好ましい態様として、メチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニルが挙げられる。 “Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
　「アルケニルカルボニル」とは、上記「アルケニル」がカルボニル基に結合した基を意味する。「アルケニルカルボニル」としては、例えば、エチレニルカルボニル、プロペニルカルボニル等が挙げられる。 “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. Examples of “alkenylcarbonyl” include ethylenylcarbonyl, propenylcarbonyl and the like.
　「アルキニルカルボニル」とは、上記「アルキニル」がカルボニル基に結合した基を意味する。「アルキニルカルボニル」としては、例えば、エチニルカルボニル、プロピニルカルボニル等が挙げられる。 “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. Examples of “alkynylcarbonyl” include ethynylcarbonyl, propynylcarbonyl and the like.
　「シクロアルキルカルボニル」とは、上記「シクロアルキル」がカルボニル基に結合した基を意味する。「シクロアルキルカルボニル」としては、例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロへキセニルカルボニル等が挙げられる。 “Cycloalkylcarbonyl” means a group in which the above “cycloalkyl” is bonded to a carbonyl group. Examples of “cycloalkylcarbonyl” include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
　「シクロアルケニルカルボニル」とは、上記「シクロアルケニル」がカルボニル基に結合した基を意味する。「シクロアルケニルカルボニル」としては、例えば、シクロへキセニルカルボニル等が挙げられる。 “Cycloalkenylcarbonyl” means a group in which the above “cycloalkenyl” is bonded to a carbonyl group. Examples of “cycloalkenylcarbonyl” include cyclohexenylcarbonyl and the like.
　「アリールカルボニル」とは、上記「アリール」がカルボニル基に結合した基を意味する。「アリールカルボニル」としては、例えば、フェニルカルボニル、ナフチルカルボニル等が挙げられる。 “Arylcarbonyl” means a group in which the above “aryl” is bonded to a carbonyl group. Examples of “arylcarbonyl” include phenylcarbonyl, naphthylcarbonyl and the like.
　「ヘテロアリールカルボニル」とは、上記「ヘテロアリール」がカルボニル基に結合した基を意味する。「ヘテロアリールカルボニル」としては、例えば、ピリジルカルボニル、オキサゾリルカルボニル等が挙げられる。 “Heteroarylcarbonyl” means a group in which the above “heteroaryl” is bonded to a carbonyl group. Examples of “heteroarylcarbonyl” include pyridylcarbonyl, oxazolylcarbonyl and the like.
　「非芳香族複素環カルボニル」とは、上記「非芳香族複素環式基」がカルボニル基に結合した基を意味する。「非芳香族複素環カルボニル」としては、例えば、ピペリジニルカルボニル、テトラヒドロフリルカルボニル等が挙げられる。 “Non-aromatic heterocyclic carbonyl” means a group in which the above “non-aromatic heterocyclic group” is bonded to a carbonyl group. Examples of the “non-aromatic heterocyclic carbonyl” include piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like.
　「アルキルカルボニルオキシ」とは、上記「アルキルカルボニル」が酸素原子に結合した基を意味する。「アルキルカルボニルオキシ」としては、例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ、イソブチルカルボニルオキシ、ｓｅｃ－ブチルカルボニルオキシ等が挙げられる。「アルキルカルボニルオキシ」の好ましい態様としては、メチルカルボニルオキシ、エチルカルボニルオキシが挙げられる。 “Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples of “alkylcarbonyloxy” include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like. Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
　「アルケニルカルボニルオキシ」とは、上記「アルケニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチレニルカルボニルオキシ、プロペニルカルボニルオキシ等が挙げられる。 “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
　「アルキニルカルボニルオキシ」とは、上記「アルキニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチニルカルボニルオキシ、プロピニルカルボニルオキシ等が挙げられる。 “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
　「シクロアルキルカルボニルオキシ」とは、上記「シクロアルキルカルボニル」が酸素原子に結合した基を意味する。「シクロアルキルカルボニルオキシ」としては、例えば、シクロプロピルカルボニルオキシ、シクロヘキシルカルボニルオキシ、シクロへキセニルカルボニルオキシ等が挙げられる。 “Cycloalkylcarbonyloxy” means a group in which the above “cycloalkylcarbonyl” is bonded to an oxygen atom. Examples of “cycloalkylcarbonyloxy” include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy, cyclohexenylcarbonyloxy and the like.
　「シクロアルケニルカルボニルオキシ」とは、上記「シクロアルケニルカルボニル」が酸素原子に結合した基を意味する。「シクロアルケニルカルボニルオキシ」としては、例えば、シクロへキセニルカルボニルオキシ等が挙げられる。 “Cycloalkenylcarbonyloxy” means a group in which the above “cycloalkenylcarbonyl” is bonded to an oxygen atom. Examples of “cycloalkenylcarbonyloxy” include cyclohexenylcarbonyloxy and the like.
　「アリールカルボニルオキシ」とは、上記「アリールカルボニル」が酸素原子に結合した基を意味する。「アリールカルボニルオキシ」としては、例えば、フェニルカルボニルオキシ、ナフチルカルボニルオキシ等が挙げられる。 “Arylcarbonyloxy” means a group in which the above “arylcarbonyl” is bonded to an oxygen atom. Examples of “arylcarbonyloxy” include phenylcarbonyloxy, naphthylcarbonyloxy and the like.
　「ヘテロアリールカルボニルオキシ」とは、上記「ヘテロアリールカルボニル」が酸素原子に結合した基を意味する。「ヘテロアリールカルボニルオキシ」としては、例えば、ピリジルカルボニルオキシ、オキサゾリルカルボニルオキシ等が挙げられる。 “Heteroarylcarbonyloxy” means a group in which the above “heteroarylcarbonyl” is bonded to an oxygen atom. Examples of “heteroarylcarbonyloxy” include pyridylcarbonyloxy, oxazolylcarbonyloxy and the like.
　「非芳香族複素環カルボニルオキシ」とは、上記「非芳香族複素環カルボニル」が酸素原子に結合した基を意味する。「非芳香族複素環カルボニルオキシ」としては、例えば、ピペリジニルカルボニルオキシ、テトラヒドロフリルカルボニルオキシ等が挙げられる。 “Non-aromatic heterocyclic carbonyloxy” means a group in which the above “non-aromatic heterocyclic carbonyl” is bonded to an oxygen atom. Examples of “non-aromatic heterocyclic carbonyloxy” include piperidinylcarbonyloxy, tetrahydrofurylcarbonyloxy and the like.
　「アルキルオキシカルボニル」とは、上記「アルキルオキシ」がカルボニル基に結合した基を意味する。「アルキルオキシカルボニル」としては、例えば、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル、イソブチルオキシカルボニル、ｓｅｃ－ブチルオキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、へキシルオキシカルボニル等が挙げられる。「アルキルオキシカルボニル」の好ましい態様としては、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニルが挙げられる。 “Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. Examples of the “alkyloxycarbonyl” include, for example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl , Hexyloxycarbonyl and the like. Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
　「アルケニルオキシカルボニル」とは、上記「アルケニルオキシ」がカルボニル基に結合した基を意味する。「アルケニルオキシカルボニル」としては、例えば、エチレニルオキシカルボニル、プロペニルオキシカルボニル等が挙げられる。 “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. Examples of “alkenyloxycarbonyl” include ethylenyloxycarbonyl, propenyloxycarbonyl and the like.
　「アルキニルオキシカルボニル」とは、上記「アルキニルオキシ」がカルボニル基に結合した基を意味する。「アルキニルオキシカルボニル」としては、例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル等が挙げられる。 “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. Examples of “alkynyloxycarbonyl” include ethynyloxycarbonyl, propynyloxycarbonyl and the like.
　「シクロアルキルオキシカルボニル」とは、上記「シクロアルキルオキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロピルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロへキセニルオキシカルボニル等が挙げられる。 “Cycloalkyloxycarbonyl” means a group in which the above “cycloalkyloxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
　「シクロアルケニルオキシカルボニル」とは、上記「シクロアルケニルオキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロペニルオキシカルボニル、シクロヘキセニルオキシカルボニル等が挙げられる。 “Cycloalkenyloxycarbonyl” means a group in which the above “cycloalkenyloxy” is bonded to a carbonyl group. For example, cyclopropenyloxycarbonyl, cyclohexenyloxycarbonyl, etc. are mentioned.
　「アリールオキシカルボニル」とは、上記「アリールオキシ」がカルボニル基に結合した基を意味する。例えば、フェニルオキシカルボニル、ナフチルオキシカルボニル等が挙げられる。 “Aryloxycarbonyl” means a group in which the above “aryloxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
　「ヘテロアリールオキシカルボニル」とは、上記「ヘテロアリールオキシ」がカルボニル基に結合した基を意味する。例えば、ピリジルオキシカルボニル、オキサゾリルオキシカルボニル等が挙げられる。 “Heteroaryloxycarbonyl” means a group in which the above “heteroaryloxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
　「非芳香族複素環オキシカルボニル」とは、上記「非芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピペリジニルオキシカルボニル、テトラヒドロフリルオキシカルボニル等が挙げられる。 “Non-aromatic heterocyclic oxycarbonyl” means a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、及びヨウ素原子を包含する。特にフッ素原子、及び塩素原子が好ましい。 “Halogen” includes fluorine atom, chlorine atom, bromine atom and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
　環Ｂにおける「非芳香族炭素環」とは、炭素原子のみにより構成された芳香族性を有さない単環または多環の環を意味する。例えば、シクロアルカン、シクロアルケン、それらが縮合または架橋して形成された多環の炭素環、それらがスピロ結合を形成して結合した多環の炭素環を意味する。具体的には、単環のシクロアルカン、単環のシクロアルケン、２－３個のシクロアルカン環が縮合した環、２－３個のシクロアルケン環が縮合した環、シクロアルカンとシクロアルケンと合わせて２－３個が縮合した環、シクロアルカンとシクロアルカンとのスピロ環、シクロアルケンとシクロアルケンとのスピロ環、シクロアルカンとシクロアルケンとのスピロ環、架橋しているシクロアルカン、架橋しているシクロアルケン等を包含する。
　環Ｂにおける「非芳香族炭素環」としては、例えば、以下の式：
Figure JPOXMLDOC01-appb-C000076
で示される環も非芳香族炭素環として例示される。
　環Ｂにおける「非芳香族炭素環」としては、単環のシクロアルカンが好ましい。単環のシクロアルカンとしては、４～６員のシクロアルカンが好ましく、シクロブタンがより好ましい。 The “non-aromatic carbocycle” in ring B means a monocyclic or polycyclic ring having only aromaticity and composed only of carbon atoms. For example, it means a cycloalkane, a cycloalkene, a polycyclic carbocyclic ring formed by condensing or bridging them, and a polycyclic carbocyclic ring in which they are bonded by forming a spiro bond. Specifically, a monocyclic cycloalkane, a monocyclic cycloalkene, a ring fused with 2-3 cycloalkane rings, a ring fused with 2-3 cycloalkene rings, a cycloalkane and a cycloalkene 2 to 3 condensed rings, cycloalkane and cycloalkane spiro ring, cycloalkene and cycloalkene spiro ring, cycloalkane and cycloalkene spiro ring, bridged cycloalkane, bridged Including cycloalkene.
Examples of the “non-aromatic carbocycle” in ring B include the following formulas:
Figure JPOXMLDOC01-appb-C000076
Is also exemplified as a non-aromatic carbocycle.
As the “non-aromatic carbocycle” in ring B, a monocyclic cycloalkane is preferable. As the monocyclic cycloalkane, a 4- to 6-membered cycloalkane is preferable, and cyclobutane is more preferable.
　環Ｂにおける「非芳香族複素環」とは、単環の非芳香族複素環又は構成する何れの環も芳香属性を有さない多環の複素環を意味し、単環の非芳香族複素環、２－３個の単環の非芳香族複素環が縮合した環、単環の非芳香族複素環とシクロアルカン又は／及びシクロアルケンが縮合した環、非芳香族複素環同士のスピロ環、非芳香族複素環と非芳香族炭素環とのスピロ環、架橋している非芳香族複素環等を包含する。 The “non-aromatic heterocycle” in ring B means a monocyclic non-aromatic heterocycle or a polycyclic heterocycle in which none of the constituent rings has an aromatic attribute. A ring, a ring obtained by condensing two or three monocyclic non-aromatic heterocycles, a ring obtained by condensing a monocyclic non-aromatic heterocycle and cycloalkane or / and cycloalkene, or a spiro ring composed of non-aromatic heterocycles And a spiro ring of a non-aromatic heterocyclic ring and a non-aromatic carbocyclic ring, a bridged non-aromatic heterocyclic ring, and the like.
　環Ｂにおける「非芳香族複素環」としては、例えば、以下の式：
Figure JPOXMLDOC01-appb-C000077
で示される環も、非芳香族複素環として例示される。
　環Ｂにおける「非芳香族複素環」としては、単環の非芳香族複素環又は単環の非芳香族複素環とシクロアルカンとが縮合した２環の非芳香族複素環が好ましい。単環の非芳香族環としては、４～６員の非芳香族複素環が好ましく、４員の非芳香族複素環がより好ましく、アゼチジンがさらに好ましい。単環の非芳香族複素環とシクロアルカンとが縮合した２環の非芳香族複素環としては、以下の式：
Figure JPOXMLDOC01-appb-C000078
で示される環が好ましい。 Examples of the “non-aromatic heterocycle” in ring B include the following formulas:
Figure JPOXMLDOC01-appb-C000077
Is also exemplified as a non-aromatic heterocyclic ring.
The “non-aromatic heterocycle” in ring B is preferably a monocyclic non-aromatic heterocycle or a bicyclic non-aromatic heterocycle in which a monocyclic non-aromatic heterocycle and a cycloalkane are condensed. The monocyclic non-aromatic ring is preferably a 4- to 6-membered non-aromatic heterocyclic ring, more preferably a 4-membered non-aromatic heterocyclic ring, and further preferably azetidine. A bicyclic non-aromatic heterocycle in which a monocyclic non-aromatic heterocycle and a cycloalkane are condensed includes the following formula:
Figure JPOXMLDOC01-appb-C000078
A ring represented by is preferred.
　環Ｃにおける「６員の芳香族炭素環」とは、ベンゼンを意味する。 The “6-membered aromatic carbocycle” in ring C means benzene.
　環Ｃにおける「５員の芳香族複素環」とは、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する５員の芳香族へテロ環を意味する。例えば、ピロール、イミダゾール、ピラゾール、トリアゾール、テトラゾール、イソオキサゾール、オキサゾール、オキサジアゾール、イソチアゾール、チアゾール、チアジアゾール、フラン、チオフェン等が挙げられる。イソオキサゾール、チアゾール、オキサジアゾール等が特に好ましい。
　環Ｃにおける「６員の芳香族複素環」とは、Ｏ、Ｓ及びＮから任意に選択されるヘテロ原子を環内に１以上有する５員の芳香族へテロ環を意味する。例えば、ピリジン、ピリダジン、ピリミジン、ピラジン、トリアジン等が挙げられる。 The “5-membered aromatic heterocycle” in ring C means a 5-membered aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Examples thereof include pyrrole, imidazole, pyrazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene. Particularly preferred are isoxazole, thiazole, oxadiazole and the like.
The “6-membered aromatic heterocycle” in ring C means a 5-membered aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring. For example, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like can be mentioned.
　上記「置換若しくは非置換のアミノ」、「置換若しくは非置換のカルバモイル」、「置換若しくは非置換のスルファモイル」、「置換若しくは非置換のアミジノ」及び「置換若しくは非置換のアミノスルフィニル」の窒素原子上の置換基には、次の置換基が包含される。窒素原子上の水素原子が次の置換基から選択される１～２個の基で置換されていてもよい。
　置換基：
アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルケニル、ハロゲン、ヒドロキシ、カルボキシ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルキルオキシアルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、トリアルキルシリルオキシ、シアノアルキルオキシ、アルキルカルボニル、ハロアルキルカルボニル、カルバモイルアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、モノアルキルオキシカルボニルアミノ、ジアルキルオキシカルボニルアミノ、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルキルカルボニルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、モノ（ヒドロキシアルキル）カルバモイル、ジアルキルカルバモイル、ヒドロキシカルバモイル、シアノカルバモイル、カルボキシアルキルカルバモイル、モノ（ジアルキルアミノアルキル）カルバモイル、ジ（ジアルキルアミノアルキル）カルバモイル、シクロアルキルカルバモイル、非芳香族複素環アルキルカルバモイル、非芳香族複素環カルバモイル、モノアルキルオキシカルバモイル、ジアルキルオキシカルバモイル、モノアルキルオキシカルボニルアルキルカルバモイル、ジアルキルオキシカルボニルアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、アリール、シクロアルキル、シクロアルケニル、ヘテロアリール、非芳香族複素環式基、アリールオキシ、シクロアルキルオキシ、シクロアルケニルオキシ、ヘテロアリールオキシ、非芳香族複素環オキシ、アリールカルボニル、シクロアルキルカルボニル、シクロアルケニルカルボニル、ヘテロアリールカルボニル、非芳香族複素環カルボニル、シクロアルキルカルボニルオキシ、シクロアルケニルカルボニルオキシ、アリールカルボニルオキシ、ヘテロアリールカルボニルオキシ、非芳香族複素環カルボニルオキシ、アリールオキシカルボニル、シクロアルキルオキシカルボニル、シクロアルケニルオキシカルボニル、ヘテロアリールオキシカルボニル、非芳香族複素環オキシカルボニル、アリールアルキル、シクロアルキルアルキル、シクロアルケニルアルキル、ヘテロアリールアルキル、非芳香族複素環アルキル、アリールアルキルオキシ、シクロアルキルアルキルオキシ、シクロアルケニルアルキルオキシ、ヘテロアリールアルキルオキシ、非芳香族複素環アルキルオキシ、アリールアルキルオキシカルボニル、シクロアルキルアルキルオキシカルボニル、シクロアルケニルアルキルオキシカルボニル、ヘテロアリールアルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、アリールアルキルアミノ、シクロアルキルアルキルアミノ、シクロアルケニルアルキルアミノ、ヘテロアリールアルキルアミノ、非芳香族複素環アルキルアミノ、アリールスルファニル、シクロアルキルスルファニル、シクロアルケニルスルファニル、ヘテロアリールスルファニル、非芳香族複素環スルファニル、アリールスルホニル、シクロアルキルスルホニル、シクロアルケニルスルホニル、ヘテロアリールスルホニル、非芳香族複素環スルホニル、アルキルスルホニルオキシ、アルケニルスルホニルオキシ、アルキニルスルホニルオキシ、シクロアルキルスルホニルオキシ、シクロアルケニルスルホニルオキシ、アリールスルホニルオキシ、ヘテロアリールスルホニルオキシ、非芳香族複素環スルホニルオキシ、アルキルオキシカルボニルアルキル、カルボキシアルキル、ヒドロキシアルキル、ジアルキルアミノアルキル、ヒドロキシアルキル、アルキルオキシアルキル、アリールアルキルオキシアルキル、シクロアルキルアルキルオキシアルキル、シクロアルケニルアルキルオキシアルキル、ヘテロアリールアルキルオキシアルキル及び非芳香族複素環アルキルオキシアルキル。 On the nitrogen atom of the above “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted sulfamoyl”, “substituted or unsubstituted amidino” and “substituted or unsubstituted aminosulfinyl” The substituents include the following substituents. The hydrogen atom on the nitrogen atom may be substituted with 1 to 2 groups selected from the following substituents.
Substituent:
Alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, halogen, hydroxy, carboxy, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide , Hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkyloxyalkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, trialkylsilyloxy, cyanoalkyloxy, alkylcarbonyl, haloalkylcarbonyl, carbamoylalkylcarbonyl, alkenyl Carbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkynyl Sulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino Alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, monoalkyloxycarbonylamino, dialkyloxycarbonylamino, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkylcarbonylsulfanyl , Lukenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, mono (hydroxyalkyl) carbamoyl, dialkylcarbamoyl, hydroxycarbamoyl, cyanocarbamoyl, carboxyalkylcarbamoyl, mono (dialkylaminoalkyl) carbamoyl, di ( Dialkylaminoalkyl) carbamoyl, cycloalkylcarbamoyl, non-aromatic heterocyclic alkylcarbamoyl, non-aromatic heterocyclic carbamoyl, monoalkyloxycarbamoyl, dialkyloxycarbamoyl, monoalkyloxycarbonylalkylcarbamoyl, dialkyloxycarbonylalkylcarbamoyl, monoalkylsulfamoyl Famoyl, dialkyl sul Famoyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, non-aromatic heterocyclic group, aryloxy, cycloalkyloxy, cycloalkenyloxy, heteroaryloxy, non-aromatic heterocyclic oxy, arylcarbonyl, cycloalkylcarbonyl, Cycloalkenylcarbonyl, heteroarylcarbonyl, non-aromatic heterocyclic carbonyl, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, non-aromatic heterocyclic carbonyloxy, aryloxycarbonyl, cycloalkyloxycarbonyl , Cycloalkenyloxycarbonyl, heteroaryloxycarbonyl, non-aromatic heterocyclic oxycarbonyl, arylalkyl, cycloalkyl Alkyl, cycloalkenylalkyl, heteroarylalkyl, non-aromatic heterocyclic alkyl, arylalkyloxy, cycloalkylalkyloxy, cycloalkenylalkyloxy, heteroarylalkyloxy, non-aromatic heterocyclic alkyloxy, arylalkyloxycarbonyl, cyclo Alkylalkyloxycarbonyl, cycloalkenylalkyloxycarbonyl, heteroarylalkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, arylalkylamino, cycloalkylalkylamino, cycloalkenylalkylamino, heteroarylalkylamino, non-aromatic heterocyclic Alkylamino, arylsulfanyl, cycloalkylsulfanyl, cycloalkenylsulfanyl, heteroary Sulfanyl, non-aromatic heterocyclic sulfanyl, arylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heteroarylsulfonyl, non-aromatic heterocyclic sulfonyl, alkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, cycloalkylsulfonyloxy, cycloalkenyl Sulfonyloxy, arylsulfonyloxy, heteroarylsulfonyloxy, non-aromatic heterocyclic sulfonyloxy, alkyloxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, dialkylaminoalkyl, hydroxyalkyl, alkyloxyalkyl, arylalkyloxyalkyl, cycloalkylalkyl Oxyalkyl, cycloalkenylalkyloxyalkyl, hetero Arylalkyloxyalkyl and non-aromatic heterocyclic alkyloxyalkyl.
　上記「置換若しくは非置換のアルキル」、「置換若しくは非置換のアルケニル」、「置換若しくは非置換のアルキニル」、「置換若しくは非置換のアルキルオキシ」、「置換若しくは非置換のアルケニルオキシ」、「置換若しくは非置換のアルキニルオキシ」、「置換若しくは非置換のアルキルスルファニル」、「置換若しくは非置換のアルケニルスルファニル」、「置換若しくは非置換のアルキニルスルファニル」、「置換若しくは非置換のアルキルスルフィニル」、「置換若しくは非置換のアルケニルスルフィニル」、「置換若しくは非置換のアルキニルスルフィニル」、「置換若しくは非置換のアルキルスルホニル」、「置換若しくは非置換のアルケニルスルホニル」、「置換若しくは非置換のアルキニルスルホニル」、「置換若しくは非置換のアルキルスルホニルオキシ」、「置換若しくは非置換のアルケニルスルホニルオキシ」、「置換若しくは非置換のアルキニルスルホニルオキシ」、「置換若しくは非置換のアルキルカルボニル」、「置換若しくは非置換のアルケニルカルボニル」、「置換若しくは非置換のアルキニルカルボニル」、「置換若しくは非置換のアルキルカルボニルオキシ」、「置換若しくは非置換のアルケニルカルボニルオキシ」、「置換若しくは非置換のアルキニルカルボニルオキシ」、「置換若しくは非置換のアルキルオキシカルボニル」、「置換若しくは非置換のアルケニルオキシカルボニル」、「置換若しくは非置換のアルキニルオキシカルボニル」の置換基には、次の置換基が包含される。任意の位置の炭素原子上の水素原子が次の置換基から選択される１以上の基に置換されていてもよい。
　置換基：
ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルキルオキシアルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、トリアルキルシリルオキシ、シアノアルキルオキシ、アルキルカルボニル、ハロアルキルカルボニル、カルバモイルアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、モノアルキルオキシカルボニルアミノ、ジアルキルオキシカルボニルアミノ、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルキルカルボニルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、モノ（ヒドロキシアルキル）カルバモイル、ジアルキルカルバモイル、ヒドロキシカルバモイル、シアノカルバモイル、カルボキシアルキルカルバモイル、モノ（ジアルキルアミノアルキル）カルバモイル、ジ（ジアルキルアミノアルキル）カルバモイル、シクロアルキルカルバモイル、非芳香族複素環アルキルカルバモイル、非芳香族複素環カルバモイル、モノアルキルオキシカルバモイル、ジアルキルオキシカルバモイル、モノアルキルオキシカルボニルアルキルカルバモイル、ジアルキルオキシカルボニルアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、アリール、シクロアルキル、シクロアルケニル、ヘテロアリール、非芳香族複素環式基、アリールオキシ、シクロアルキルオキシ、シクロアルケニルオキシ、ヘテロアリールオキシ、非芳香族複素環オキシ、アリールカルボニル、シクロアルキルカルボニル、シクロアルケニルカルボニル、ヘテロアリールカルボニル、非芳香族複素環カルボニル、シクロアルキルカルボニルオキシ、シクロアルケニルカルボニルオキシ、アリールカルボニルオキシ、ヘテロアリールカルボニルオキシ、非芳香族複素環カルボニルオキシ、アリールオキシカルボニル、シクロアルキルオキシカルボニル、シクロアルケニルオキシカルボニル、ヘテロアリールオキシカルボニル、非芳香族複素環オキシカルボニル、アリールアルキルオキシ、シクロアルキルアルキルオキシ、シクロアルケニルアルキルオキシ、ヘテロアリールアルキルオキシ、非芳香族複素環アルキルオキシ、アリールアルキルオキシカルボニル、シクロアルキルアルキルオキシカルボニル、シクロアルケニルアルキルオキシカルボニル、ヘテロアリールアルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、アリールアルキルアミノ、シクロアルキルアルキルアミノ、シクロアルケニルアルキルアミノ、ヘテロアリールアルキルアミノ、非芳香族複素環アルキルアミノ、アリールスルファニル、シクロアルキルスルファニル、シクロアルケニルスルファニル、ヘテロアリールスルファニル、非芳香族複素環スルファニル、シクロアルキルスルホニル、シクロアルケニルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、非芳香族複素環スルホニル、アルキルスルホニルオキシ、アルケニルスルホニルオキシ、アルキニルスルホニルオキシ、シクロアルキルスルホニルオキシ、シクロアルケニルスルホニルオキシ、アリールスルホニルオキシ、ヘテロアリールスルホニルオキシ及び非芳香族複素環スルホニルオキシ。 “Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted” Or “unsubstituted alkynyloxy”, “substituted or unsubstituted alkylsulfanyl”, “substituted or unsubstituted alkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”, “substituted or unsubstituted alkylsulfinyl”, “substituted” Or “unsubstituted alkenylsulfinyl”, “substituted or unsubstituted alkynylsulfinyl”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted” Young "Unsubstituted alkylsulfonyloxy", "substituted or unsubstituted alkenylsulfonyloxy", "substituted or unsubstituted alkynylsulfonyloxy", "substituted or unsubstituted alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", “Substituted or unsubstituted alkynylcarbonyl”, “substituted or unsubstituted alkylcarbonyloxy”, “substituted or unsubstituted alkenylcarbonyloxy”, “substituted or unsubstituted alkynylcarbonyloxy”, “substituted or unsubstituted alkyl” The substituents of “oxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”, and “substituted or unsubstituted alkynyloxycarbonyl” include the following substituents. A hydrogen atom on a carbon atom at an arbitrary position may be substituted with one or more groups selected from the following substituents.
Substituent:
Halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, Hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkyloxyalkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, trialkylsilyloxy, cyanoalkyloxy, alkylcarbonyl, haloalkylcarbonyl, carbamoylalkylcarbonyl, alkenylcarbonyl , Alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl Alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyl Oxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, monoalkyloxycarbonylamino, dialkyloxycarbonylamino, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkylcarbonylsulfanyl, alkenyl The Fanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, mono (hydroxyalkyl) carbamoyl, dialkylcarbamoyl, hydroxycarbamoyl, cyanocarbamoyl, carboxyalkylcarbamoyl, mono (dialkylaminoalkyl) carbamoyl, di (dialkylamino) Alkyl) carbamoyl, cycloalkylcarbamoyl, nonaromatic heterocyclic alkylcarbamoyl, nonaromatic heterocyclic carbamoyl, monoalkyloxycarbamoyl, dialkyloxycarbamoyl, monoalkyloxycarbonylalkylcarbamoyl, dialkyloxycarbonylalkylcarbamoyl, monoalkylsulfamoyl Dialkylsulfamoyl, Aryl, cycloalkyl, cycloalkenyl, heteroaryl, non-aromatic heterocyclic group, aryloxy, cycloalkyloxy, cycloalkenyloxy, heteroaryloxy, non-aromatic heterocyclic oxy, arylcarbonyl, cycloalkylcarbonyl, cycloalkenyl Carbonyl, heteroarylcarbonyl, non-aromatic heterocyclic carbonyl, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, non-aromatic heterocyclic carbonyloxy, aryloxycarbonyl, cycloalkyloxycarbonyl, cyclo Alkenyloxycarbonyl, heteroaryloxycarbonyl, non-aromatic heterocyclic oxycarbonyl, arylalkyloxy, cycloalkylalkyl Ruoxy, cycloalkenylalkyloxy, heteroarylalkyloxy, non-aromatic heterocyclic alkyloxy, arylalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, cycloalkenylalkyloxycarbonyl, heteroarylalkyloxycarbonyl, non-aromatic heterocyclic alkyloxy Carbonyl, arylalkylamino, cycloalkylalkylamino, cycloalkenylalkylamino, heteroarylalkylamino, non-aromatic heterocyclic alkylamino, arylsulfanyl, cycloalkylsulfanyl, cycloalkenylsulfanyl, heteroarylsulfanyl, nonaromatic heterocyclic sulfanyl , Cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heteroaryl Rusuruhoniru, non-aromatic heterocyclic sulfonyl, alkylsulfonyloxy, alkenyloxy sulfonyloxy, alkynyloxy sulfonyloxy, cycloalkyl alkylsulfonyloxy, cycloalkenyl sulfonyloxy, arylsulfonyloxy, heteroaryl arylsulfonyloxy and non-aromatic heterocyclic sulfonyloxy.
