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WO2012108478A1 - Composé monocyclique - Google Patents

Composé monocyclique Download PDF

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Publication number
WO2012108478A1
WO2012108478A1 PCT/JP2012/052899 JP2012052899W WO2012108478A1 WO 2012108478 A1 WO2012108478 A1 WO 2012108478A1 JP 2012052899 W JP2012052899 W JP 2012052899W WO 2012108478 A1 WO2012108478 A1 WO 2012108478A1
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group
compound
optionally substituted
reaction
substituted
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Japanese (ja)
Inventor
藤本　卓也
信 鎌田
山下　徹
英喜 廣瀬
正鷹 村上
朝人 喜名
善一 池田
常雄 安間
亮 溝尻
郁男 藤森
淳平 会田
響子 豊福
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Priority to TW101128195A priority Critical patent/TW201332945A/zh
Publication of WO2012108478A1 publication Critical patent/WO2012108478A1/fr
Anticipated expiration legal-status Critical
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    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C323/40—Y being a hydrogen or a carbon atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D261/10—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention has an inhibitory action on acetyl-CoA carboxylase (which may be abbreviated as ACC in the present specification), and is obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic complications, metabolic syndrome Further, the present invention relates to a monocyclic compound useful for prevention / treatment of sarcopenia, cancer and the like.
  • acetyl-CoA carboxylase which may be abbreviated as ACC in the present specification
  • ACC acetyl-CoA carboxylase
  • ACC is an enzyme that converts acetyl-CoA to malonyl-CoA and catalyzes the rate-limiting reaction in fatty acid metabolism or synthesis.
  • Malonyl-CoA the product of the ACC catalytic reaction, inhibits mitochondrial fatty acid oxidation by feedback inhibition of carnitine palmitoyltransferase-1 (CPT-1).
  • CPT-1 carnitine palmitoyltransferase-1
  • Decreased malonyl-CoA levels due to ACC inhibition include increased fatty acid oxidation, inhibition of fatty acid synthesis, decreased triglyceride (TG) rich lipoprotein (VLDL) secretion in the liver, regulation of insulin secretion in the pancreas, and May improve insulin sensitivity in liver, skeletal muscle and adipose tissue.
  • long-term administration of a compound having an ACC inhibitory action by promoting fatty acid oxidation and suppressing fatty acid de novo synthesis is a TG of liver and adipose tissue in obese subjects ingesting a low-fat diet.
  • the content can be greatly reduced and body fat can be selectively reduced.
  • a compound having an ACC inhibitory action is extremely useful for the prevention and treatment of metabolic syndrome, obesity, hypertension, diabetes, cardiovascular diseases related to atherosclerosis, and the like.
  • Patent Document 1 includes the following compounds:
  • Patent Document 2 includes the following compounds:
  • a 1 , A 4 and A 5 independently represent N, C (R 1 ) (R 1 represents H, alkyl, halogen or haloalkyl); A 2 and A 3 independently represent C (—L 2 —R 2 ) (L 2 represents O or the like, R 2 represents alkyl or the like); L 1 represents O, N (R X ), S, S (O), S (O) 2 or C (R y R z ) m; m represents 1, 2 or 3; A represents phenyl or monocyclic heteroaryl; X represents —O— (CR y R z ) p—NR d R e or the like; R d represents —C (O) alkyl or the like; Re represents H or the like] Has been reported as a compound having an ACC inhibitory action.
  • Non-patent Document 1 Journal of Medicinal Chemistry, 2010, 53, 8679-8687 (Non-patent Document 1) includes the following compounds:
  • Patent Document 3 includes the following compounds:
  • A represents an acyl group or an optionally substituted 5- to 6-membered aromatic ring group
  • Ring M represents a 5- to 7-membered ring which may be further substituted and optionally condensed
  • Ring P and Ring Q are (1) Ring P represents a 5-membered heterocyclic ring which may be further substituted, Ring Q represents a 6-membered ring which may be further substituted, and further condensed by condensing ring P and ring Q Forming a bicyclic aromatic heterocycle which may be (2)
  • Ring P represents an optionally substituted 5-membered non-aromatic ring, Ring Q represents an optionally further substituted 6-membered aromatic ring, and ring P and ring Q are condensed Forming an optionally substituted bicyclic non-aromatic ring;
  • R 1 represents an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
  • L 1 and L 2 are (1) independently represents optionally substituted methylene, O,
  • A represents H, lower alkyl, cycloalkyl or —NR 3 R 4 (R 3 and R 4 independently represent H, lower alkyl, etc.);
  • Ar 1 represents arylene or heteroarylene;
  • Ar 2 represents an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroarylalkyl;
  • R 1 represents H, optionally substituted lower alkyl, or optionally substituted lower alkenyl;
  • R 2a is
  • JP 2008-031064 A discloses the following compounds:
  • R 41 and R 42 independently represent H or lower alkyl; R 1 represents —R 00 -optionally substituted aryl (R 00 : lower alkylene) or the like] has been reported as a compound having a DPP4 inhibitory action.
  • Patent Document 6 includes the following compounds:
  • Has ACC inhibitory action is useful for the prevention and treatment of obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic complications, metabolic syndrome, sarcopenia, cancer, etc. Development of the compound which has is desired.
  • R 1 represents a group represented by the formula: —COR 2 (R 2 represents a hydrogen atom or a substituent), or an optionally substituted 5- or 6-membered aromatic ring group;
  • R 3 represents a C 1-6 alkyl group which may be substituted with a halogen atom, or a C 3-6 cycloalkyl group which may be substituted;
  • R 4a and R 4b independently represent a hydrogen atom or a substituent, or R 4a and R 4b may be bonded to each other to form an optionally substituted 3- or 4-membered ring;
  • R 5a and R 5b independently represent a hydrogen atom or a substituent, or R 5a and R 5b may be bonded to each other to form an optionally substituted 3- or 4-membered ring;
  • R 6 represents an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-6 cycloalkyl group;
  • X is O, CO, CR 7a R 7b (R
  • R 1 is represented by the formula: —COR 2 (R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, a substituted
  • R 1 is substituted with the formula: —COR 2 (R 2 is substituted with a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, or 1 to 2 C 1-6 alkyl groups.
  • a compound represented by the above-mentioned [1] or a salt thereof which is a group represented by: [4] The compound or a salt thereof according to the above [1], [2] or [3], wherein R 3 is a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms; [5] The compound or salt thereof according to [1], [2], [3] or [4] above, wherein R 4a and R 4b are hydrogen atoms; [6] The compound or salt thereof according to the above [1], [2], [3], [4] or [5], wherein R 5a and R 5b are hydrogen atoms; [7] The compound according to the above [1], [2], [3], [4], [5] or [6], wherein R 6 is an optionally substituted C 1-6 alkyl group or Its salt; [8] R 6 is (a) a halogen atom, (b) a C 3-6 cycloalkyl group optionally substituted with 1 to 3
  • R 3 is a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms
  • R 4a and R 4b are hydrogen atoms
  • R 5a and R 5b are hydrogen atoms
  • R 6 is (a) a halogen atom, (b) a C 3-6 cycloalkyl group optionally substituted with 1 to 3 halogen atoms or 1 to 3 C 1-6 alkyl groups, (c) a 4- to 7-membered heterocyclic group optionally substituted with 1 to 3 halogen atoms or 1 to 3 C 1-6 alkyl groups, and (d) substituted with 1 to 7 substituents selected from 1 to 3 halogen atoms or C 6-14 aryl group optionally substituted with 1 to 3 C 1-6 alkyl groups; Or a C 1-6 alkyl group;
  • X is O, CO, CH 2 , NR 7c (R 7c represents a hydrogen atom or a
  • Compound (I) has an ACC inhibitory action and is useful for the prevention and treatment of obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic complications, metabolic syndrome, sarcopenia, cancer, etc. And has excellent medicinal properties.
  • halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-3 alkylenedioxy group in the present specification means methylenedioxy, ethylenedioxy and the like unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-6 alkoxy group in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like unless otherwise specified.
  • C 1-6 alkoxy-carbonyl group in the present specification means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
  • C 1-6 alkyl-carbonyl group in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like, unless otherwise specified.
  • examples of the “ optionally substituted C 6-14 arylsulfonyloxy group” include a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.
  • examples of the “optionally substituted C 1-6 alkylsulfonyloxy group” include a methanesulfonyloxy group and a trifluoromethanesulfonyloxy group.
