WO2014061693A1 - Nouveau dérivé carbocyclique non aromatique ou hétérocyclique non aromatique - Google Patents

Nouveau dérivé carbocyclique non aromatique ou hétérocyclique non aromatique 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
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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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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
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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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    • C07D261/06—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.

Abstract

L'objectif de la présente invention est de décrire un nouveau composé qui a une activité inhibitrice de ACC2. L'invention concerne en outre une composition médicinale contenant le composé. L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Dans la formule (I) : le groupe représenté par la formule (formule chimique 2) est un aryle non substitué, etc. ; le groupe substituant α est un alkyle substitué ou non substitué, etc. ; le cycle B est un carbocycle non aromatique substitué ou non substitué, etc. ; le cycle C est un carbocycle aromatique à 6 chaînons substitué ou non substitué, etc. ; U est -CR4R5-, etc. ; T est -CR7R8-, etc. ; L est -CR10R11-, etc. ; p est 0 ou 1 ; q est 0 ou 1 ; r est 0 ou 1 ; R4, R5, R7, R8, R10 et R11 sont indépendamment hydrogène, etc. ;R6 et R9 sont indépendamment hydrogène ou alkyle substitué ou non substitué ; R13 est alkyle substitué ou non substitué ; R14 est alkylcarbonyle substitué ou non substitué, etc. ;et R16 hydrogène ou alkyle substitué ou non substitué.
PCT/JP2013/078047 2012-10-17 2013-10-16 Nouveau dérivé carbocyclique non aromatique ou hétérocyclique non aromatique WO2014061693A1 (fr)

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