　上記「置換若しくは非置換の非芳香族炭素環」、「置換若しくは非置換の非芳香族複素環」、「置換若しくは非置換の６員の芳香族炭素環」、「置換若しくは非置換の５員の芳香族複素環」、「置換若しくは非置換の６員の芳香族複素環」、「置換若しくは非置換のシクロアルキル」、「置換若しくは非置換のシクロアルケニル」、「置換若しくは非置換のアリール」、「置換若しくは非置換のヘテロアリール」、「置換若しくは非置換の非芳香族複素環式基」、「置換若しくは非置換のシクロアルキルオキシ」、「置換若しくは非置換のシクロアルケニルオキシ」、「置換若しくは非置換のアリールオキシ」、「置換若しくは非置換のヘテロアリールオキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換のシクロアルキルスルファニル」、「置換若しくは非置換のシクロアルケニルスルファニル」、「置換若しくは非置換のアリールスルファニル」、「置換若しくは非置換のヘテロアリールスルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換若しくは非置換のシクロアルキルスルフィニル」、「置換若しくは非置換のシクロアルケニルスルフィニル」、「置換若しくは非置換のアリールスルフィニル」、「置換若しくは非置換のヘテロアリールスルフィニル」、「置換若しくは非置換の非芳香族複素環スルフィニル」、「置換若しくは非置換のシクロアルキルスルホニル」、「置換若しくは非置換のシクロアルケニルスルホニル」、「置換若しくは非置換のアリールスルホニル」、「置換若しくは非置換のヘテロアリールスルホニル」、「置換若しくは非置換の非芳香族複素環スルホニル」、「置換若しくは非置換のシクロアルキルスルホニルオキシ」、「置換若しくは非置換のシクロアルケニルスルホニルオキシ」、「置換若しくは非置換のアリールスルホニルオキシ」、「置換若しくは非置換のヘテロアリールスルホニルオキシ」、「置換若しくは非置換の非芳香族複素環スルホニルオキシ」、「置換若しくは非置換のシクロアルキルカルボニル」、「置換若しくは非置換のシクロアルケニルカルボニル」、「置換若しくは非置換のアリールカルボニル」、「置換若しくは非置換のヘテロアリールカルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換のシクロアルキルカルボニルオキシ」、「置換若しくは非置換のシクロアルケニルカルボニルオキシ」、「置換若しくは非置換のアリールカルボニルオキシ」、「置換若しくは非置換のヘテロアリールカルボニルオキシ」、「置換若しくは非置換の非芳香族複素環カルボニルオキシ」、「置換若しくは非置換のシクロアルケニルオキシカルボニル」、「置換若しくは非置換のアリールオキシカルボニル」、「置換若しくは非置換のヘテロアリールオキシカルボニル」及び「置換若しくは非置換の非芳香族複素環オキシカルボニル」の環上の置換基には、次の置換基が包含される。環上の任意の位置の原子上の水素原子が次の置換基から選択される１以上の基に置換されていてもよい。
　置換基：
アルキル、アルケニル、アルキニル、ハロアルキル、ハロアルケニル、ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルキルオキシアルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、トリアルキルシリルオキシ、シアノアルキルオキシ、アルキルカルボニル、ハロアルキルカルボニル、カルバモイルアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、モノアルキルオキシカルボニルアミノ、ジアルキルオキシカルボニルアミノ、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルキルカルボニルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、モノ（ヒドロキシアルキル）カルバモイル、ジアルキルカルバモイル、ヒドロキシカルバモイル、シアノカルバモイル、カルボキシアルキルカルバモイル、モノ（ジアルキルアミノアルキル）カルバモイル、ジ（ジアルキルアミノアルキル）カルバモイル、シクロアルキルカルバモイル、非芳香族複素環アルキルカルバモイル、非芳香族複素環カルバモイル、モノアルキルオキシカルバモイル、ジアルキルオキシカルバモイル、モノアルキルオキシカルボニルアルキルカルバモイル、ジアルキルオキシカルボニルアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、アリール、シクロアルキル、シクロアルケニル、ヘテロアリール、非芳香族複素環式基、アリールオキシ、シクロアルキルオキシ、シクロアルケニルオキシ、ヘテロアリールオキシ、非芳香族複素環オキシ、アリールカルボニル、シクロアルキルカルボニル、シクロアルケニルカルボニル、ヘテロアリールカルボニル、非芳香族複素環カルボニル、シクロアルキルカルボニルオキシ、シクロアルケニルカルボニルオキシ、アリールカルボニルオキシ、ヘテロアリールカルボニルオキシ、非芳香族複素環カルボニルオキシアリールオキシカルボニル、シクロアルキルオキシカルボニル、シクロアルケニルオキシカルボニル、ヘテロアリールオキシカルボニル、非芳香族複素環オキシカルボニル、アリールアルキル、シクロアルキルアルキル、シクロアルケニルアルキル、ヘテロアリールアルキル、非芳香族複素環アルキル、アリールアルキルオキシ、シクロアルキルアルキルオキシ、シクロアルケニルアルキルオキシ、ヘテロアリールアルキルオキシ、非芳香族複素環アルキルオキシ、アリールアルキルオキシカルボニル、シクロアルキルアルキルオキシカルボニル、シクロアルケニルアルキルオキシカルボニル、ヘテロアリールアルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、アリールアルキルアミノ、シクロアルキルアルキルアミノ、シクロアルケニルアルキルアミノ、ヘテロアリールアルキルアミノ、非芳香族複素環アルキルアミノ、アリールスルファニル、シクロアルキルスルファニル、シクロアルケニルスルファニル、ヘテロアリールスルファニル、非芳香族複素環スルファニル、アリールスルホニル、シクロアルキルスルホニル、シクロアルケニルスルホニル、ヘテロアリールスルホニル、非芳香族複素環スルホニル、アルキルスルホニルオキシ、アルケニルスルホニルオキシ、アルキニルスルホニルオキシ、シクロアルキルスルホニルオキシ、シクロアルケニルスルホニルオキシ、アリールスルホニルオキシ、ヘテロアリールスルホニルオキシ、非芳香族複素環スルホニルオキシ、アルキルオキシカルボニルアルキル、カルボキシアルキル、ヒドロキシアルキル、ジアルキルアミノアルキル、ヒドロキシアルキル、アルキルオキシアルキル、アリールアルキルオキシアルキル、シクロアルキルアルキルオキシアルキル、シクロアルケニルアルキルオキシアルキル、ヘテロアリールアルキルオキシアルキル及び非芳香族複素環アルキルオキシアルキル。 "Substituted or unsubstituted non-aromatic carbocycle", "Substituted or unsubstituted non-aromatic heterocycle", "Substituted or unsubstituted 6-membered aromatic carbocycle", "Substituted or unsubstituted 5-membered""Aromaticheterocycle","Substituted or unsubstituted 6-membered aromatic heterocycle", "Substituted or unsubstituted cycloalkyl", "Substituted or unsubstituted cycloalkenyl", "Substituted or unsubstituted aryl" , “Substituted or unsubstituted heteroaryl”, “substituted or unsubstituted non-aromatic heterocyclic group”, “substituted or unsubstituted cycloalkyloxy”, “substituted or unsubstituted cycloalkenyloxy”, “substituted Or “substituted aryloxy”, “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted nonaromatic heterocyclic oxy”, “substituted or unsubstituted "Roalkylsulfanyl", "substituted or unsubstituted cycloalkenylsulfanyl", "substituted or unsubstituted arylsulfanyl", "substituted or unsubstituted heteroarylsulfanyl", "substituted or unsubstituted nonaromatic heterocyclic sulfanyl" , “Substituted or unsubstituted cycloalkylsulfinyl”, “substituted or unsubstituted cycloalkenylsulfinyl”, “substituted or unsubstituted arylsulfinyl”, “substituted or unsubstituted heteroarylsulfinyl”, “substituted or unsubstituted “Non-aromatic heterocyclic sulfinyl”, “substituted or unsubstituted cycloalkylsulfonyl”, “substituted or unsubstituted cycloalkenylsulfonyl”, “substituted or unsubstituted arylsulfonyl”, “substituted or unsubstituted heteroaryl” Rusulfonyl "," Substituted or unsubstituted non-aromatic heterocyclic sulfonyl "," Substituted or unsubstituted cycloalkylsulfonyloxy "," Substituted or unsubstituted cycloalkenylsulfonyloxy "," Substituted or unsubstituted arylsulfonyl " Oxy, substituted or unsubstituted heteroarylsulfonyloxy, substituted or unsubstituted non-aromatic heterocyclic sulfonyloxy, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl ”,“ Substituted or unsubstituted arylcarbonyl ”,“ substituted or unsubstituted heteroarylcarbonyl ”,“ substituted or unsubstituted nonaromatic heterocyclic carbonyl ”,“ substituted or unsubstituted cycloalkylcarbonyloxy ”,“ Substituted or unsubstituted Cycloalkenylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, substituted or unsubstituted heteroarylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted The substituent on the ring of “cycloalkenyloxycarbonyl”, “substituted or unsubstituted aryloxycarbonyl”, “substituted or unsubstituted heteroaryloxycarbonyl” and “substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl” Includes the following substituents. One or more groups selected from the following substituents may be substituted for a hydrogen atom on an atom at any position on the ring.
Substituent:
Alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, Thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkyloxyalkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, trialkylsilyloxy, cyanoalkyloxy, alkyl Carbonyl, haloalkylcarbonyl, carbamoylalkylcarbonyl, alkenylcarbonyl, alkynylcar Nyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonyl Imino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, monoalkyloxycarbonylamino, dialkyloxycarbonylamino, alkenyloxycarbonyl, alkynyl Oxycarboni , Alkylsulfanyl, alkylcarbonylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, mono (hydroxyalkyl) carbamoyl, dialkylcarbamoyl, hydroxycarbamoyl, cyanocarbamoyl, carboxyalkylcarbamoyl, mono (dialkyl) Aminoalkyl) carbamoyl, di (dialkylaminoalkyl) carbamoyl, cycloalkylcarbamoyl, non-aromatic heterocyclic alkylcarbamoyl, non-aromatic heterocyclic carbamoyl, monoalkyloxycarbamoyl, dialkyloxycarbamoyl, monoalkyloxycarbonylalkylcarbamoyl, dialkyloxy Carbonylalkyl Rucarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, non-aromatic heterocyclic group, aryloxy, cycloalkyloxy, cycloalkenyloxy, heteroaryloxy, non-aromatic Heterocyclic oxy, arylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, heteroarylcarbonyl, non-aromatic heterocyclic carbonyl, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, non-aromatic heterocyclic Carbonyloxyaryloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heteroaryloxycarbonyl, non-aromatic Heterocyclic oxycarbonyl, arylalkyl, cycloalkylalkyl, cycloalkenylalkyl, heteroarylalkyl, non-aromatic heterocyclic alkyl, arylalkyloxy, cycloalkylalkyloxy, cycloalkenylalkyloxy, heteroarylalkyloxy, non-aromatic hetero Ring alkyloxy, arylalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, cycloalkenylalkyloxycarbonyl, heteroarylalkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, arylalkylamino, cycloalkylalkylamino, cycloalkenylalkylamino, Heteroarylalkylamino, non-aromatic heterocyclic alkylamino, arylsulfanyl, cycloalkyl Rufanyl, cycloalkenylsulfanyl, heteroarylsulfanyl, non-aromatic heterocyclic sulfanyl, arylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heteroarylsulfonyl, non-aromatic heterocyclic sulfonyl, alkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy , Cycloalkylsulfonyloxy, cycloalkenylsulfonyloxy, arylsulfonyloxy, heteroarylsulfonyloxy, non-aromatic heterocyclic sulfonyloxy, alkyloxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, dialkylaminoalkyl, hydroxyalkyl, alkyloxyalkyl, Arylalkyloxyalkyl, cycloalkylalkyloxy Alkyl, cycloalkenylalkyloxyalkyl, heteroarylalkyloxyalkyl and non-aromatic heterocyclic alkyloxyalkyl.
　上記「置換若しくは非置換の非芳香族炭素環」、「置換若しくは非置換の非芳香族複素環」、「置換若しくは非置換のシクロアルキル」、「置換若しくは非置換のシクロアルケニル」及び「置換若しくは非置換の非芳香族複素環式基」は「オキソ」で置換されていてもよい。この場合、以下のように炭素原子上の２個の水素原子が＝Ｏ基で置換されている基を意味する。
Figure JPOXMLDOC01-appb-C000079
 The above-mentioned “substituted or unsubstituted non-aromatic carbocycle”, “substituted or unsubstituted non-aromatic heterocycle”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl” and “substituted or An “unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted with a ═O group as follows.
Figure JPOXMLDOC01-appb-C000079
　上記「置換若しくは非置換の非芳香族複素環式基」、「置換若しくは非置換のシクロアルキルオキシ」、「置換若しくは非置換のシクロアルケニルオキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換のシクロアルキルスルファニル」、「置換若しくは非置換のシクロアルケニルスルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換若しくは非置換のシクロアルキルスルフィニル」、「置換若しくは非置換のシクロアルケニルスルフィニル」、「置換若しくは非置換の非芳香族複素環スルフィニル」、「置換若しくは非置換のシクロアルキルスルホニル」、「置換若しくは非置換のシクロアルケニルスルホニル」、「置換若しくは非置換の非芳香族複素環スルホニル」、「置換若しくは非置換のシクロアルキルスルホニルオキシ」、「置換若しくは非置換のシクロアルケニルスルホニルオキシ」、「置換若しくは非置換の非芳香族複素環スルホニルオキシ」、「置換若しくは非置換のシクロアルキルカルボニル」、「置換若しくは非置換のシクロアルケニルカルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換のシクロアルキルカルボニルオキシ」、「置換若しくは非置換のシクロアルケニルカルボニルオキシ」、「置換若しくは非置換の非芳香族複素環カルボニルオキシ」、「置換若しくは非置換のシクロアルケニルオキシカルボニル」及び「置換若しくは非置換の非芳香族複素環オキシカルボニル」のシクロアルキル、シクロアルケニル及び非芳香族複素環部分も上記と同様に「オキソ」で置換されていてもよい。 The above-mentioned “substituted or unsubstituted non-aromatic heterocyclic group”, “substituted or unsubstituted cycloalkyloxy”, “substituted or unsubstituted cycloalkenyloxy”, “substituted or unsubstituted non-aromatic heterocyclic oxy” ”,“ Substituted or unsubstituted cycloalkylsulfanyl ”,“ substituted or unsubstituted cycloalkenylsulfanyl ”,“ substituted or unsubstituted nonaromatic heterocyclic sulfanyl ”,“ substituted or unsubstituted cycloalkylsulfinyl ”,“ Substituted or unsubstituted cycloalkenylsulfinyl "," substituted or unsubstituted non-aromatic heterocyclic sulfinyl "," substituted or unsubstituted cycloalkylsulfonyl "," substituted or unsubstituted cycloalkenylsulfonyl "," substituted or unsubstituted Substituted non-aromatic heterocyclic sulfonyl ”,“ substituted Or “unsubstituted cycloalkylsulfonyloxy”, “substituted or unsubstituted cycloalkenylsulfonyloxy”, “substituted or unsubstituted nonaromatic heterocyclic sulfonyloxy”, “substituted or unsubstituted cycloalkylcarbonyl”, “ "Substituted or unsubstituted cycloalkenylcarbonyl", "Substituted or unsubstituted non-aromatic heterocyclic carbonyl", "Substituted or unsubstituted cycloalkylcarbonyloxy", "Substituted or unsubstituted cycloalkenylcarbonyloxy", "Substituted Or cycloalkyl, cycloalkenyl and non-aromatic heterocycles of “unsubstituted non-aromatic heterocyclic carbonyloxy”, “substituted or unsubstituted cycloalkenyloxycarbonyl” and “substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl”. The ring part is the same as above It may be substituted with "oxo".
　「アルキルカルボニルスルファニル」とは、上記「アルキルカルボニル」が硫黄原子に結合した基を意味する。例えば、メチルカルボニルスルファニル、エチルカルボニルスルファニル、ｎ－プロピルカルボニルスルファニル、イソプロピルカルボニルスルファニル、ｎ－ブチルカルボニルスルファニル、ｔｅｒｔ－ブチルカルボニルスルファニル、イソブチルカルボニルスルファニル、ｓｅｃ－ブチルカルボニルスルファニル、ペンチルカルボニルスルファニル、イソペンチルカルボニルスルファニル、へキシルカルボニルスルファニル等が挙げられる。「アルキルカルボニルスルファニル」の好ましい態様として、例えば、メチルカルボニルスルファニル、エチルカルボニルスルファニル、プロピルカルボニルスルファニル、イソプロピルカルボニルスルファニル、ｔｅｒｔ－ブチルカルボニルスルファニル、イソブチルカルボニルスルファニル、ｓｅｃ－ブチルカルボニルスルファニル等が挙げられる。 “Alkylcarbonylsulfanyl” means a group in which the above “alkylcarbonyl” is bonded to a sulfur atom. For example, methylcarbonylsulfanyl, ethylcarbonylsulfanyl, n-propylcarbonylsulfanyl, isopropylcarbonylsulfanyl, n-butylcarbonylsulfanyl, tert-butylcarbonylsulfanyl, isobutylcarbonylsulfanyl, sec-butylcarbonylsulfanyl, pentylcarbonylsulfanyl, isopentylcarbonylsulfanyl And hexylcarbonylsulfanyl. Preferable embodiments of “alkylcarbonylsulfanyl” include, for example, methylcarbonylsulfanyl, ethylcarbonylsulfanyl, propylcarbonylsulfanyl, isopropylcarbonylsulfanyl, tert-butylcarbonylsulfanyl, isobutylcarbonylsulfanyl, sec-butylcarbonylsulfanyl and the like.
　「ハロアルキル」とは、上記「アルキル」の一以上の任意の水素原子が上記「ハロゲン」で置換された基を意味する。例えば、モノフルオロメチル、モノフルオロエチル、モノフルオロプロピル、２，２，３，３，３－ペンタフルオロプロピル、モノクロロメチル、トリフルオロメチル、トリクロロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、１，２－ジブロモエチル、１，１，１－トリフルオロプロパン－２－イル等が挙げられる。
　「ハロアルキルカルボニル」とは、上記「ハロアルキル」がカルボニル基に結合した基を意味する。例えば、モノフルオロメチルカルボニル、ジフルオロメチルカルボニル、モノフルオロエチルカルボニル、モノフルオロプロピルカルボニル、２，２，３，３，３－ペンタフルオロプロピルカルボニル、モノクロロメチルカルボニル、トリフルオロメチルカルボニル、トリクロロメチルカルボニル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチルカルボニル、１，２－ジブロモエチルカルボニル、１，１，１－トリフルオロプロパン－２－イルカルボニル等が挙げられる。 “Haloalkyl” means a group in which one or more arbitrary hydrogen atoms of the above “alkyl” are substituted with the above “halogen”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
“Haloalkylcarbonyl” means a group in which the above “haloalkyl” is bonded to a carbonyl group. For example, monofluoromethylcarbonyl, difluoromethylcarbonyl, monofluoroethylcarbonyl, monofluoropropylcarbonyl, 2,2,3,3,3-pentafluoropropylcarbonyl, monochloromethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, 2 2,2-trifluoroethyl, 2,2,2-trichloroethylcarbonyl, 1,2-dibromoethylcarbonyl, 1,1,1-trifluoropropan-2-ylcarbonyl and the like.
　「ハロアルケニル」とは、上記「アルケニル」の一以上の任意の水素原子が上記「ハロゲン」で置換された基を意味する。 “Haloalkenyl” means a group in which one or more arbitrary hydrogen atoms of the above “alkenyl” are substituted with the above “halogen”.
　「ヒドロキシアルキル」とは、上記「アルキル」の一以上の任意の水素原子がヒドロキシで置換された基を意味する。 “Hydroxyalkyl” means a group in which one or more arbitrary hydrogen atoms of the above “alkyl” are substituted with hydroxy.
　「トリアルキルシリル」とは、上記「アルキル」３個がケイ素原子に結合している基を意味する。３個のアルキルは同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル、トリイソプロピルシリル等が挙げられる。 “Trialkylsilyl” means a group in which the above three “alkyls” are bonded to a silicon atom. The three alkyls may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl and the like can be mentioned.
　「トリアルキルシリルオキシ」とは、上記「トリアルキルシリル」が酸素原子に結合した基を意味する。例えば、トリメチルシリルオキシ、トリエチルシリルオキシ、ｔｅｒｔ－ブチルジメチルシリルオキシ、トリイソプロピルシリルオキシ等が挙げられる。 “Trialkylsilyloxy” means a group in which the above “trialkylsilyl” is bonded to an oxygen atom. For example, trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, triisopropylsilyloxy and the like can be mentioned.
　「シアノアルキル」とは、上記「アルキル」の１以上の任意の水素原子がシアノで置換された基を意味する。例えば、シアノメチル等が挙げられる。 “Cyanoalkyl” means a group in which one or more arbitrary hydrogen atoms of the above “alkyl” are substituted with cyano. For example, cyanomethyl and the like can be mentioned.
　「シアノアルキルオキシ」とは、上記「シアノアルキル」が酸素原子に結合した基を意味する。例えば、シアノメチルオキシ等が挙げられる。 “Cyanoalkyloxy” means a group in which the above “cyanoalkyl” is bonded to an oxygen atom. For example, cyanomethyloxy and the like can be mentioned.
　「ハロアルキルオキシ」とは、上記「ハロアルキル」が酸素原子に結合した基を意味する。例えば、モノフルオロメトキシ、モノフルオロエトキシ、トリフルオロメトキシ、トリクロロメトキシ、トリフルオロエトキシ、トリクロロエトキシ等が挙げられる。
　「ハロアルキルオキシ」の好ましい態様として、トリフルオロメトキシ、トリクロロメトキシが挙げられる。 “Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
　「カルバモイルアルキルカルボニル」とは、カルバモイルで置換されている上記「アルキルカルボニル」を意味する。たとえば、カルバモイルメチルカルボニル、カルバモイルエチルカルボニル等が挙げられる。 “Carbamoylalkylcarbonyl” means the above “alkylcarbonyl” substituted with carbamoyl. Examples include carbamoylmethylcarbonyl, carbamoylethylcarbonyl, and the like.
　「モノアルキルアミノ」とは、上記「アルキル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルアミノ、エチルアミノ、イソプロピルアミノ等が挙げられる。
　「モノアルキルアミノ」の好ましい態様として、メチルアミノ、エチルアミノが挙げられる。 “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
Preferable embodiments of “monoalkylamino” include methylamino and ethylamino.
　「ジアルキルアミノ」とは、上記「アルキル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルアミノ、ジエチルアミノ、Ｎ，Ｎ－ジイソプロピルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、Ｎ－イソプロピル－Ｎ－エチルアミノ等が挙げられる。
　「ジアルキルアミノ」の好ましい態様として、ジメチルアミノ、ジエチルアミノが挙げられる。 “Dialkylamino” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
Preferred embodiments of “dialkylamino” include dimethylamino and diethylamino.
　「モノアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルボニルアミノ、エチルカルボニルアミノ、プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ｔｅｒｔ－ブチルカルボニルアミノ、イソブチルカルボニルアミノ、ｓｅｃ－ブチルカルボニルアミノ等が挙げられる。
　「モノアルキルカルボニルアミノ」の好ましい態様としては、メチルカルボニルアミノ、エチルカルボニルアミノが挙げられる。 “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
Preferable embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
　「ジアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルカルボニル基は、同一でも異なっていてもよい。例えば、ジメチルカルボニルアミノ、ジエチルカルボニルアミノ、Ｎ，Ｎ－ジイソプロピルカルボニルアミノ等が挙げられる。
　「ジアルキルカルボニルアミノ」の好ましい態様として、ジメチルカルボニルアミノ、ジエチルカルボニルアミノが挙げられる。 “Dialkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
Preferred embodiments of “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
　「モノアルキルオキシカルボニルアミノ」とは、上記「アルキルオキシカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。「モノアルキルオキシカルボニルアミノ」の好ましい態様として、メチルオキシカルボニルアミノ、エチルオキシカルボニルアミノが挙げられる。 “Monoalkyloxycarbonylamino” means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Preferable embodiments of “monoalkyloxycarbonylamino” include methyloxycarbonylamino and ethyloxycarbonylamino.
　「ジアルキルオキシカルボニルアミノ」とは、上記「アルキルオキシカルボニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルオキシカルボニル基は、同一でも異なっていてもよい。 “Dialkyloxycarbonylamino” means a group in which the above “alkyloxycarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyloxycarbonyl groups may be the same or different.
　「モノアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｓｅｃ－ブチルスルホニルアミノ等が挙げられる。
　「モノアルキルスルホニルアミノ」の好ましい態様としては、メチルスルホニルアミノ、エチルスルホニルアミノが挙げられる。 “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
Preferable embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
　「ジアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルスルホニル基は、同一でも異なっていてもよい。例えば、ジメチルスルホニルアミノ、ジエチルスルホニルアミノ、Ｎ，Ｎ－ジイソプロピルスルホニルアミノ等が挙げられる。
　「ジアルキルカルボニルアミノ」の好ましい態様として、ジメチルスルホニルアミノ、ジエチルスルホニルアミノが挙げられる。 “Dialkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
Preferred embodiments of “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
　「アルキルイミノ」とは、上記「アルキル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルイミノ、エチルイミノ、ｎ－プロピルイミノ、イソプロピルイミノ等が挙げられる。 “Alkylimino” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
　「アルケニルイミノ」とは、上記「アルケニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルイミノ、プロペニルイミノ等が挙げられる。 “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
　「アルキニルイミノ」とは、上記「アルキニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルイミノ、プロピニルイミノ等が挙げられる。 “Alkynylimino” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.
　「アルキルカルボニルイミノ」とは、上記「アルキルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルカルボニルイミノ、エチルカルボニルイミノ、ｎ－プロピルカルボニルイミノ、イソプロピルカルボニルイミノ等が挙げられる。 “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
　「アルケニルカルボニルイミノ」とは、上記「アルケニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルカルボニルイミノ、プロペニルカルボニルイミノ等が挙げられる。 “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
　「アルキニルカルボニルイミノ」とは、上記「アルキニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルカルボニルイミノ、プロピニルカルボニルイミノ等が挙げられる。 “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
　「アルキルオキシイミノ」とは、上記「アルキルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルオキシイミノ、エチルオキシイミノ、ｎ－プロピルオキシイミノ、イソプロピルオキシイミノ等が挙げられる。 “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
　「アルケニルオキシイミノ」とは、上記「アルケニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルオキシイミノ、プロペニルオキシイミノ等が挙げられる。 “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
　「アルキニルオキシイミノ」とは、上記「アルキニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルオキシイミノ、プロピニルオキシイミノ等が挙げられる。 “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.
　「モノアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルバモイル、エチルカルバモイル等が挙げられる。 “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
　「モノアルキルカルバモイルアルキルオキシ」とは、１以上の上記「モノアルキルカルバモイル」で置換されている上記「アルキルオキシ」を意味する。例えば、メチルカルバモイルメチルオキシなどが挙げられる。 “Monoalkylcarbamoylalkyloxy” means the above “alkyloxy” substituted with one or more of the above “monoalkylcarbamoyl”. For example, methylcarbamoylmethyloxy and the like can be mentioned.
　「モノ（ヒドロキシアルキル）カルバモイル」とは、上記「モノアルキルカルバモイル」のアルキル基の任意の水素原子がヒドロキシで置き換わった基を意味する。例えば、ヒドロキシメチルカルバモイル、ヒドロキシエチルカルバモイル等が挙げられる。 “Mono (hydroxyalkyl) carbamoyl” means a group in which any hydrogen atom of the alkyl group of the above “monoalkylcarbamoyl” is replaced with hydroxy. Examples thereof include hydroxymethylcarbamoyl and hydroxyethylcarbamoyl.
　「ジアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
　「アルキルオキシカルボニルアルキル」とは、１以上の上記「アルキルオキシカルボニル」で置換されている上記「アルキル」を意味する。 “Alkyloxycarbonylalkyl” means the above “alkyl” substituted with one or more of the above “alkyloxycarbonyl”.
　「モノアルキルオキシカルボニルアルキルカルバモイル」とは、上記「アルキルオキシカルボニルアルキル」がカルバモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルオキシカルボニルメチルカルバモイル、エチルオキシカルカルボニルメチルカルバモイル等が挙げられる。 “Monoalkyloxycarbonylalkylcarbamoyl” means a group in which the above “alkyloxycarbonylalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. For example, methyloxycarbonylmethylcarbamoyl, ethyloxycarcarbonylmethylcarbamoyl and the like can be mentioned.
　「ジアルキルオキシカルボニルアルキルカルバモイル」とは、上記「アルキルオキシカルボニルアルキル」がカルバモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。 “Dialkyloxycarbonylalkylcarbamoyl” means a group in which the above “alkyloxycarbonylalkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
　「カルボキシアルキル」とは、１以上の「カルボキシ」で置換されている上記「アルキル」を意味する。 “Carboxyalkyl” means the above “alkyl” substituted with one or more “carboxy”.
　「カルボキシアルキルカルバモイル」とは、１以上の上記「カルボキシアルキル」がカルバモイル基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、カルボキシメチルカルバモイル等が挙げられる。 “Carboxyalkylcarbamoyl” means a group in which one or more of the above “carboxyalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, carboxymethylcarbamoyl etc. are mentioned.
　「ジアルキルアミノアルキル」とは、１以上の「ジアルキルアミノ」で置換されている上記「アルキル」を意味する。例えば、ジメチルアミノメチル、ジメチルアミノエチルなどが挙げられる。 “Dialkylaminoalkyl” means the above “alkyl” substituted with one or more “dialkylamino”. Examples thereof include dimethylaminomethyl and dimethylaminoethyl.
　「モノ（ジアルキルアミノアルキル）カルバモイル」とは、上記「ジアルキルアミノアルキル」がカルバモイル基の窒素原子と結合している水素原子1個と置き換わった基を意味する。例えばジメチルアミノメチルカルバモイル、ジメチルアミノエチルカルバモイルなどが挙げられる。 “Mono (dialkylaminoalkyl) carbamoyl” means a group in which the above “dialkylaminoalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include dimethylaminomethylcarbamoyl, dimethylaminoethylcarbamoyl and the like.
　「ジ（ジアルキルアミノアルキル）カルバモイル」とは、上記「ジアルキルアミノアルキル」がカルバモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。例えば、ジ（メチルオキシカルボニルメチル）カルバモイル、ジ（エチルオキシカルカルボニルメチル）カルバモイル等が挙げられる。 “Di (dialkylaminoalkyl) carbamoyl” means a group in which the above “dialkylaminoalkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, di (methyloxycarbonylmethyl) carbamoyl, di (ethyloxycarbcarbonylmethyl) carbamoyl and the like can be mentioned.
　「シクロアルキルカルバモイル」とは、１以上の上記「シクロアルキル」がカルバモイル基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、シクロプロピルカルバモイル等が挙げられる。 “Cycloalkylcarbamoyl” means a group in which one or more of the above “cycloalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, cyclopropylcarbamoyl etc. are mentioned.
　「非芳香族複素環カルバモイル」とは、１以上の上記「非芳香族複素環式基」がカルバモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、以下の式で示される基が挙げられる。
Figure JPOXMLDOC01-appb-C000080
 “Non-aromatic heterocyclic carbamoyl” means a group in which one or more of the above “non-aromatic heterocyclic groups” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. For example, groups represented by the following formulas can be mentioned.
Figure JPOXMLDOC01-appb-C000080
　「モノアルキルオキシカルバモイル」とは、上記「アルキルオキシ」がカルバモイル基の窒素原子と結合している水素原子1個と置き換わった基を意味する。例えばメチルオキシカルバモイルなどが挙げられる。 “Monoalkyloxycarbamoyl” means a group in which the above “alkyloxy” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. For example, methyloxycarbamoyl etc. are mentioned.
　「ジアルキルオキシカルバモイル」とは、上記「アルキルオキシ」がカルバモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。例えばジ（メチルオキシ）カルバモイルなどが挙げられる。 “Dialkyloxycarbamoyl” means a group in which the above “alkyloxy” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Examples thereof include di (methyloxy) carbamoyl.
　「モノアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルファモイル、ジメチルスルファモイルモイル等が挙げられる。 “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoylmoyl, etc. are mentioned.
　「ジアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
　「アリールアルキル」とは、１以上の上記「アリール」で置換されている上記「アルキル」を意味する。例えば、ベンジル、フェネチル、フェニルプロピニル、ベンズヒドリル、トリチル、ナフチルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000081
等が挙げられる。
　「アリールアルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリルが挙げられる。 “Arylalkyl” means the above “alkyl” substituted with one or more of the above “aryl”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000081
Etc.
Preferable embodiments of “arylalkyl” include benzyl, phenethyl and benzhydryl.
　「シクロアルキルアルキル」とは、１以上の上記「シクロアルキル」で置換されている上記「アルキル」を意味する。また、「シクロアルキルアルキル」は、アルキル部分がさらに上記「アリール」で置換されている「シクロアルキルアルキル」も包含する。例えば、シクロペンチルメチル、シクロへキシルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000082
等が挙げられる。 “Cycloalkylalkyl” means the above “alkyl” substituted with one or more of the above “cycloalkyl”. “Cycloalkylalkyl” also includes “cycloalkylalkyl” in which the alkyl moiety is further substituted with the above “aryl”. For example, cyclopentylmethyl, cyclohexylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000082
Etc.
　「シクロアルケニルアルキル」とは、１以上の上記「シクロアルケニル」で置換されている上記「アルキル」を意味する。また、「シクロアルケニルアルキル」は、アルキル部分がさらに上記「アリール」で置換されている「シクロアルケニルアルキル」も包含する。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロへキシルメチル、等が挙げられる。 “Cycloalkenylalkyl” means the above “alkyl” substituted with one or more of the above “cycloalkenyl”. “Cycloalkenylalkyl” also includes “cycloalkenylalkyl” in which the alkyl moiety is further substituted with the above “aryl”. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
　「ヘテロアリールアルキル」とは、１以上の上記「ヘテロアリール」で置換されている上記「アルキル」を意味する。また、「ヘテロアリールアルキル」は、アルキル部分がさらに上記「アリール」及び／又は「シクロアルキル」で置換されている「ヘテロアリールアルキル」も包含する。例えば、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000083
等が挙げられる。 “Heteroarylalkyl” means the above “alkyl” substituted with one or more of the above “heteroaryl”. “Heteroarylalkyl” also includes “heteroarylalkyl” in which the alkyl moiety is further substituted with the above “aryl” and / or “cycloalkyl”. For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
Figure JPOXMLDOC01-appb-C000083
Etc.
　「非芳香族複素環アルキル」とは、１以上の上記「非芳香族複素環式基」で置換されている上記「アルキル」を意味する。また、「非芳香族複素環アルキル」は、アルキル部分がさらに上記「アリール」、「シクロアルキル」及び／又は「ヘテロアリール」で置換されている「非芳香族複素環アルキル」も包含する。例えば、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000084
等が挙げられる。 The “non-aromatic heterocyclic alkyl” means the above “alkyl” substituted with one or more of the above “non-aromatic heterocyclic group”. The “non-aromatic heterocyclic alkyl” also includes “non-aromatic heterocyclic alkyl” in which the alkyl moiety is further substituted with the above “aryl”, “cycloalkyl” and / or “heteroaryl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000084
Etc.
　「非芳香族複素環アルキルカルバモイル」とは、１以上の上記「非芳香族複素環アルキル」がカルバモイル基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、以下の式で示される基を挙げることが出来る。
Figure JPOXMLDOC01-appb-C000085
 “Non-aromatic heterocyclic alkylcarbamoyl” means a group in which one or more of the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, groups represented by the following formulas can be exemplified.
Figure JPOXMLDOC01-appb-C000085
　「アリールアルキルオキシ」とは、１以上の上記「アリール」で置換されている上記「アルキルオキシ」を意味する。例えば、ベンジルオキシ、フェネチルオキシ、フェニルプロピニルオキシ、ベンズヒドリルオキシ、トリチルオキシ、ナフチルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000086
等が挙げられる。 “Arylalkyloxy” means the above “alkyloxy” substituted with one or more of the above “aryl”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000086
Etc.