  • R 1 represents a group represented by the formula: —COR 2 (R 2 represents a hydrogen atom or a substituent), or an optionally substituted 5- or 6-membered aromatic ring group.
  • Examples of the “substituent” represented by R 2 include “optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group”, “optionally substituted hydroxy group”, “substituted” And optionally substituted amino group, “optionally substituted sulfanyl group”, “acyl group”, “halogen atom”, “cyano group”, “nitro group” and the like.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” include a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, and a C 3-10 cycloalkyl group.
  • examples of the C 1-10 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
  • a C 1-6 alkyl group is preferable.
  • Examples of the C 2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like. Of these, a C 2-6 alkenyl group is preferable.
  • Examples of the C 2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C 2-6 alkynyl group is preferable.
  • Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, a C 3-6 cycloalkyl group is preferable.
  • Examples of the C 3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Of these, a C 3-6 cycloalkenyl group is preferable.
  • Examples of the C 4-10 cycloalkadienyl group include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like. . Of these, a C 4-6 cycloalkadienyl group is preferable.
  • the above C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkadienyl group may each be condensed with a benzene ring to form a condensed ring group.
  • Examples of the condensed ring group include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group and the C 4-10 cycloalkadienyl group may be a C 7-10 bridged hydrocarbon group.
  • Examples of the C 7-10 bridged hydrocarbon group include bicyclo [2.2.1] heptyl (norbornyl), bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3. 2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like.
  • C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkadienyl group are respectively C 3-10 cycloalkane, C 3-10 cycloalkene or C 4-10.
  • a cycloalkadiene may form a spiro ring group.
  • C 3-10 cycloalkane, C 3-10 cycloalkene and C 4-10 cycloalkadiene the above C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkane are mentioned. Examples include rings corresponding to alkadienyl groups. Examples of such a spiro ring group include spiro [4.5] decan-8-yl.
  • Examples of the C 6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, a C 6-12 aryl group is preferable.
  • Examples of the C 7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
  • Examples of the C 8-13 arylalkenyl group include styryl and the like.
  • the C 1-10 alkyl group, the C 2-10 alkenyl group and the C 2-10 alkynyl group exemplified as the “hydrocarbon group” have 1 to 7 (preferably 1 to 3) substituted positions. It may have a substituent.
  • a substituent for example, (1) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from halogen atoms.
  • a C 3-10 cycloalkyl group eg, cyclopropyl, cyclohexyl
  • (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from hal
  • aryl groups eg, phenyl, naphthyl
  • (3) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (d) an aromatic complex which may be substituted with 1 to 3 substituents selected from halogen atoms.
  • a cyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl); (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (d) a non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl) optionally substituted with 1 to 3 substituents selected from halogen atoms and (e) oxo groups ); (5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3
  • a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from: (8) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl); (9) a carbamoyl group which may be mono- or di-substituted with a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms; (10) a thiocarbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (11) a sulfamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms; (12) a carboxy group; (1
  • a C 1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from: (15) a C 2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms; (16) C 7-13 aralkyloxy group (eg, benzyloxy); (17) C 6-14 aryloxy group (eg, phenyloxy, naphthyloxy); (18) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy); (19) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms A C 6-14 aryl-carbonyl group (eg, benzoyl); (20) a non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C
  • the group and the C 8-13 arylalkenyl group may have 1 to 3 substituents at substitutable positions.
  • substituents for example, (1) groups exemplified as substituents in the aforementioned C 1-10 alkyl group and the like; (2) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • a 1-6 alkyl group (3) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • 2-6 alkenyl groups eg, ethenyl, 1-propenyl
  • (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) a C 7-13 aralkyl group (eg, benzyl) optionally substituted with 1 to 3 substituents selected from halogen atoms; Etc.
  • each substituent may be the same or different.
  • heterocyclic group in the “optionally substituted heterocyclic group” includes an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • the aromatic heterocyclic group is, for example, a 4 to 7 member (preferably 5 or 5) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • 6-membered) monocyclic aromatic heterocyclic group and condensed aromatic heterocyclic group examples include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • Furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl
  • 5-pyrimidinyl pyridazinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl Eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • thiazolyl e
  • non-aromatic heterocyclic group examples include 4 to 7 members (preferably 5 or 6 members) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • Monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group examples include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring
  • a heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle containing one sulfur atom eg, thiophene
  • benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
  • Azetidinyl eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl
  • pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl
  • piperidinyl eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl
  • morpholinyl eg, morpholino
  • thiomorpholinyl eg, thiomorpholino
  • piperazinyl eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl
  • hexamethyleneiminyl eg, hexamethyleneimin-1-yl
  • oxazolidinyl eg, Oxazolidin-2-yl
  • thiazolidinyl eg, thiazolidin-2-yl
  • imidazolidinyl eg,
  • heterocyclic group in the “optionally substituted heterocyclic group” may have 1 to 3 substituents at substitutable positions. Examples of such substituents are the same as the substituents that the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have. Can be mentioned.
  • the heterocyclic group is a “non-aromatic heterocyclic group”
  • an oxo group is further included as a substituent.
  • each substituent may be the same or different.
  • Examples of the “optionally substituted hydroxy group” include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, and a C 3-10 which may each be substituted. It may be substituted with a substituent selected from a cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group, a C 1-6 alkyl-carbonyl group, a heterocyclic group and the like. Good hydroxy groups are mentioned.
  • Examples of the 13 arylalkenyl group include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group”.
  • heterocyclic group examples include “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group”.
  • the arylalkenyl group, C 1-6 alkyl-carbonyl group and heterocyclic group each may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • the substituent of the C 1-10 alkyl group, the C 2-10 alkenyl group and the C 1-6 alkyl-carbonyl group is the “hydrocarbon group” in the “optionally substituted hydrocarbon group”. Examples thereof include the same substituents as the exemplified C 1-10 alkyl group and the like.
  • examples of the substituent for the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, the C 6-14 aryl group, the C 7-13 aralkyl group, and the C 8-13 arylalkenyl group include the above-mentioned “substituted Examples thereof include the same substituents that the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optional hydrocarbon group” may have.
  • Examples of the substituent of the heterocyclic group include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” may have.
  • Examples of the “optionally substituted sulfanyl group” include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, and a C 3-10 which may each be substituted. It may be substituted with a substituent selected from a cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group, a C 1-6 alkyl-carbonyl group, a heterocyclic group and the like. A good sulfanyl group is mentioned.
  • substituents examples include those exemplified as the substituent in the “optionally substituted hydroxy group”.
  • Examples of the “optionally substituted amino group” include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, and a C 3-10 which may each be substituted.
  • a cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group and a heterocyclic group; an amino group which may be mono- or di-substituted with a substituent selected from an acyl group and the like Is mentioned.
  • Examples of the 13 arylalkenyl group include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group”.
  • heterocyclic group examples include the “aromatic heterocyclic group” and the “non-aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group”. Is a 5- to 7-membered monocyclic aromatic heterocyclic group.
  • the alkenyl group and the heterocyclic group each may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • examples of the substituent of the C 1-10 alkyl group and the C 2-10 alkenyl group include the C 1-10 alkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” and the like. The same thing as the substituent which may have is mentioned.
  • examples of the substituent for the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, the C 6-14 aryl group, the C 7-13 aralkyl group, and the C 8-13 arylalkenyl group include the above-mentioned “substituted Examples thereof include the same substituents that the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optional hydrocarbon group” may have.
  • Examples of the substituent of the heterocyclic group include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” may have.
  • acyl group exemplified as the substituent of the “optionally substituted amino group” include those similar to the “acyl group” exemplified as the “substituent” represented by R 2 shown below.
  • the “acyl group” exemplified as the “substituent” represented by R 2 includes, for example, the formula: —COR A , —CO—OR A , —SO 3 R A , —S (O) 2 R A , —SOR A , -CO-NR A 'R B ', -CS-NR A 'R B ', -S (O) 2 NR A 'R B ' [wherein R A is a hydrogen atom, substituted A good hydrocarbon group or an optionally substituted heterocyclic group is shown.
  • R A ′ and R B ′ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R A ′ and R B ′ are A nitrogen-containing heterocyclic ring which may be substituted with an adjacent nitrogen atom may be formed], and the like.
  • R A , R A ′ or R B ′ are the “substituent” represented by R 2 , respectively. Examples thereof are the same as the exemplified “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”.
  • the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R A ′ and R B ′ together with the adjacent nitrogen atom includes, for example, at least one ring-constituting atom other than a carbon atom And a 5- to 7-membered nitrogen-containing heterocyclic ring which may further contain 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
  • the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
  • the nitrogen-containing heterocycle may have 1 to 5 (preferably 1 or 2) substituents at substitutable positions.