　「シクロアルキルアルキルオキシ」とは、１以上の上記「シクロアルキル」で置換されている上記「アルキルオキシ」を意味する。また、「シクロアルキルアルキルオキシ」は、アルキル部分がさらに上記「アリール」で置換されている「シクロアルキルアルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロへキシルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000087
等が挙げられる。 “Cycloalkylalkyloxy” means the above “alkyloxy” substituted with one or more of the above “cycloalkyl”. “Cycloalkylalkyloxy” also includes “cycloalkylalkyloxy” in which the alkyl moiety is further substituted with the above “aryl”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000087
Etc.
　「シクロアルケニルアルキルオキシ」とは、１以上の上記「シクロアルケニル」で置換されている上記「アルキルオキシ」を意味する。また、「シクロアルケニルアルキルオキシ」は、アルキル部分がさらに上記「アリール」、「シクロアルキル」又はその両方で置換されている「シクロアルケニルアルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロへキシルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000088
等が挙げられる。 “Cycloalkenylalkyloxy” means the above “alkyloxy” substituted with one or more of the above “cycloalkenyl”. “Cycloalkenylalkyloxy” also includes “cycloalkenylalkyloxy” in which the alkyl moiety is further substituted with the above “aryl”, “cycloalkyl”, or both. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000088
Etc.
　「ヘテロアリールアルキルオキシ」とは、１以上の上記「ヘテロアリール」で置換されている上記「アルキルオキシ」を意味する。また、「ヘテロアリールアルキルオキシ」は、アルキル部分がさらに上記「アリール」及び／又は「シクロアルキル」で置換されている「ヘテロアリールアルキルオキシ」も包含する。例えば、ピリジルメチルオキシ、フラニルメチルオキシ、イミダゾリルメチルオキシ、インドリルメチルオキシ、ベンゾチオフェニルメチルオキシ、オキサゾリルメチルオキシ、イソキサゾリルメチルオキシ、チアゾリルメチルオキシ、イソチアゾリルメチルオキシ、ピラゾリルメチルオキシ、イソピラゾリルメチルオキシ、ピロリジニルメチルオキシ、ベンズオキサゾリルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000089
等が挙げられる。 “Heteroarylalkyloxy” means the above “alkyloxy” substituted with one or more “heteroaryl”. “Heteroarylalkyloxy” also includes “heteroarylalkyloxy” in which the alkyl moiety is further substituted with the above “aryl” and / or “cycloalkyl”. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000089
Etc.
　「非芳香族複素環アルキルオキシ」とは、１以上の上記「非芳香族複素環式基」で置換されている上記「アルキルオキシ」を意味する。また、「非芳香族複素環アルキルオキシ」は、アルキル部分がさらに上記「アリール」、「シクロアルキル」及び／又は「ヘテロアリール」で置換されている「非芳香族複素環アルキルオキシ」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000090
等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means the above “alkyloxy” substituted with one or more of the above “non-aromatic heterocyclic groups”. “Non-aromatic heterocyclic alkyloxy” also includes “non-aromatic heterocyclic alkyloxy” in which the alkyl moiety is further substituted with the above-mentioned “aryl”, “cycloalkyl” and / or “heteroaryl”. . For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000090
Etc.
　「アリールアルキルオキシカルボニル」とは、１以上の上記「アリール」で置換されている上記「アルキルオキシカルボニル」を意味する。例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル、フェニルプロピニルオキシカルボニル、ベンズヒドリルオキシカルボニル、トリチルオキシカルボニル、ナフチルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000091
等が挙げられる。 “Arylalkyloxycarbonyl” means the above “alkyloxycarbonyl” substituted with one or more of the above “aryl”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000091
Etc.
　「シクロアルキルアルキルオキシカルボニル」とは、１以上の上記「シクロアルキル」で置換されている上記「アルキルオキシカルボニル」を意味する。また、「シクロアルキルアルキルオキシカルボニル」は、アルキル部分がさらに上記「アリール」で置換されている「シクロアルキルアルキルオキシカルボニル」も包含する。例えば、シクロプロピルメチルオキシカルボニル、シクロブチルメチルオキシカルボニル、シクロペンチルメチルオキシカルボニル、シクロへキシルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000092
等が挙げられる。 “Cycloalkylalkyloxycarbonyl” means the above “alkyloxycarbonyl” substituted with one or more “cycloalkyl”. “Cycloalkylalkyloxycarbonyl” also includes “cycloalkylalkyloxycarbonyl” in which the alkyl moiety is further substituted with the above “aryl”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000092
Etc.
　「シクロアルケニルアルキルオキシカルボニル」とは、１以上の上記「シクロアルケニル」で置換されている上記「アルキルオキシカルボニル」を意味する。 “Cycloalkenylalkyloxycarbonyl” means the above “alkyloxycarbonyl” substituted by one or more of the above “cycloalkenyl”.
　「ヘテロアリールアルキルオキシカルボニル」とは、１以上の上記「ヘテロアリール」で置換されている上記「アルキルオキシカルボニル」を意味する。また、「ヘテロアリールアルキルオキシカルボニル」は、アルキル部分がさらに上記「アリール」「シクロアルキル」及び／又は「シクロアルケニル」で置換されている「ヘテロアリールアルキルオキシカルボニル」も包含する。例えば、ピリジルメチルオキシカルボニル、フラニルメチルオキシカルボニル、イミダゾリルメチルオキシカルボニル、インドリルメチルオキシカルボニル、ベンゾチオフェニルメチルオキシカルボニル、オキサゾリルメチルオキシカルボニル、イソキサゾリルメチルオキシカルボニル、チアゾリルメチルオキシカルボニル、イソチアゾリルメチルオキシカルボニル、ピラゾリルメチルオキシカルボニル、イソピラゾリルメチルオキシカルボニル、ピロリジニルメチルオキシカルボニル、ベンズオキサゾリルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000093
等が挙げられる。 “Heteroarylalkyloxycarbonyl” means the above “alkyloxycarbonyl” substituted with one or more “heteroaryl”. “Heteroarylalkyloxycarbonyl” also includes “heteroarylalkyloxycarbonyl” in which the alkyl moiety is further substituted with the above “aryl”, “cycloalkyl” and / or “cycloalkenyl”. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000093
Etc.
　「非芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族複素環式基」で置換されている上記「アルキルオキシカルボニル」を意味する。また、「非芳香族複素環アルキルオキシカルボニル」は、アルキル部分がさらに上記「アリール」、「シクロアルキル」、「シクロアルキニル」及び／又は「ヘテロアリール」で置換されている「非芳香族複素環アルキルオキシカルボニル」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000094
等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means the above “alkyloxycarbonyl” substituted with one or more of the above “non-aromatic heterocyclic groups”. The “non-aromatic heterocyclic alkyloxycarbonyl” is a “non-aromatic heterocyclic ring” in which the alkyl part is further substituted with the above “aryl”, “cycloalkyl”, “cycloalkynyl” and / or “heteroaryl”. Also includes “alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000094
Etc.
　「アリールアルキルアミノ」とは、上記「アリールアルキル」がアミノ基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、ベンジルアミノ、フェネチルアミノ、フェニルプロピニルアミノ、ベンズヒドリルアミノ、トリチルアミノ、ナフチルメチルアミノ、ジベンジルアミノ等が挙げられる。 “Arylalkylamino” means a group in which the above “arylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
　「シクロアルキルアルキルアミノ」とは、上記「シクロアルキルアルキル」がアミノ基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、シクロプロピルメチルアミノ、シクロブチルメチルアミノ、シクロペンチルメチルアミノ、シクロへキシルメチルアミノ等が挙げられる。 “Cycloalkylalkylamino” means a group in which the above “cycloalkylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
　「シクロアルケニルアルキルアミノ」とは、上記「シクロアルケニルアルキル」がアミノ基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。 “Cycloalkenylalkylamino” means a group in which the above “cycloalkenylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
　「ヘテロアリールアルキルアミノ」とは、上記「ヘテロアリールアルキル」がアミノ基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、ピリジルメチルアミノ、フラニルメチルアミノ、イミダゾリルメチルアミノ、インドリルメチルアミノ、ベンゾチオフェニルメチルアミノ、オキサゾリルメチルアミノ、イソキサゾリルメチルアミノ、チアゾリルメチルアミノ、イソチアゾリルメチルアミノ、ピラゾリルメチルアミノ、イソピラゾリルメチルアミノ、ピロリジニルメチルアミノ、ベンズオキサゾリルメチルアミノ等が挙げられる。 “Heteroarylalkylamino” means a group in which the above “heteroarylalkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
　「非芳香族複素環アルキルアミノ」とは、上記「非芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個又は２個と置き換わった基を意味する。例えば、テトラヒドロピラニルメチルアミノ、モルホリニルエチルアミノ、ピペリジニルメチルアミノ、ピペラジニルメチルアミノ等が挙げられる。 “Non-aromatic heterocyclic alkylamino” means a group in which the above-mentioned “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
　「アルキルオキシアルキル」とは、上記「アルキルオキシ」が１～２個置換した上記「アルキル」を意味する。例えば、メチルオキシメチル、メチルオキシエチル、エチルオキシメチル等が挙げられる。 “Alkyloxyalkyl” means the above “alkyl” substituted with 1 or 2 of the above “alkyloxy”. For example, methyloxymethyl, methyloxyethyl, ethyloxymethyl and the like can be mentioned.
　「アリールアルキルオキシアルキル」とは、１以上の上記「アリール」で置換されている上記「アルキルオキシアルキル」を意味する。例えば、ベンジルオキシメチル、フェネチルオキシメチル、フェニルプロピニルオキシメチル、ベンズヒドリルオキシメチル、トリチルオキシメチル、ナフチルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000095
等が挙げられる。 “Arylalkyloxyalkyl” means the above “alkyloxyalkyl” substituted with one or more of the above “aryl”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000095
Etc.
　「シクロアルキルアルキルオキシアルキル」とは、１以上の上記「シクロアルキル」で置換されている上記「アルキルオキシアルキル」を意味する。また、「シクロアルキルアルキルオキシアルキル」は、シクロアルキルが結合しているアルキル部分がさらに上記「アリール」で置換されている「シクロアルキルアルキルオキシアルキル」も包含する。例えば、シクロプロピルメチルオキシメチル、シクロブチルメチルオキシメチル、シクロペンチルメチルオキシメチル、シクロへキシルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000096
等が挙げられる。 “Cycloalkylalkyloxyalkyl” means the above “alkyloxyalkyl” substituted by one or more of the above “cycloalkyl”. “Cycloalkylalkyloxyalkyl” also includes “cycloalkylalkyloxyalkyl” in which the alkyl moiety to which cycloalkyl is bonded is further substituted with the above “aryl”. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000096
Etc.
　「シクロアルケニルアルキルオキシアルキル」とは、１以上の上記「シクロアルケニル」で置換されている上記「アルキルオキシアルキル」を意味する。また、「シクロアルケニルアルキルオキシアルキル」は、シクロアルケニルが結合しているアルキル部分がさらに上記「アリール」、「シクロアルキル」又はその両方で置換されている「シクロアルケニルアルキルオキシアルキル」も包含する。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000097
等が挙げられる。 “Cycloalkenylalkyloxyalkyl” means the above “alkyloxyalkyl” substituted with one or more of the above “cycloalkenyl”. “Cycloalkenylalkyloxyalkyl” also includes “cycloalkenylalkyloxyalkyl” in which the alkyl moiety to which cycloalkenyl is bonded is further substituted with the above “aryl”, “cycloalkyl”, or both. For example, the group shown below
Figure JPOXMLDOC01-appb-C000097
Etc.
　「ヘテロアリールアルキルオキシアルキル」とは、１以上の上記「ヘテロアリール」で置換されている上記「アルキルオキシアルキル」を意味する。また、「ヘテロアリールアルキルオキシアルキル」は、芳香族複素環が結合しているアルキル部分がさらに上記「アリール」「シクロアルキル」及び／又は「シクロアルケニル」で置換されている「ヘテロアリールアルキルオキシアルキル」も包含する。例えば、ピリジルメチルオキシメチル、フラニルメチルオキシメチル、イミダゾリルメチルオキシメチル、インドリルメチルオキシメチル、ベンゾチオフェニルメチルオキシメチル、オキサゾリルメチルオキシメチル、イソキサゾリルメチルオキシメチル、チアゾリルメチルオキシメチル、イソチアゾリルメチルオキシメチル、ピラゾリルメチルオキシメチル、イソピラゾリルメチルオキシメチル、ピロリジニルメチルオキシメチル、ベンズオキサゾリルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000098
等が挙げられる。 “Heteroarylalkyloxyalkyl” means the above “alkyloxyalkyl” substituted with one or more of the above “heteroaryl”. In addition, “heteroarylalkyloxyalkyl” is a “heteroarylalkyloxyalkyl” in which the alkyl moiety to which the aromatic heterocycle is bonded is further substituted with the above “aryl”, “cycloalkyl” and / or “cycloalkenyl”. Is also included. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000098
Etc.
　「非芳香族複素環アルキルオキシアルキル」とは、１以上の上記「非芳香族複素環式基」で置換されている上記「アルキルオキシアルキル」を意味する。また、「非芳香族複素環アルキルオキシ」は、非芳香族複素環が結合しているアルキル部分がさらに上記「アリール」、「シクロアルキル」、「シクロアルケニル」及び／又は「ヘテロアリール」で置換されている「非芳香族複素環アルキルオキシアルキル」も包含する。例えば、テトラヒドロピラニルメチルオキシメチル、モルホリニルエチルオキシメチル、ピペリジニルメチルオキシメチル、ピペラジニルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000099
等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means the above “alkyloxyalkyl” substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is further substituted with the above “aryl”, “cycloalkyl”, “cycloalkenyl” and / or “heteroaryl”. Also included are “non-aromatic heterocyclic alkyloxyalkyl”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000099
Etc.
　「アルキルオキシアルキルオキシ」とは、上記「アルキルオキシアルキル」が酸素原子に結合した基を意味する。 “Alkyloxyalkyloxy” means a group in which the above “alkyloxyalkyl” is bonded to an oxygen atom.
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000100
で示される化合物における、式：
Figure JPOXMLDOC01-appb-C000101
で示される基、環Ｂ、環Ｃ、Ｕ、Ｔ、Ｌ、ｐ、ｑ、ｒ、Ｒ１３、Ｒ１４及びＲ１６の好ましい態様を以下に示す。下記に示す可能な組合せの化合物が好ましい。 Formula (I):
Figure JPOXMLDOC01-appb-C000100
In the compound represented by:
Figure JPOXMLDOC01-appb-C000101
Preferred embodiments of the group represented by the formula: Ring B, Ring C, U, T, L, p, q, r, R 13 , R 14 and R 16 are shown below. The possible combinations of compounds shown below are preferred.
Figure JPOXMLDOC01-appb-C000102
で示される基は、非置換のアリール、置換基群αより選択される１以上の基で置換されたアリール、非置換のヘテロアリール、又は置換基群αより選択される１以上の基で置換されたヘテロアリールである。好ましくは、置換基群αより選択される１以上の基で置換されたアリール又は置換基群αより選択される１以上の基で置換されたヘテロアリールである。より好ましくは、非置換の６員のアリール、置換基群αより選択される１以上の基で置換された６員のアリール、非置換の６員のヘテロアリール、置換基群αより選択される１以上の基で置換された６員のヘテロアリール又は式：
Figure JPOXMLDOC01-appb-C000103
で示される基である。
Figure JPOXMLDOC01-appb-C000102
The group represented by is substituted with one or more groups selected from unsubstituted aryl, aryl substituted with one or more groups selected from substituent group α, unsubstituted heteroaryl, or substituent group α Heteroaryl. Preferably, it is aryl substituted with one or more groups selected from substituent group α or heteroaryl substituted with one or more groups selected from substituent group α. More preferably, it is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group α, unsubstituted 6-membered heteroaryl, substituent group α 6-membered heteroaryl substituted with one or more groups or formula:
Figure JPOXMLDOC01-appb-C000103
It is group shown by these.
　置換基群αは、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換若しくは非置換の非芳香族複素環式基、
置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換の非芳香族複素環オキシ、
置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のシクロアルキルスルファニル、置換若しくは非置換のシクロアルケニルスルファニル、置換若しくは非置換のアリールスルファニル、置換若しくは非置換のヘテロアリールスルファニル、置換若しくは非置換の非芳香族複素環スルファニル、
置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のシクロアルキルスルフィニル、置換若しくは非置換のシクロアルケニルスルフィニル、置換若しくは非置換のアリールスルフィニル、置換若しくは非置換のヘテロアリールスルフィニル、置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアミノスルフィニル、
置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換の非芳香族複素環スルホニル、
置換若しくは非置換のアルキルスルホニルオキシ、置換若しくは非置換のアルケニルスルホニルオキシ、置換若しくは非置換のアルキニルスルホニルオキシ、置換若しくは非置換のシクロアルキルスルホニルオキシ、置換若しくは非置換のシクロアルケニルスルホニルオキシ、置換若しくは非置換のアリールスルホニルオキシ、置換若しくは非置換のヘテロアリールスルホニルオキシ、置換若しくは非置換の非芳香族複素環スルホニルオキシ、
置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換の非芳香族複素環カルボニル、
置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアルケニルカルボニルオキシ、置換若しくは非置換のアルキニルカルボニルオキシ、置換若しくは非置換のシクロアルキルカルボニルオキシ、置換若しくは非置換のシクロアルケニルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、置換若しくは非置換のヘテロアリールカルボニルオキシ、置換若しくは非置換の非芳香族複素環カルボニルオキシ、
置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル、
ハロゲン、ヒドロキシ、メルカプト、シアノ、アジド、置換若しくは非置換のアミジノ、グアニジノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル及びカルボキシからなる群である。
　置換基群αとしては、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、ハロゲン、ヒドロキシ及びシアノからなる群が好ましい。
　置換基群αの別の態様としては、ハロゲン、シアノ、アルキル、ヒドロキシアルキル、シアノアルキル、アリールアルケニル、アルキルオキシ、ハロアルキルオキシ、アルキルオキシアルキルオキシ、シクロアルキルアルキルオキシ、ハロシクロアルキルアルキルオキシ、アリールアルキルオキシ、シクロアルキル、ハロシクロアルキル、アルキルシクロアルキル、アルキルアリール、ハロアリール、シアノアリール、ヘテロアリール、ハロヘテロアリール、非芳香族複素環基、アルキルアミノ、アリールアミノ、アリールカルボニルアミノ、ハロアルキルスルホニルオキシ、アルキルカルバモイル、アルキルスルホニル、アルキルカルボニル、アルキルオキシカルボニル及びオキソからなる群が好ましい。 Substituent group α is
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group,
Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, Substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy,
Substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted cycloalkylsulfanyl, substituted or unsubstituted cycloalkenylsulfanyl, substituted or unsubstituted arylsulfanyl, Substituted or unsubstituted heteroarylsulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl,
Substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted arylsulfinyl, Substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aminosulfinyl,
Substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, Substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl,
Substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy, substituted or unsubstituted alkynylsulfonyloxy, substituted or unsubstituted cycloalkylsulfonyloxy, substituted or unsubstituted cycloalkenylsulfonyloxy, substituted or unsubstituted Substituted arylsulfonyloxy, substituted or unsubstituted heteroarylsulfonyloxy, substituted or unsubstituted non-aromatic heterocyclic sulfonyloxy,
Substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, Substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl,
Substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted cycloalkylcarbonyloxy, substituted or unsubstituted cycloalkenylcarbonyloxy, substituted or unsubstituted Substituted arylcarbonyloxy, substituted or unsubstituted heteroarylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy,
Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted Substituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl,
A group consisting of halogen, hydroxy, mercapto, cyano, azide, substituted or unsubstituted amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and carboxy.
Substituent group α includes substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl The group consisting of oxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy and cyano is preferred.
As another embodiment of the substituent group α, halogen, cyano, alkyl, hydroxyalkyl, cyanoalkyl, arylalkenyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, cycloalkylalkyloxy, halocycloalkylalkyloxy, arylalkyl Oxy, cycloalkyl, halocycloalkyl, alkylcycloalkyl, alkylaryl, haloaryl, cyanoaryl, heteroaryl, haloheteroaryl, non-aromatic heterocyclic group, alkylamino, arylamino, arylcarbonylamino, haloalkylsulfonyloxy, alkyl The group consisting of carbamoyl, alkylsulfonyl, alkylcarbonyl, alkyloxycarbonyl and oxo is preferred.
　上記の式：
Figure JPOXMLDOC01-appb-C000104
で示される基において、環Ｅは５員の芳香族複素環であり、環Ｆは６員の芳香族炭素環又は６員の芳香族複素環であり、環Ｅと環Ｆは縮合して二環性の芳香族複素環を形成している。環Ｅ及び／又は環Ｆは置換基群αより選択される１以上の基で置換されていてもよい。好ましくは、環Ｅ及び／又は環Ｆは、置換若しくは非置換のアルキルオキシ及び／又はハロゲンで置換されている。より好ましくは、環Ｅが置換若しくは非置換のアルキルオキシ又はハロゲンで置換されている。 Above formula:
Figure JPOXMLDOC01-appb-C000104
Ring E is a 5-membered aromatic heterocyclic ring, ring F is a 6-membered aromatic carbocyclic ring or 6-membered aromatic heterocyclic ring, and ring E and ring F are condensed to form It forms a cyclic aromatic heterocycle. Ring E and / or ring F may be substituted with one or more groups selected from substituent group α. Preferably, ring E and / or ring F are substituted with substituted or unsubstituted alkyloxy and / or halogen. More preferably, ring E is substituted with substituted or unsubstituted alkyloxy or halogen.
　式：
Figure JPOXMLDOC01-appb-C000105
で示される基として、具体的には、以下の式：
Figure JPOXMLDOC01-appb-C000106
で示される基が好ましく、
　以下の式：
Figure JPOXMLDOC01-appb-C000107
で示される基がより好ましい。
　上記式中の環上の炭素原子は置換基群αより選択される１以上の基で置換されていてもよい。好ましい置換基として、置換若しくは非置換のアルキルオキシ又はハロゲン等が挙げられる。 formula:
Figure JPOXMLDOC01-appb-C000105
Specifically, as the group represented by the following formula:
Figure JPOXMLDOC01-appb-C000106
Is preferably a group represented by
The following formula:
Figure JPOXMLDOC01-appb-C000107
Is more preferable.
The carbon atom on the ring in the above formula may be substituted with one or more groups selected from the substituent group α. Preferable substituents include substituted or unsubstituted alkyloxy or halogen.
式：
Figure JPOXMLDOC01-appb-C000108
で示される基が「置換基群αより選択される１以上の基で置換された６員のアリール」である場合、具体的には、式：
Figure JPOXMLDOC01-appb-C000109
で示される基が好ましい。
　Ｘ１はそれぞれ独立して－Ｃ（Ｈ）＝又は－Ｃ（Ｒ１２）＝である。
　Ｒ１７は置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換の非芳香族複素環オキシである。
　Ｒ１７としては、置換若しくは非置換のアルキルオキシが好ましい。
　Ｒ１２はそれぞれ独立して置換基群αより選択される基であり、それぞれ独立して置換若しくは非置換のアルキル、ハロゲン、ヒドロキシ、スルファニル、シアノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又はカルボキシが好ましい。
　Ｒ１２としては、ハロゲン（たとえば、フッ素原子、塩素原子など）が好ましい。 formula:
Figure JPOXMLDOC01-appb-C000108
Is a “6-membered aryl substituted with one or more groups selected from substituent group α”, specifically, the group represented by the formula:
Figure JPOXMLDOC01-appb-C000109
Is preferred.
X 1 is independently —C (H) ═ or —C (R 12 ) ═.
R 17 represents substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted Aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy.
R 17 is preferably substituted or unsubstituted alkyloxy.
R 12 is each independently a group selected from the substituent group α, and is independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted. Carbamoyl, substituted or unsubstituted sulfamoyl or carboxy is preferred.
R 12 is preferably halogen (for example, fluorine atom, chlorine atom, etc.).
式：

で示される基が「置換基群αより選択される１以上の基で置換された６員のアリール」である場合、別の態様としては、式：
Figure JPOXMLDOC01-appb-C000111
で示される基が好ましい。
　Ｘ１はそれぞれ独立して－Ｃ（Ｈ）＝又は－Ｃ（Ｒ１２）＝である。
　Ｒ１７は置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換の非芳香族複素環オキシである。
　Ｒ１７としては、置換若しくは非置換のアルキルオキシが好ましい。
　Ｒ１２はそれぞれ独立して置換基群αより選択される基であり、それぞれ独立して置換若しくは非置換のアルキル、ハロゲン、ヒドロキシ、スルファニル、シアノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又はカルボキシが好ましい。
　Ｒ１２’としては、ハロゲン（たとえば、フッ素原子、塩素原子など）が好ましい。 formula:

Is a “6-membered aryl substituted with one or more groups selected from the substituent group α”, another embodiment includes a group represented by the formula:
Figure JPOXMLDOC01-appb-C000111
Is preferred.
X 1 is independently —C (H) ═ or —C (R 12 ) ═.
R 17 represents substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted Aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy.
R 17 is preferably substituted or unsubstituted alkyloxy.
R 12 is each independently a group selected from the substituent group α, and is independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted. Carbamoyl, substituted or unsubstituted sulfamoyl or carboxy is preferred.
R 12 ′ is preferably a halogen (eg, fluorine atom, chlorine atom).
Figure JPOXMLDOC01-appb-C000112
で示される基としては、
Figure JPOXMLDOC01-appb-C000113
（式中、
Ｒ１ａ、Ｒ１ｂ、Ｒ１ｃ、Ｒ１ｄ、及びＲ１ｅはそれぞれ独立して、水素、ハロゲン、ヒドロキシ、カルボキシ、シアノ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、
Ｒ１ｆは水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル又は置換若しくは非置換のアルキニルカルボニルである。）で示される基が好ましい。
　Ｒ１ａとしては置換もしくは非置換のアルキル又は置換もしくは非置換のアルキルオキシが好ましい。
　Ｒ１ｂおよびＲ１ｃとしては、それぞれ独立して、水素又はハロゲン（たとえば、フッ素原子、塩素原子など）が好ましい。
Figure JPOXMLDOC01-appb-C000112
As the group represented by
Figure JPOXMLDOC01-appb-C000113
(Where
R 1a , R 1b , R 1c , R 1d , and R 1e are each independently hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarb Cycloalkenyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
R 1f is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, or substituted or unsubstituted alkynylcarbonyl. is there. ) Is preferred.
R 1a is preferably substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
R 1b and R 1c are each independently preferably hydrogen or halogen (for example, a fluorine atom, a chlorine atom, etc.).
　式（Ｉ）における環Ｂは、置換若しくは非置換の非芳香族炭素環又は置換若しくは非置換の非芳香族複素環である。
　環Ｂは、好ましくは置換若しくは非置換の４員の非芳香族炭素環又は置換若しくは非置換の４員の非芳香族複素環であり、より好ましくは、置換若しくは非置換の４員の非芳香族炭素環であり、さらに好ましくは置換若しくは非置換のシクロブタンである。。 Ring B in formula (I) is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
Ring B is preferably a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 4-membered non-aromatic heterocyclic ring, more preferably a substituted or unsubstituted 4-membered non-aromatic ring. Group carbocycle, more preferably substituted or unsubstituted cyclobutane. .
　式：
Figure JPOXMLDOC01-appb-C000114
で示される基としては、式：
Figure JPOXMLDOC01-appb-C000115
で示される基が好ましい。
　Ｒ１５はそれぞれ独立して水素、置換若しくは非置換のアルキル、ハロゲン又はヒドロキシであり、好ましくは水素である。
　環Ｂに相当する環上のメチレン基は置換されていてもよい。置換基としては置換基群αから選択される環を挙げられる。好ましくはハロゲン、置換若しくは非置換のアルキルである。 formula:
Figure JPOXMLDOC01-appb-C000114
As the group represented by the formula:
Figure JPOXMLDOC01-appb-C000115
Is preferred.
Each R 15 is independently hydrogen, substituted or unsubstituted alkyl, halogen or hydroxy, preferably hydrogen.
The methylene group on the ring corresponding to ring B may be substituted. Examples of the substituent include a ring selected from the substituent group α. Preferred is halogen, substituted or unsubstituted alkyl.
　式：
Figure JPOXMLDOC01-appb-C000116
で示される基の別の好ましい態様として、式：
Figure JPOXMLDOC01-appb-C000117
で示される基が挙げられる。 formula:
Figure JPOXMLDOC01-appb-C000116
In another preferred embodiment of the group represented by formula:
Figure JPOXMLDOC01-appb-C000117
The group shown by these is mentioned.
　環Ｃは置換若しくは非置換の６員の芳香族炭素環、置換若しくは非置換の５員の芳香族複素環又は置換若しくは非置換の６員の芳香族複素環である。好ましくは、置換若しくは非置換の５員の芳香族複素環である。
　環Ｃにおける「６員の芳香族炭素環」としては、ベンゼンが好ましい。
　環Ｃにおける「５員の芳香族複素環」としては、イソオキサゾール、チアゾール又はオキサジアゾールが好ましく、特にイソキサゾールが好ましい。 Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring, or a substituted or unsubstituted 6-membered aromatic heterocyclic ring. Preferably, it is a substituted or unsubstituted 5-membered aromatic heterocyclic ring.
As the “6-membered aromatic carbocycle” in ring C, benzene is preferable.
As the “5-membered aromatic heterocycle” in ring C, isoxazole, thiazole or oxadiazole is preferable, and isoxazole is particularly preferable.
　Ｕは－ＣＲ４Ｒ５－、－ＣＲ４Ｒ５－Ｏ－、－ＣＲ４Ｒ５－Ｓ－、－ＣＲ４Ｒ５－ＮＲ６－、－Ｏ－、－Ｓ－、－ＮＲ６－、－Ｏ－ＣＲ４Ｒ５－、－Ｓ－ＣＲ４Ｒ５－又は－ＮＲ６－ＣＲ４Ｒ５－であり、ここで、左の結合手は環Ａに結合し、右の結合手は環Ｂに結合する。好ましくは、－Ｏ－、－ＣＲ４Ｒ５－又は－Ｏ－ＣＲ４Ｒ５－であり、より好ましくは、－Ｏ－である。 U is -CR 4 R 5 -, - CR 4 R 5 -O -, - CR 4 R 5 -S -, - CR 4 R 5 -NR 6 -, - O -, - S -, - NR 6 -, —O—CR 4 R 5 —, —S—CR 4 R 5 — or —NR 6 —CR 4 R 5 —, wherein the left bond is bonded to ring A and the right bond is a ring Bind to B. Preferred is —O—, —CR 4 R 5 — or —O—CR 4 R 5 —, and more preferred is —O—.
　Ｔは－ＣＲ７Ｒ８－、－ＣＲ７Ｒ８－Ｏ－、－ＣＲ７Ｒ８－Ｓ－、－ＣＲ７Ｒ８－ＮＲ９－、－Ｏ－、－Ｓ－、－ＮＲ９－、－Ｃ（＝Ｏ）－又は－ＳＯ２－であり、ここで、左の結合手は環Ｂに結合し、右の結合手は環Ｃに結合する。好ましくは、－ＣＲ７Ｒ８－又は－Ｏ－である。 T is -CR 7 R 8 -, - CR 7 R 8 -O -, - CR 7 R 8 -S -, - CR 7 R 8 -NR 9 -, - O -, - S -, - NR 9 -, —C (═O) — or —SO 2 —, wherein the left bond is bonded to ring B and the right bond is bonded to ring C. Preferred is —CR 7 R 8 — or —O—.
　Ｌは－ＣＲ１０Ｒ１１－又は－Ｃ（＝Ｏ）－である。 L is —CR 10 R 11 — or —C (═O) —.
　Ｒ４、Ｒ５、Ｒ７、Ｒ８、Ｒ１０及びＲ１１はそれぞれ独立して水素、ヒドロキシ、ハロゲン、置換若しくは非置換のアルキル又はシアノである。好ましくは水素又はハロゲンであり、より好ましくは水素である。
Ｒ６及びＲ９はそれぞれ独立して水素又は置換若しくは非置換のアルキルであり、好ましくは水素である。 R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl or cyano. Preferred is hydrogen or halogen, and more preferred is hydrogen.
R 6 and R 9 are each independently hydrogen or substituted or unsubstituted alkyl, preferably hydrogen.
　ｐは０又は１である。好ましくは０である。 P is 0 or 1. Preferably it is 0.
　ｑは０又は１である。好ましくは０である。 Q is 0 or 1. Preferably it is 0.
　ｒは０又は１である。好ましくは０である。 R is 0 or 1. Preferably it is 0.
　Ｒ１３はハロゲン、ヒドロキシ及びシアノからなる群から選択される１以上の置換基で置換されていてもよいメチルである。
　Ｒ１３としては、ハロゲン及びヒドロキシからなる群から選択される１以上の置換基で置換されていてもよいメチルが好ましく、さらに好ましくはメチルである。 R 13 is methyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and cyano.
R 13 is preferably methyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxy, more preferably methyl.
　Ｒ１４はハロゲン、ヒドロキシ、シアノ、メチルオキシ及び置換若しくは非置換のカルバモイルからなる群から選択される１以上の置換基で置換されていてもよいメチルカルボニルである。
　Ｒ１４としては、：ハロゲン及びヒドロキシからなる群から選択される１以上の置換基で置換されていてもよいメチルカルボニルが好ましく、さらに好ましくはメチルカルボニルである。 R 14 is methylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, methyloxy and substituted or unsubstituted carbamoyl.
R 14 is preferably methylcarbonyl optionally substituted with one or more substituents selected from the group consisting of: halogen and hydroxy, and more preferably methylcarbonyl.
　Ｒ１６は水素又は置換若しくは非置換のアルキルであり、水素が好ましい。 R 16 is hydrogen or substituted or unsubstituted alkyl, preferably hydrogen.