  • substituents are the same as the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” exemplified as the “substituent” represented by R 2 may have. Can be mentioned. When there are two or more substituents, each substituent may be the same or different.
  • acyl group (1) formyl group; (2) a carboxy group; (3) a C 1-6 alkyl-carbonyl group (eg acetyl) optionally substituted by 1 to 3 halogen atoms; (4) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) optionally substituted by 1 to 3 halogen atoms; (5) C 3-10 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl); (6) a C 6-14 aryl-carbonyl group (eg, benzoyl, 1-naphthoyl, 2-naphthoyl) optionally substituted with 1 to 3 halogen atoms; (7) (a) a C 1-6 alkyl group which may be substituted with 1 to 3
  • R 2 is preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, Or it is an amino group which may be substituted.
  • R 2 is more preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, a optionally substituted C 1-6 alkoxy group or an optionally substituted amino group.
  • R 2 is more preferably a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-6 alkyl groups (eg, An amino group which may be substituted with (methyl).
  • R 2 is particularly preferably a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-6 alkyl groups (eg, methyl). An amino group which may be substituted.
  • the “group represented by the formula: —COR 2 ” represented by R 1 is preferably —COR 2 (wherein R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, substituted An optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted amino group.
  • the “group represented by the formula: —COR 2 ” represented by R 1 is more preferably —COR 2 (wherein R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, A C 1-6 alkoxy group which may be substituted, or an amino group which may be substituted.
  • the “group represented by the formula: —COR 2 ” represented by R 1 is more preferably —COR 2 (wherein R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), C And a group represented by a 1-6 alkoxy group (eg, methoxy) or an amino group optionally substituted by 1 to 2 C 1-6 alkyl groups (eg, methyl).
  • the “group represented by the formula: —COR 2 ” represented by R 1 is particularly preferably —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl), C 1-6 And a group represented by an alkoxy group (eg, methoxy) or an amino group optionally substituted by 1 to 2 C 1-6 alkyl groups (eg, methyl).
  • Examples of the “5- or 6-membered aromatic ring group” in the “optionally substituted 5- or 6-membered aromatic ring group” represented by R 1 include, for example, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (1, 2, 3 -Triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. It is done.
  • the “5- or 6-membered aromatic ring group” is preferably a 5-membered aromatic heterocyclic group, more preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, etc., particularly preferably isoxazolyl. .
  • the “5- or 6-membered aromatic ring group” in the “optionally substituted 5- or 6-membered aromatic ring group” represented by R 1 may have 1 to 3 substituents at substitutable positions. Good. Examples of such a substituent include a C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as the “substituent” represented by R 2 and the like. The same thing as the substituent which may have is mentioned.
  • the “optionally substituted 5- or 6-membered aromatic ring group” represented by R 1 is preferably substituted with 1 to 3 substituents selected from C 1-6 alkyl groups (eg, methyl). And may be a 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably isoxazolyl).
  • the “optionally substituted 5- or 6-membered aromatic ring group” represented by R 1 is more preferably a 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably Isoxazolyl).
  • a 5-membered aromatic heterocyclic group eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably Isoxazolyl.
  • R 1 is preferably (1) —COR 2 (wherein R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or optionally substituted) A C 1-6 alkoxy group, or an optionally substituted amino group.); Or (2) an optionally substituted 5- or 6-membered aromatic ring group; It is.
  • R 1 is more preferably (1) -COR 2 (wherein, R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group or may be substituted, A group represented by: an amino group; or (2) an optionally substituted 5- or 6-membered aromatic ring group; It is.
  • R 1 is more preferably (1) —COR 2 (wherein R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally substituted by methyl); or (2) an optionally substituted 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably isoxazolyl); It is.
  • R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally substituted by methyl); or (2) an optionally substituted 5-membered aromatic heterocyclic
  • R 1 is even more preferably (1) —COR 2 (wherein R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally substituted by methyl); or (2) a 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl), preferably Isoxazolyl); It is.
  • R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally
  • R 1 is particularly preferably (1) —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-6 alkyl groups) (Eg, an amino group optionally substituted with methyl)) or (2) a 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl), preferably Isoxazolyl); It is.
  • R 2 is a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-6 alkyl groups) (Eg, an amino group optionally substituted with methyl)) or (2) a 5-membered aromatic heterocyclic group (eg,
  • R 1 is particularly preferably (1) —COR 2 (wherein R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally substituted by methyl); or (2) a 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably isoxazolyl); It is.
  • R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally substituted by methyl); or (2) a 5-membered aromatic heterocyclic group (eg,
  • R 3 represents a C 1-6 alkyl group which may be substituted with a halogen atom, or a C 3-6 cycloalkyl group which may be substituted.
  • the “C 1-6 alkyl group” in the “C 1-6 alkyl group optionally substituted with a halogen atom” for R 3 is preferably 1 to 7, more preferably 1 to 3, in the substitutable position. May have one halogen atom.
  • Examples of the “C 3-6 cycloalkyl group” in the “optionally substituted C 3-6 cycloalkyl group” represented by R 3 include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Represented by R 3 "C 3-6 cycloalkyl group" of the "optionally substituted C 3-6 cycloalkyl group” may have 1 to 3 substituents at substitutable position . Examples of such a substituent include a C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as the “substituent” represented by R 2 and the like. The same thing as the substituent which may have is mentioned.
  • R 3 is preferably a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms.
  • R 3 is more preferably a C 1-6 alkyl group (eg, methyl, ethyl).
  • R 4a and R 4b independently represent a hydrogen atom or a substituent, or R 4a and R 4b are bonded to each other to form an optionally substituted 3- or 4-membered ring.
  • Examples of the “substituent” represented by R 4a or R 4b include those similar to the “substituent” represented by R 2 .
  • the “3- or 4-membered ring” in the “optionally substituted 3- or 4-membered ring” formed by R 4a and R 4b bonded to each other has 1 to 6 substituents at substitutable positions. It may be. Examples of such a substituent are the same as the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” exemplified as the “substituent” represented by R 2 may have. Can be mentioned.
  • R 4a and R 4b are preferably both hydrogen atoms.
  • R 5a and R 5b independently represent a hydrogen atom or a substituent, or R 5a and R 5b are bonded to each other to form an optionally substituted 3- or 4-membered ring.
  • Examples of the “substituent” represented by R 5a or R 5b include the same “substituent” as represented by R 2 .
  • the “3- or 4-membered ring” in the “optionally substituted 3- or 4-membered ring” formed by R 5a or R 5b bonded to each other has 1 to 6 substituents at substitutable positions. It may be. Examples of such a substituent are the same as the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” exemplified as the “substituent” represented by R 2 may have. Can be mentioned.
  • R 5a or R 5b is preferably independently a hydrogen atom, a carboxy group or a C 1-6 alkoxy-carbonyl group.
  • R 5a or R 5b is more preferably both a hydrogen atom.
  • R 6 represents an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group.
  • the “C 1-6 alkyl group” in the “ optionally substituted C 1-6 alkyl group” for R 6 may have 1 to 3 substituents at substitutable positions.
  • substituents include a C 1-10 alkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as the “substituent” represented by R 2 and the like. Examples thereof are the same as the substituents that may be present.
  • R 6 is more preferably (a) a halogen atom (eg, fluorine atom), (b) C 3-6 cycloalkyl group (eg, optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) or 1 to 3 C 1-6 alkyl group (eg, methyl)) Cyclopropyl, cyclobutyl), (c) a 4- to 7-membered heterocyclic group (preferably substituted with 1 to 3 halogen atoms (eg, fluorine atom) or 1 to 3 C 1-6 alkyl groups (eg, methyl)) Is a 4- to 7-membered (preferably 5- or 6-membered) non-aromatic hetero group (eg tetradofryl), and (d) a C 6-14 aryl group (eg, phenyl) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom) or 1 to 3 C 1-6 alkyl groups (
  • R 6 is more preferably (a) a halogen atom (eg, fluorine atom), (b) C 3-6 cycloalkyl group (eg, optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) or 1 to 3 C 1-6 alkyl group (eg, methyl)) Cyclopropyl, cyclobutyl), (c) a 4- to 7-membered heterocyclic group (preferably a 4- to 7-membered (preferably 5- or 6-membered) non-aromatic heterocyclic group (eg, tetradrofuryl)), and (d) C 6-14 aryl group (eg, phenyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted by 1 to 7 (preferably 1 to 3) substituents selected from
  • X is O, CO, CR 7a R 7b (R 7a and R 7b independently represent a hydrogen atom or a substituent), NR 7c (R 7c is a hydrogen atom or an optionally substituted hydrocarbon) Group), S, SO or S (O) 2 .