　式（Ｉ）で示される化合物において、環Ｃが置換若しくは非置換の５員の芳香族複素環である場合、Ｔ又は環Ｂと結合する環Ｃ上の原子の位置番号を１位とした場合の３位又は４位に位置する環Ｃ上の原子に、式：
Figure JPOXMLDOC01-appb-C000118
で示される基が結合する化合物又はその製薬上許容される塩が好ましい。具体的には、置換若しくは非置換の５員の芳香族複素環である環Ｃを、以下の式：
Figure JPOXMLDOC01-appb-C000119
で示した場合、以下の式：
Figure JPOXMLDOC01-appb-C000120
又は、以下の式：
Figure JPOXMLDOC01-appb-C000121
で示される化合物又はその製薬上許容される塩が好ましい。 In the compound represented by formula (I), when ring C is a substituted or unsubstituted 5-membered aromatic heterocycle, the position number of the atom on ring C bonded to T or ring B is the 1-position To the atom on ring C located in the 3- or 4-position of
Figure JPOXMLDOC01-appb-C000118
Or a pharmaceutically acceptable salt thereof is preferred. Specifically, a ring C that is a substituted or unsubstituted 5-membered aromatic heterocycle is represented by the following formula:
Figure JPOXMLDOC01-appb-C000119
The following formula:
Figure JPOXMLDOC01-appb-C000120
Or the following formula:
Figure JPOXMLDOC01-appb-C000121
Or a pharmaceutically acceptable salt thereof is preferred.
　式（Ｉ）で示される化合物において、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環である場合、
Figure JPOXMLDOC01-appb-C000122
で示される基が、Ｔ又は環Ｂに対してメタ位又はパラ位の位置で環Ｃと結合している化合物又はその製薬上許容される塩が好ましい。環Ｃがベンゼン環である場合、式（Ｉ）は以下の式：
Figure JPOXMLDOC01-appb-C000123
で示される化合物又はその製薬上許容される塩が好ましい。 In the compound represented by the formula (I), when the ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
Figure JPOXMLDOC01-appb-C000122
Or a pharmaceutically acceptable salt thereof, in which the group represented by is bonded to ring C at the meta-position or para-position relative to T or ring B. When ring C is a benzene ring, formula (I) is represented by the following formula:
Figure JPOXMLDOC01-appb-C000123
Or a pharmaceutically acceptable salt thereof is preferred.
　環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環である場合、Ｕ又は環Ａと結合する環Ｂ上の原子の位置番号を１位とした場合の４位に位置する環Ｂ上の原子にＴ又は環Ｃが結合する化合物又はその製薬上許容される塩が好ましい。
When Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, the position number of the atom on Ring B bonded to U or Ring A is A compound or a pharmaceutically acceptable salt thereof in which T or ring C is bonded to an atom on ring B located at the 4-position when it is located at the 1-position.
　但し、本願発明の化合物に、以下の（i）～（iii）の化合物は含まれない。
（i）環Ｂが置換若しくは非置換の５員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０であり、環Ｃが環Ｂ上の窒素原子に結合している化合物、
（ii）環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０である化合物、
（iii）環Ｂが置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが１であり、Ｔが環Ｂ上の窒素原子に結合している化合物。 However, the compounds of the present invention do not include the following compounds (i) to (iii).
(I) Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring A compound in which p is 0, q is 0, and ring C is bonded to a nitrogen atom on ring B;
(Ii) Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
(Iii) Ring B is a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring Wherein p is 0, q is 1 and T is bonded to a nitrogen atom on ring B.
　上記（i）の化合物として、以下の式：
Figure JPOXMLDOC01-appb-C000124
で示される化合物が挙げられる。 As a compound of the above (i), the following formula:
Figure JPOXMLDOC01-appb-C000124
The compound shown by these is mentioned.
　上記（ii）の化合物として、以下の式：
Figure JPOXMLDOC01-appb-C000125
で示される化合物が挙げられる。 As a compound of the above (ii), the following formula:
Figure JPOXMLDOC01-appb-C000125
The compound shown by these is mentioned.
　上記（iii）の化合物として、以下の式：
Figure JPOXMLDOC01-appb-C000126
で示される化合物が挙げられる。 As the compound of the above (iii), the following formula:
Figure JPOXMLDOC01-appb-C000126
The compound shown by these is mentioned.
　「ＡＣＣ２の関与する疾患」としては、メタボリックシンドローム、肥満症、糖尿病、インスリン抵抗性、耐糖能異常、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、脂質異常症、高血圧症、心血管疾患、動脈硬化症、アテローム性動脈硬化症、心不全、心筋梗塞、感染症、腫瘍等が挙げられる。 “Diseases involving ACC2” include metabolic syndrome, obesity, diabetes, insulin resistance, impaired glucose tolerance, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, dyslipidemia Disease, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, heart failure, myocardial infarction, infection, tumor and the like.
　式（Ｉ）で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等）、ラセミ体又はそれらの混合物を含む。 The compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers etc.), racemates or mixtures thereof.
　式（Ｉ）で示される化合物において、Ｒ１３が結合する炭素原子は不斉炭素であり、R体及びS体が存在するが、本発明には、ラセミ体及び光学活性体（Ｒ体及びＳ体）のいずれも包含される。 In the compound represented by the formula (I), the carbon atom to which R 13 is bonded is an asymmetric carbon, and R and S forms exist. In the present invention, racemates and optically active forms (R and S forms) are present. Any body).
　式（Ｉ）で示される化合物は、式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000127
で示される化合物が好ましい。 The compound of formula (I) is represented by formula (II):
Figure JPOXMLDOC01-appb-C000127
The compound shown by these is preferable.
　式（Ｉ）で示される化合物の一つ以上の水素、炭素及び／又は他の原子は、それぞれ水素、炭素及び／又は他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉ及び３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素及び塩素が包含される。式（Ｉ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究及び／又は診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
　式（Ｉ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下又は非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）を参照にできる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. In this method, a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
　式（Ｉ）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）及びアミノ酸との塩、又は無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、及び有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等）との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium). , Barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline) , Quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, propion) Acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid Oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Can be mentioned. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
　本発明の式（Ｉ）で示される化合物又はその製薬上許容される塩は、溶媒和物（例えば、水和物等）及び／又は結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物及び結晶多形も包含する。「溶媒和物」は、式（Ｉ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）で示される化合物又はその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）で示される化合物又はその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention Various solvates and crystal polymorphs are also included. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
　本発明の式（Ｉ）で示される化合物又はその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法及び製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
　式（Ｉ）で示される化合物又はその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。 When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
　プロドラッグに使用する保護基としては、例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、p-ＣＨ３-Ｏ-ＰｈＳＯ３－、ＰｈＳＯ３－、p-ＣＨ３ＰｈＳＯ３－が挙げられる。 Examples of the protective group used for the prodrug include CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 — CF 3 CH 2 SO 3 —, p—CH 3 —O—PhSO 3 —, PhSO 3 —, and p—CH 3 PhSO 3 —.
　本発明に係る化合物の一般的合成方法を以下に示す。これら合成に用いる出発物質及び反応試薬はいずれも、商業的に入手可能であるか、又は商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。 The general synthesis method of the compound according to the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds.
　本発明に係る式（Ｉ）で示される化合物は、例えば、以下の製法Ａ～Ｌに示す合成ルートによって製造することができる。 The compound represented by the formula (I) according to the present invention can be produced, for example, by the synthetic route shown in the following production methods A to L.
　本発明に係る化合物の一般的合成方法を以下に示す。これら合成に用いる出発物質及び反応試薬はいずれも、商業的に入手可能であるか、又は商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。 The general synthesis method of the compound according to the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds.
　本発明に係る式（Ｉ）が以下の式（Ｉ－ａ）：
Figure JPOXMLDOC01-appb-C000128
（式中、Ｘ４は－Ｓ－，－ＮＲ６－又は－Ｏ－であり、ｎは０又は１であり、ｍは０又は１であり、他の記号は前記と同意義である。）で示される化合物である場合、例えば、以下の製法Ａで示す合成ルートによって製造することができる。 Formula (I) according to the present invention is represented by the following formula (Ia):
Figure JPOXMLDOC01-appb-C000128
(Wherein X 4 is —S—, —NR 6 — or —O—, n is 0 or 1, m is 0 or 1, and other symbols are as defined above.) For example, it can be produced by the synthesis route shown in the following production method A.
製法Ａ
Figure JPOXMLDOC01-appb-C000129
（式中、Ｙ１はアルキルであり、その他の記号は前記と同意義である。） Manufacturing method A
Figure JPOXMLDOC01-appb-C000129
(Wherein Y 1 is alkyl, and other symbols are as defined above.)
工程１
　式（Ｉａ１）で示される化合物と式（Ｉａ２）で示される化合物を反応させ、式（Ｉａ３）で示される化合物を製造する工程である。トリフェニルホスフィン及び縮合剤の存在下で行なうことができ、または活性化剤によって式（Ｉａ１）で示される化合物を活性化した後に塩基存在下で、式（Ｉａ２）で示される化合物と反応させて行うこともできる。
　縮合剤としては、ＤＥＡＤ、ＤＩＡＤ等が挙げられ、式（Ｉａ１）で示される化合物に対して１～５当量を用いることができる。
　活性化剤としては、メタンスルホニルクロリド、ｐ－トルエンスルホニルクロリドなどを用いることができる。
　塩基としては、例えば金属水素化物（例、水素化ナトリウムなど）、金属水酸化物（例、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなど）、金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなど）、金属アルコキシド（例、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ－ブトキシドなど）、炭酸水素ナトリウム、金属酢酸塩（例、酢酸ナトリウム、酢酸カリウム、酢酸セシウムなど）、金属リン酸塩（リン酸ナトリウム、リン酸カリウムなど）、金属ナトリウム、金属アミド、有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、ピリジン、２，６－ルチジンなど）、ピリジン、アルキルリチウム（ｎ－ＢｕＬｉ、ｓｅｃ－ＢｕＬｉ、ｔｅｒｔ－ＢｕＬｉ）、グリニャール試薬等が挙げられる。好ましくは、金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなど）または有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、２，６－ルチジンなど）を用いればよい。
　反応温度は、０℃～加熱還流下である。
　反応時間は、０．１時間～１２時間、好ましくは０．２時間～６時間である。
　反応溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）、エステル類（例、酢酸メチル、酢酸エチルなど）、ケトン類（例、アセトン、メチルエチルケトンなど）、ニトリル類（例、アセトニトリルなど）、アルコール類（例、メタノール、エタノール、ｔ－ブタノールなど）、水及びそれらの混合溶媒等が挙げられ、単独又は混合して用いることができる。好ましくはエーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）を用いればよい。 Process 1
In this step, a compound represented by formula (Ia3) is reacted with a compound represented by formula (Ia2) to produce a compound represented by formula (Ia3). Can be carried out in the presence of triphenylphosphine and a condensing agent, or can be reacted with a compound of formula (Ia2) in the presence of a base after activating the compound of formula (Ia1) with an activator. It can also be done.
Examples of the condensing agent include DEAD and DIAD, and 1 to 5 equivalents can be used with respect to the compound represented by the formula (Ia1).
As the activator, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be used.
Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Potassium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal acetate (eg, sodium acetate, potassium acetate, cesium acetate) Etc.), metal phosphate (sodium phosphate, potassium phosphate, etc.), metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU, pyridine, 2,6-lutidine, etc.), pyridine, alkyllithium (N-BuLi, sec-BuLi, tert BuLi), the Grignard reagent, and the like. Preferably, a metal carbonate (eg, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.) or an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
The reaction temperature is 0 ° C. to heating under reflux.
The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.
Reaction solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) Halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, Ethyl acetate, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water, and mixed solvents thereof. These can be used alone or in combination. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
工程２
　式（Ｉａ３）で示される化合物と還元剤を反応させ、式（Ｉａ４）で示される化合物を製造する工程である。
　還元剤としては、水素化ホウ素リチウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム等が挙げられ、式（Ｉａ３）で示される化合物に対して、１～１０当量を用いることができる。
　反応温度は、０℃～加熱還流下である。
　反応時間は、０．２時間～４８時間、好ましくは０．５時間～２４時間である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、ジクロロメタン等を単独又は混合して用いればよい。 Process 2
In this step, the compound represented by the formula (Ia3) is reacted with a reducing agent to produce the compound represented by the formula (Ia4).
Examples of the reducing agent include lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, and 1 to 10 equivalents can be used with respect to the compound represented by the formula (Ia3).
The reaction temperature is 0 ° C. to heating under reflux.
The reaction time is 0.2 to 48 hours, preferably 0.5 to 24 hours.
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane, or the like may be used alone or in combination.
工程３
　式（Ｉａ４）で示される化合物と酸化剤を反応させ、式（Ｉａ５）で示される化合物を製造する工程である。
　酸化剤としては、デス・マーチン・ペルヨ－ジナン、ＩＢＸ（２-ヨードキシ安息香酸）、クロム・マンガン・銀等の金属塩や金属酸化物、有機酸化剤が挙げられ、化合物Ｉａ４に対して、１～１０モル当量を用いることができる。
　反応温度は、０℃～加熱還流下、好ましくは２０℃～加熱還流下である。
　反応時間は、０．２時間～４８時間、好ましくは１時間～２４時間である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）を用いればよい。本酸化反応工程は、Ｓｗｅｒｎ酸化、ＴＥＭＰＯ酸化等の条件で行うこともできる。 Process 3
In this step, the compound represented by the formula (Ia4) is reacted with an oxidizing agent to produce the compound represented by the formula (Ia5).
Examples of the oxidizing agent include metal salts and metal oxides such as Dess-Martin, periodinane, IBX (2-iodoxybenzoic acid), chromium, manganese, and silver, and an organic oxidizing agent. Up to 10 molar equivalents can be used.
The reaction temperature is 0 ° C. to heating under reflux, preferably 20 ° C. to heating under reflux.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) may be used. This oxidation reaction step can also be performed under conditions such as Swern oxidation and TEMPO oxidation.
工程４
　式（Ｉａ５）で示される化合物とヒドロキシルアミン塩酸塩を塩基存在下で反応させ、式（Ｉａ６）で示される化合物を製造する工程である。
　工程１記載の塩基を用いることができる。好ましくは、金属酢酸塩（例、酢酸ナトリウム、酢酸カリウム、酢酸セシウムなど）、金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなど）又は有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、２，６－ルチジンなど）を用いればよい。
　反応温度は、０℃～加熱還流下である。好ましくは０℃～３０℃である。
　反応時間は、０．２時間～４８時間、好ましくは１時間～２４時間である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独又は混合して用いればよい。 Process 4
In this step, the compound represented by the formula (Ia5) is reacted with hydroxylamine hydrochloride in the presence of a base to produce a compound represented by the formula (Ia6).
The base described in Step 1 can be used. Preferably, metal acetate (eg, sodium acetate, potassium acetate, cesium acetate, etc.), metal carbonate (eg, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.) or organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
The reaction temperature is 0 ° C. to heating under reflux. The temperature is preferably 0 ° C to 30 ° C.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, methanol, ethanol, propanol, isopropanol, butanol, water and the like can be mentioned, and these may be used alone or in combination.
工程５
　式（Ｉａ６）で示される化合物とＮＣＳを反応させた後、式（Ｉａ７）で示される化合物を反応させ、式（Ｉａ８）で示される化合物を製造する工程である。塩基存在下で行うことができる。
　塩基としては、工程１記載の塩基を用いることができる。好ましくは、トリエチルアミン、ＤＩＥＡ等が挙げられ、式（Ｉａ６）で示される化合物に対して、１～１０当量を用いることができる。
　反応温度は、０℃～溶媒の加熱還流下である。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、トルエン、ＤＭＦ、ＤＭＡ、ＮＭＰ、ジオキサン等が挙げられ、単独又は混合して用いることができる。 Process 5
In this step, the compound represented by the formula (Ia6) is reacted with NCS, and then the compound represented by the formula (Ia7) is reacted to produce the compound represented by the formula (Ia8). It can be carried out in the presence of a base.
As the base, the base described in Step 1 can be used. Preferable examples include triethylamine, DIEA, and the like, and 1 to 10 equivalents can be used with respect to the compound represented by the formula (Ia6).
The reaction temperature is 0 ° C. to solvent reflux.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane and the like can be mentioned, and these can be used alone or in combination.
工程６
　式（Ｉａ８）で示される化合物と脱保護剤を反応させ、式（Ｉａ９）で示される化合物を得る工程である。
　脱保護剤としては、ヒドラジン、メチルヒドラジン等が挙げられ、式（Ｉａ８）で示される化合物に対して、１～２０当量を用いることができる。
　反応温度は、２０℃～溶媒の加熱還流下、場合によってはマイクロウェーブ照射下の温度で行う。
　反応時間は、０．１時間～１２０時間、好ましくは１時間～８０時間である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、ジオキサン、メタノール、エタノール、クロロホルム、ジクロロメタン、水等が挙げられ、単独又は混合して用いればよい。 Step 6
In this step, a compound represented by the formula (Ia8) is reacted with a deprotecting agent to obtain a compound represented by the formula (Ia9).
Examples of the deprotecting agent include hydrazine, methyl hydrazine and the like, and 1 to 20 equivalents can be used with respect to the compound represented by the formula (Ia8).
The reaction temperature is 20 ° C. to a temperature under reflux of the solvent, optionally under microwave irradiation.
The reaction time is 0.1 hour to 120 hours, preferably 1 hour to 80 hours.
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, dichloromethane, water and the like can be mentioned, and these may be used alone or in combination.
工程７
　式（Ｉａ９）で示される化合物から、式（Ｉ-ａ）で示される化合物を製造する工程である。導入するＲ１４によって、各種条件を用いることができる。たとえば、イソシアナート、酸クロライド、混合酸無水物を塩基条件下で反応させる方法、縮合剤の存在下、カルボン酸等を反応させる方法を用いることができる。
　縮合剤としては、ジシクロへキシルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド－Ｎ－ヒドロキシベンゾトリアゾール、ＥＤＣ、４－（４，６－ジメトキシ－１，３，５，－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、ＨＡＴＵ等が挙げられ、式（Ｉａ８）で示される化合物に対して１～５当量を用いることができる。
　塩基としては、工程１記載の塩基を用いることができる。好ましくは、ピリジン、トリエチルアミン、ＤＩＥＡ、炭酸ナトリウム、炭酸水素ナトリウム等を式（Ｉａ９）で示される化合物に対して１～１０当量用いればよい。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、メタノール、テトラヒドロフラン、トルエン、ＤＭＦ、ジオキサン、ジクロロメタン、水等が挙げられ、単独又は混合して用いればよい。 Step 7
In this step, the compound represented by the formula (Ia) is produced from the compound represented by the formula (Ia9). Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used.
Examples of condensing agents include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 equivalents can be used with respect to the compound represented by the formula (Ia8).
As the base, the base described in Step 1 can be used. Preferably, 1 to 10 equivalents of pyridine, triethylamine, DIEA, sodium carbonate, sodium hydrogen carbonate and the like may be used with respect to the compound represented by the formula (Ia9).
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, methanol, tetrahydrofuran, toluene, DMF, dioxane, dichloromethane, water and the like can be mentioned, and these may be used alone or in combination.
　本発明に係る式（Ｉ）で示される化合物が、式（Ｉ－ｂ）：
Figure JPOXMLDOC01-appb-C000130
（式中、各記号は前記と同意義である。）
で示される化合物である場合、以下に示す製法Ｂによって製造することもできる。
製法Ｂ
Figure JPOXMLDOC01-appb-C000131
（式中、Ｙ３はＢｏｃやベンジルなどの保護基であり、Ｙ４はハロゲン、－Ｏ－Ｔｆ、－Ｏ－Ｍｓ、－Ｏ－Ｔｓ等であり、その他の記号は前記と同意義である） The compound represented by the formula (I) according to the present invention is represented by the formula (Ib):
Figure JPOXMLDOC01-appb-C000130
(In the formula, each symbol is as defined above.)
Can be produced by the production method B shown below.
Manufacturing method B
Figure JPOXMLDOC01-appb-C000131
(Wherein Y 3 is a protecting group such as Boc and benzyl, Y 4 is halogen, —O—Tf, —O—Ms, —O—Ts, etc., and other symbols are as defined above.) )
工程１
　式（Ｉｂ１）で示される化合物を還元剤と反応させ、式（Ｉｂ２）で示される化合物を製造する工程である。本工程は、製法Ａの工程２と同様に行うことができる。 Process 1
In this step, the compound represented by the formula (Ib1) is reacted with a reducing agent to produce the compound represented by the formula (Ib2). This step can be performed in the same manner as in step 2 of production method A.
工程２
　式（Ｉｂ２）で示される化合物と酸化剤を反応させ、式（Ｉｂ３）で示される化合物を製造する工程である。本工程は、製法Ａの工程３と同様に行うことができる。 Process 2
In this step, the compound represented by the formula (Ib2) is reacted with an oxidizing agent to produce the compound represented by the formula (Ib3). This step can be performed in the same manner as in step 3 of production method A.
工程３
式（Ｉｂ３）で示される化合物とヒドロキシルアミン塩酸塩を塩基存在下で反応させ、式（Ｉｂ４）で示される化合物を製造する工程である。本工程は、製法Ａの工程１と同様に行うことができる。 Process 3
In this step, the compound represented by the formula (Ib3) is reacted with hydroxylamine hydrochloride in the presence of a base to produce the compound represented by the formula (Ib4). This step can be performed in the same manner as in step 1 of production method A.
工程４
　　式（Ｉｂ４）で示される化合物とＮＣＳを反応させた後、式（Ｉｂ５）で示される化合物を反応させ、式（Ｉｂ６）で示される化合物を製造する工程である。塩基存在下で行うことができる。本工程は、製法Ａの工程５と同様に行うことができる。 Process 4
In this step, the compound represented by the formula (Ib4) is reacted with NCS and then the compound represented by the formula (Ib5) is reacted to produce the compound represented by the formula (Ib6). It can be carried out in the presence of a base. This step can be performed in the same manner as in step 5 of production method A.
工程５
　式（Ｉｂ６）で示される化合物と脱保護剤を反応させ、式（Ｉｂ７）で示される化合物を得る工程である。本工程は、製法Ａの工程６と同様に行うことができる。 Process 5
In this step, a compound represented by the formula (Ib6) is reacted with a deprotecting agent to obtain a compound represented by the formula (Ib7). This step can be performed in the same manner as in step 6 of production method A.
工程６
　式（Ｉｂ７）で示される化合物から、式（Ｉｂ８）で示される化合物を製造する工程である。導入するＲ１４によって、各種条件を用いることができる。たとえば、イソシアナート、酸クロライド、混合酸無水物を塩基条件下で反応させる方法、縮合剤の存在下、カルボン酸等を反応させる方法を用いることができる。本工程は、製法Ａの工程７と同様に行うことができる。 Step 6
In this step, the compound represented by the formula (Ib8) is produced from the compound represented by the formula (Ib7). Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used. This step can be performed in the same manner as in step 7 of production method A.
工程７
　式（Ｉｂ８）で示される化合物の脱保護を行い、式（Ｉｂ９）で示される化合物を製造する工程である。保護基の脱保護反応は公知であり、例えばGreene's Protective Groups in Organic Synthesis, 4th Edition　( Peter G. M. Wuts, Theodora W. Greene, Wiley, 2006) に記載の方法で実施することができる。反応溶媒としては、工程１記載の溶媒を単独又は混合して用いることができる。 Step 7
In this step, the compound represented by the formula (Ib8) is deprotected to produce the compound represented by the formula (Ib9). The deprotection reaction of the protecting group is known and can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 4th Edition (Peter G. M. Wuts, Theodora W. Greene, Wiley, 2006). As the reaction solvent, the solvents described in Step 1 can be used alone or in combination.
工程８
　式（Ｉｂ９）で示される化合物と式（Ｉｂ１０）で示される化合物を反応させ、式（Ｉ－ｂ）で示される化合物を得る工程である。塩基、金属触媒、配位子存在下で行うことができる。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム、ビス（シクロペンタジエニル）ジルコニウムクロリドヒドリドなどが挙げられ、式（Ｉｂ１０）で示される化合物に対して、０．００１～０．５当量を用いることができる。
　配位子としては、トリフェニルホスフィン、Ｘａｎｔｐｈｏｓ、ＢＩＮＡＰ、Ｘ－ｐｈｏｓなどが挙げられ、０．００１～１当量を用いることができる。
　塩基としては、製法Ａの工程１記載の塩基を用いることができる。好ましくは、トリエチルアミン、ジイソプロピルエチルアミン、ＤＢＵ、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム、リン酸カリウム等が挙げられ、式（Ｉｂ１０）で示される化合物に対して、１～１０当量を用いればよい。
　反応温度は、０℃～溶媒の加熱還流下、場合によってはマイクロウェーブ照射下の温度で行う。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、製法Ａの工程１記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、ジメトキシエタン、トルエン、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＤＭＳＯ，ジオキサン、水等が挙げられ、単独又は混合して用いればよい。 Process 8
In this step, the compound represented by the formula (Ib9) is reacted with the compound represented by the formula (Ib10) to obtain a compound represented by the formula (Ib). The reaction can be performed in the presence of a base, a metal catalyst, and a ligand.
Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri -Tert-butylphosphine) palladium, bis (cyclopentadienyl) zirconium chloride hydride, and the like, and 0.001-0.5 equivalents can be used with respect to the compound represented by the formula (Ib10).
Examples of the ligand include triphenylphosphine, Xantphos, BINAP, X-phos and the like, and 0.001 to 1 equivalent can be used.
As the base, the base described in Step 1 of production method A can be used. Preferably, triethylamine, diisopropylethylamine, DBU, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, etc. 1 to 10 equivalents may be used with respect to the compound represented by the formula (Ib10).
The reaction is carried out at a temperature from 0 ° C. to refluxing with a solvent, optionally under microwave irradiation.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferred examples include tetrahydrofuran, dimethoxyethane, toluene, DMF, DMA, NMP, DMSO, dioxane, water, and the like, which may be used alone or in combination.
　本発明に係る式（Ｉ）で示される化合物が、式（Ｉ－ｃ）：
Figure JPOXMLDOC01-appb-C000132
（式中、環Ｆは置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、Ｘ２は－Ｓ－、－Ｏ－又は－ＮＲ１８－であり、Ｒ１８は水素または置換基群αから選択される置換基であり、その他の記号は前記と同意義である。）で示される化合物である場合、以下に示す製法Ｃによって製造することもできる。 The compound represented by the formula (I) according to the present invention is represented by the formula (Ic):
Figure JPOXMLDOC01-appb-C000132
Wherein ring F is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring, and X 2 represents —S—, —O— or —NR 18 —. And R 18 is a hydrogen or a substituent selected from the substituent group α, and other symbols are as defined above.), It is produced by the production method C shown below. You can also.
製法Ｃ
Figure JPOXMLDOC01-appb-C000133
（式中、各記号は前記と同意義である） Manufacturing method C
Figure JPOXMLDOC01-appb-C000133
(Wherein each symbol is as defined above)
工程１
　式（Ｉｃ１）で示される化合物と式（Ｉｃ２）で示される化合物とを反応させ、式（Ｉｃ３）で示される化合物を製造する工程である。縮合剤を用いてアミノ基とカルボン酸を縮合させアミド化した後に脱水剤を用いる方法で製造できる。
　ＤＭＦ，ＤＭＡ，ＮＭＰ，ジクロロメタン、テトラヒドロフランなどの溶媒中、縮合剤として、ジシクロへキシルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド－Ｎ－ヒドロキシベンゾトリアゾール、ＥＤＣ、４－（４，６－ジメトキシ－１，３，５，－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、ＨＡＴＵ等を、式（Ｉｃ１）で示される化合物に対して１～５当量を用いることができる。
　脱水剤として、トリフェニルホスフィンとともにＤＩＡＤ又はＤＥＡＤ等を用いる方法や酸性条件下で行なう方法（例、ｐ－トシル酸、トリフルオロ酢酸、メタンスルホン酸、硫酸など）が挙げられる。反応溶媒としては、製法Ａ工程１記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、トルエンなどを用いればよい。
　反応温度は、０℃～溶媒の加熱還流下である。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。 Process 1
In this step, the compound represented by the formula (Ic1) is reacted with the compound represented by the formula (Ic2) to produce a compound represented by the formula (Ic3). It can be produced by a method using a dehydrating agent after condensing an amino group and a carboxylic acid using a condensing agent to amidate.
In a solvent such as DMF, DMA, NMP, dichloromethane, tetrahydrofuran, etc., as a condensing agent, dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3 , 5, -triazin-2-yl) -4-methylmorpholinium chloride, HATU and the like can be used in an amount of 1 to 5 equivalents with respect to the compound represented by the formula (Ic1).
Examples of the dehydrating agent include a method using DIAD or DEAD together with triphenylphosphine, and a method performed under acidic conditions (eg, p-tosylic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid, etc.). As the reaction solvent, the solvent described in Production Method A, Step 1 can be used. Preferably, tetrahydrofuran, toluene or the like may be used.
The reaction temperature is 0 ° C. to solvent reflux.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
工程２
　式（Ｉｃ３）で示される化合物と水素化ホウ素化合物を反応させた後に酸化剤で処理することによって、式（Ｉｃ４）で示される化合物を製造する工程である。
　水素化ホウ素化合物として、ボラン・テトラヒドロフラン錯体、ボラン・ジメチルスルフィド錯体、カテコールボラン、９－ボラビシクロ[３.３.１]ノナンなどが挙げられ、式（Ｉｃ３）で示される化合物に対して１～１０モル当量を用いることができる。
　酸化剤として、過酸化水素、過ホウ酸ナトリウムなどが挙げられ、式（Ｉｃ３）で示される化合物に対して１～１５モル当量を用いることができる。
　反応温度は、０℃～加熱還流下である。
　反応時間は、０．２時間～４８時間、好ましくは１時間～２４時間である。
　反応溶媒としては、製法Ａ工程１記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、ジメトキシエタン、ジオキサン等が挙げられ、単独又は混合して用いればよい。 Process 2
In this step, the compound represented by the formula (Ic3) is reacted with the borohydride compound and then treated with an oxidizing agent to produce the compound represented by the formula (Ic4).
Boron hydride compounds include borane / tetrahydrofuran complex, borane / dimethyl sulfide complex, catecholborane, 9-borabicyclo [3.3.1] nonane, and the like. Molar equivalents can be used.
Examples of the oxidizing agent include hydrogen peroxide and sodium perborate, and 1 to 15 molar equivalents can be used with respect to the compound represented by the formula (Ic3).
The reaction temperature is 0 ° C. to heating under reflux.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
As the reaction solvent, the solvent described in Production Method A, Step 1 can be used. Preferred examples include tetrahydrofuran, dimethoxyethane, dioxane and the like, which may be used alone or in combination.
工程３
式（Ｉｃ４）で示される化合物を酸化剤と反応させ、式（Ｉｃ５）で示される化合物を製造する工程である。
本工程は、製法Ａの工程３と同様に行うことができる。 Process 3
In this step, the compound represented by the formula (Ic4) is reacted with an oxidizing agent to produce the compound represented by the formula (Ic5).
This step can be performed in the same manner as in step 3 of production method A.
工程４
　式（Ｉｃ５）で示される化合物とヒドロキシルアミン塩酸塩を反応させ、式（Ｉｃ６）で示される化合物を製造する工程である。塩基存在下で行うことができる。
本工程は、製法Ａの工程４と同様に行うことができる。 Process 4
In this step, the compound represented by the formula (Ic5) is reacted with hydroxylamine hydrochloride to produce the compound represented by the formula (Ic6). It can be carried out in the presence of a base.
This step can be performed in the same manner as in step 4 of production method A.
工程５
　式（Ｉｃ６）で示される化合物とＮＣＳを反応させた後、式（Ｉｃ７）で示される化合物を反応させ、式（Ｉｃ８）で示される化合物を製造する工程である。塩基存在下で行うことができる。
本工程は、製法Ａの工程５と同様に行うことができる。 Process 5
In this step, the compound represented by the formula (Ic6) is reacted with NCS and then the compound represented by the formula (Ic7) is reacted to produce the compound represented by the formula (Ic8). It can be carried out in the presence of a base.
This step can be performed in the same manner as in step 5 of production method A.
　工程６
　式（Ｉｃ８）で示される化合物と脱保護剤を反応させ、式（Ｉｃ９）で示される化合物を得る工程である。
本工程は、製法Ａの工程６と同様に行うことができる。 Step 6
In this step, the compound represented by the formula (Ic8) is reacted with a deprotecting agent to obtain the compound represented by the formula (Ic9).
This step can be performed in the same manner as in step 6 of production method A.
工程７
　式（Ｉｃ９）で示される化合物から、式（Ｉ－ｃ）で示される化合物を製造する工程である。導入するＲ１４によって、各種条件を用いることができる。たとえば、イソシアナート、酸クロライド、混合酸無水物を塩基条件下で反応させる方法、縮合剤の存在下、カルボン酸等を反応させる方法を用いることができる。本工程は、製法Ａの工程７と同様に行うことができる。 Step 7
In this step, the compound represented by the formula (Ic) is produced from the compound represented by the formula (Ic9). Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used. This step can be performed in the same manner as in step 7 of production method A.
　本発明に係る式（Ｉ）で示される化合物が、式（Ｉ－ｄ）：
Figure JPOXMLDOC01-appb-C000134
（式中、各記号は前記と同意義である。）で示される化合物は、以下に示す製法Ｄによって製造することもできる。
製法Ｄ
Figure JPOXMLDOC01-appb-C000135
（式中、Ｙ５及びＹ６はアミノ基の保護基であるか、一方は水素でもよく、Ｙ５とＹ６とがアミノ基の保護基として環を形成してもよく、その他の記号は前記と同意義である。） The compound represented by formula (I) according to the present invention is represented by formula (Id):
Figure JPOXMLDOC01-appb-C000134
(Wherein each symbol has the same meaning as described above) can also be produced by the production method D shown below.
Manufacturing method D
Figure JPOXMLDOC01-appb-C000135
(In the formula, Y 5 and Y 6 are amino-protecting groups, or one of them may be hydrogen, and Y 5 and Y 6 may form a ring as an amino-protecting group. It is the same meaning as above.)
工程１
　式（Ｉａ５）で示される化合物と（１－ジアゾ－２－オキソプロピル）ホスホン酸ジメチルと反応させ、式（Ｉｄ１）で示される化合物を製造する工程である。塩基存在下で行なうことができる。
　塩基としては、炭酸カリウム等を用いることができる。
　反応温度は、０℃～加熱還流下である。
　反応時間は、０．２時間～４８時間、好ましくは１時間～２４時間である。
　反応溶媒としては、メタノール、エタノール、水等が挙げられ、単独又は混合して用いることができる。 Process 1
In this step, the compound represented by the formula (Ia5) is reacted with dimethyl (1-diazo-2-oxopropyl) phosphonate to produce the compound represented by the formula (Id1). It can be carried out in the presence of a base.
As the base, potassium carbonate or the like can be used.
The reaction temperature is 0 ° C. to heating under reflux.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
Examples of the reaction solvent include methanol, ethanol, water and the like, and these can be used alone or in combination.
工程２
　式（Ｉｄ２）（公知文献に合成法記載；Bioorganic & Medicinal Chemistry, 1996，Vol. 4, 209-225）で示される化合物とＮＣＳを反応させた後、式（Ｉｄ１）で示される化合物を反応させ、式（Ｉｄ３）で示される化合物を製造する工程である。塩基存在下で行うことができる。本工程は、製法Ａの工程５と同様に行うことができる。 Process 2
After reacting the compound represented by the formula (Id2) (described in the synthesis method in known literature; Bioorganic & Medicinal Chemistry, 1996, Vol. 4, 209-225) with NCS, the compound represented by the formula (Id1) is reacted. And a step for producing a compound represented by the formula (Id3). It can be carried out in the presence of a base. This step can be performed in the same manner as in step 5 of production method A.
工程３
　式（Ｉｄ３）で示される化合物と脱保護剤を反応させ、式（Ｉｄ４）で示される化合物を得る工程である。本工程は、製法Bの工程７と同様に行うことができる。 Process 3
In this step, the compound represented by the formula (Id3) is reacted with a deprotecting agent to obtain the compound represented by the formula (Id4). This step can be performed in the same manner as in step 7 of production method B.
工程４
　式（Ｉｄ４）で示される化合物から、式（Ｉ－ｄ）で示される化合物を製造する工程である。導入するＲ１４によって、各種条件を用いることができる。たとえば、イソシアナート、酸クロライド、混合酸無水物を塩基条件下で反応させる方法、縮合剤の存在下、カルボン酸等を反応させる方法を用いることができる。本工程は、製法Ａの工程７と同様に行うことができる。 Process 4
In this step, the compound represented by the formula (Id) is produced from the compound represented by the formula (Id4). Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used. This step can be performed in the same manner as in step 7 of production method A.
　本発明に係る化合物（Ｉ）が、式（Ｉ－ｅ）：
Figure JPOXMLDOC01-appb-C000136
（式中、Ｘ３は－Ｓ－，－ＮＲ９－又は－Ｏ－であり、各記号は前記と同意義である。）で示される化合物である場合、以下に示す製法Ｅによって製造することもできる。
製法Ｅ
Figure JPOXMLDOC01-appb-C000137
（式中、各記号は前記と同意義である。） The compound (I) according to the present invention is represented by the formula (Ie):
Figure JPOXMLDOC01-appb-C000136
(Wherein X 3 represents —S—, —NR 9 — or —O—, and each symbol has the same meaning as described above). You can also.
Manufacturing method E
Figure JPOXMLDOC01-appb-C000137
(In the formula, each symbol is as defined above.)
工程１
　式（Ｉｅ１）で示される化合物を（Ｉｅ２）で示される化合物と反応させ、式（Ｉｅ３）で示される化合物を製造する工程である。
本工程は、製法Ｂの工程８と同様に行うことができる。 Process 1
In this step, a compound represented by formula (Ie1) is reacted with a compound represented by (Ie2) to produce a compound represented by formula (Ie3).
This step can be performed in the same manner as in step 8 of production method B.
工程２
　式（Ｉｅ３）で示される化合物と（Ｉｅ４）で示される化合物を反応させ、式（Ｉ－ｅ）で示される化合物を製造する工程である。本工程は、製法Ａの工程１と同様に行うことができる。 Process 2
In this step, a compound represented by the formula (Ie) is reacted with a compound represented by the formula (Ie4) to produce a compound represented by the formula (Ie). This step can be performed in the same manner as in step 1 of production method A.
　本発明に係る式（Ｉ）で示される化合物が、式（Ｉ－ｆ）：
Figure JPOXMLDOC01-appb-C000138
で示される化合物である場合、以下に示す製法Ｆによって製造することもできる。
製法Ｆ
Figure JPOXMLDOC01-appb-C000139
（式中、ｋは０又は１であり、その他の記号は前記と同意義である。） The compound represented by formula (I) according to the present invention is represented by formula (If):
Figure JPOXMLDOC01-appb-C000138
Can also be produced by the production method F shown below.
Manufacturing method F
Figure JPOXMLDOC01-appb-C000139
(In the formula, k is 0 or 1, and other symbols are as defined above.)
工程１
　式（Ｉｆ１）で示される化合物を式（Ｉｆ２）で示される化合物と反応させ、式（Ｉｆ３）で示される化合物を製造する工程である。本工程は、製法Ａの工程１と同様に行うことができる。 Process 1
In this step, the compound represented by the formula (If1) is reacted with the compound represented by the formula (If2) to produce a compound represented by the formula (If3). This step can be performed in the same manner as in step 1 of production method A.
工程２
　式（Ｉｆ３）で示される化合物と脱保護剤を反応させ、式（Ｉｆ４）で示される化合物を得る工程である。本工程は、製法Bの工程７と同様に行うことができる。 Process 2
In this step, a compound represented by the formula (If3) is reacted with a deprotecting agent to obtain a compound represented by the formula (If4). This step can be performed in the same manner as in step 7 of production method B.
工程３
式（Ｉｆ４）で示される化合物とチオホスゲンを塩基存在下で反応させた後、アンモニアで処理することによって式（Ｉｆ５）で示される化合物を製造する工程である。塩基としては、製法Ａの工程１に記載の塩基を用いることができる。好ましくは、ピリジン、トリエチルアミン、ＤＩＥＡ等を式（Ｉｆ４）で示される化合物に対して１～１０当量用いればよい。
　反応温度は、０℃～加熱還流下である。
　反応時間は、０．２時間～４８時間、好ましくは１時間～２４時間である。
　反応溶媒としては、製法Ａの工程１記載の溶媒を単独又は混合して用いることができる。 Process 3
In this step, the compound represented by the formula (If4) is reacted with thiophosgene in the presence of a base and then treated with ammonia to produce the compound represented by the formula (If5). As the base, the base described in Step 1 of Production Method A can be used. Preferably, 1 to 10 equivalents of pyridine, triethylamine, DIEA or the like may be used with respect to the compound represented by the formula (If4).
The reaction temperature is 0 ° C. to heating under reflux.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
As the reaction solvent, the solvents described in Step 1 of Production Method A can be used alone or in combination.
工程４
　式（Ｉｆ６）で示される化合物をジオール類（エチレングリコール、プロパン－１，３－ジオールなど）とトリメチルシリルブロミドを反応させ、式（Ｉｆ７）で示される化合物を製造する工程である。
　反応温度は、０℃～３０℃である。
　反応時間は、０．２時間～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を単独又は混合して用いることができる。好ましくは、アセトニトリルを用いればよい。 Process 4
In this step, the compound represented by the formula (If6) is reacted with diols (ethylene glycol, propane-1,3-diol, etc.) and trimethylsilyl bromide to produce the compound represented by the formula (If7).
The reaction temperature is 0 ° C to 30 ° C.
The reaction time is 0.2 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, the solvents described in Step 1 of Production Method A can be used alone or in combination. Preferably, acetonitrile may be used.
工程５
式（Ｉｆ７）で示される化合物をフタルイミドカリウム塩と反応させ、式（Ｉｆ８）で示される化合物を製造する工程である。
　反応温度は、０℃～加熱還流下である。
　反応時間は、０．２時間～４８時間、好ましくは１時間～２４時間である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を単独又は混合して用いることができる。 Process 5
In this step, the compound represented by the formula (If7) is reacted with phthalimide potassium salt to produce the compound represented by the formula (If8).
The reaction temperature is 0 ° C. to heating under reflux.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
As the reaction solvent, the solvents described in Step 1 of Production Method A can be used alone or in combination.
工程６
　式（Ｉｆ８）で示される化合物と脱保護剤を反応させ、式（Ｉｆ９）で示される化合物を得る工程である。保護基の脱保護反応は公知であり、例えばGreene's Protective Groups in Organic Synthesis, 4th Edition (Peter G. M. Wuts, Theodora W. Greene, Wiley, 2006)に記載の方法で実施することができる。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を単独又は混合して用いることができる。
　又は、脱保護剤として、ＴＭＳ－Ｏ－Ｔｆ、2，6－ルチジンを用いることもできる。
　この場合、反応温度は、－７８℃～３０℃で好ましくは－３０℃～０℃である。
　反応時間は、０．２時間～６時間、好ましくは１時間～３時間である。
　反応溶媒はジクロロメタンなどを用いることができる。 Step 6
In this step, a compound represented by the formula (If8) is reacted with a deprotecting agent to obtain a compound represented by the formula (If9). The deprotection reaction of the protecting group is known and can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 4th Edition (Peter G. M. Wuts, Theodora W. Greene, Wiley, 2006).
As the reaction solvent, the solvents described in Step 1 of Production Method A can be used alone or in combination.
Alternatively, TMS-O-Tf, 2,6-lutidine can also be used as a deprotecting agent.
In this case, the reaction temperature is −78 ° C. to 30 ° C., preferably −30 ° C. to 0 ° C.
The reaction time is 0.2 to 6 hours, preferably 1 to 3 hours.
As the reaction solvent, dichloromethane or the like can be used.
工程７
式（Ｉｆ９）で示される化合物とブロモ化剤を反応させ、式（Ｉｆ１０）で示される化合物を得る工程である。
　ブロモ化剤としては、ＮＢＳ、臭素、５，５－ジブロモヘキサヒドロピリミジン－２，４，６－トリオン等を用いることができる。
　反応温度は、－７８℃～加熱還流下で好ましくは０℃～加熱還流下である。
　反応時間は、０．２時間～１２時間である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を単独又は混合して用いることができる。 Step 7
In this step, a compound represented by the formula (If9) is reacted with a brominating agent to obtain a compound represented by the formula (If10).
As the brominating agent, NBS, bromine, 5,5-dibromohexahydropyrimidine-2,4,6-trione and the like can be used.
The reaction temperature is −78 ° C. to heating under reflux, preferably 0 ° C. to heating under reflux.
The reaction time is 0.2 hours to 12 hours.
As the reaction solvent, the solvents described in Step 1 of Production Method A can be used alone or in combination.
工程８
式（Ｉｆ１０）で示される化合物と式（Ｉｆ５）で示される化合物を反応させ、式（Ｉｆ１１）で示される化合物を得る工程である。
　反応温度は、０℃～溶媒の加熱還流下である。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を用いることができる。好ましくは、エタノール、ＤＭＦ等が挙げられ、単独又は混合して用いればよい。 Process 8
In this step, the compound represented by the formula (If10) is reacted with the compound represented by the formula (If5) to obtain a compound represented by the formula (If11).
The reaction temperature is 0 ° C. to solvent reflux.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferably, ethanol, DMF, etc. are mentioned, What is necessary is just to use individually or in mixture.
工程９
　式（Ｉｆ１１）で示される化合物と脱保護剤を反応させ、式（Ｉｆ１２）で示される化合物を得る工程である。本工程は、製法Ａの工程６と同様に行うことができる。 Step 9
In this step, a compound represented by the formula (If11) is reacted with a deprotecting agent to obtain a compound represented by the formula (If12). This step can be performed in the same manner as in step 6 of production method A.
工程１０
　式（Ｉｆ１２）で示される化合物から、式（Ｉ－ｆ）で示される化合物を製造する工程である。導入するＲ１４によって、各種条件を用いることができる。たとえば、イソシアナート、酸クロライド、混合酸無水物を塩基条件下で反応させる方法、縮合剤の存在下、カルボン酸等を反応させる方法を用いることができる。本工程は、製法Ａの工程７と同様に行うことができる。 Step 10
In this step, the compound represented by the formula (If) is produced from the compound represented by the formula (If12). Various conditions can be used depending on R 14 to be introduced. For example, a method of reacting isocyanate, acid chloride, or mixed acid anhydride under basic conditions, or a method of reacting carboxylic acid in the presence of a condensing agent can be used. This step can be performed in the same manner as in step 7 of production method A.
　本発明に係る化合物（Ｉ）において、ｑ＝１であり、Ｔが－ＣＲ７Ｒ８－Ｏ－、－ＣＲ７Ｒ８－Ｓ－、－ＣＲ７Ｒ８－ＮＲ９－、－Ｏ－、－Ｓ－又は－ＮＲ９－（ここで、左の結合手は環Ｂに結合し、右の結合手は環Ｃに結合する。）である場合、式（Ｉ）で示される化合物は、以下の式（Ｉ－ｇ）：
Figure JPOXMLDOC01-appb-C000140
（式中、各記号は前記と同意義である。）で示すことができる。例えば、以下に示す製法Ｇによって式（Ｉ－ｇ）で示される化合物を製造することができる。
製法Ｇ
Figure JPOXMLDOC01-appb-C000141
（式中、Ｘ３は－Ｏ－、－Ｓ－又は－ＮＲ９－であり、他の記号は前記と同意義である。） In the compounds according to the present invention (I), the a q = 1, T is -CR 7 R 8 -O -, - CR 7 R 8 -S -, - CR 7 R 8 -NR 9 -, - O-, -S- or -NR 9 - (. here, the left bond is attached to the ring B, the right bond is to be attached to the ring C) If it is, the compound represented by formula (I) below Formula (Ig):
Figure JPOXMLDOC01-appb-C000140
(Wherein each symbol has the same meaning as described above). For example, the compound represented by the formula (Ig) can be produced by the following production method G.
Manufacturing method G
Figure JPOXMLDOC01-appb-C000141
(Wherein X 3 is —O—, —S— or —NR 9 —, and other symbols are as defined above.)
工程１
　式（Ｉｇ１）で示される化合物と（Ｉｇ２）で示される化合物を反応させ、式（Ｉ－ｇ）で示される化合物を製造する工程である。本工程は、製法Ａの工程１と同様に行うことができる。 Process 1
In this step, the compound represented by the formula (Ig) is reacted with the compound represented by the formula (Ig2) to produce the compound represented by the formula (Ig). This step can be performed in the same manner as in step 1 of production method A.
　本発明に係る化合物（Ｉ）において、ｑ＝０である場合、式（Ｉ）で示される化合物は、以下の式（Ｉ－ｈ）：
Figure JPOXMLDOC01-appb-C000142
（式中、各記号は前記と同意義である。）で示すことができる。例えば、以下に示す製法Ｈによって式（Ｉ－ｈ）で示される化合物を製造することができる。
製法Ｈ
Figure JPOXMLDOC01-appb-C000143
（式中、Ｙ７はハロゲン（好ましくは臭素またはヨウ素）であり、その他の記号は前記と同意義である。） In the compound (I) according to the present invention, when q = 0, the compound represented by the formula (I) is represented by the following formula (Ih):
Figure JPOXMLDOC01-appb-C000142
(Wherein each symbol has the same meaning as described above). For example, the compound represented by the formula (Ih) can be produced by the following production method H.
Manufacturing method H
Figure JPOXMLDOC01-appb-C000143
(Wherein Y 7 is halogen (preferably bromine or iodine), and other symbols are as defined above.)
工程１
　式（Ｉｈ１）で示される化合物を（Ｉｈ２）で示される化合物と反応させ、式（Ｉｈ３）で示される化合物を製造する工程である。塩基存在下で行なうことができる。
　塩基としては、アルキルリチウム、グリニャール試薬等を用いることができる。
　反応温度は－７８℃～３０℃、好ましくは－７８℃～０℃である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、ジエチルエーテル等が挙げられ、単独または混合して用いればよい。 Process 1
In this step, the compound represented by the formula (Ih1) is reacted with the compound represented by the formula (Ih2) to produce a compound represented by the formula (Ih3). It can be carried out in the presence of a base.
As the base, alkyl lithium, Grignard reagent and the like can be used.
The reaction temperature is -78 ° C to 30 ° C, preferably -78 ° C to 0 ° C.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferably, tetrahydrofuran, diethyl ether, etc. are mentioned, What is necessary is just to use individually or in mixture.
工程２
　式（Ｉｈ３）で示される化合物を還元剤と反応させ、式（Ｉ―ｈ）で示される化合物を製造する工程である。酸性条件下で行うことができる。
　還元剤としては、トリエチルシランなどが挙げられる。
　酸としては、トリフルオロ酢酸などが挙げられる。
　反応温度は－７８℃～加熱還流下、好ましくは０℃～加熱還流下である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を用いることができる。好ましくは、ハロゲン化炭化水素類（ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）が挙げられ、単独または混合して用いればよい。
　本工程は、水素雰囲気下、パラジウムや白金触媒などの遷移金属触媒による還元反応により製造することもできる。 Process 2
In this step, the compound represented by the formula (Ih3) is reacted with a reducing agent to produce the compound represented by the formula (Ih). It can be performed under acidic conditions.
Examples of the reducing agent include triethylsilane.
Examples of the acid include trifluoroacetic acid.
The reaction temperature is −78 ° C. to heating under reflux, preferably 0 ° C. to heating under reflux.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferred are halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.), which may be used alone or in combination.
This step can also be produced by a reduction reaction with a transition metal catalyst such as palladium or platinum catalyst in a hydrogen atmosphere.
　本発明に係る化合物（Ｉ）において、ｑ＝１、Ｔ＝－Ｃ（＝Ｏ）－である場合、式（Ｉ）で示される化合物は、以下の式（Ｉ－ｉ）：
Figure JPOXMLDOC01-appb-C000144
（式中、各記号は前記と同意義である。）で示すことができる。例えば、以下に示す製法Ｉによって式（Ｉ－ｉ）で示される化合物を製造することができる。 In the compound (I) according to the present invention, when q = 1 and T = —C (═O) —, the compound represented by the formula (I) is represented by the following formula (Ii):
Figure JPOXMLDOC01-appb-C000144
(Wherein each symbol has the same meaning as described above). For example, the compound represented by the formula (Ii) can be produced by the following production method I.
製法Ｉ
Figure JPOXMLDOC01-appb-C000145
（式中、各記号は前記と同意義である。）
工程１
　式（Ｉｉ１）で示される化合物を（Ｉｈ２）で示される化合物と反応させ、式（Ｉ－ｉ）で示される化合物を製造する工程である。塩基存在下で行なうことができる。
　塩基としては、アルキルリチウム、グリニャール試薬等を用いることができる。
　反応温度は－７８℃～３０℃、好ましくは－７８℃～０℃である。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、ジエチルエーテル等が挙げられ、単独または混合して用いればよい Manufacturing method I
Figure JPOXMLDOC01-appb-C000145
(In the formula, each symbol is as defined above.)
Process 1
In this step, the compound represented by formula (Ii1) is reacted with the compound represented by (Ih2) to produce a compound represented by formula (Ii). It can be carried out in the presence of a base.
As the base, alkyl lithium, Grignard reagent and the like can be used.
The reaction temperature is -78 ° C to 30 ° C, preferably -78 ° C to 0 ° C.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferably, tetrahydrofuran, diethyl ether and the like can be mentioned, and they may be used alone or in combination.
　本発明に係る化合物（Ｉ）において、ｑ＝１、Ｔ＝－Ｃ（＝Ｏ）－であり、環Ｂ上の窒素原子とＴとが結合する場合、式（Ｉ）で示される化合物は、以下の式（Ｉ－ｊ）：
Figure JPOXMLDOC01-appb-C000146
（式中、各記号は前記と同意義である。）で示すことができる。以下に示す製法Ｊによって式（Ｉ－ｊ）で示される化合物を製造することができる。 In the compound (I) according to the present invention, when q = 1, T = —C (═O) — and a nitrogen atom on the ring B and T are bonded, the compound represented by the formula (I) is The following formula (Ij):
Figure JPOXMLDOC01-appb-C000146
(Wherein each symbol has the same meaning as described above). A compound represented by the formula (Ij) can be produced by the production method J shown below.
製法Ｊ
Figure JPOXMLDOC01-appb-C000147
（式中、各記号は前記と同意義である。）
工程１
　式（Ｉｊ１）で示される化合物を（Ｉｊ２）で示される化合物と縮合剤を用いて反応させ、式（Ｉ－ｊ）で示される化合物を製造する工程である。
　縮合剤としては、製法Aの工程７記載の縮合剤を用いることができる。
　反応溶媒としては、製法Aの工程１に記載の溶媒を用いることができる。 Manufacturing method J
Figure JPOXMLDOC01-appb-C000147
(In the formula, each symbol is as defined above.)
Process 1
In this step, a compound represented by formula (Ij) is reacted with a compound represented by formula (Ij2) using a condensing agent to produce a compound represented by formula (Ij).
As the condensing agent, the condensing agent described in Step 7 of production method A can be used.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used.
　本発明に係る化合物（Ｉ）において、ｑ＝１、Ｔ＝－ＣＲ７Ｒ８－である場合、式（Ｉ）で示される化合物は、以下の式（Ｉ－ｋ）：
Figure JPOXMLDOC01-appb-C000148
（式中、各記号は前記と同意義である。）で示すことができる。以下に示す製法Ｋによって式（Ｉ－Ｋ）で示される化合物を製造することができる。 In the compound (I) according to the present invention, when q = 1 and T = —CR 7 R 8 —, the compound represented by the formula (I) is represented by the following formula (Ik):
Figure JPOXMLDOC01-appb-C000148
(Wherein each symbol has the same meaning as described above). A compound represented by the formula (IK) can be produced by the following production method K.
製法Ｋ
Figure JPOXMLDOC01-appb-I000149

（式中、Ｙ８はハロゲン（好ましくは臭素またはヨウ素）であり、その他の記号は前記と同意義である。） Manufacturing method K
Figure JPOXMLDOC01-appb-I000149

(Wherein Y 8 is halogen (preferably bromine or iodine), and other symbols are as defined above.)
工程１
　　式（Ｉｋ１）で示される化合物を金属で活性化した後に、（Ｉｈ２）で示される化合物と反応させ、式（Ｉ－ｋ）で示される化合物を製造する工程である。配位子および遷移金属触媒存在下で行なうことができる。
　金属としては亜鉛、マグネシウムなどが挙げられる。
　遷移金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム、ビス（シクロペンタジエニル）、１，１‘-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリドなどが挙げられ、式（Ｉｂ１０）で示される化合物に対して、０．００１～０．５当量を用いることができる。
　配位子としては、トリフェニルホスフィン、Ｘａｎｔｐｈｏｓ、ＢＩＮＡＰ、Ｘ－ｐｈｏｓなどが挙げられ、０．００１～１当量を用いることができる。
　反応溶媒としては、製法Ａの工程１に記載の溶媒を用いることができる。好ましくは、テトラヒドロフラン、トルエンなどが挙げられ、単独または混合して用いればよい。 Process 1
In this step, the compound represented by the formula (Ik1) is activated with a metal and then reacted with the compound represented by the formula (Ih2) to produce the compound represented by the formula (Ik). The reaction can be performed in the presence of a ligand and a transition metal catalyst.
Examples of the metal include zinc and magnesium.
Transition metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis ( And tri-tert-butylphosphine) palladium, bis (cyclopentadienyl), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride, and the like. For the compound represented by the formula (Ib10) 0.001 to 0.5 equivalent can be used.
Examples of the ligand include triphenylphosphine, Xantphos, BINAP, X-phos and the like, and 0.001 to 1 equivalent can be used.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferably, tetrahydrofuran, toluene, etc. are mentioned, and they may be used alone or in combination.
　本発明に係る化合物（Ｉ）において、ｑ＝１、Ｔ＝－ＳＯ２－である場合、式（Ｉ）で示される化合物は、以下の式（Ｉ－ｌ）：
Figure JPOXMLDOC01-appb-C000150
（式中、各記号は前記と同意義である。）で示すことができる。以下に示す製法Ｌによって式（Ｉ－ｌ）で示される化合物を製造することができる。
製法Ｌ
Figure JPOXMLDOC01-appb-C000151
（式中、各記号は前記と同意義である。） In the compound (I) according to the present invention, when q = 1 and T = —SO 2 —, the compound represented by the formula (I) is represented by the following formula (Il):
Figure JPOXMLDOC01-appb-C000150
(Wherein each symbol has the same meaning as described above). The compound represented by the formula (I-1) can be produced by the production method L shown below.
Manufacturing method L
Figure JPOXMLDOC01-appb-C000151
(In the formula, each symbol is as defined above.)
工程１
　式（Ｉｌ１）で示される化合物を酸化剤と反応させ、式（Ｉ－ｌ）で示される化合物を製造する工程である。
　式（Ｉｌ１）で示される化合物は、上記の製造方法Ｇにより製造できる。
　酸化剤としては、ｍＣＰＢＡなどが挙げられ、２～１０当量を用いることができるる。
　反応溶媒としては、製法Aの工程１に記載の溶媒を用いることができる。好ましくは、ハロゲン化炭化水素類（ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）を用いることができる。 Process 1
In this step, the compound represented by the formula (Il1) is reacted with an oxidizing agent to produce the compound represented by the formula (Il).
The compound represented by the formula (Il1) can be produced by the production method G described above.
Examples of the oxidizing agent include mCPBA, and 2 to 10 equivalents can be used.
As the reaction solvent, the solvent described in Step 1 of Production Method A can be used. Preferably, halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.) can be used.
　本発明に係る化合物は、ＡＣＣ２阻害活性を有する。さらに本発明に係る化合物は、ＡＣＣ１に比べ、ＡＣＣ２に対する選択性が高いため、副作用が軽減された医薬品となりうる。また、本発明に係る化合物は、心血管系のリスクやＭＢＩのリスク等が低いため、副作用が軽減された医薬品となりうる。本発明に係る化合物を含有する医薬組成物は、ＡＣＣ２の関与する疾患の治療剤及び／又は予防剤として有用である。ＡＣＣ２が関与する疾患とは、ＡＣＣ２によって産生されるマロニル－ＣｏＡにより引き起こされる疾患を意味し、具体的には、メタボリックシンドローム、肥満症、糖尿病、インスリン抵抗性、耐糖能異常、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、脂質異常症、高血圧症、心血管疾患、動脈硬化症、アテローム性動脈硬化症、心不全、心筋梗塞、感染症、腫瘍等が挙げられる。本発明に係る化合物を含有する医薬組成物は、それら疾患の治療剤及び／又は予防剤として有用である。
　本発明化合物は、ＡＣＣ２阻害作用のみならず、医薬としての有用性を備えており、下記いずれか、あるいは全ての優れた特徴を有している。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
ｂ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｃ）代謝安定性が高い。
ｄ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、本明細書に記載する測定条件の濃度範囲内で不可逆的阻害作用を示さない。
ｅ）変異原性を有さない。
ｆ）心血管系のリスクが低い。
ｇ）高い溶解性を示す。 The compound according to the present invention has ACC2 inhibitory activity. Furthermore, since the compound according to the present invention has higher selectivity for ACC2 than ACC1, it can be a pharmaceutical with reduced side effects. In addition, since the compound according to the present invention has low cardiovascular risk, MBI risk and the like, it can be a pharmaceutical with reduced side effects. The pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diseases involving ACC2. A disease involving ACC2 means a disease caused by malonyl-CoA produced by ACC2, specifically, metabolic syndrome, obesity, diabetes, insulin resistance, impaired glucose tolerance, diabetic peripheral neuropathy , Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, heart failure, myocardial infarction, infection, tumor, etc. It is done. The pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for these diseases.
The compound of the present invention has not only an ACC2 inhibitory action but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
　本発明の医薬組成物を投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、注射剤等の通常用いられるいずれの剤型でも好適に投与することができる。本発明に係る化合物は経口吸収性が高いため、経口剤として好適に使用できる。 When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。 Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
　以下に本発明の実施例及び参考例、調製例ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Preparation Examples and Test Examples of the present invention, but the present invention is not limited thereto.
　また、本明細書中で用いる略語は以下の意味を表す。
Ａｃ：アセチル
ａｃａｃ：アセチルアセトン
ＢＩＮＡＰ：２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
Ｂｏｃ２Ｏ：ジ－ｔｅｒｔ－ブチルジカーボネート
Ｂｕ：ブチル
ＣＤＩ：カルボニルジイミダゾール
ＤＢＵ：１，８－ジアザビシクロ［５．４．０］－７－ウンデセン
ｄｂａ：ジベンジリデンアセトン
ＤＥＡＤ：ジエチルアゾジカルボキシレート
ＤＩＡＤ：ジイソプロピルアゾジカルボキシレート
ＤＩＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＤＭＡ：Ｎ，Ｎ－ジメチルアセトアミド
ＤＭＡＰ：４－ジメチルアミノピリジン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＥＤＣ：1-エチル-3-（3-ジメチルアミノプロピル）カルボジイミド
ＷＳＣＤ：１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド
Ｅｔ：エチル
ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート
ｍＣＰＢＡ：ｍ－クロロ過安息香酸
Ｍｅ：メチル
ＭＥＫ：メチルエチルケトン
Ｍｓ：メタンスルホニル
ＮＢＳ：Ｎ－ブロモスクシイミド
ＮＣＳ：Ｎ－クロロスクシイミド
ＮＭＰ：Ｎ－メチルピロリドン
Ｐｄ２（ｄｂａ）３：トリス（ジベンジリデンアセトン）ビスパラジウム
Ｐｈ：フェニル
ＳＥＭ：２－（トリメチルシリル）エトキシメチル
ＴＢＡＦ：テトラブチルアンモニウムフルオリド
ＴＢＳ：ｔｅｒｔ－ブチルジメチルシリル
ＴＥＳＨ：トリエチルシラン
Ｔｆ：トリフルオロメタンスルホニル
ＴＦＡ：トリフルオロ酢酸
ＴＨＦ：テトラヒドロフラン
ＴＩＰＳＣｌ：トリイソプロピルシリルクロリド
ＴＭＳＯＴｆ：トリメチルシリルトリフラート
Ｔｓ：ｐ－トルエンスルホニル
Ｘａｎｔｐｈｏｓ：４，５’－ビス（ジフェニルホスフィノ）－９，９’－ジメチルキサンテン
Ｘ－Ｐｈｏｓ：２，４，６－トリイソプロピル－２’－（ジシクロヘキシルホスフィノ）ビフェニル Moreover, the abbreviation used in this specification represents the following meaning.
Ac: acetyl acac: acetylacetone BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl Boc: tert-butoxycarbonyl Boc 2 O: di-tert-butyl dicarbonate Bu: butyl CDI: carbonyl di Imidazole DBU: 1,8-diazabicyclo [5.4.0] -7-undecene dba: dibenzylideneacetone DEAD: diethyl azodicarboxylate DIAD: diisopropyl azodicarboxylate DIEA: N, N-diisopropylethylamine DMA: N, N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N, N-dimethylformamide EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide WSCD: 1-ethyl-3- (3-dimethyla Nopropyl) carbodiimide Et: ethyl HATU: O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate mCPBA: m-chloroperbenzoic acid Me: methyl MEK: Methyl ethyl ketone Ms: methanesulfonyl NBS: N-bromosuccinimide NCS: N-chlorosuccinimide NMP: N-methylpyrrolidone Pd 2 (dba) 3 : tris (dibenzylideneacetone) bispalladium Ph: phenyl SEM: 2- ( Trimethylsilyl) ethoxymethyl TBAF: tetrabutylammonium fluoride TBS: tert-butyldimethylsilyl TESH: triethylsilane Tf: trifluoromethanesulfonyl TFA: trifluoroacetic acid THF: tetrahydrofuran TIP Cl: triisopropylsilyl chloride TMSOTf: trimethylsilyl triflate Ts: p-toluenesulfonyl Xantphos: 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene X-Phos: 2,4,6-triisopropyl- 2 '-(Dicyclohexylphosphino) biphenyl
　各参考例及び実施例で得られたＮＭＲ分析は３００ＭＨｚもしくは４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３等を用いて測定した。 The NMR analysis obtained in each Reference Example and Example was performed at 300 MHz or 400 MHz and measured using DMSO-d 6 , CDCl 3 or the like.