  • R 7a or R 7b examples include the same “substituent” represented by R 2 .
  • R 7a and R 7b are preferably independently a hydrogen atom or a halogen atom (eg, fluorine atom).
  • R 7a and R 7b are more preferably a hydrogen atom.
  • R 7c examples include the same “optionally substituted hydrocarbon group” exemplified as the “substituent” represented by R 2 .
  • R 7c is preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group, and more preferably a C 1-6 alkyl group (eg, methyl).
  • X is preferably O, CO, CR 7a R 7b (R 7a and R 7b are each independently a hydrogen atom or a halogen atom (eg, a fluorine atom)), NR 7c (R 7c is a hydrogen atom) Or an optionally substituted C 1-6 alkyl group), S, SO or S (O) 2 .
  • X is more preferably O, CO, CR 7a R 7b (R 7a and R 7b are independently a hydrogen atom or a halogen atom (eg, fluorine atom)), NR 7c (R 7c is C 1-6 alkyl group (eg, methyl)), S, SO or S (O) 2 .
  • X is more preferably O, CO, CH 2 , NR 7c (R 7c is a hydrogen atom or a C 1-6 alkyl group (eg, methyl)), S, SO or S (O) 2 .
  • X is particularly preferably O, CO, CH 2 , NR 7c (R 7c is a C 1-6 alkyl group (eg, methyl)), S, SO or S (O) 2 .
  • Y is O, CO, CR 8a R 8b (R 8a and R 8b independently represent a hydrogen atom or a substituent), NR 8c (R 8c is a hydrogen atom or an optionally substituted hydrocarbon) Group), S, SO or S (O) 2 .
  • R 8a or R 8b examples include those similar to the “substituent” represented by R 2 .
  • R 8a and R 8b are preferably independently a hydrogen atom or a halogen atom (eg, fluorine atom).
  • R 8a and R 8b are more preferably a hydrogen atom.
  • R 8c is preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • Y is preferably O, CO, or CR 8a R 8b (R 8a and R 8b are independently a hydrogen atom or a halogen atom (eg, a fluorine atom)).
  • Y is more preferably O, CO or CH 2 .
  • Y is more preferably O.
  • Ring P represents a 3- to 7-membered ring which may be further substituted.
  • Examples of the “3- to 7-membered ring” in the “optionally substituted 3- to 7-membered ring” represented by ring P include benzene, C 3-7 cycloalkane, C 3-7 cycloalkene, C 4-7. And cycloalkadienes and 3- to 7-membered heterocycles (preferably 5- or 6-membered aromatic heterocycles and 3- to 7-membered non-aromatic heterocycles).
  • the C 3-7 cycloalkane includes cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, preferably C 4-6 cycloalkane, and particularly preferably cyclobutane and cyclohexane.
  • Examples of C 3-7 cycloalkene include cyclopentene, cyclobutene, cyclopentene, cyclohexene, and cycloheptene, and C 4-6 cycloalkene is preferable.
  • C 4-7 cycloalkadiene examples include 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene, and preferably C 4-6 cycloalkadiene.
  • the 5- or 6-membered aromatic heterocycle include pyrrole, pyrazole, imidazole, triazole (1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole), tetrazole, oxazole, Examples include isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like, preferably a 6-membered nitrogen-containing aromatic heterocyclic ring (preferably pyridine, pyridazine , Pyrimidine, pyrazine, particularly preferably pyridine).
  • the “3- to 7-membered ring” in the “optionally substituted 3- to 7-membered ring” represented by ring P is a group —XC (R 4a ) (R 4b ) CH (R 3 ) —NH—R 1
  • —YC (R 5a ) (R 5b ) — it may have 1 to 9 substituents at substitutable positions. Examples of such a substituent are the same as the substituent that the “heterocyclic group” in the “optionally substituted heterocyclic group” exemplified as the “substituent” represented by R 2 may have. Can be mentioned.
  • Ring P is preferably benzene, C 3-7 cycloalkane or 3- to 7-membered heterocycle (preferably 5- or 6-membered aromatic heterocycle or 3- to 7-membered non-aromatic, each of which may be further substituted. Family heterocycle).
  • Ring P is more preferably benzene, C 4-6 cycloalkane (preferably cyclobutane, cyclohexane) or 3- to 7-membered heterocyclic ring (preferably 5- or 6-membered (preferably Is a 6-membered) nitrogen-containing aromatic heterocycle (preferably pyridine, pyridazine, pyrimidine, pyrazine, particularly preferably pyridine), or a 5- or 6-membered (preferably 6-membered) nitrogen-containing non-aromatic heterocycle (preferably , Pyrrolidine, piperidine, piperazine, particularly preferably piperidine)).
  • C 4-6 cycloalkane preferably cyclobutane, cyclohexane
  • 3- to 7-membered heterocyclic ring preferably 5- or 6-membered (preferably Is a 6-membered) nitrogen-containing aromatic heterocycle (preferably pyridine, pyridazine, pyrimidine, pyrazine, particularly preferably pyr
  • Ring P is more preferably 1 to 4 (preferably selected from a halogen atom (eg, fluorine atom), a C 1-6 alkyl group (eg, methyl) and a C 1-6 alkoxy group (eg, methoxy).
  • a halogen atom eg, fluorine atom
  • C 1-6 alkyl group eg, methyl
  • C 1-6 alkoxy group eg, methoxy
  • Benzene, C 4-6 cycloalkane preferably cyclobutane, cyclohexane
  • 3- to 7-membered heterocycle preferably 5- or 6-membered (preferably 5 to 6-membered) each optionally further substituted with 1 to 3 substituents.
  • 6-membered) nitrogen-containing aromatic heterocycle preferably pyridine, pyridazine, pyrimidine, pyrazine, particularly preferably pyridine
  • 5- or 6-membered (preferably 6-membered) nitrogen-containing non-aromatic heterocycle preferably Is pyrrolidine, piperidine, piperazine, particularly preferably piperidine
  • Ring P is more preferably 1 to 4 (preferably 1 to 3) substituents selected from a C 1-6 alkyl group (eg, methyl) and a C 1-6 alkoxy group (eg, methoxy).
  • Ring P is particularly preferably 1 to 4 (preferably 1 to 3) substituents selected from a C 1-6 alkyl group (eg, methyl) and a C 1-6 alkoxy group (eg, methoxy). They are each optionally further substituted benzene, C 4-6 cycloalkane (preferably cyclobutane, cyclohexane), pyridine or piperidine.
  • substituents selected from a C 1-6 alkyl group (eg, methyl) and a C 1-6 alkoxy group (eg, methoxy). They are each optionally further substituted benzene, C 4-6 cycloalkane (preferably cyclobutane, cyclohexane), pyridine or piperidine.
  • Ring Q represents a 5- or 6-membered aromatic ring which may be further substituted.
  • Examples of the “5- or 6-membered aromatic ring” in the “optionally substituted 5- or 6-membered aromatic ring” represented by ring Q include benzene, pyrrole, pyrazole, imidazole, triazole (1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole), tetrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.
  • a 6-membered aromatic ring eg, benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine
  • benzene and pyridine are particularly preferable.
  • the “5- or 6-membered aromatic ring” in the “optionally substituted 5- or 6-membered aromatic ring” represented by ring Q is a group —O—R 6 and —C (R 5a ) (R 5b ) Y— In addition, it may have 1 to 4 substituents at substitutable positions. Examples of such a substituent include a C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as the “substituent” represented by R 2 and the like. The same thing as the substituent which may have is mentioned.
  • the further substituent of the “5- or 6-membered aromatic ring” in the “optionally substituted 5- or 6-membered aromatic ring” represented by ring Q is preferably a halogen atom (eg, fluorine atom, chlorine atom). is there.
  • Ring Q is preferably (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (c) a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), and (d) benzene or a 5- or 6-membered aromatic heterocycle (eg, pyridine, pyridazine) which may be further substituted with 1 to 4 (preferably 1 to 3) substituents selected from a cyano group, respectively.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • a C 1-6 alkyl group eg, methyl
  • a C 1-6 alkoxy group eg, methoxy
  • Ring Q is more preferably (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), (c) a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 5 halogen atoms (eg, fluorine atom), and (d) a cyano group, Benzene, pyridine or isoxazole, each of which may be further substituted with 1 to 4 (preferably 1 to 3) substituents selected from
  • Preferred examples of compound (I) include the following compounds.