　各参考例及び実施例又は表中に「保持時間」又は「ＲＴ」とあるのは、ＬＣ／ＭＳ：液体クロマトグラフィー／質量分析でのリテンションタイムを表し、以下の条件で測定した。
　測定条件１：ＡＣＱＵＩＴＹ　ＵＰＬＣ（Ｒ）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：０．８ ｍL/分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、０．５分間、１００％溶媒［Ｂ］を維持した。
　測定条件２:カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）　（Ｓｈｉｍａｄｚｕ）
流速：１．６　ｍＬ/分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０.５分間、１００％溶媒［Ｂ］を維持した。
　測定条件３:カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（Ｒ）ＢＥＨ　Ｃ１８　
流速：０．５５　ｍＬ/分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０.５分間、１００％溶媒［Ｂ］を維持した。 “Retention time” or “RT” in each reference example and example or table represents a retention time in LC / MS: liquid chromatography / mass spectrometry, and was measured under the following conditions.
Measurement condition 1: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, [B] was 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes Thereafter, 100% solvent [B] was maintained for 0.5 minutes.
Measurement condition 2: Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 10% -100% solvent [B] is performed for 3 minutes. 100% solvent [B] was maintained for 5 minutes.
Measurement condition 3: Column: ACQUITY UPLC (R) BEH C18
Flow rate: 0.55 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 5% -100% solvent [B] is performed for 3 minutes. 100% solvent [B] was maintained for 5 minutes.
実施例００１　化合物Ｉ－００１の合成
Figure JPOXMLDOC01-appb-C000152
 Example 001 Synthesis of Compound I-001
Figure JPOXMLDOC01-appb-C000152
工程１　化合物２の合成
　窒素雰囲気下、4－エトキシフェノール（４．０ｇ、２９．０ｍｍｏｌ）をクロロホルム（４０ｍＬ）溶解し、氷冷下で塩化スルフリル（２．４７ｍＬ、３０．４ｍｍｏｌ）を滴下し、室温で14時間撹拌した。
　反応混合物を１０％亜硫酸水素ナトリウム水溶液にゆっくり注ぎ、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物２（４．３１ｇ、収率８６％）を薄黄色液体として得た。 Step 1 Synthesis of Compound 2 Under a nitrogen atmosphere, 4-ethoxyphenol (4.0 g, 29.0 mmol) was dissolved in chloroform (40 mL), and sulfuryl chloride (2.47 mL, 30.4 mmol) was added dropwise under ice cooling. Stir at room temperature for 14 hours.
The reaction mixture was slowly poured into 10% aqueous sodium hydrogen sulfite and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 2 (4.31 g, yield 86%) as a pale yellow liquid.
工程２　化合物４の合成
　化合物２（８６２ｍｇ、４．９９ｍｍｏｌ）、化合物３（３００ｍｇ、２．０８ｍｍｏｌ）及びトリフェニルホスフィン（６５５ｍｇ、２．５０ｍｍｏｌ）をＴＨＦ（１５ｍＬ）に溶解し、ＤＩＡＤ（４８６μＬ、２．５０ｍｍoｌ）を加え、３０分間室温で撹拌した後、加熱還流下で４０分間撹拌した。
　溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して化合物４（４６０ｍｇ、収率７４％）を無色液体として得た。
1H-NMR (CDCl3) δ: 1.28 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.47-2.55 (m, 2H), 2.67-2.73 (m, 2H), 3.12-3.20 (m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.83-4.89 (m, 1H), 6.67-6.73 (m, 2H), 6.94 (s, 1H). Step 2 Synthesis of Compound 4 Compound 2 (862 mg, 4.99 mmol), Compound 3 (300 mg, 2.08 mmol) and triphenylphosphine (655 mg, 2.50 mmol) were dissolved in THF (15 mL), and DIAD (486 μL, 2 .50 mmol) was added, and the mixture was stirred for 30 minutes at room temperature, and then stirred for 40 minutes under reflux with heating.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 4 (460 mg, yield 74%) as a colorless liquid.
1 H-NMR (CDCl 3 ) δ: 1.28 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.47-2.55 (m, 2H), 2.67-2.73 (m, 2H ), 3.12-3.20 (m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.83-4.89 (m, 1H), 6.67-6.73 (m, 2H), 6.94 (s, 1H).
工程３　化合物５の合成
　窒素雰囲気下、化合物４（４５９ｍｇ、１．５４ｍｍｏｌ）をＴＨＦ（１５ｍＬ）に溶解し、０℃冷却下にて１ｍｏｌ／Ｌ水素化ジイソブチルアルミニウムのヘキサン溶液（３．３８ｍＬ、３．３８ｍｍoｌ）を滴下し、０℃で３０分間撹拌した。
　水を加え、続いて飽和ロッシェル塩水溶液を加えて室温で１．５時間撹拌した。その後、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物５（３７８ｍｇ、収率９６％）を無色液体として得た。
1H-NMR (CDCl3) δ: 1.37-1.43 (m, 4H), 2.28-2.42 (m, 4H), 2.51-2.61 (br m, 1H), 3.70-3.72 (m, 2H), 3.96 (q, J = 7.0 Hz, 2H), 4.68-4.75 (m, 1H), 6.65-6.72 (m, 2H), 6.94 (d, J = 2.6 Hz, 1H). Step 3 Synthesis of Compound 5 Compound 4 (459 mg, 1.54 mmol) was dissolved in THF (15 mL) under a nitrogen atmosphere, and 1 mol / L diisobutylaluminum hydride in hexane (3.38 mL, 3 mL) was cooled at 0 ° C. .38 mmol) was added dropwise and stirred at 0 ° C. for 30 minutes.
Water was added, followed by a saturated aqueous Rochelle salt solution, and the mixture was stirred at room temperature for 1.5 hours. Then, it extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 5 (378 mg, yield 96%) as a colorless liquid.
1 H-NMR (CDCl 3 ) δ: 1.37-1.43 (m, 4H), 2.28-2.42 (m, 4H), 2.51-2.61 (br m, 1H), 3.70-3.72 (m, 2H), 3.96 (q , J = 7.0 Hz, 2H), 4.68-4.75 (m, 1H), 6.65-6.72 (m, 2H), 6.94 (d, J = 2.6 Hz, 1H).
工程４　化合物６の合成
　化合物５（３７６ｍｇ、１．４７ｍｍｏｌ）をジクロロメタン（１５ｍＬ）に溶解し、デス・マーチン・ペルヨージナン（８７０ｍｇ、２．０５ｍｍｏｌ）を加え、室温で１２時間撹拌した。
　反応混合液に１０％チオ硫酸ナトリウム水溶液と飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物６（２００ｍｇ、収率５４％）を薄黄色液体として得た。
1H-NMR (CDCl3) δ: 1.39 (t, J = 7.0 Hz, 3H), 2.44-2.51 (m, 2H), 2.73-2.79 (br m, 2H), 3.25-3.31 (br m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 4.63-4.70 (m, 1H), 6.66-6.73 (m, 2H), 6.94 (d, J = 2.3 Hz, 1H), 9.89 (s, 1H). Step 4 Synthesis of Compound 6 Compound 5 (376 mg, 1.47 mmol) was dissolved in dichloromethane (15 mL), Dess-Martin periodinane (870 mg, 2.05 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 6 (200 mg, yield 54%) as a pale yellow liquid.
1 H-NMR (CDCl 3 ) δ: 1.39 (t, J = 7.0 Hz, 3H), 2.44-2.51 (m, 2H), 2.73-2.79 (br m, 2H), 3.25-3.31 (br m, 1H) , 3.96 (q, J = 6.9 Hz, 2H), 4.63-4.70 (m, 1H), 6.66-6.73 (m, 2H), 6.94 (d, J = 2.3 Hz, 1H), 9.89 (s, 1H).
工程５　化合物７の合成
　化合物６（２００ｍｇ、０．７８５ｍｍｏｌ）をエタノール（１０ｍＬ）に溶解し、酢酸ナトリウム（１９３ｍｇ、２．３６ｍｍｏｌ）を加えた後、０℃冷却下にてヒドロキシルアミン塩酸塩（１３６ｍｇ、１．９６ｍｍｏｌ）を少しずつ加え、室温で３時間撹拌した。
　反応混合液に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物７（２０８ｍｇ、収率９８％）をジアステレオ混合物の粗生成物として得た。 Step 5 Synthesis of Compound 7 Compound 6 (200 mg, 0.785 mmol) was dissolved in ethanol (10 mL), sodium acetate (193 mg, 2.36 mmol) was added, and hydroxylamine hydrochloride (136 mg) was cooled at 0 ° C. 1.96 mmol) was added little by little and stirred at room temperature for 3 hours.
Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 7 (208 mg, yield 98%) as a crude product of a diastereo mixture.
工程６　化合物９の合成
　化合物７（２０７ｍｇ、０．７６７ｍｍｏｌ）をＤＭＦ（２ｍＬ）に溶解し、ＮＣＳ（１３３ｍｇ、０．９９８ｍｍｏｌ）を加え、室温で１．５時間撹拌した。
　得られた反応混合物に、化合物８（１８３ｍｇ、０．９２１ｍｍｏｌ、合成法はＵＳ２００６／０１７８４００に記載）とトリエチルアミン（１６０μＬ、１．１５ｍｍｏｌ）とのＤＭＦ（１ｍＬ）溶液を室温で滴下した後、室温で終夜撹拌した。
　反応混合液に０．１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物９（１３２ｍｇ、収率３７％）を無色液体として得た。 Step 6 Synthesis of Compound 9 Compound 7 (207 mg, 0.767 mmol) was dissolved in DMF (2 mL), NCS (133 mg, 0.998 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours.
To the obtained reaction mixture, a DMF (1 mL) solution of compound 8 (183 mg, 0.921 mmol, synthesis method described in US2006 / 0178400) and triethylamine (160 μL, 1.15 mmol) was added dropwise at room temperature, and then at room temperature. Stir overnight.
0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 9 (132 mg, 37% yield) as a colorless liquid.
工程７　化合物I－００１の合成
　化合物９（１３１ｍｇ、０．２８１ｍｍｏｌ）をエタノール（３ｍＬ）とクロロホルム（０．５ｍＬ）の混合溶媒に溶解し、ヒドラジン一水和物（０．１３６ｍＬ、２．８１ｍｍｏｌ）を加え、室温で１５時間撹拌した。
　反応混合物に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、アミンを粗生成物として得た。
　得られたアミンとピリジン（１１３μＬ、０．１４０ｍｍｏｌ）をジクロロメタン（３ｍＬ）に溶解し、無水酢酸（４０μＬ、０．４２１ｍｍｏｌ）を加え、室温で３０分撹拌した。
　反応混合物に０．１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和炭酸水素ナトリウム、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製して、化合物I－００１（７４ｍｇ、収率７０％）を白色固体として得た。
1H-NMR (CDCl3) δ: 1.39 (t, J = 6.9 Hz, 3H), 1.54 (d, J = 7.0 Hz, 3H), 2.03 (s, 3H), 2.65-2.72 (m, 4H), 3.59-3.66 (m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 4.84-4.90 (m, 1H), 5.29-5.37 (m, 1H), 5.79 (d, J = 7.9 Hz, 1H), 6.04 (s, 1H), 6.70-6.71 (m, 2H), 6.95 (s, 1H). Step 7 Synthesis of Compound I-001 Compound 9 (131 mg, 0.281 mmol) was dissolved in a mixed solvent of ethanol (3 mL) and chloroform (0.5 mL), and hydrazine monohydrate (0.136 mL, 2.81 mmol) was dissolved. And stirred at room temperature for 15 hours.
Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain amine as a crude product.
The obtained amine and pyridine (113 μL, 0.140 mmol) were dissolved in dichloromethane (3 mL), acetic anhydride (40 μL, 0.421 mmol) was added, and the mixture was stirred at room temperature for 30 minutes.
0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated sodium bicarbonate, and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-001 (74 mg, yield 70%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.39 (t, J = 6.9 Hz, 3H), 1.54 (d, J = 7.0 Hz, 3H), 2.03 (s, 3H), 2.65-2.72 (m, 4H), 3.59-3.66 (m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 4.84-4.90 (m, 1H), 5.29-5.37 (m, 1H), 5.79 (d, J = 7.9 Hz, 1H) , 6.04 (s, 1H), 6.70-6.71 (m, 2H), 6.95 (s, 1H).
実施例００２　化合物Ｉ－００２の合成
Figure JPOXMLDOC01-appb-C000153
工程１　化合物１１の合成
　実施例００１の工程５の化合物６の代わりに、化合物１０を用いることにより化合物１１をジアステレオ混合物として得た。 Example 002 Synthesis of Compound I-002
Figure JPOXMLDOC01-appb-C000153
Step 1 Synthesis of Compound 11 Compound 11 was obtained as a diastereomeric mixture by using Compound 10 instead of Compound 6 of Step 5 of Example 001.
工程２　化合物１２の合成
　実施例００１の工程６の化合物７の代わりに化合物１１を用いることにより化合物１２を得た。
1H-NMR (CDCl3) δ: 1.45 (s, 9H), 1.89 (d, J = 7.3 Hz, 3H), 3.79-3.86 (m, 1H), 4.01-4.04 (m, 2H), 4.29 (m, 2H), 5.65 (q, J = 7.2 Hz, 1H), 6.34 (s, 1H), 7.75-7.77 (m, 2H), 7.86-7.88 (m, 2H). Step 2 Synthesis of Compound 12 Compound 12 was obtained by using Compound 11 instead of Compound 7 of Step 6 of Example 001.
1 H-NMR (CDCl 3 ) δ: 1.45 (s, 9H), 1.89 (d, J = 7.3 Hz, 3H), 3.79-3.86 (m, 1H), 4.01-4.04 (m, 2H), 4.29 (m , 2H), 5.65 (q, J = 7.2 Hz, 1H), 6.34 (s, 1H), 7.75-7.77 (m, 2H), 7.86-7.88 (m, 2H).
工程３　化合物１３の合成
　実施例００１の工程７の化合物９の代わりに化合物１２を用いることにより化合物１３を得た。 Step 3 Synthesis of Compound 13 Compound 13 was obtained by using Compound 12 instead of Compound 9 of Step 7 of Example 001.
工程４　化合物１４の合成
　化合物１３（４０１ｍｇ、１．３０ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、トリフルオロ酢酸（１ｍＬ）を加え、反応が完結するまで室温で撹拌した。
　反応混合物の溶媒を減圧留去し、得られた残渣にジクロロメタンを加え、溶媒の減圧留去を３回繰り返した。この残渣をメタノールに溶解し、２ｍｏｌ／ｍＬ塩酸のメタノール溶液を加えた後、溶媒を減圧留去し、化合物１４（３５９ｍｇ）を粗生成物として得た。
測定条件２、RT = 0.40min, Ｍ+Ｈ 210.30 Step 4 Synthesis of Compound 14 Compound 13 (401 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature until the reaction was complete.
The solvent of the reaction mixture was distilled off under reduced pressure, dichloromethane was added to the resulting residue, and the solvent was distilled off under reduced pressure three times. This residue was dissolved in methanol, a 2 mol / mL hydrochloric acid methanol solution was added, and then the solvent was distilled off under reduced pressure to obtain Compound 14 (359 mg) as a crude product.
Measurement condition 2, RT = 0.40min, M + H 210.30
工程５　化合物１６の合成
　窒素雰囲気下、０℃で化合物１４（３５ｍｇ、０．１４２ｍｍｏｌ）と化合物１５（２４．２ｍｇ、０．１４２ｍｍｏｌ、ＵＳ２０１１／０２６３５６２に合成法記載）をＤＭＦ（１ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（８７μＬ、０．４９９ｍｍｏｌ）を加え、室温で３時間撹拌した。
　水と１０％クエン酸水溶液を加え、ｐＨ＝５程度にした後、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１６を粗生成物として得た。
測定条件２、ＲＴ＝１．０６ｍｉｎ，Ｍ＋Ｈ　３４２．９５ Step 5 Synthesis of Compound 16 In a nitrogen atmosphere, compound 14 (35 mg, 0.142 mmol) and compound 15 (24.2 mg, 0.142 mmol, described in US2011 / 0263562 as a synthesis method) were dissolved in DMF (1 mL) at 0 ° C. , N, N-diisopropylethylamine (87 μL, 0.499 mmol) was added, and the mixture was stirred at room temperature for 3 hours.
Water and 10% aqueous citric acid solution were added to adjust the pH to about 5, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 16 as a crude product.
Measurement condition 2, RT = 1.06 min, M + H 342.95
工程６　化合物Ｉ－００２の合成
化合物１６の粗生成物をＤＭＦ（１ｍＬ）に溶解し、炭酸カリウム（２９．５ｍｇ、０．２１４ｍｍｏｌ）と（ブロモメチル）シクロプロパン（２８．８ｍｇ、０．２１４ｍｍｏｌ）を加え、６０℃で３時間撹拌した。その後、炭酸カリウム（２９．５ｍｇ、０．２１４ｍｍｏｌ）と（ブロモメチル）シクロプロパン（２８．８ｍｇ、０．２１４ｍｍｏｌ）を追加し、６０℃で１時間撹拌した。（ブロモメチル）シクロプロパン（２８．８ｍｇ、０．２１４ｍｍｏｌ）を追加し、６０℃で４時間撹拌した。炭酸カリウム（２９．５ｍｇ、０．２１４ｍｍｏｌ）と（ブロモメチル）シクロプロパン（２８．８ｍｇ、０．２１４ｍｍｏｌ）を追加し、６０℃で３時間撹拌した。
　反応混合物に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄し、硫酸ナトリウム乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製して、化合物Ｉ－００２（１６ｍｇ、収率２８％）を白色固体として得た。
測定条件２、RT = 1.71 min, Ｍ+Ｈ 397.20 Step 6 Synthesis of Compound I-002 The crude product of Compound 16 was dissolved in DMF (1 mL), and potassium carbonate (29.5 mg, 0.214 mmol) and (bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) were added. In addition, the mixture was stirred at 60 ° C. for 3 hours. Thereafter, potassium carbonate (29.5 mg, 0.214 mmol) and (bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) were added, and the mixture was stirred at 60 ° C. for 1 hour. (Bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. Potassium carbonate (29.5 mg, 0.214 mmol) and (bromomethyl) cyclopropane (28.8 mg, 0.214 mmol) were added, and the mixture was stirred at 60 ° C. for 3 hours.
Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-002 (16 mg, 28% yield) as a white solid.
Measurement condition 2, RT = 1.71 min, M + H 397.20
実施例００３　化合物Ｉ－００３の合成
Figure JPOXMLDOC01-appb-C000154
 Example 003 Synthesis of Compound I-003
Figure JPOXMLDOC01-appb-C000154
工程１　化合物１８の合成
　窒素雰囲気下、化合物１７（８０５ｍｇ、７．１８ｍｍｏｌ）をＤＭＦ（７ｍＬ）に溶解し、０℃冷却下でＨＡＴＵ（３．５５ｇ、９．３３ｍｍｏｌ）を加え、続けてトリエチルアミン（１．２９ｍＬ、９．３３ｍｍｏｌ）を滴下した。得られた反応混合物を、窒素雰囲気、０℃冷却下にて、４－アミノレゾルシノール塩酸塩（２．３２ｇ、１４．３６ｍｍｏｌ）とトリエチルアミン（１．４９ｍＬ、１０．８ｍｍｏｌ）とのＤＭＦ（１４ｍＬ）懸濁液中に滴下し、０℃で１時間撹拌した。
　反応混合液に１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで４回抽出した。有機層を合わせ、０．１ｍｏｌ／Ｌ塩酸、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をＴＨＦ（６０ｍＬ）に溶解させた。反応混合物にトリフェニルホスフィン（２．２６ｇ、８．６２ｍｍｏｌ）を加えた後、ＤＩＡＤ（１．６７５ｍＬ，８．６２ｍｍｏｌ）を加えた。反応混合物を室温で撹拌し、さらにトリフェニルホスフィン（２．８３ｇ、１０．８ｍｍｏｌ）、ＤＩＡＤ（２．０９ｍＬ，１０．８ｍｍｏｌ）を続けて加え、室温で３０分間撹拌した。
　得られた反応混合液を減圧留去し得られた残渣に水を加え、酢酸エチルで２回抽出した。有機層を合わせて、水、飽和食塩水で洗浄し、硫酸ナトリウム乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製した。得られた固体をヘキサンで洗浄して、化合物１８（８７９ｍｇ、収率６１％）を白色固体として得た。
1H-NMR (CDCl3) δ: 3.14-3.27 (m, 4H), 3.72-3.80 (m, 1H), 4.90 (s, 2H), 5.49 (s, 1H), 6.82 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H). Step 1 Synthesis of Compound 18 Compound 17 (805 mg, 7.18 mmol) was dissolved in DMF (7 mL) under a nitrogen atmosphere, and HATU (3.55 g, 9.33 mmol) was added under cooling at 0 ° C., followed by triethylamine ( 1.29 mL, 9.33 mmol) was added dropwise. The obtained reaction mixture was suspended in DMF (14 mL) of 4-aminoresorcinol hydrochloride (2.32 g, 14.36 mmol) and triethylamine (1.49 mL, 10.8 mmol) under cooling at 0 ° C. in a nitrogen atmosphere. The solution was added dropwise to the suspension and stirred at 0 ° C. for 1 hour.
1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The organic layers were combined, washed with 0.1 mol / L hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in THF (60 mL). Triphenylphosphine (2.26 g, 8.62 mmol) was added to the reaction mixture followed by DIAD (1.675 mL, 8.62 mmol). The reaction mixture was stirred at room temperature, and further triphenylphosphine (2.83 g, 10.8 mmol) and DIAD (2.09 mL, 10.8 mmol) were added successively and stirred at room temperature for 30 minutes.
The obtained reaction mixture was evaporated under reduced pressure, water was added to the resulting residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained solid was washed with hexane to obtain Compound 18 (879 mg, 61% yield) as a white solid.
1 H-NMR (CDCl 3 ) δ: 3.14-3.27 (m, 4H), 3.72-3.80 (m, 1H), 4.90 (s, 2H), 5.49 (s, 1H), 6.82 (d, J = 8.5 Hz , 1H), 7.00 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H).
工程２　化合物１９の合成
　化合物１８（３４０ｍｇ、１．６９ｍｍｏｌ）をＤＭＦ（１３ｍＬ）に溶解し、炭酸カリウム（３５０ｍｇ、２．５３ｍｍｏｌ）を加えた後、（ブロモメチル）シクロプロパン（４５６ｍｇ、３．３８ｍｍｏｌ）を加え、６０℃で４時間撹拌した。反応混合物に炭酸カリウム（３５０ｍｇ、２．５３ｍｍｏｌ）と（ブロモメチル）シクロプロパン（４５６ｍｇ、３．３８ｍｍｏｌ）を追加し、６０℃で４時間撹拌した。
反応混合液に０．１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで３回抽出した。有機層を合わせ、水で２回、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去して、化合物１９（４２４ｍｇ、収率９８％）を粗生成物として得た。
1H-NMR (CDCl3) δ: 0.35-0.39 (m, 2H), 0.64-0.69 (m, 2H), 1.26-1.33 (m, 1H), 3.13-3.27 (m, 4H), 3.71-3.79 (m, 1H), 3.83 (d, J = 7.0 Hz, 2H), 4.90 (br s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H). Step 2 Synthesis of Compound 19 Compound 18 (340 mg, 1.69 mmol) was dissolved in DMF (13 mL), potassium carbonate (350 mg, 2.53 mmol) was added, and (bromomethyl) cyclopropane (456 mg, 3.38 mmol) was then added. And stirred at 60 ° C. for 4 hours. To the reaction mixture were added potassium carbonate (350 mg, 2.53 mmol) and (bromomethyl) cyclopropane (456 mg, 3.38 mmol), and the mixture was stirred at 60 ° C. for 4 hours.
0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed twice with water and with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 19 (424 mg, yield 98%) as a crude product.
1 H-NMR (CDCl 3 ) δ: 0.35-0.39 (m, 2H), 0.64-0.69 (m, 2H), 1.26-1.33 (m, 1H), 3.13-3.27 (m, 4H), 3.71-3.79 ( m, 1H), 3.83 (d, J = 7.0 Hz, 2H), 4.90 (br s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H).
工程３　化合物２０の合成
　窒素雰囲気下、０℃冷却下にて化合物１９（３６５ｍｇ、１．４３ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液に、０．９ｍｏｌ／ＬボランＴＨＦ錯体のＴＨＦ溶液（９．５３ｍＬ、８．５８ｍｍｏｌ）を滴下し、室温で３０分間撹拌した。さらに、０℃冷却下にて０．９ｍｏｌ／ＬボランＴＨＦ錯体のＴＨＦ溶液（４．７７ｍＬ、４．２９ｍｍｏｌ）を滴下し、室温で１時間撹拌した。０℃冷却下にて反応混合物に過ホウ酸ナトリウム一水和物（２．１４ｇ、２１．４ｍｍｏｌ）の水（３０ｍＬ）懸濁液を加え、室温で４時間撹拌した。
　反応混合物をセライト濾過し、水を加えた後、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物２０（２２３ｍｇ、収率５７％）を赤褐色液体の立体異性体の混合物として得た。
測定条件２、RT = 1.86min, M+H 274.25 Step 3 Synthesis of Compound 20 A THF solution (9.53 mL, 8) of a 0.9 mol / L borane THF complex was added to a THF (10 mL) solution of Compound 19 (365 mg, 1.43 mmol) under cooling at 0 ° C. in a nitrogen atmosphere. .58 mmol) was added dropwise and stirred at room temperature for 30 minutes. Furthermore, 0.9 mol / L borane THF complex in THF (4.77 mL, 4.29 mmol) was added dropwise under cooling at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Under cooling at 0 ° C., a suspension of sodium perborate monohydrate (2.14 g, 21.4 mmol) in water (30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was filtered through celite, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 20 (223 mg, 57% yield) as a mixture of stereoisomers of a reddish brown liquid.
Measurement condition 2, RT = 1.86min, M + H 274.25
工程４　化合物２１の合成
　化合物２０（２２２ｍｇ、０．８１２ｍｍｏｌ）をジクロロメタン（８ｍＬ）に溶解し、デス－マーチンペルヨージナン（５１７ｍｇ、１．２２ｍｍｏｌ）を加え、室温で３時間撹拌した。
　酢酸エチルを加えた後、セライト濾過し、濾液を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物２１（６２ｍｇ、収率２８％）とその立体異性体であるシス体（７７ｍｇ、収率３５％）を得た。
1H-NMR (CDCl3) δ: 0.36-0.39 (m, 2H), 0.65-0.70 (m, 2H), 1.25-1.34 (m, 1H), 2.68-2.83 (m, 4H), 3.38-3.45 (m, 1H), 3.68-3.76 (m, 1H), 3.84 (d, J = 6.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 9.91 (s, 1H).
シス体；1H-NMR (CDCl3) δ: 0.36-0.39 (m, 2H), 0.65-0.69 (m, 2H), 1.26-1.34 (m, 1H), 2.62-2.69 (m, 2H), 2.75-2.82 (m, 2H), 3.24-3.33 (m, 1H), 3.76-3.84 (m, 3H), 6.93 (d, J = 8.8 Hz, 1H), 7.01 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 9.78 (s, 1H). Step 4 Synthesis of Compound 21 Compound 20 (222 mg, 0.812 mmol) was dissolved in dichloromethane (8 mL), Dess-Martin periodinane (517 mg, 1.22 mmol) was added, and the mixture was stirred at room temperature for 3 hours.
After adding ethyl acetate, the mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 21 (62 mg, 28% yield) and its steric form. The cis isomer (77 mg, yield 35%) was obtained.
1 H-NMR (CDCl 3 ) δ: 0.36-0.39 (m, 2H), 0.65-0.70 (m, 2H), 1.25-1.34 (m, 1H), 2.68-2.83 (m, 4H), 3.38-3.45 ( m, 1H), 3.68-3.76 (m, 1H), 3.84 (d, J = 6.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 9.91 (s, 1H).
Cis isomer; 1 H-NMR (CDCl 3 ) δ: 0.36-0.39 (m, 2H), 0.65-0.69 (m, 2H), 1.26-1.34 (m, 1H), 2.62-2.69 (m, 2H), 2.75 -2.82 (m, 2H), 3.24-3.33 (m, 1H), 3.76-3.84 (m, 3H), 6.93 (d, J = 8.8 Hz, 1H), 7.01 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 9.78 (s, 1H).
工程５　化合物２２の合成
　０℃氷冷下、化合物２１（６２ｍｇ、０．２３ｍｍｏｌ）と酢酸ナトリウム（５６ｍｇ、０．６９ｍｍｏｌ）のエタノール（４ｍＬ）懸濁液にヒドロキシルアミン塩酸塩（２４ｍｇ、０．３４ｍｍｏｌ）を少しずつ加え、室温で終夜撹拌した。
　反応混合液に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去して、粗生成物として化合物２２を得た。 Step 5 Synthesis of Compound 22 Hydroxylamine hydrochloride (24 mg, 0.34 mmol) in a suspension of Compound 21 (62 mg, 0.23 mmol) and sodium acetate (56 mg, 0.69 mmol) in ethanol (4 mL) under ice-cooling at 0 ° C. ) Was added little by little and stirred at room temperature overnight.
Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 22 as a crude product.
工程６　化合物２３の合成
　窒素雰囲気下、工程５で得られた粗生成物の化合物２２をＤＭＦ（２ｍＬ）に溶解し、ＮＣＳ（３０．５ｍｇ、０．２３ｍｍｏｌ）を加え、室温で２時間撹拌した。得られた反応混合物に、化合物８（５９.2ｍｇ、０．２９７ｍｍｏｌ）とトリエチルアミン（６３μＬ、０．４５７ｍｍｏｌ）とのＤＭＦ（１ｍＬ）溶液を加え、室温で６時間撹拌した。
　反応混合液に０．１ｍｏｌ／Ｌ塩酸を加えた後、酢酸エチルで３回抽出した。有機層を合わせ、水で２回、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物２３（３３ｍｇ、収率３０％）で得た。
1H-NMR (CDCl3) δ: 0.36-0.39 (m, 2H), 0.64-0.69 (m, 2H), 1.24-1.33 (m, 1H), 1.90 (d, J = 7.3 Hz, 3H), 2.74-2.81 (m, 2H), 2.88-2.95 (m, 2H), 3.83-3.89 (m, 4H), 5.66 (q, J = 7.1 Hz, 1H), 6.24 (s, 1H), 6.93 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.74-7.76 (m, 2H), 7.86-7.87 (m, 2H). Step 6 Synthesis of Compound 23 Under nitrogen atmosphere, the crude product Compound 22 obtained in Step 5 was dissolved in DMF (2 mL), NCS (30.5 mg, 0.23 mmol) was added, and the mixture was stirred at room temperature for 2 hours. . To the obtained reaction mixture, a DMF (1 mL) solution of compound 8 (59.2 mg, 0.297 mmol) and triethylamine (63 μL, 0.457 mmol) was added, and the mixture was stirred at room temperature for 6 hours.
0.1 mol / L hydrochloric acid was added to the reaction mixture, followed by extraction three times with ethyl acetate. The organic layers were combined, washed twice with water and with saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 23 (33 mg, 30% yield).
1 H-NMR (CDCl 3 ) δ: 0.36-0.39 (m, 2H), 0.64-0.69 (m, 2H), 1.24-1.33 (m, 1H), 1.90 (d, J = 7.3 Hz, 3H), 2.74 -2.81 (m, 2H), 2.88-2.95 (m, 2H), 3.83-3.89 (m, 4H), 5.66 (q, J = 7.1 Hz, 1H), 6.24 (s, 1H), 6.93 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.74-7.76 (m, 2H), 7.86-7.87 (m, 2H).
化合物Ｉ－００３の合成
　化合物２３（３２ｍｇ、０．０６６ｍｍｏｌ）をエタノール（０．５ｍＬ）とクロロホルム（０．２５ｍＬ）の混合溶媒に溶解し、ヒドラジン水和物（３．７μＬ、０．０７６ｍｍｏｌ）を加え、室温で２１時間撹拌した。さらにヒドラジン水和物（０．６４μＬ、０．０７６ｍｍｏｌ）を追加し、室温で８４時間撹拌した
　反応混合物に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、目的のアミンを粗生成物として得た。
　得られたアミンとピリジン（２７μＬ、０．３３１ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解し、無水酢酸（９．４μＬ、０．０９９ｍｍｏｌ）を加え、室温で３０分撹拌した。
　反応混合物に０．１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和炭酸水素ナトリウム、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をジオールシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物Ｉ－００３（２０ｍｇ、収率７６％）を白色固体として得た。
1H-NMR (CDCl3) δ: 0.36-0.40 (m, 2H), 0.65-0.70 (m, 2H), 1.25-1.34 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H), 2.03 (s, 3H), 2.73-2.80 (m, 2H), 2.89-2.96 (m, 2H), 3.81-3.91 (m, 4H), 5.31-5.38 (m, 1H), 5.87 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 7.03 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H). Synthesis of Compound I-003 Compound 23 (32 mg, 0.066 mmol) was dissolved in a mixed solvent of ethanol (0.5 mL) and chloroform (0.25 mL), and hydrazine hydrate (3.7 μL, 0.076 mmol) was dissolved. The mixture was further stirred at room temperature for 21 hours. Further, hydrazine hydrate (0.64 μL, 0.076 mmol) was added, and the mixture was stirred at room temperature for 84 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target amine as a crude product.
The obtained amine and pyridine (27 μL, 0.331 mmol) were dissolved in dichloromethane (2 mL), acetic anhydride (9.4 μL, 0.099 mmol) was added, and the mixture was stirred at room temperature for 30 minutes.
0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by diol silica gel column chromatography (hexane-ethyl acetate) to obtain compound I-003 (20 mg, yield 76%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 0.36-0.40 (m, 2H), 0.65-0.70 (m, 2H), 1.25-1.34 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H), 2.03 (s, 3H), 2.73-2.80 (m, 2H), 2.89-2.96 (m, 2H), 3.81-3.91 (m, 4H), 5.31-5.38 (m, 1H), 5.87 (d, J = 8.0 Hz , 1H), 6.09 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 7.03 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H).