  • R 1 is (1) a group represented by —COR 2 (wherein R 2 is an optionally substituted C 1-6 alkyl group or an optionally substituted amino group); or (2) an optionally substituted 5- or 6-membered aromatic ring group; Is; R 3 is a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are independently a hydrogen atom, a carboxy group or a C 1-6 alkoxy-carbonyl group; R 6 is an optionally substituted C 1-6 alkyl group; X is O, CO, CR 7a R 7b (R 7a and R 7b are each independently a hydrogen atom or a halogen atom (eg, a fluorine atom)), NR 7c (R 7c is a hydrogen atom or a substituted atom) Is an optionally substituted C 1-6 alkyl group), S, SO or S (O)
  • R 1 is (1) a group represented by —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl) or an amino group); or (2) 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl), preferably Isoxazolyl) Is; R 3 is a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are both hydrogen atoms; R 6 may be substituted with 1 to 5 halogen atoms (eg, fluorine atom), or may be substituted with 1 to 3 C 3-6 cycloalkyl groups (eg, cycloalkyl
  • a C 1-6 alkyl group (eg, methyl, ethyl, propyl);
  • X is O, CO, CR 7a R 7b (R 7a and R 7b are each independently a hydrogen atom or a halogen atom (eg, a fluorine atom)), NR 7c (R 7c is a C 1-6 alkyl) A group (eg, methyl)), S, SO or S (O) 2 ;
  • Y is O, CO or CR 8a R 8b (R 8a and R 8b are independently a hydrogen atom or a halogen atom (eg, fluorine atom));
  • Ring P is further substituted with 1 to 4 substituents selected from a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy) and a halogen atom (eg, fluorine atom), respectively.
  • halogen atoms eg, fluorine atom, chlorine atom
  • R 1 is (1) a group represented by —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl) or an amino group); or (2) 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl), preferably Isoxazolyl) Is; R 3 is a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are both hydrogen atoms; R 6 is (a) a C 3-6 cycloalkyl group (eg, cyclopropyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine
  • Benzene, C 4-6 cycloalkane preferably cyclohexane
  • 5 or 6 membered preferably 6 membered
  • nitrogen-containing aromatic heterocycle preferably pyridine, pyridazine, pyrimidine, pyrazine, Pyridine
  • a 5- or 6-membered preferably 6-membered
  • nitrogen-containing non-aromatic heterocyclic ring preferably pyrrolidine, piperidine, piperazine, particularly preferably piperidine
  • ring Q is 1 to Compound which is benzene or pyridine, each of which may be further substituted with 4 halogen atoms (eg, fluorine atom, chlorine atom) I).
  • R 1 is (1) a group represented by —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl) or an amino group); or (2) 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl), preferably Isoxazolyl) Is; R 3 is a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are both hydrogen atoms; R 6 is (a) a C 3-6 cycloalkyl group (eg, cyclopropyl) optionally substituted with 1 to 5 halogen atoms (eg, fluorine
  • Benzene, C 4-6 cycloalkane preferably cyclohexane
  • 5 or 6 membered preferably 6 membered
  • nitrogen-containing aromatic heterocycle preferably pyridine, pyridazine, pyrimidine, pyrazine, Pyridine
  • a 5- or 6-membered preferably 6-membered
  • nitrogen-containing non-aromatic heterocyclic ring preferably pyrrolidine, piperidine, piperazine, particularly preferably piperidine
  • ring Q is 1 to Compound which is benzene or pyridine, each of which may be further substituted with 4 halogen atoms (eg, fluorine atom, chlorine atom) I).
  • R 1 is (1) —COR 2 (wherein R 2 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-1 A group represented by a 6 alkyl group (eg, an amino group optionally substituted by methyl); or (2) an optionally substituted 5-membered aromatic heterocyclic group (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably isoxazolyl); Is; R 3 is a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are both hydrogen atoms; R 6 is (a) a halogen atom (eg, fluorine atom),
  • R 1 is (1) —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-6 alkyl groups) (Eg, an amino group optionally substituted with methyl)) or (2) 5-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl) (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably Isoxazolyl); Is; R 3 is a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are both hydrogen atoms; R 6 is (a) a halogen atom (eg, methyl),
  • R 1 is (1) —COR 2 (wherein R 2 is a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy), or 1 to 2 C 1-6 alkyl groups) (Eg, an amino group optionally substituted with methyl)) or (2) 5-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl) (eg, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, preferably Isoxazolyl); Is; R 3 is a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms; R 4a and R 4b are both hydrogen atoms; R 5a and R 5b are both hydrogen atoms; R 6 is (a) a halogen atom (eg, methyl),
  • the salt of the compound represented by formula (I) is preferably a pharmacologically acceptable salt.
  • a salt with an inorganic base examples include a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid.
  • the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. Or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (I).
  • Compound (I) may be labeled with an isotope (eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) or the like.
  • compound (I) may be a hydrate, a non-hydrate, a solvate or a solvate.
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) or a prodrug thereof (hereinafter, sometimes simply abbreviated as the compound of the present invention) has low toxicity and should be used as it is or mixed with a pharmacologically acceptable carrier to form a pharmaceutical composition.
  • a pharmaceutical composition e.g, a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys).
  • the pharmacologically acceptable carrier various conventional organic or inorganic carrier substances are used as a pharmaceutical material, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
  • excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
  • Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
  • buffers such as phosphate, acetate, carbonate and citrate.
  • a preferred example of the soothing agent is benzyl alcohol.
  • Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Preferable examples of the antioxidant include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, ⁇ -carotene, chlorophyll, bengara).
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • the medicament containing the compound of the present invention can be used alone or mixed with a pharmacologically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia).
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills powders, granules, capsules (including soft capsules and microcapsules), troches Agent, syrup, solution, emulsion, suspension, controlled release formulation (eg, immediate release formulation, sustained release formulation, sustained release microcapsule), aerosol, film agent (eg, orally disintegrating film, Oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch, sitting Suppositories (eg, rectal suppositories) Vaginal suppositories), pellets,
  • compositions may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
  • coating base used for coating examples include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
  • sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
  • enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
  • cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
  • methacrylic acid copolymer L (Eudragit L (trade name) ]
  • Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer
  • sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • the above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.
  • the compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, pulmonary toxicity, carcinogenicity), has few side effects, and prevents or treats or diagnoses various diseases for mammals. It can be used as a medicine.
  • the compound of the present invention has an excellent ACC (acetyl-CoA carboxylase) inhibitory action.
  • examples of ACC include liver, adipose tissue, pancreas-specific isozyme (ACC1); muscle-specific isozyme (ACC2).
  • the compound of the present invention is excellent in metabolic stability, and has advantages such as a long half-life of the compound and difficulty in being metabolized in vivo.
  • the compounds of the present invention have ACC2 selectivity, and in particular, the example compounds of the present invention have high ACC2 selectivity.
  • the compound of the present invention is excellent in pharmacokinetics (eg, oral absorbability, bioavailability).
  • the compound of the present invention contains obesity, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, high LDL cholesterolemia). , Low HDL cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetic complications [eg, neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macrovascular disorder, osteopenia, Diabetic hyperosmotic coma, infections (eg, respiratory infections, urinary tract infections, gastrointestinal infections, soft skin tissue infections, lower limb infections), diabetic gangrene, xerostomia, hearing loss, Cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (high triglyceride (TG) emia, low HDL cholesterol (HDL-C) emia, hypertension, abdominal obesity and glucose intolerance) State), it can be used as an agent for preventing or treating sarcopenia or cancer, or the like.
  • diabetes
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
  • 75 gOGTT 75 g oral glucose tolerance test
  • a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
  • a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.
  • glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose).
  • the IFG is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
  • the compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
  • the mammal to be applied may be any mammal that wishes to avoid weight gain, may be a mammal that is genetically at risk of weight gain, and may have diabetes, hypertension and / or hyperlipidemia.
  • Weight gain may be due to excessive dietary intake or a diet lacking nutritional balance, and has a PPAR ⁇ agonist-like action such as concomitant drugs (eg, troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone) It may be a weight gain derived from an insulin resistance improving agent or the like. The weight gain may be a weight gain before reaching obesity or may be a weight gain of an obese patient.
  • concomitant drugs eg, troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone
  • the weight gain may be a weight gain before reaching obesity or may be a weight gain of an obese patient.
  • the compound of the present invention is also useful as a prophylactic / therapeutic agent for metabolic syndrome (metabolic syndrome).
  • metabolic syndrome a prophylactic / therapeutic agent for metabolic syndrome.
  • Patients with metabolic syndrome have a significantly higher rate of developing cardiovascular disease than patients with a single lifestyle-related disease, so preventing or treating metabolic syndrome prevents cardiovascular disease It is extremely important to do.
  • Criteria for metabolic syndrome were published by WHO in 1999 and NCEP in 2001. According to WHO criteria, metabolic syndrome is diagnosed in patients with visceral obesity, dyslipidemia (high TG or low HDL), or hypertension based on hyperinsulinemia or impaired glucose tolerance. (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999).
  • the compound of the present invention is, for example, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine disease cachexia, infectious cachexia or acquired cachexia).
  • cachexia eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine disease cachexia, infectious cachexia or acquired cachexia.
  • Cachexia due to immunodeficiency syndrome fatty liver, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), Muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder (eg, cerebral infarction, stroke), Alzheimer's disease, Parkinson's disease, anxiety, dementia, insulin resistance syndrome, syndrome X, hyperinsulinemia, hyperinsulinemia Sensory impairment, acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis spondylitis, osteoarthritis, low back pain, gout, postoperative or traumatic inflammation, swelling, nerves Pharyngopharyngitis, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease
  • the compound of the present invention is used for various cancers (among others breast cancer (for example, invasive breast cancer, non-invasive breast cancer, inflammatory breast cancer, etc.)), prostate cancer (for example, hormone-dependent prostate cancer, hormone-independent). Prostate cancer, etc.), pancreatic cancer (eg, pancreatic duct cancer, etc.), stomach cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma) ), Colon cancer (eg, gastrointestinal stromal tumor), rectal cancer (eg, gastrointestinal stromal tumor), colorectal cancer (eg, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal tract) Tumor, etc.), small intestine cancer (eg, non-Hodgkin lymphoma, gastrointestinal strom
  • the compound of the present invention is also used for secondary prevention and progression suppression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).
  • cardiovascular events such as myocardial infarction
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to an adult obese patient, it is usually about 0.01 to 100 mg / kg body weight as a single dose.
  • the dose is preferably 0.05 to 30 mg / kg body weight, more preferably 0.5 to 10 mg / kg body weight, and this amount is desirably administered once to three times a day.
  • the compound of the present invention is used for the purpose of enhancing the action of the compound or reducing the dose of the compound, etc., a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic It can be used in combination with a drug such as an agent or an antithrombotic drug (hereinafter abbreviated as a concomitant drug).
  • a concomitant drug a drug such as an agent or an antithrombotic drug
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these concomitant drugs may be low molecular compounds, and may be high molecular proteins, polypeptides, antibodies, vaccines and the like.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli or yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation
  • insulin resistance improving agent eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), metaglidacene (Metaglidasen), AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT -505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 09979 4), ⁇ -glucosidase inhibitors (eg, voglib
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its increasing drug (Eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5 [3- (2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), nerve regeneration promoters (eg, Y-128), PKC inhibitors (eg, ruboxistaurin mesylate) AGE inhibitors (eg, ALT946, pyratoxatin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-22 6, pyridoline (Py
  • statin compounds eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt)
  • squalene synthase inhibitors Eg, compounds described in WO97 / 10224, for example, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxy Phenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (eg, bezafibrate, clofibrate, Simfibrate, clinofibrate), anion exchange resin (eg, cholestyramine), probucol, nicotin
  • statin compounds eg
  • antihypertensive agent examples include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan , Olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (eg, manidipine, nifedipine, amlodipine, nifodipine, nicardipine, amlodipine, cilnidipine, etc.), ⁇ -blockers (eg, metoprolol, atenolol, propranolol, propranolol, propranolol, proprano
  • anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor , GABA modulators (eg, topiramate), MCH receptor antagonists (eg, SB-568849; SNAP-7941; compounds described in WO01 / 82925 or WO01 / 87834), neuropeptide Y antagonists (eg, Berneperit) , Cannabinoid receptor antagonists (eg, rimonabant, taranaban), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase inhibitors, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, Melanocortin 4 receptor agonist, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors
  • FGF21 preparation eg, animal FGF21 preparation extracted from bovine and porcine pancreas; human FGF21 preparation genetically engineered using E. coli and yeast; FGF21 fragment or derivative)
  • Naltrexone hydrochloride sustained-release preparation and bupropion hydrochloride sustained-release preparation feeding inhibitors (eg, P-57), and the like.
  • diuretics examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penfluthiazide.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penfluthiazide.
  • Polythiazide, meticlotiazide), anti-aldosterone formulations eg, spironolactone, triamterene
  • carbonic anhydrase inhibitors eg, acetazolamide
  • chlorobenzenesulfonamides eg, chlorthalidone, mefluside, indapamide
  • azosemide isosorbide, etacrine
  • Examples include acid, piretanide, bumetanide, furosemide and the like.
  • Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparinsodium), warfarin (eg, warfarin potassium), antithrombin drugs (eg, argatroban) ), Dabigatran), thrombolytic drugs (eg, urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor ( Examples, ticlopidine hydrochloride, clopidogrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, prasugrel, E5555, SH C530348), FXa inhibitors (eg, compounds described in rivaroxaban, apixaban, edoxaban, YM150
  • the administration time of the aforementioned concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such dosage forms include: 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, 2) Simultaneous administration by the same route of administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, 3) Administration of the two compounds obtained by formulating the compound of the present invention and the concomitant drug separately with a time difference in the same administration route, 4) Simultaneous administration by different administration routes of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug, 5) Administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention and concomitant drug, or vice versa) Administration in this order).
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • Each raw material compound may form a salt as long as it does not inhibit the reaction.
  • a salt those exemplified as the salt of the compound represented by the aforementioned formula (I) are used.
  • a raw material compound can be easily obtained and used commercially, or can be produced according to a method known per se or a method analogous thereto.
  • the product of each reaction can be used in the next reaction as a reaction mixture or as a crude product, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography and HPLC. It can be purified by separation means.
  • a separation means such as a diastereomeric salt method, chromatography, HPLC, or SFC (supercritical fluid chromatography). For example, it can be carried out by the method described in the examples or a method analogous thereto.
  • Reagents and reagents used in each reaction can be used as they are when commercially available, or can be produced according to a method known per se or a method analogous thereto, or a method described in Examples. it can.
  • the reagents and reagents described in the examples can be used.
  • the solvent for each reaction is not particularly limited as long as the reaction proceeds, and the reaction can be performed in a solvent inert to the reaction or in the absence of a solvent. You may mix and use.
  • the solvents described in the examples can be used.
  • the equivalent amounts of reagents and reagents used in each reaction are 0.001 to 100 equivalents relative to the substrate of each reaction.
  • equivalent amounts of reagents and reactants described in the examples can be used.
  • reaction time for each reaction is usually from 5 minutes to 72 hours.
  • the reaction can be performed with the reaction times described in the examples.
  • reaction temperature of each reaction is from ice-cooling to heating under reflux. For example, it can be carried out at the reaction temperature described in the examples.
  • a protective group generally used in peptide chemistry or the like is introduced into these functional groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • the reaction for introducing a protecting group into these functional groups was described as “protection reaction”, and the reaction for removing the protecting group was described as “deprotection reaction”.
  • the protecting group introduction method (protection reaction) and the protecting group removal method (deprotection reaction) are known per se, for example, Greens Protective Groups in Organic Synthesis in ORGANIC SYNTHESIS, 4th edition. The methods described in Wiley-Interscience, 2006, etc., or the methods described in the examples can be used.
  • examples of the “amino-protecting group” include a formyl group, a C 1-6 alkyl-carbonyl group, a C 1-6 alkoxy-carbonyl group, a benzoyl group, a C 7-10 aralkyl-carbonyl group ( Example, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group ( Examples, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl), substituted C 7-10 aralkyl groups (eg, 2, 4-dimethoxybenzyl), a
  • examples of the “carboxy group protecting group” include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, Triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • examples of the “protecting group for hydroxy group” include C 1-6 alkyl group, phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl.
  • -Carbonyl group benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • examples of the “carbonyl-protecting group” include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • examples of the “protecting group for sulfanyl group” include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a C 1-6 alkyl-carbonyl group.