実施例００４　化合物Ｉ－００４の合成
Figure JPOXMLDOC01-appb-C000155
 Example 004 Synthesis of Compound I-004
Figure JPOXMLDOC01-appb-C000155
工程１　化合物２４の合成
　実施例００１の工程２の化合物２の代わりにｐ－エトキシフェノールを用いることにより、化合物２４を得た。
1H-NMR (CDCl3) δ: 1.29 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 2.40-2.47 (m, 2H), 2.67-2.73 (m, 2H), 3.10-3.17 (m, 1H), 3.97 (q, J = 6.9 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.79-4.86 (m, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H). Step 1 Synthesis of Compound 24 Compound 24 was obtained by using p-ethoxyphenol in place of Compound 2 in Step 2 of Example 001.
1 H-NMR (CDCl 3 ) δ: 1.29 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 2.40-2.47 (m, 2H), 2.67-2.73 (m, 2H ), 3.10-3.17 (m, 1H), 3.97 (q, J = 6.9 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.79-4.86 (m, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H).
工程２　化合物２５の合成
　実施例００１の工程３の化合物４の代わりに化合物２４を用いることにより、化合物２５を得た。
1H-NMR (CDCl3) δ: 1.38-1.39 (m, 4H), 2.29-2.32 (m, 4H), 2.49-2.59 (m, 1H), 3.71 (dd, J = 5.5, 5.5 Hz, 2H), 3.97 (q, J = 6.9 Hz, 2H), 4.65-4.71 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H). Step 2 Synthesis of Compound 25 Compound 25 was obtained by using Compound 24 instead of Compound 4 of Step 3 of Example 001.
1 H-NMR (CDCl 3 ) δ: 1.38-1.39 (m, 4H), 2.29-2.32 (m, 4H), 2.49-2.59 (m, 1H), 3.71 (dd, J = 5.5, 5.5 Hz, 2H) , 3.97 (q, J = 6.9 Hz, 2H), 4.65-4.71 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H).
工程３　化合物２６の合成
　実施例００１の工程４の化合物５の代わりに化合物２５を用いることにより化合物２６を得た。
1H-NMR (CDCl3) δ: 1.38 (t, J = 7.0 Hz, 3H), 2.36-2.43 (m, 2H), 2.72-2.78 (m, 2H), 3.20-3.27 (m, 1H), 3.97 (q, J = 6.9 Hz, 2H), 4.60-4.67 (m, 1H), 6.71 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 9.88 (s, 1H). Step 3 Synthesis of Compound 26 Compound 26 was obtained by using Compound 25 instead of Compound 5 of Step 4 of Example 001.
1 H-NMR (CDCl 3 ) δ: 1.38 (t, J = 7.0 Hz, 3H), 2.36-2.43 (m, 2H), 2.72-2.78 (m, 2H), 3.20-3.27 (m, 1H), 3.97 (q, J = 6.9 Hz, 2H), 4.60-4.67 (m, 1H), 6.71 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 9.88 (s, 1H) .
工程４　化合物２７の合成
　化合物２６（１５０ｍｇ、０．６８１ｍｍｏｌ）と炭酸カリウム（１８８ｍｇ、１．３６ｍｍｏｌ）をメタノール(３ｍＬ)に加え、（１－ジアゾ－２－オキソプロピル）ホスホン酸ジメチル（１４４ｍｇ、０．７４９ｍｍｏｌ）を加え、０℃で２時間撹拌した。終夜静置後、反応混合物に０．１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物２７（１０６ｍｇ、収率７２％）を白色固体として得た。
1H-NMR (CDCl3) δ: 1.38 (t, J = 6.9 Hz, 3H), 2.18 (s, 1H), 2.43-2.59 (m, 4H), 3.08-3.13 (br m, 1H), 3.97 (q, J = 6.9 Hz, 2H), 4.83-4.89 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H). Step 4 Synthesis of Compound 27 Compound 26 (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.36 mmol) were added to methanol (3 mL), and dimethyl (1-diazo-2-oxopropyl) phosphonate (144 mg, 0 749 mmol) and stirred at 0 ° C. for 2 hours. After standing overnight, 0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 27 (106 mg, yield 72%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.38 (t, J = 6.9 Hz, 3H), 2.18 (s, 1H), 2.43-2.59 (m, 4H), 3.08-3.13 (br m, 1H), 3.97 ( q, J = 6.9 Hz, 2H), 4.83-4.89 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H).
工程５　化合物２９の合成
　化合物２８（１１０ｍｇ、０．５８３ｍｍｏｌ、公知文献に合成法記載；Bioorganic & Medicinal Chemistry, 1996，Vol. 4, 209-225）をＤＭＦ（２ｍＬ）に溶解し、ＮＣＳ（９１ｍｇ、０．６８０ｍｍｏｌ）を加え、室温で１時間撹拌した。ＮＣＳ（２５．９ｍｇ、０．１９４ｍｍｏｌ）を追加し、室温で１時間撹拌した。得られた反応混合物に、化合物２７（１０５ｍｇ、０．４８５ｍｍｏｌ）とトリエチルアミン(１３５ｍｇ、０．９７１ｍｍｏｌ)とのＤＭＦ（２ｍＬ）溶液を滴下し、室温で反応が完結するまで撹拌した。
反応混合物に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水で２回、飽和食塩水で１回洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物２９（７９ｍｇ、収率４０％）を粉末として得た。 Step 5 Synthesis of Compound 29 Compound 28 (110 mg, 0.583 mmol, synthesis method described in known literature; Bioorganic & Medicinal Chemistry, 1996, Vol. 4, 209-225) was dissolved in DMF (2 mL) and NCS (91 mg, 0.680 mmol) was added and stirred at room temperature for 1 hour. NCS (25.9 mg, 0.194 mmol) was added and stirred at room temperature for 1 hour. To the resulting reaction mixture, a DMF (2 mL) solution of compound 27 (105 mg, 0.485 mmol) and triethylamine (135 mg, 0.971 mmol) was added dropwise and stirred at room temperature until the reaction was complete.
Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed twice with water and once with saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 29 (79 mg, yield 40%) as a powder.
工程６　化合物３０の合成
　化合物２９（７９ｍｇ、０．１９６ｍｍｏｌ）をジオキサン（１ｍＬ）に溶解し、４ｍｏｌ／Ｌ塩酸のジオキサン溶液（１ｍＬ）を加え、室温で３．５時間撹拌した。
溶媒を減圧留去し得られた残渣に酢酸エチルを加え、溶媒を減圧留去した。もう一度酢酸エチルを加え溶媒を減圧留去し得られた残渣に、メタノールを加え同様に減圧留去を２回繰り返し、化合物３０（６６ｍｇ、収率１００％）を粉末として得た。
測定条件２、RT=1.16min, M+H 303.00 Step 6 Synthesis of Compound 30 Compound 29 (79 mg, 0.196 mmol) was dissolved in dioxane (1 mL), 4 mol / L hydrochloric acid in dioxane (1 mL) was added, and the mixture was stirred at room temperature for 3.5 hours.
The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting residue, and the solvent was distilled off under reduced pressure. Ethyl acetate was added once more, and the solvent was distilled off under reduced pressure. Methanol was added to the residue, and distillation under reduced pressure was repeated twice to obtain Compound 30 (66 mg, yield 100%) as a powder.
Measurement condition 2, RT = 1.16min, M + H 303.00
工程７　化合物I－００４の合成
　窒素雰囲気下、化合物３０（２６ｍｇ、０．０７７ｍｍｏｌ）とピリジン（３１μＬ、０．３８４ｍｍｏｌ）にジクロロメタン（１ｍＬ）を加えた後、無水酢酸（８．７μＬ、０．０９２ｍｍｏｌ）を加え、室温で３０分間撹拌した。
　反応混合物に０．１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで３回抽出した。有機層を合わせ、水、飽和炭酸水素ナトリウム及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製した後、ジオールシリカゲルクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物I－００４（１９ｍｇ、収率７２％）を白色粉末として得た。
測定条件２、RT= 1.94, M+H 344.95 Step 7 Synthesis of Compound I-004 Under a nitrogen atmosphere, dichloromethane (1 mL) was added to Compound 30 (26 mg, 0.077 mmol) and pyridine (31 μL, 0.384 mmol), and then acetic anhydride (8.7 μL, 0.092 mmol). ) And stirred at room temperature for 30 minutes.
0.1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water, saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol), and then purified by diol silica gel chromatography (hexane-ethyl acetate) to give compound I-004 (19 mg, yield 72). %) As a white powder.
Measurement condition 2, RT = 1.94, M + H 344.95
実施例００５　化合物Ｉ－００５の合成
Figure JPOXMLDOC01-appb-C000156
 Example 005 Synthesis of Compound I-005
Figure JPOXMLDOC01-appb-C000156
工程1　化合物３１の合成
　化合物３０（cis/trans混合物　２００ｍｇ、０．９０８ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解し、デス・マーチンペルヨージナン（４０４ｍｇ、０．９５３ｍｍｏｌ）を加え、室温で１５分撹拌した。
　チオ硫酸ナトリウムを加え、酢酸エチルで２回抽出した。有機層を合わせ、飽和重曹水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物３１（５８ｍｇ、収率２９％）とその立体異性体(８７ｍｇ、収率４４％)をそれぞれ無色液体として得た。 Step 1 Synthesis of Compound 31 Compound 30 (cis / trans mixture 200 mg, 0.908 mmol) was dissolved in dichloromethane (2 mL), Dess Martin periodinane (404 mg, 0.953 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. .
Sodium thiosulfate was added and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 31 (58 mg, 29% yield) and its stereoisomer (87 mg, 44% yield). Were obtained as colorless liquids.
工程２　化合物３２の合成
　実施例００１の工程５の化合物６の代わりに化合物３１を用いることにより得られた粗生成物のオキシムを、実施例００１の工程６の化合物７の代わりに用いことにより化合物３２を得た。
測定条件２、ＲＴ＝２．３８ｍｉｎ、Ｍ＋Ｈ　４３１．１５ Step 2 Synthesis of Compound 32 By using the oxime of the crude product obtained by using Compound 31 instead of Compound 6 of Step 5 of Example 001 instead of Compound 7 of Step 6 of Example 001, Compound 32 was obtained.
Measurement condition 2, RT = 2.38 min, M + H 431.15
工程３　化合物３３の合成
　実施例００１の工程７の化合物９の代わりに化合物３２を用いることにより化合物３３を得た。
測定条件２、ＲＴ＝１．７９ｍｉｎ、Ｍ＋Ｈ　３４２．９５ Step 3 Synthesis of Compound 33 Compound 33 was obtained by using Compound 32 instead of Compound 9 of Step 7 of Example 001.
Measurement condition 2, RT = 1.79 min, M + H 342.95
工程４　化合物３４の合成
　化合物３３（１７２ｍｇ、０．５０２ｍｍｏｌ）をTHF（１．５ｍＬ）に溶解し、氷冷下、水素化ホウ素リチウム（５５ｍｇ、２．５１ｍｍｏｌ）、メタノール（０．１０ｍL、２．５ｍｍｏｌ）を加え、室温で３時間撹拌した。
　氷冷下、飽和塩化アンモニウム水溶液を加え、クロロホルム/メタノール（１０：１）で１０回抽出した。有機層を合わせ、硫酸マグネシウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製して、化合物３４（１２０ｍｇ、収率１００％）を無色液体として得た。
測定条件２、ＲＴ＝１．０２ｍｉｎ、Ｍ＋Ｈ　２３９．１５ Step 4 Synthesis of Compound 34 Compound 33 (172 mg, 0.502 mmol) was dissolved in THF (1.5 mL), and lithium borohydride (55 mg, 2.51 mmol), methanol (0.10 mL, 2. 5 mmol) was added and stirred at room temperature for 3 hours.
A saturated aqueous ammonium chloride solution was added under ice cooling, and the mixture was extracted 10 times with chloroform / methanol (10: 1). The organic layers were combined and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 34 (120 mg, 100% yield) as a colorless liquid.
Measurement condition 2, RT = 1.02 min, M + H 239.15
工程５　化合物Ｉ－００５の合成
　実施例００１の工程２の化合物２の代わりにｐ－エトキシフェノール、化合物３の代わりに化合物３４を用い、反応温度を５０℃にして反応を行うことにより化合物Ｉ－５を得た。
1H-NMR (CDCl3) δ: 1.40 (t, J = 6.9 Hz, 3H), 1.54 (d, J = 7.0 Hz, 3H), 2.03 (s, 3H), 2.32-2.45 (m, 4H), 2.81-2.88 (m, 1H), 3.61-3.69 (m, 1H), 3.96-4.01 (m, 4H), 5.30-5.37 (m, 1H), 5.79 (d, J = 8.2 Hz, 1H), 6.08 (s, 1H), 6.82-6.87 (m, 4H). Step 5 Synthesis of Compound I-005 Using p-ethoxyphenol in place of Compound 2 in Step 2 of Example 001 and Compound 34 in place of Compound 3, the reaction was carried out at a reaction temperature of 50 ° C. 5 was obtained.
1 H-NMR (CDCl 3 ) δ: 1.40 (t, J = 6.9 Hz, 3H), 1.54 (d, J = 7.0 Hz, 3H), 2.03 (s, 3H), 2.32-2.45 (m, 4H), 2.81-2.88 (m, 1H), 3.61-3.69 (m, 1H), 3.96-4.01 (m, 4H), 5.30-5.37 (m, 1H), 5.79 (d, J = 8.2 Hz, 1H), 6.08 ( s, 1H), 6.82-6.87 (m, 4H).
実施例００６　化合物Ｉ－００６の合成
Figure JPOXMLDOC01-appb-C000157
 Example 006 Synthesis of Compound I-006
Figure JPOXMLDOC01-appb-C000157
工程１　化合物３７の合成
　化合物３６（３．００ｇ、２１．９ｍｍｏｌ）にＤＭＦ（１０ｍＬ）、トリエチルアミン（６．６７ｍＬ、４８．１ｍｍｏｌ）を加え、氷冷した。溶液にアセチルクロリド（１．７２ｍＬ、２４．１ｍｍｏｌ）を加え、室温で３時間攪拌した。溶媒を６０℃で減圧留去し、２ｍｏｌ／Ｌ塩酸（３０ｍL）を加え、食塩を加えて飽和にした。水層をクロロホルム－メタノール（９７：１）で抽出し、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物３７（１．７９ｇ、収率４５％）を得た。
1H-NMR（DMSO-d6）δ：1.28 (d, J = 7.3Hz, 3H), 1.80 (s, 3H), 4.80 (m, 1H), 6.69 (d, J = 7.8Hz, 2H), 7.08 (d, J = 7.8Hz, 2H), 8.15 (d, J = 8.0Hz, 1H), 9.26 (s, 1H). Step 1 Synthesis of Compound 37 To Compound 36 (3.00 g, 21.9 mmol) was added DMF (10 mL) and triethylamine (6.67 mL, 48.1 mmol), and the mixture was ice-cooled. Acetyl chloride (1.72 mL, 24.1 mmol) was added to the solution and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure at 60 ° C., 2 mol / L hydrochloric acid (30 mL) was added, and sodium chloride was added to saturate. The aqueous layer was extracted with chloroform-methanol (97: 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 37 (1.79 g, yield 45%).
1 H-NMR (DMSO-d 6 ) δ: 1.28 (d, J = 7.3Hz, 3H), 1.80 (s, 3H), 4.80 (m, 1H), 6.69 (d, J = 7.8Hz, 2H), 7.08 (d, J = 7.8Hz, 2H), 8.15 (d, J = 8.0Hz, 1H), 9.26 (s, 1H).
工程２　化合物３９の合成
　化合物３８（１．５０ｇ、７．５３ｍｍｏｌ）にTHF（３０ｍＬ）、アゼチジン-３-オール塩酸塩（０．９９１ｇ、９．０４ｍｍｏｌ）、（２-ビフェニル）ジシクロヘキシルホスフィン（０．３３０ｇ、０．９４２ｍｍｏｌ）を加えた。溶液を脱気した後、トリス(ジベンジリデンアセトン)ジパラジウム（０．６９０ｇ、０．７５３ｍｍｏｌ）を加え再び脱気し、１．３ｍｏｌ／ＬリチウムヘキサメチルジシラジンTHF溶液（１９．１ｍＬ、２４．９ｍｍｏｌ）を加え、窒素雰囲気下、７時間加熱還流した。反応混合物を氷冷後、２ｍｏｌ／Ｌ塩酸（１５ｍL）を加え、室温で５分間攪拌し、飽和重曹水（３０ｍL）を加え、食塩を加えて飽和にした。水層を酢酸エチル（３００ｍL）で抽出し、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物３９（５４０ｍｇ、収率３８％）を得た。
1H-NMR（CDCl3）δ：0.92 (t, J = 7.4Hz, 3H), 1.59 (m, 2H), 2.10 (brs, 1H), 2.49 (t, J = 7.7Hz, 2H), 3.61-3.64 (m, 2H), 4.11-4.17 (m, 2H), 4.73 (brs, 1H), 6.43 (d, J = 7.4Hz, 2H), 7.04 (d, J = 7.4Hz, 2H). Step 2 Synthesis of Compound 39 Compound 38 (1.50 g, 7.53 mmol) was added to THF (30 mL), azetidin-3-ol hydrochloride (0.991 g, 9.04 mmol), (2-biphenyl) dicyclohexylphosphine (0. 330 g, 0.942 mmol) was added. After degassing the solution, tris (dibenzylideneacetone) dipalladium (0.690 g, 0.753 mmol) was added to degas again, and a 1.3 mol / L lithium hexamethyldisilazine THF solution (19.1 mL, 24. 9 mmol) was added and the mixture was heated to reflux for 7 hours under a nitrogen atmosphere. The reaction mixture was ice-cooled, 2 mol / L hydrochloric acid (15 mL) was added, the mixture was stirred at room temperature for 5 min, saturated aqueous sodium hydrogen carbonate (30 mL) was added, and sodium chloride was added to saturate. The aqueous layer was extracted with ethyl acetate (300 mL), washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 39 (540 mg, yield 38%).
1 H-NMR (CDCl 3 ) δ: 0.92 (t, J = 7.4Hz, 3H), 1.59 (m, 2H), 2.10 (brs, 1H), 2.49 (t, J = 7.7Hz, 2H), 3.61- 3.64 (m, 2H), 4.11-4.17 (m, 2H), 4.73 (brs, 1H), 6.43 (d, J = 7.4Hz, 2H), 7.04 (d, J = 7.4Hz, 2H).
工程３　化合物Ｉ－００６の合成
　化合物３９（１００ｍｇ、０．５２３ｍｍｏｌ）にTHF（２ｍＬ）に溶解し、氷冷した。反応混合物にトリエチルアミン（０．０８７ｍＬ、０．６２７ｍｍｏｌ）、メタンスルホニルクロリド（０．０４９ｍＬ、０．６２７ｍｍｏｌ）を加え、０℃で１５分間攪拌した。これを溶液Aとした。
　化合物３７（９４．０ｍｇ、０．５２３ｍｍｏｌ）をDMF(１ｍＬ)に溶解し、氷冷した。溶液に６０％水素化ナトリウム（２３．０ｍｇ、０．５７５ｍｍｏｌ）を加え、３分間攪拌した。反応溶液に溶液Aを加え、８０℃で１時間攪拌した。さらに、カリウムt-ブトキシド（７０．４ｍｇ、０．６２７ｍｍｏｌ）を加え、マイクロウエーブ、１６０℃で１５分間加熱した。溶液を逆相HPLC（水－アセトニトリル）により精製して、化合物Ｉ－００６の合成（２６．５ｍｇ、収率１４％）を得た。
1H-NMR（CDCl3）δ：0.92 (t, J = 7.2Hz, 3H), 1.47 (d, J = 6.8Hz, 3H), 1.59 (m, 2H), 1.98 (s, 3H), 2.49 (t, J = 7.9Hz, 2H), 3.83-3.86 (m, 2H), 4.27-4.31 (m, 2H), 5.03-5.21 (m, 2H), 6.44 (d, J = 7.7Hz, 2H), 6.76 (d, J = 8.2Hz, 2H), 7.05 (d, J = 7.7Hz, 2H), 7.25 (d, J = 8.2Hz, 2H). Step 3 Synthesis of Compound I-006 Compound 39 (100 mg, 0.523 mmol) was dissolved in THF (2 mL) and cooled on ice. Triethylamine (0.087 mL, 0.627 mmol) and methanesulfonyl chloride (0.049 mL, 0.627 mmol) were added to the reaction mixture, and the mixture was stirred at 0 ° C. for 15 minutes. This was designated as Solution A.
Compound 37 (94.0 mg, 0.523 mmol) was dissolved in DMF (1 mL) and cooled on ice. 60% sodium hydride (23.0 mg, 0.575 mmol) was added to the solution and stirred for 3 minutes. Solution A was added to the reaction solution and stirred at 80 ° C. for 1 hour. Furthermore, potassium t-butoxide (70.4 mg, 0.627 mmol) was added, and the mixture was heated at 160 ° C. for 15 minutes. The solution was purified by reverse phase HPLC (water-acetonitrile) to give compound I-006 synthesis (26.5 mg, 14% yield).
1 H-NMR (CDCl 3 ) δ: 0.92 (t, J = 7.2 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.59 (m, 2H), 1.98 (s, 3H), 2.49 ( t, J = 7.9Hz, 2H), 3.83-3.86 (m, 2H), 4.27-4.31 (m, 2H), 5.03-5.21 (m, 2H), 6.44 (d, J = 7.7Hz, 2H), 6.76 (d, J = 8.2Hz, 2H), 7.05 (d, J = 7.7Hz, 2H), 7.25 (d, J = 8.2Hz, 2H).
実施例００７　化合物Ｉ－００７の合成
Figure JPOXMLDOC01-appb-C000158
 Example 007 Synthesis of Compound I-007
Figure JPOXMLDOC01-appb-C000158
工程１　化合物４２の合成
　化合物４１（７００ｍｇ、２．７９ｍｍｏｌ）とｐ－エトキシフェノール（４４３ｍｇ、３．２０ｍｍｏｌ）をＤＭＦ（６ｍＬ）に溶解し、炭酸セシウム（１９９７ｍｇ、６．１３ｍｍｏｌ）を加え、９０℃で４．５時間撹拌した。
　反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出した。有機層を合わせて、水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、ｐ－エトキシフェノールを含む状態で化合物４２（６９０ｍｇ）を無色液体として得た。
測定条件２、ＲＴ＝２．３３ｍｉｎ、Ｍ＋Ｈ　２９４．２０ Step 1 Synthesis of Compound 42 Compound 41 (700 mg, 2.79 mmol) and p-ethoxyphenol (443 mg, 3.20 mmol) were dissolved in DMF (6 mL), cesium carbonate (1997 mg, 6.13 mmol) was added, and 90 ° C. For 4.5 hours.
A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 42 (690 mg) as a colorless liquid in a state containing p-ethoxyphenol.
Measurement condition 2, RT = 2.33 min, M + H 294.20
工程２　化合物４３の合成
　工程１で得られた、ｐ－エトキシフェノールを含む化合物４２（６９０ｍｇ）に４ｍｏｌ／Ｌ塩酸の酢酸エチル溶液（４ｍＬ）を加え、室温で１５時間撹拌した。
　反応混合物にヘキサンを加え、析出した固体を濾過、ヘキサンで洗浄して、化合物４３（４５３ｍｇ、収率８４％(２工程)）を無色固体として得た。 Step 2 Synthesis of Compound 43 To Compound 42 (690 mg) containing p-ethoxyphenol obtained in Step 1, 4 mol / L hydrochloric acid in ethyl acetate (4 mL) was added and stirred at room temperature for 15 hours.
Hexane was added to the reaction mixture, and the precipitated solid was filtered and washed with hexane to obtain Compound 43 (453 mg, 84% yield (2 steps)) as a colorless solid.
工程３　化合物４４の合成
　チオホスゲン（０．３３５ｍＬ，４．３８ｍｍｏｌ）をジクロロメタン（８ｍＬ）に溶解し、０℃冷却下にて化合物４３（４０２ｍｇ、１．７５ｍｍｏｌ）とトリエチルアミン（１．４６ｍＬ、１０．５０ｍｍｏｌ）とのジクロロメタン（２ｍＬ）溶液をゆっくりと加え、室温で１時間撹拌した。チオホスゲン（０．０３４ｍＬ、０．４４ｍｍｏｌ）とトリエチルアミン（０．１４ｍＬ、０．１０ｍｍｏｌ）を追加し、室温で１時間撹拌した。
　２８％アンモニア水（１４ｍＬ）を加え、続けてＴＨＦ（１６ｍＬ）を加えて室温で２日間撹拌した。反応混合物を酢酸エチルで３回抽出し、有機層を合わせて水で洗浄して、硫酸マグネシウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物４４（１９３ｍｇ、収率４４％）を固体として得た。
測定条件２、ＲＴ＝２．２５ｍｉｎ、Ｍ＋Ｈ　２５３．００ Step 3 Synthesis of Compound 44 Thiophosgene (0.335 mL, 4.38 mmol) was dissolved in dichloromethane (8 mL), and compound 43 (402 mg, 1.75 mmol) and triethylamine (1.46 mL, 10.50 mmol) were cooled at 0 ° C. ) In dichloromethane (2 mL) was added slowly and stirred at room temperature for 1 hour. Thiophosgene (0.034 mL, 0.44 mmol) and triethylamine (0.14 mL, 0.10 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
28% aqueous ammonia (14 mL) was added, followed by THF (16 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was extracted three times with ethyl acetate, the organic layers were combined, washed with water, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 44 (193 mg, yield 44%) as a solid.
Measurement condition 2, RT = 2.25 min, M + H 253.00
工程４　化合物４６の合成
　化合物４５（２．６１ｇ、１２．４８ｍｍｏｌ、合成法はＥｕｒ．Ｊ．Ｏｒｇ．Ｃｈｅｍ．２０１１，７０９７－７１０６に記載）をＤＭＦ（１３ｍＬ）に溶解し、フタルイミドカリウム（２．５４ｇ、１３．７３ｍｍｏｌ）を加え、１００℃で７時間撹拌した。
　反応混合物に水を加え、酢酸エチルで３回抽出した。有機層を合わせ、水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物４６（２．１６ｇ）をフタルイミドを８%含む状態で得た。
測定条件２、ＲＴ＝１．７８ｍｉｎ、Ｍ＋Ｈ　２７６．００ Step 4 Synthesis of Compound 46 Compound 45 (2.61 g, 12.48 mmol, synthesis method described in Eur. J. Org. Chem. 2011, 7097-7106) was dissolved in DMF (13 mL), and potassium phthalimide (2. 54 g, 13.73 mmol) was added, and the mixture was stirred at 100 ° C. for 7 hours.
Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 46 (2.16 g) in a state containing 8% phthalimide.
Measurement condition 2, RT = 1.78 min, M + H 276.00
工程５　化合物４７の合成
　工程４で得られた８％フタルイミドを含む化合物４６（５００ｍｇ）と２，６－ルチジン（３．８１ｍＬ、３２．７ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、０℃冷却下にてトリメチルシリルトリフラート（３．９４ｍＬ、２１．７９ｍｍｏｌ）を加え、０℃で２時間撹拌した。０℃で水（１５ｍＬ）を加え、室温で１時間撹拌した後、酢酸エチルで３回抽出した。有機層を合わせ、１ｍｏｌ／Ｌ塩酸で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物４７（３２１ｍｇ、収率８１％）を白色固体として得た。
測定条件２、ＲＴ＝１．４４ｍｉｎ、Ｍ＋Ｈ　２１８．２０ Step 5 Synthesis of Compound 47 Compound 46 (500 mg) containing 8% phthalimide obtained in Step 4 and 2,6-lutidine (3.81 mL, 32.7 mmol) were dissolved in dichloromethane (5 mL) and cooled to 0 ° C. Trimethylsilyl triflate (3.94 mL, 21.79 mmol) was added and stirred at 0 ° C. for 2 hours. Water (15 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour, and extracted three times with ethyl acetate. The organic layers were combined, washed with 1 mol / L hydrochloric acid, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 47 (321 mg, 81% yield) as a white solid.
Measurement condition 2, RT = 1.44 min, M + H 218.20
工程６　化合物４８の合成
　化合物４７（５０ｍｇ、０．２３ｍｍｏｌ）をアセトニトリル（０．４ｍＬ）に溶解し、０℃冷却下にて５，５－ジブロモピリミジン－２，４，６（１Ｈ，３Ｈ，５Ｈ）トリオン（３０．９ｍｇ、０．１０８ｍｍｏｌ）を加え、続けて２５％臭化水素の酢酸溶液（１０μＬ、０．０４６ｍｍｏｌ）を加え、室温で３０分間撹拌した。
　反応混合物を飽和炭酸水素ナトリウム水溶液へ注ぎ、酢酸エチルで２回抽出した。有機層を合わせ、水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、化合物４８（６７ｍｇ、収率９８％）を無色液体として得た。 Step 6 Synthesis of Compound 48 Compound 47 (50 mg, 0.23 mmol) was dissolved in acetonitrile (0.4 mL), and cooled to 0 ° C., 5,5-dibromopyrimidine-2,4,6 (1H, 3H, 5H) ) Trione (30.9 mg, 0.108 mmol) was added followed by 25% hydrogen bromide in acetic acid (10 μL, 0.046 mmol) and stirred at room temperature for 30 minutes.
The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 48 (67 mg, yield 98%) as a colorless liquid.
工程７　化合物４９の合成
　化合物４８（６７ｍｇ、０．２２６ｍｍｏｌ）をＤＭＦ（０．７ｍＬ）に溶解し、化合物４４（５１．９ｍｇ、０．２０６ｍｍｏｌ）を加え、５０℃で２２時間撹拌した。
　飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで２回抽出した。有機層を合わせ、水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製して、化合物４９（４５ｍｇ、収率４９％）を橙色液体として得た。
測定条件２、ＲＴ＝２．２５ｍｉｎ、Ｍ＋Ｈ　４５０．１０ Step 7 Synthesis of Compound 49 Compound 48 (67 mg, 0.226 mmol) was dissolved in DMF (0.7 mL), compound 44 (51.9 mg, 0.206 mmol) was added, and the mixture was stirred at 50 ° C. for 22 hours.
Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 49 (45 mg, yield 49%) as an orange liquid.
Measurement condition 2, RT = 2.25 min, M + H 450.10
工程８　化合物Ｉ－００７の合成
　実施例００１の工程７の化合物９の代わりに化合物４９を用いることにより化合物Ｉ－００７を得た。
1H-NMR (DMSO-d6) δ: 1.29 (t, J = 6.9 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.79 (s, 3H), 387-3.98 (m, 4H), 4.37-4.41 (m, 2H), 4.96-5.01 (m, 1H), 5.08-5.12 (m, 1H), 6.79 (d,, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.95 (1H, s), 8.30 (d, J = 7.9 Hz, 1H). Step 8 Synthesis of Compound I-007 Compound I-007 was obtained by substituting Compound 49 for Compound 9 in Step 7 of Example 001.
1 H-NMR (DMSO-d6) δ: 1.29 (t, J = 6.9 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.79 (s, 3H), 387-3.98 (m, 4H) , 4.37-4.41 (m, 2H), 4.96-5.01 (m, 1H), 5.08-5.12 (m, 1H), 6.79 (d ,, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.95 (1H, s), 8.30 (d, J = 7.9 Hz, 1H).
実施例００８～０２８　化合物Ｉ－０８～０２８の合成
　上記実施例００１～００７と同様に、化合物Ｉ－００８～Ｉ－２０６を合成した。以下にその化学構造式及び物理恒数を示す。 Examples 008 to 028 Synthesis of Compounds I-08 to 028 Compounds I-008 to I-206 were synthesized in the same manner as in the above Examples 001 to 007. The chemical structural formula and physical constant are shown below.
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
　上記実施例と同様に、以下の本発明化合物を合成することができる。
Figure JPOXMLDOC01-appb-C000188
 Similar to the above examples, the following compounds of the present invention can be synthesized.
Figure JPOXMLDOC01-appb-C000188
　以下に、本発明化合物の生物試験例を記載する。 Hereinafter, biological test examples of the compounds of the present invention will be described.
調製例１：リコンビナントヒトＡＣＣ２の調製
　ヒトＡＣＣ２蛋白質（Ｎ末より２７アミノ酸残基～２４５８アミノ酸残基）をコードするｃＤＮＡをヒト腎臓ｃＤＮＡライブラリー（クロンテック社）よりクローニングし、５’末端にＨｉｓ－ｔａｇ配列を導入後、ｐＦａｓｔＢａｃ１（インビトロジェン社）に挿入した。Ｂａｃ－ｔｏ－Ｂａｃバキュロウイルス発現システム　（Ｉｎｖｉｔｒｏｇｅｎ社）のプロトコールに従い、組換えバキュロウィルスを作製後、Ｓｆ－９細胞に感染させ、ヒトＡＣＣ２蛋白質を発現させた。回収した細胞を破砕し、フィルターろ過後、Ｎｉアフィニティクロマトグラフィー及び陰イオン交換クロマトグラフィーに供した。ヒトＡＣＣ２蛋白質が含まれている画分を回収し、リコンビナントヒトＡＣＣ２を得た。 Preparation Example 1: Preparation of Recombinant Human ACC2 A cDNA encoding the human ACC2 protein (27 amino acid residues to 2458 amino acid residues from the N terminus) was cloned from a human kidney cDNA library (Clontech) and His- After the tag sequence was introduced, it was inserted into pFastBac1 (Invitrogen). According to the protocol of the Bac-to-Bac baculovirus expression system (Invitrogen), a recombinant baculovirus was prepared and then infected with Sf-9 cells to express the human ACC2 protein. The collected cells were crushed, filtered, and subjected to Ni affinity chromatography and anion exchange chromatography. The fraction containing human ACC2 protein was collected to obtain recombinant human ACC2.