  • Benzoyl group C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl), C 7-14 aralkyl Oxy-carbonyl groups (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl groups, C 1-6 alkylamino-carbonyl groups (eg, methylaminocarbonyl, ethylaminocarbonyl), etc. Can be mentioned. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • a 1 is a protecting group for a hydroxy group
  • L 1 is a hydroxy group, a halogen atom, an optionally substituted C 6-14 arylsulfonyloxy group, or an optionally substituted C 1-6 alkylsulfonyl group
  • Compound (1) can be produced, for example, according to the methods described in Reaction Schemes 5 and 8, a method known per se, or a method analogous thereto.
  • Compound (2) can be produced, for example, by deprotection of compound (1).
  • compound (I) can be produced, for example, by an alkylation reaction of compound (2) and compound (3).
  • the alkylation reaction is carried out, for example, by reacting compound (2) and compound (3) with a base (for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4.0] undeca-7-ene). Etc.) in the presence of an inert solvent (for example, DMF (dimethylformamide), acetonitrile, THF (tetrahydrofuran), toluene, water, etc.).
  • a base for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4.0] undeca-7-ene).
  • Etc. in the presence of an inert solvent (for example, DMF (dimethylformamide), acetonitrile, THF (tetrahydrofuran), toluene, water, etc.).
  • an inert solvent
  • a phase transfer catalyst for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.
  • compound (3) is an alcohol
  • compound (I) can be produced, for example, by Mitsunobu reaction between compound (2) and compound (3).
  • Mitsunobu reaction can be carried out, for example, by converting compound (2) and compound (3) into a hydroxy group activator (eg, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl).
  • a hydroxy group activator eg, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl
  • the reaction is carried out in the presence of phosphine, ADDP (1,1 ′-(azodicarbonyl) dipiperidine and tributylphosphine), etc.) in an inert solvent (for example, toluene, THF, etc.).
  • an inert solvent for example, toluene, THF, etc.
  • a compound in which X or Y of compound (I) is an oxidized sulfur atom that is, a sulfone derivative or a sulfoxide derivative can be produced by an oxidation reaction of compound (I) in which X or Y is a sulfur atom.
  • an oxidation reaction for example, the method described in 4th edition Experimental Chemistry Course 20 (Edited by The Chemical Society of Japan), pages 276 to 278, 503 or a method analogous thereto is used.
  • Y 1 represents a sulfur atom, an oxygen atom, or a nitrogen atom which may be substituted with a substituent R 8c
  • L 2 is a halogen atom or an optionally substituted C 6-14 arylsulfonyloxy group Or an optionally substituted C 1-6 alkylsulfonyloxy group, and other symbols are as defined above.
  • Compound (5) can be produced, for example, according to the method described in Reaction Formula 6, Reaction Formula 9, Reaction Formula 10, and Reaction Formula 11, a method known per se, or a method analogous thereto.
  • Compound (I-1) can be produced, for example, by Mitsunobu reaction between compound (4) and compound (5).
  • compound (4) and compound (5) are converted into a hydroxy group activator (for example, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl). Phosphine, etc.) in the presence of an inert solvent (for example, toluene, THF, etc.).
  • a hydroxy group activator for example, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl.
  • Phosphine, etc. in the presence of an inert solvent (for example, toluene, THF, etc.).
  • Compound (6) can be produced, for example, by halogenation reaction or sulfonylation reaction of compound (4). This reaction is performed, for example, by reacting compound (4) with a halogenating agent (eg, thionyl chloride, phosphorus tribromide, etc.) in an inert solvent (eg, THF, toluene, diethyl ether, etc.).
  • a halogenating agent eg, thionyl chloride, phosphorus tribromide, etc.
  • an inert solvent eg, THF, toluene, diethyl ether, etc.
  • this reaction may be carried out, for example, by reacting compound (4) and a sulfonylating agent (eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.) in the presence of a base (eg, triethylamine, pyridine, etc.) in an inert solvent (eg, THF). , Toluene, diethyl ether, etc.).
  • a sulfonylating agent eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.
  • a base eg, triethylamine, pyridine, etc.
  • an inert solvent eg, THF.
  • Compound (I-1) can also be produced, for example, by an alkylation reaction of compound (5) and compound (6).
  • compound (5) and compound (6) are reacted with an inert solvent (eg, DMF, acetonitrile, etc.) in the presence of a base (eg, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, DBU, etc.).
  • a base eg, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, DBU, etc.
  • a phase transfer catalyst for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.
  • phase transfer catalyst for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.
  • a 2 represents an amino-protecting group, and other symbols are as defined above.
  • Compound (7) can be produced, for example, according to the method described in Reaction Formula 15 and Reaction Formula 16, a method known per se, or a method analogous thereto.
  • Compound (8) can be produced by, for example, deprotection reaction of compound (7).
  • Compound (I-2) can be produced, for example, by an acylation reaction of compound (8).
  • the “acylation reaction” includes, for example, a synthesis reaction of an amide derivative, a carbamate derivative or a urea derivative. This reaction is performed, for example, by reacting compound (8) with an acylating agent in an inert solvent (eg, DMF, acetonitrile, dichloromethane, THF, etc.).
  • an acylating agent include carboxylic acids, reactive derivatives of carboxylic acids (eg, acid chloride, acid anhydrides, mixed acid anhydrides, active esters, active amides, etc.), dicarbonates, chloroformates, isocyanates, And carbamoyl chloride derivatives.
  • a dehydrating condensing agent for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC), N-[(dimethylamino) (3H- [1,2 , 3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methylmethanaminium hexafluorophosphate (HATU), etc., additives (for example, 1-hydroxybenzotriazole (HOBt), etc. ) Or a base (for example, triethylamine, pyridine, etc.) may be reacted.
  • DCC dicyclohexylcarbodiimide
  • WSC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • Compound (9) can be produced, for example, according to the method described in Reaction Scheme 4, Reaction Formula 7, and Reaction Formula 14, a method known per se, or a method analogous thereto.
  • Compound (10) can be produced, for example, by halogenation or sulfonylation reaction of compound (9). This reaction is performed, for example, in the same manner as in the method for producing compound (6) of reaction formula 2.
  • Compound (11) can be produced, for example, by subjecting compound (10) to an azidation reaction.
  • the compound (10) and an azide for example, sodium azide, diphenylphosphoryl azide (DPPA), trimethylsilyl azide, etc.
  • an inert solvent for example, DMF, acetonitrile, THF, etc.
  • the reaction is carried out at 0 ° C. to 150 ° C. for 5 minutes to 72 hours. If necessary, the reaction may be performed in the presence of a base (for example, triethylamine, pyridine, DBU, etc.).
  • a base for example, triethylamine, pyridine, DBU, etc.
  • Compound (8) can also be produced, for example, by a reduction reaction of compound (11).
  • the compound (11) is reacted with an inert solvent (eg, ethanol, for example) in the presence of a metal catalyst (eg, palladium-carbon, platinum oxide, etc.) and a hydrogen source (eg, hydrogen gas, formic acid, ammonium formate, etc.).
  • an inert solvent eg, ethanol, for example
  • a metal catalyst eg, palladium-carbon, platinum oxide, etc.
  • a hydrogen source eg, hydrogen gas, formic acid, ammonium formate, etc.
  • This reaction can also be carried out, for example, by reacting compound (11), triphenylphosphine and water in an inert solvent (for example, THF).
  • R 1a and R 9 each independently represents an optionally substituted 5- or 6-membered aromatic ring group, and other symbols are as defined above.
  • Compound (12) can be produced, for example, according to the method described in Reaction Scheme 7, a method known per se, or a method analogous thereto.
  • Compound (I-3) can be produced, for example, by a reductive amination reaction of compound (12) and compound (13).
  • compound (12) and compound (13) are reacted with an inert solvent (for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, decaborane, etc.) in the presence of a reducing agent.
  • an inert solvent for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, decaborane, etc.
  • a reducing agent for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, decaborane, etc.
  • Compound (9) can be produced, for example, by a reduction reaction of compound (12).
  • compound (12) is converted into an inert solvent (for example, ethanol, methanol, etc.) in the presence of a reducing agent (for example, sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium aluminum hydride, etc.).
  • a reducing agent for example, sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium aluminum hydride, etc.
  • Compound (15) can be produced, for example, by Mitsunobu reaction between compound (9) and compound (14).
  • compound (9) and compound (14) are converted into a hydroxy group activator (for example, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl). Phosphine, etc.) in the presence of an inert solvent (for example, toluene, THF, etc.).
  • a hydroxy group activator for example, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl.
  • Phosphine, etc. in the presence of an inert solvent (for example, toluene, THF, etc.).