調製例２：リコンビナントヒトＡＣＣ１の調製
　ヒトＡＣＣ１蛋白質（Ｎ末より１アミノ酸残基～２３４６アミノ酸残基）をコードするｃＤＮＡをヒト肝臓ｃＤＮＡライブラリー（ＢｉｏＣｈａｉｎ社）よりクローニングし、３’末端にｍｙｃタグ及びＨｉｓ－ｔａｇ配列を導入後、ｐＩＥＸＢＡＣ３（ノバジェン社）に挿入した。ＦｌａｓｈＢＡＣＧＯＬＤ（オックスフォード　エクスプレッション　テクノロジーズ社）のプロトコールに従い、組換えバキュロウィルスを作製後、Ｓｆ－９細胞に感染させ、ヒトＡＣＣ１蛋白質を発現させた。回収した細胞を破砕し、フィルターろ過後、Ｎｉアフィニティクロマトグラフィー及び陰イオン交換クロマトグラフィーに供した。ヒトＡＣＣ１蛋白質が含まれている画分を回収し、リコンビナントヒトＡＣＣ１を得た。 Preparation Example 2: Preparation of Recombinant Human ACC1 A cDNA encoding the human ACC1 protein (1 to 2346 amino acid residues from the N terminus) was cloned from a human liver cDNA library (BioChain) and a myc tag at the 3 ′ end. And His-tag sequence were introduced, and then inserted into pIEXBAC3 (Novagen). According to the protocol of FlashBACGOLD (Oxford Expression Technologies), a recombinant baculovirus was prepared and then infected with Sf-9 cells to express the human ACC1 protein. The collected cells were crushed, filtered, and subjected to Ni affinity chromatography and anion exchange chromatography. Fractions containing human ACC1 protein were collected to obtain recombinant human ACC1.
試験例１：ヒトＡＣＣ１及びＡＣＣ２阻害活性の測定
　上記の調製例により得たリコンビナントヒトＡＣＣ１及びリコンビナントヒトＡＣＣ２を、アッセイ緩衝液（50 mM HEPES-KOH (pH 7.4), 10 mM 塩化マグネシウム、6～10 mM クエン酸カリウム、4 mM 還元型グルタチオン、1.5 mg/ml 牛血清アルブミン）中で1時間プレインキュベーションを行った。ついで、0.2μLの各々の本発明化合物溶液（DMSO）を分注した384穴マイクロプレートに、プレインキュベーションした酵素溶液5μLと基質溶液（50 mM HEPES-KOH (pH 7.4)、1 mM ATP、0.8 mM アセチルCoA、25～50 mM 炭酸水素カリウム）5μLを添加し、遠心、振とう後、湿潤箱中で室温、1～3時間インキュベーションした。インキュベーション後にEDTAの添加により酵素反応を停止し、その後、MALDIターゲットプレート上でCHCA (α-cyano-4-hydroxy cinnamic acid)マトリックスと共結晶させ、マトリックス支援レーザー脱離イオン化－飛行時間型質量分析計（MALDI-TOF MS）を用いて、リフレクターネガティブモードで測定を行った。基質のアセチルCoA (AcCoA)と反応産物であるマロニルCoA (MalCoA)の脱プロトン化イオンを検出し、それぞれのシグナル強度を用いてマロニルCoA又はスクシニルCoAへの変換率Intensity of [MalCoA-H]―/(Intensity of [MalCoA-H]― + Intensity of [AcCoA-H]―)を算出した。各化合物濃度における酵素反応の阻害率から５０％阻害濃度（ＩＣ５０値）を算出した。なお、アッセイ緩衝液中のクエン酸カリウム濃度、基質溶液中の炭酸水素カリウム濃度及びインキュベーションの時間は、使用する酵素のロット毎に上記の濃度又は反応時間内で調整した。 Test Example 1: Measurement of human ACC1 and ACC2 inhibitory activity Recombinant human ACC1 and recombinant human ACC2 obtained by the above preparation examples were mixed with assay buffer (50 mM HEPES-KOH (pH 7.4), 10 mM magnesium chloride, 6 to 10 Preincubation was carried out for 1 hour in mM potassium citrate, 4 mM reduced glutathione, 1.5 mg / ml bovine serum albumin). Next, 5 μL of the pre-incubated enzyme solution and the substrate solution (50 mM HEPES-KOH (pH 7.4), 1 mM ATP, 0.8 mM) were added to a 384-well microplate into which 0.2 μL of each compound solution of the present invention (DMSO) was dispensed. 5 μL of acetyl CoA (25-50 mM potassium bicarbonate) was added, centrifuged, shaken, and incubated in a humid box at room temperature for 1-3 hours. After incubation, the enzyme reaction is stopped by adding EDTA, then co-crystallized with CHCA (α-cyano-4-hydroxy cinnamic acid) matrix on MALDI target plate, and matrix-assisted laser desorption / ionization-time-of-flight mass spectrometer (MALDI-TOF MS) was used for measurement in the reflector negative mode. Deprotonated ions of substrate acetyl CoA (AcCoA) and reaction product malonyl CoA (MalCoA) are detected, and the respective signal intensity is used to convert to malonyl CoA or succinyl CoA Intensity of [MalCoA-H] ― / (Intensity of [MalCoA-H] — + Intensity of [AcCoA-H] — ) was calculated. The 50% inhibition concentration (IC50 value) was calculated from the inhibition rate of the enzyme reaction at each compound concentration. The potassium citrate concentration in the assay buffer, the potassium bicarbonate concentration in the substrate solution, and the incubation time were adjusted within the above concentrations or reaction times for each lot of enzyme used.
　ヒトＡＣＣ１阻害活性については化合物Ｉ－００８、Ｉ－０１９、Ｉ－０２３、Ｉ－０３４、Ｉ－０３７、Ｉ－０４５、Ｉ－０５０、Ｉ－０５４、Ｉ－０６７、Ｉ－０７９、Ｉ－０９０、Ｉ－１２４、Ｉ－１２５、Ｉ－１２６，Ｉ－１２７、Ｉ－１２８、Ｉ－１３１、Ｉ－１３２、Ｉ－１４５、Ｉ－１４８、Ｉ－１５５、Ｉ－１５８及びＩ－１９７ついてＩＣ５０値を測定し、いずれの化合物もＩＣ５０値は１０μＭ以上であった。 Regarding the human ACC1 inhibitory activity, compounds I-008, I-019, I-023, I-034, I-037, I-045, I-050, I-054, I-067, I-079, I-090 IC50 for I-124, I-125, I-126, I-127, I-128, I-131, I-132, I-145, I-148, I-155, I-158 and I-197 The values were measured and all compounds had an IC50 value of 10 μM or more.
　各本発明化合物のヒトＡＣＣ２の阻害活性を以下に示す。
Figure JPOXMLDOC01-appb-T000189
 The human ACC2 inhibitory activity of each compound of the present invention is shown below.
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
　以上のように本発明化合物は強いＡＣＣ２阻害活性を示す。したがって、ＡＣＣ２が関与する疾患の予防及び／又は治療に用いることが出来る。
Figure JPOXMLDOC01-appb-T000191
As described above, the compound of the present invention exhibits strong ACC2 inhibitory activity. Therefore, it can be used for prevention and / or treatment of diseases involving ACC2.
試験例２：ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価する。 Test Example 2: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始する。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止する。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量する。 As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction. To start. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) , Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。 The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
）
試験例３：ＢＡ試験
経口吸収性の検討実験材料と方法
（１）使用動物：マウスあるいはＳＤラットを使用する。
（２）飼育条件：マウスあるいはＳＤラットは、固形飼料及び滅菌水道水を自由摂取させる。
（３）投与量、群分けの設定：経口投与、静脈内投与を所定の投与量により投与する。以下のように群を設定する。（化合物ごとで投与量は変更有）
　経口投与　１～３０ｍｇ／ｋｇ（ｎ＝２～３）
　静脈内投与　０．５～１０ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：経口投与は溶液又は懸濁液として投与する。静脈内投与は可溶化して投与する。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与する。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与する。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定する。
（７）統計解析：血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群のＡＵＣから本発明化合物のバイオアベイラビリティ（ＢＡ）を算出する。 )
Test Example 3: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice or SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration are administered at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with a needle.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (registered trademark) for the plasma concentration of the compound of the present invention, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the AUC of the group.
試験例４：代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価する。 Test Example 4: Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させる（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心する。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の本発明化合物の残存量を０分反応時の化合物量を１００％として計算する。なお、加水分解反応はＮＡＤＰＨ非存在下で、グルクロン酸抱合反応はＮＡＤＰＨに換えて５ｍｍｏｌ／Ｌ　ＵＤＰ－グルクロン酸の存在下で反応を行い、以後同じ操作を実施する。 In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
試験例５：ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による本発明化合物のＣＹＰ３Ａ４阻害の増強を調べる試験である。ＣＹＰ３Ａ４酵素（大腸菌発現酵素）により７－ベンジルオキシトリフルオロメチルクマリン（７－ＢＦＣ）が脱ベンジル化されて、蛍光を発する代謝物７－ハイドロキシトリフルオロメチルクマリン（７－ＨＦＣ）が生じる。７－ＨＦＣ生成反応を指標としてＣＹＰ３Ａ４阻害を評価する。 Test Example 5: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
　反応条件は以下のとおり：基質、５．６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０又は３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ、反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；本発明化合物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止する。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始する。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定する。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ） The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate A part of the solution was transferred so that it was diluted to 1/10, and the reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L Tris The reaction is stopped by adding (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。ＩＣ５０値の差が５μｍｏｌ／Ｌ以上の場合を（＋）とし、３μｍｏｌ／Ｌ以下の場合を（－）とする。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Is used to calculate IC 50 by inverse estimation using a logistic model. The case where the difference in IC 50 value is 5 μmol / L or more is (+), and the case where it is 3 μmol / L or less is (−).
試験例６：Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価する。
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養する。ＴＡ９８株は９ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去する。９ｍＬのＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１１０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加する。ＴＡ１００株は３．１６ｍＬ菌液に対しＥｘｐｏｓｕｒｅ培地１２０ｍＬに添加し試験菌液を調製する。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養する。本発明化合物を暴露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養する。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。 Test Example 6: Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L) Buffer). The TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under the metabolic activation conditions, 498 μL of the test bacterial solution and S9 mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each and dispense into 48 wells / dose of the microplate, followed by static culture at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).
試験例７：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャンネルを発現させたＨＥＫ２９３細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討する。
　全自動パッチクランプシステム（ＰａｔｃｈＸｐｒｅｓｓ　７０００Ａ、ＡｘｏｎＩｎｓｔｒｕｍｅｎｔｓ　Ｉｎｃ．）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持した後、＋４０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録する。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１３５　ｍｍｏｌ／Ｌ、ＫＣｌ：５．４　ｍｍｏｌ／Ｌ、ＮａＨ２ＰＯ４：０．３ｍｍｏｌ／Ｌ、ＣａＣｌ２・２Ｈ２Ｏ：１．８ｍｍｏｌ／Ｌ、ＭｇＣｌ２・６Ｈ２Ｏ：１ｍｍｏｌ／Ｌ、グルコース：１０ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－１－ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｅｓｕｌｆｏｎｉｃ　ａｃｉｄ、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温条件下で、１０分間細胞に適用させる。得られたＩＫｒから、解析ソフト（ＤａｔａＸｐｒｅｓｓ　ｖｅｒ．１、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ　Ｃｏｒｐｏｒａｔｉｏｎ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価する。 Test Example 7: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process Consider the action of the compounds of the present invention on the delayed rectifier K + current (I Kr ) that plays a role.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cells were held at a membrane potential of −80 mV by the whole cell patch clamp method, followed by a +40 mV depolarization stimulus for 2 seconds and a further −50 mV repolarization. Record the I Kr elicited when the stimulus is applied for 2 seconds. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH 2 PO 4 : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl 2 · 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) is applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
試験例８：溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定する。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液６　μＬをｐＨ６．８人工腸液（０．２ｍｏｌ／Ｌ　リン酸二水素カリウム試液　２５０ｍＬに０．２ｍｏｌ／Ｌ　ＮａＯＨ試液１１８ｍＬ、水を加えて１０００ｍＬとする。）５９４μＬに添加する。２５℃で１６時間静置させた後、混液を吸引濾過する。濾液をメタノール／水＝１／１（Ｖ／Ｖ）にて２倍希釈し、絶対検量線法によりＨＰＬＣ又はＬＣ／ＭＳ／ＭＳを用いて濾液中濃度を測定する。 Test Example 8: Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) Add to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. The filtrate is diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate is measured by HPLC or LC / MS / MS by the absolute calibration method.
試験例９：粉末溶解度試験
　適当な容器に本発明化合物を適量入れ、各容器にＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとする。）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加える。）、２０ｍｍｏｌ／Ｌ　タウロコール酸ナトリウム（ＴＣＡ）／ＪＰ－２液（ＴＣＡ１．０８ｇにＪＰ－２液を加え１００ｍＬとする。）を２００μＬずつ添加する。試験液添加後に全量溶解する場合には、適宜、本発明化合物を追加する。密閉して３７℃で１時間振とう後に濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡及び析出物がないかを確認し、密閉して振とうする。絶対検量線法によりＨＰＬＣを用いて本発明化合物を定量する。 Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL), JP-2. Solution (add 500 mL of water to 500 mL of phosphate buffer at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (add JP-2 solution to 1.08 g of TCA to make 100 mL) Is added in 200 μL aliquots. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１　錠剤
　　本発明化合物　　　　　　　　　１５ｍｇ
　　乳糖　　　　　　　　　　　　　１５ｍｇ
　　ステアリン酸カルシウム　　　　　３ｍｇ
　ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例２　カプセル剤
　　本発明化合物　　　　　　　　　１０ｍｇ
　　ステアリン酸マグネシウム　　　１０ｍｇ
　　乳糖　　　　　　　　　　　　　８０ｍｇ
を均一に混合して粉末又は細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
製剤例３　顆粒剤
　　本発明化合物　　　　　　　　　　　３０ｇ
　　乳糖　　　　　　　　　　　　　　２６５ｇ
　　ステアリン酸マグネシウム　　　　　　５ｇ
　よく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
　本発明化合物はＡＣＣ２阻害作用を有しており、ＡＣＣ２が関与する疾患の治療又は予防に有用である。 The compound of the present invention has an ACC2 inhibitory action and is useful for treatment or prevention of diseases involving ACC2.

Claims (31)

  1. 式（I）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    式：
    Figure JPOXMLDOC01-appb-C000002
    で示される基は非置換のアリール、置換基群αより選択される１以上の基で置換されたアリール、非置換のヘテロアリール、又は置換基群αより選択される１以上の基で置換されたヘテロアリールであり、
    置換基群αは、
    置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のシクロアルキルスルファニル、置換若しくは非置換のシクロアルケニルスルファニル、置換若しくは非置換のアリールスルファニル、置換若しくは非置換のヘテロアリールスルファニル、置換若しくは非置換の非芳香族複素環スルファニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のシクロアルキルスルフィニル、置換若しくは非置換のシクロアルケニルスルフィニル、置換若しくは非置換のアリールスルフィニル、置換若しくは非置換のヘテロアリールスルフィニル、置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアミノスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換の非芳香族複素環スルホニル、置換若しくは非置換のアルキルスルホニルオキシ、置換若しくは非置換のアルケニルスルホニルオキシ、置換若しくは非置換のアルキニルスルホニルオキシ、置換若しくは非置換のシクロアルキルスルホニルオキシ、置換若しくは非置換のシクロアルケニルスルホニルオキシ、置換若しくは非置換のアリールスルホニルオキシ、置換若しくは非置換のヘテロアリールスルホニルオキシ、置換若しくは非置換の非芳香族複素環スルホニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルカルボニルオキシ、置換若しくは非置換のアルケニルカルボニルオキシ、置換若しくは非置換のアルキニルカルボニルオキシ、置換若しくは非置換のシクロアルキルカルボニルオキシ、置換若しくは非置換のシクロアルケニルカルボニルオキシ、置換若しくは非置換のアリールカルボニルオキシ、置換若しくは非置換のヘテロアリールカルボニルオキシ、置換若しくは非置換の非芳香族複素環カルボニルオキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル、ハロゲン、ヒドロキシ、メルカプト、シアノ、アジド、置換若しくは非置換のアミジノ、グアニジノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル及びカルボキシからなる群であり、
    環Ｂは置換若しくは非置換の非芳香族炭素環又は置換若しくは非置換の非芳香族複素環であり、
    環Ｃは置換若しくは非置換の６員の芳香族炭素環、置換若しくは非置換の５員の芳香族複素環又は置換若しくは非置換の６員の芳香族複素環であり、
    Ｕは－ＣＲ４Ｒ５－、－ＣＲ４Ｒ５－Ｏ－、－ＣＲ４Ｒ５－Ｓ－、－ＣＲ４Ｒ５－ＮＲ６－、－Ｏ－、－Ｓ－、－ＮＲ６－、－Ｏ－ＣＲ４Ｒ５－、－Ｓ－ＣＲ４Ｒ５－又は－ＮＲ６－ＣＲ４Ｒ５－（ここで、左の結合手は環Ａに結合し、右の結合手は環Ｂに結合する。）であり、
    Ｔは－ＣＲ７Ｒ８－、－ＣＲ７Ｒ８－Ｏ－、－ＣＲ７Ｒ８－Ｓ－、－ＣＲ７Ｒ８－ＮＲ９－、－Ｏ－、－Ｓ－、－ＮＲ９－、－Ｃ（＝Ｏ）－又は－ＳＯ２－（ここで、左の結合手は環Ｂに結合し、右の結合手は環Ｃに結合する。）であり、
    Ｌは－ＣＲ１０Ｒ１１－又は－Ｃ（＝Ｏ）－であり、
    ｐは０又は１であり、
    ｑは０又は１であり、
    ｒは０又は１であり、
    Ｒ４、Ｒ５、Ｒ７、Ｒ８、Ｒ１０及びＲ１１はそれぞれ独立して水素、ヒドロキシ、ハロゲン、置換若しくは非置換のアルキル又はシアノであり、
    Ｒ６及びＲ９はそれぞれ独立して水素又は置換若しくは非置換のアルキルであり、
    Ｒ１３はハロゲン、ヒドロキシ及びシアノからなる群から選択される１以上の置換基で置換されていてもよいメチルあり、
    Ｒ１４はハロゲン、ヒドロキシ、シアノ、メチルオキシ及び置換若しくは非置換のカルバモイルからなる群から選択される１以上の置換基で置換されていてもよいメチルカルボニルであり、
    Ｒ１６は水素又は置換若しくは非置換のアルキルである。
    但し、以下の化合物を除く。
    （i）環Ｂが置換若しくは非置換の５員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０であり、環Ｃが環Ｂ上の窒素原子に結合している化合物、
    （ii）環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが０である化合物、
    （iii）環Ｂが置換若しくは非置換の６員の非芳香族複素環であり、環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、ｐが０であり、ｑが１であり、Ｔが環Ｂ上の窒素原子に結合している化合物。）
    で示される化合物又はその製薬上許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    formula:
    Figure JPOXMLDOC01-appb-C000002
    The group represented by is substituted with one or more groups selected from unsubstituted aryl, aryl substituted with one or more groups selected from substituent group α, unsubstituted heteroaryl, or substituent group α. Heteroaryl,
    Substituent group α is
    Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or Unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenyl The Fanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted cycloalkylsulfanyl, substituted or unsubstituted cycloalkenylsulfanyl, substituted or unsubstituted arylsulfanyl, substituted or unsubstituted heteroarylsulfanyl, substituted or unsubstituted Non-aromatic heterocyclic sulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted Or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted Is unsubstituted aminosulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy, substituted or unsubstituted Alkynylsulfonyloxy, substituted or unsubstituted cycloalkylsulfonyloxy, substituted or unsubstituted cycloalkenylsulfonyloxy, substituted or unsubstituted arylsulfonyl Oxy, substituted or unsubstituted heteroarylsulfonyloxy, substituted or unsubstituted non-aromatic heterocyclic sulfonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted Or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted nonaromatic heterocyclic carbonyl, substituted or unsubstituted Alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted cycloalkylcarbonyloxy, substituted or unsubstituted Unsubstituted cycloalkenylcarbonyloxy, substituted or unsubstituted arylcarbonyloxy, substituted or unsubstituted heteroarylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Heteroaryloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, halogen, hydroxy, mercapto, cyano, azide, substituted or unsubstituted amino Bruno, guanidino, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, a group consisting of a substituted or unsubstituted sulfamoyl, and carboxy,
    Ring B is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
    Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
    U is -CR 4 R 5 -, - CR 4 R 5 -O -, - CR 4 R 5 -S -, - CR 4 R 5 -NR 6 -, - O -, - S -, - NR 6 -, -O-CR 4 R 5 -, - S-CR 4 R 5 - or -NR 6 -CR 4 R 5 - (wherein the left bond is attached to the ring a, the right bond is to the ring B Combined)
    T is -CR 7 R 8 -, - CR 7 R 8 -O -, - CR 7 R 8 -S -, - CR 7 R 8 -NR 9 -, - O -, - S -, - NR 9 -, -C (= O)-or -SO 2- (where the left bond is bonded to ring B and the right bond is bonded to ring C);
    L is —CR 10 R 11 — or —C (═O) —,
    p is 0 or 1;
    q is 0 or 1;
    r is 0 or 1,
    R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl or cyano,
    R 6 and R 9 are each independently hydrogen or substituted or unsubstituted alkyl;
    R 13 is methyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and cyano,
    R 14 is methylcarbonyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, methyloxy and substituted or unsubstituted carbamoyl;
    R 16 is hydrogen or substituted or unsubstituted alkyl.
    However, the following compounds are excluded.
    (I) Ring B is a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring A compound in which p is 0, q is 0, and ring C is bonded to a nitrogen atom on ring B;
    (Ii) Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbon A ring or a substituted or unsubstituted 6-membered aromatic heterocycle, wherein p is 0 and q is 0,
    (Iii) Ring B is a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring, and Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring Wherein p is 0, q is 1 and T is bonded to a nitrogen atom on ring B. )
    Or a pharmaceutically acceptable salt thereof.
  2. ｒが０である、請求項１記載の化合物又はその製薬上許容される塩。 The compound according to claim 1, wherein r is 0, or a pharmaceutically acceptable salt thereof.
  3. 環Ｂが置換若しくは非置換の４員の非芳香族炭素環又は置換若しくは非置換の４員の非芳香族複素環である、請求項１又は２記載の化合物又はその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Ring B is a substituted or unsubstituted 4-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 4-membered non-aromatic heterocyclic ring.
  4. 環Ｂが置換若しくは非置換の４員の非芳香族炭素環である、請求項３記載の化合物又はその製薬上許容される塩。 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted 4-membered non-aromatic carbocycle.
  5. 式：
    Figure JPOXMLDOC01-appb-C000003
    で示される基が、式：
    Figure JPOXMLDOC01-appb-C000004
    （式中、Ｒ１５はそれぞれ独立して水素、置換若しくは非置換のアルキル、ハロゲン又はヒドロキシであり、環Ｂに相当する環上のメチレン基は置換されていてもよい。）で示される基である、請求項１又は２記載の化合物又はその製薬上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000003
    The group represented by the formula:
    Figure JPOXMLDOC01-appb-C000004
    Wherein R 15 is independently hydrogen, substituted or unsubstituted alkyl, halogen or hydroxy, and the methylene group on the ring corresponding to ring B may be substituted. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  6. Ｒ１５が水素であり、環Ｂに相当する環上のメチレン基が非置換である、請求項５記載の化合物又はその製薬上許容される塩。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen, and the methylene group on the ring corresponding to ring B is unsubstituted.
  7. 式：
    Figure JPOXMLDOC01-appb-C000005
    で示される基が、式：
    Figure JPOXMLDOC01-appb-C000006
    で示される基である、請求項１又は２記載の化合物又はその製薬上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000005
    The group represented by the formula:
    Figure JPOXMLDOC01-appb-C000006
    The compound or its pharmaceutically acceptable salt of Claim 1 or 2 which is group shown by these.
  8. ｑが１である、請求項１～７のいずれかに記載の化合物又はその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein q is 1.
  9. Ｔが－Ｏ－又は－ＣＲ７Ｒ８－である、請求項８記載の化合物又はその製薬上許容される塩。 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein T is —O— or —CR 7 R 8 —.
  10. ｐが０である、請求項８又は９記載の化合物又はその製薬上許容される塩。 The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein p is 0.
  11. ｐが１である、請求項１～７のいずれかに記載の化合物又はその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein p is 1.
  12. Ｕが－Ｏ－、－ＣＲ４Ｒ５－又は－Ｏ－ＣＲ４Ｒ５－である、請求項１１記載の化合物又はその製薬上許容される塩。 12. The compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein U is —O—, —CR 4 R 5 — or —O—CR 4 R 5 —.
  13. ｑが０である、請求項１１又は１２記載の化合物又はその製薬上許容される塩。 The compound according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein q is 0.
  14. 環Ｃが置換若しくは非置換の５員の芳香族複素環であり、Ｔ又は環Ｂと結合する環Ｃ上の原子の位置番号を１位とした場合の３位又は４位に位置する環Ｃ上の原子に、式：
    Figure JPOXMLDOC01-appb-C000007
     で示される基が結合している、請求項１～１３のいずれかに記載の化合物又はその製薬上許容される塩。     Ring C is a substituted or unsubstituted 5-membered aromatic heterocycle, and ring C located at the 3- or 4-position when the position number of the atom on ring C bonded to T or ring B is 1-position In the atom above, the formula:
    Figure JPOXMLDOC01-appb-C000007
     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, to which a group represented by the formula:
  15. 環Ｃが置換若しくは非置換のイソオキサゾール又はチアゾールである、請求項１～１４のいずれかに記載の化合物又はその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein Ring C is substituted or unsubstituted isoxazole or thiazole.
  16. 環Ｃが置換若しくは非置換の６員の芳香族炭素環又は置換若しくは非置換の６員の芳香族複素環であり、
    Figure JPOXMLDOC01-appb-C000008
     で示される基が、Ｔ又は環Ｂに対してメタ位又はパラ位の位置で環Ｃと結合している、請求項１～１３のいずれかに記載の化合物又はその製薬上許容される塩。     Ring C is a substituted or unsubstituted 6-membered aromatic carbocyclic ring or a substituted or unsubstituted 6-membered aromatic heterocyclic ring,
    Figure JPOXMLDOC01-appb-C000008
     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein the group represented by the formula (I) is bonded to ring C at a meta position or a para position with respect to T or ring B.
  17. 環Ｃが置換若しくは非置換のベンゼンである、請求項１６記載の化合物又はその製薬上許容される塩。 The compound or pharmaceutically acceptable salt thereof according to claim 16, wherein Ring C is substituted or unsubstituted benzene.
  18. 環Ｂが置換若しくは非置換の６員の非芳香族炭素環又は置換若しくは非置換の６員の非芳香族複素環であり、Ｕ又は環Ａと結合する環Ｂ上の原子の位置番号を１位とした場合の４位に位置する環Ｂ上の原子にＴ又は環Ｃが結合している、請求項１６又は１７記載の化合物又はその製薬上許容される塩。 Ring B is a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 6-membered non-aromatic heterocyclic ring. 18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein T or ring C is bonded to an atom on ring B located at the 4-position when defined as a position.
  19. 式：
    Figure JPOXMLDOC01-appb-C000009
    で示される基が置換基群αより選択される１以上の基で置換されたアリール又は置換基群αより選択される１以上の基で置換されたヘテロアリールである、請求項１～１８のいずれかに記載の化合物又はその製薬上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000009
    The group represented by is aryl substituted with one or more groups selected from substituent group α or heteroaryl substituted with one or more groups selected from substituent group α The compound according to any one of the above or a pharmaceutically acceptable salt thereof.
  20. 式：
    Figure JPOXMLDOC01-appb-C000010
    で示される基が非置換の６員のアリール、置換基群αより選択される１以上の基で置換された６員のアリール、非置換の６員のヘテロアリール、置換基群αより選択される１以上の基で置換された６員のヘテロアリール又は式：
    Figure JPOXMLDOC01-appb-C000011
    （式中、環Ｅは５員の芳香族複素環であり、環Ｆは６員の芳香族炭素環又は６員の芳香族複素環であり、環Ｅと環Ｆは縮合して二環性の芳香族複素環を形成している。環Ｅ及び／又は環Ｆは置換基群αより選択される１以上の基で置換されていてもよい。）で示される基である、請求項１～１８のいずれかに記載の化合物又はその製薬上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000010
    The group represented by is selected from unsubstituted 6-membered aryl, 6-membered aryl substituted with one or more groups selected from substituent group α, unsubstituted 6-membered heteroaryl, substituent group α A 6-membered heteroaryl substituted with one or more groups
    Figure JPOXMLDOC01-appb-C000011
    (In the formula, ring E is a 5-membered aromatic heterocycle, ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle, and ring E and ring F are condensed to be bicyclic. The ring E and / or the ring F may be substituted with one or more groups selected from the substituent group α. The compound according to any one of 18 to 18, or a pharmaceutically acceptable salt thereof.
  21. 式：
    Figure JPOXMLDOC01-appb-C000012
    で示される基が式：
    Figure JPOXMLDOC01-appb-C000013
    （式中、Ｘ１はそれぞれ独立して－Ｃ（Ｈ）＝又は－Ｃ（Ｒ１２）＝であり、Ｒ１７は置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ又は置換若しくは非置換の非芳香族複素環オキシであり、
    Ｒ１２はそれぞれ独立して置換基群αより選択される基である。）で示される基である、請求項１～１８のいずれかに記載の化合物又はその製薬上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000012
    A group represented by the formula:
    Figure JPOXMLDOC01-appb-C000013
    Wherein X 1 is independently —C (H) ═ or —C (R 12 ) ═, and R 17 is substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or substituted or unsubstituted non-aromatic heterocycle Is oxy,
    R 12 is a group independently selected from the substituent group α. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, which is a group represented by
  22. Ｒ１２がそれぞれ独立して置換若しくは非置換のアルキル、ハロゲン、ヒドロキシ、スルファニル、シアノ、置換若しくは非置換のアミノ、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又はカルボキシである、請求項２１記載の化合物又はその製薬上許容される塩。 22. Each R 12 is independently substituted or unsubstituted alkyl, halogen, hydroxy, sulfanyl, cyano, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or carboxy. The described compound or a pharmaceutically acceptable salt thereof.
  23. 式：
    Figure JPOXMLDOC01-appb-C000014
    で示される基が、
    Figure JPOXMLDOC01-appb-C000015
    （式中、環上の炭素原子は置換基群αより選択される１以上の基で置換されていてもよい。）で示される基である請求項１～１８のいずれかに記載の化合物又はその製薬上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000014
    A group represented by
    Figure JPOXMLDOC01-appb-C000015
    (Wherein the carbon atom on the ring may be substituted with one or more groups selected from the substituent group α), Its pharmaceutically acceptable salt.
  24. 環Ｂが置換若しくは非置換の４～６員のシクロアルカン又は置換若しくは非置換の４～６員の飽和複素環であり、
    環Ｃが置換若しくは非置換の５員の芳香族複素環式基であり、
    ｑが０であり、
    ｒが０である、請求項１記載の化合物又はその製薬上許容される塩。     Ring B is a substituted or unsubstituted 4- to 6-membered cycloalkane or a substituted or unsubstituted 4- to 6-membered saturated heterocyclic ring,
    Ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic group,
    q is 0,
    The compound according to claim 1, wherein r is 0, or a pharmaceutically acceptable salt thereof.
  25. 環Ｂが置換若しくは非置換のシクロブタン又は置換若しくは非置換のアゼチジンである、請求項２４記載の化合物又はその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to claim 24, wherein Ring B is substituted or unsubstituted cyclobutane or substituted or unsubstituted azetidine.
  26. 環Ｃが置換若しくは非置換のイソオキサゾール、置換若しくは非置換のチアゾール又は置換若しくは非置換のオキサジアゾールである、請求項２４又は２５記載の化合物又はその製薬上許容される塩。 26. The compound according to claim 24 or 25 or a pharmaceutically acceptable salt thereof, wherein ring C is substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole or substituted or unsubstituted oxadiazole.
  27. 式（I）で示される化合物が、式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000016
    で示される化合物である、請求項１～２６のいずれかに記載の化合物又はその製薬上許容される塩。     A compound of formula (I) is represented by formula (II):
    Figure JPOXMLDOC01-appb-C000016
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, which is a compound represented by the formula:
  28. 請求項１～２７のいずれかに記載の化合物又はその又はその製薬上許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.
  29. ＡＣＣ２が関与する疾患の治療又は予防に用いる、請求項２８記載の医薬組成物。 The pharmaceutical composition according to claim 28, which is used for treatment or prevention of a disease involving ACC2.
  30. 請求項１～２７のいずれかに記載の化合物、又はその製薬上許容される塩を投与することを特徴とする、ＡＣＣ２の関与する疾患の治療又は予防方法。 A method for treating or preventing a disease involving ACC2, comprising administering the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.
  31. ＡＣＣ２の関与する疾患を治療又は予防するための、請求項１～２７のいずれかに記載の化合物、又はその製薬上許容される塩。 The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for treating or preventing a disease involving ACC2.
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