  • Compound (I-3) can also be produced, for example, by a desulfonylation reaction of compound (15). This reaction is carried out, for example, in the presence of a compound (15), a base (for example, triethylamine, lithium hydroxide dihydrate, etc.) and an organic mercaptan (for example, sulfanyl acetic acid, etc.) and an inert solvent (for example, THF, dichloromethane, In DMF etc.).
  • a base for example, triethylamine, lithium hydroxide dihydrate, etc.
  • an organic mercaptan for example, sulfanyl acetic acid, etc.
  • an inert solvent for example, THF, dichloromethane, In DMF etc.
  • Compound (18) can be produced, for example, by alkylation of compound (16) and compound (17) or Mitsunobu reaction. This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (19) can be produced, for example, by deprotection reaction of compound (18).
  • Compound (1-1) can be produced, for example, by an acylation reaction of compound (19). This reaction is performed, for example, in the same manner as in the production of (I-2) in Reaction Scheme 3.
  • Compound (21) can be produced, for example, by an alkylation reaction or Mitsunobu reaction between compound (20) and compound (17). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (22) can be produced, for example, by deprotection of compound (21).
  • Compound (23) can be produced, for example, by deprotection of compound (22).
  • Compound (5-1) can be produced, for example, by acylation reaction of compound (23). This reaction is performed, for example, in the same manner as in the production of compound (I-2) of reaction formula 3.
  • compound (5-1) can also be produced by changing the order of the method described in Reaction Scheme 6 (deprotection reaction and acylation reaction of A 2 and A 3 ).
  • aromatic ring P of compound (21), compound (22), compound (23) or compound (5-1) is aromatic ring P 1 (5- and 6-membered aromatic ring which may be substituted)
  • aromatic ring P A compound having a corresponding saturated ring P 2 (optionally substituted 5-membered and 6-membered saturated ring) can be produced by a reduction reaction of 1 .
  • the compound (21), the compound (22), the compound (23) or the compound (5-1) is converted into a metal catalyst (for example, rhodium-carbon, palladium-carbon, platinum oxide, etc.) and a hydrogen source (for example, , Hydrogen gas, formic acid, ammonium formate, etc.) in the presence of an inert solvent (for example, ethanol, methanol, acetic acid, THF, etc.).
  • a metal catalyst for example, rhodium-carbon, palladium-carbon, platinum oxide, etc.
  • a hydrogen source for example, Hydrogen gas, formic acid, ammonium formate, etc.
  • an inert solvent for example, ethanol, methanol, acetic acid, THF, etc.
  • hydrogen pressure is usually 1 to 10 atmospheres.
  • R 3 -M represents an organometallic reagent
  • R 10a and R 10b independently represent a substituent
  • R 10a and R 10b may combine with each other to form a ring.
  • the symbols of the above are as defined above, wherein compound (9-1) is included in compound (9) and compound (12-1) is included in compound (12).
  • Compound (25) can be produced, for example, by an alkylation reaction or Mitsunobu reaction between compound (24) and compound (6). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (26) can be produced, for example, by subjecting compound (25) to deprotection.
  • Compound (26) can also be produced, for example, according to the method described in Reaction Scheme 12, a method known per se, or a method analogous thereto.
  • Compound (28) can be produced, for example, by an alkylation reaction or Mitsunobu reaction of compound (26) and compound (27). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (12-1) can be produced, for example, by subjecting compound (28) to an organometallic reagent R 3 -M.
  • organometallic reagent R 3 -M eg, methylmagnesium chloride, methylmagnesium bromide, methyllithium, etc.
  • an inert solvent eg, toluene, THF, diethyl ether, etc.
  • the reaction is performed at ⁇ 78 ° C. to 100 ° C.
  • Compound (9-1) can be produced, for example, by a reduction reaction of compound (12-1). This reaction is performed, for example, in the same manner as in the method for producing compound (9) of reaction formula 4.
  • Compound (30) can be produced, for example, by an alkylation reaction or Mitsunobu reaction of compound (29) and compound (17). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (31) can be produced, for example, by subjecting compound (30) to deprotection.
  • Compound (32) can be produced, for example, by subjecting compound (31) to an acylation reaction. This reaction is performed, for example, in the same manner as in the production of compound (I-2) of reaction formula 3.
  • Compound (34) can be produced, for example, by a coupling reaction of compound (32) and compound (33).
  • compound (32) and compound (33) are present in the presence of a metal catalyst (eg, bistriphenylphosphinedichloropalladium (II) and copper (I) iodide) and a base (eg, triethylamine, pyridine, etc.).
  • a metal catalyst eg, bistriphenylphosphinedichloropalladium (II) and copper (I) iodide
  • a base eg, triethylamine, pyridine, etc.
  • the reaction is usually carried out in an inert solvent (eg, toluene, THF, DMF, etc.) under an inert gas (eg, argon, nitrogen, etc.) atmosphere.
  • an inert solvent eg, toluene, THF, DMF, etc.
  • an inert gas eg,
  • Compound (1-2) can be produced, for example, by a reduction reaction of compound (34).
  • the compound (34) is reacted with an inert solvent (eg, rhodium-carbon, palladium-carbon, platinum oxide, etc.) and a hydrogen source (eg, hydrogen gas, formic acid, ammonium formate, etc.).
  • an inert solvent eg, rhodium-carbon, palladium-carbon, platinum oxide, etc.
  • a hydrogen source eg, hydrogen gas, formic acid, ammonium formate, etc.
  • the reaction is performed in ethanol, methanol, acetic acid, THF, or the like.
  • hydrogen pressure is usually 1 to 10 atmospheres.
  • the metal catalyst is used in the same amount (weight) or more as the compound (34).
  • a reduction reaction of the aromatic ring P 1 from the compound (30), the compound (31), the compound (32), the compound (34) or the compound (1-2) results in the corresponding saturated ring P 2 (optionally substituted 5 And 6-membered saturated rings) can be prepared.
  • compound (30), compound (31), compound (32), compound (34) or compound (1-2) is converted to a metal catalyst (eg, rhodium-carbon, palladium-carbon, platinum oxide, etc.) And a reaction in an inert solvent (eg, ethanol, methanol, acetic acid, THF, etc.) in the presence of a hydrogen source (eg, hydrogen gas, formic acid, ammonium formate, etc.).
  • a hydrogen source eg, hydrogen gas, formic acid, ammonium formate, etc.
  • Compound (37) can be produced, for example, by a coupling reaction of compound (35) and compound (36). This reaction is performed, for example, in the same manner as in the method for producing compound (34) of reaction formula 8.
  • Compound (38) can be produced, for example, by subjecting compound (37) to deprotection.
  • Compound (39) can be produced, for example, by subjecting compound (38) to an acylation reaction. This reaction is performed, for example, in the same manner as in the production of compound (I-2) of reaction formula 3.
  • Compound (40) can be produced, for example, by subjecting compound (39) to a reduction reaction. This reaction is performed, for example, in the same manner as in the method for producing compound (1-2) of reaction formula 8.
  • Compound (5-2) can be produced, for example, by deprotection of compound (40).
  • compound (5-2) can also be produced by changing the order of the method described in Reaction Scheme 9 (deprotection reaction of A 2 and A 3 , coupling reaction and reduction reaction). .
  • Reduction of the aromatic ring P 1 from the compound (37), compound (38), compound (39), compound (40) or compound (5-2) results in the corresponding saturated ring P 2 (optionally substituted 5 And 6-membered saturated rings) can be prepared.
  • compound (37), compound (38), compound (39), compound (40) or compound (5-2) is converted into a metal catalyst (eg, rhodium-carbon, palladium-carbon, platinum oxide, etc.).
  • a reaction in an inert solvent eg, ethanol, methanol, acetic acid, THF, etc.
  • a hydrogen source eg, hydrogen gas, formic acid, ammonium formate, etc.
  • hydrogen pressure is usually 1 to 10 atmospheres.
  • Compound (43) can be produced, for example, by an addition reaction of compound (41) and compound (42). This reaction is performed, for example, by reacting compound (41) with compound (42) in an inert solvent (eg, ethanol, methanol, THF, etc.). If necessary, it is carried out in the presence of a metal salt (for example, bismuth nitrate, etc.).
  • an inert solvent eg, ethanol, methanol, THF, etc.
  • a metal salt for example, bismuth nitrate, etc.
  • Compound (44) can be produced, for example, by subjecting compound (43) to deprotection.
  • Compound (5-3) can be produced, for example, by subjecting compound (44) to an acylation reaction. This reaction is performed, for example, in the same manner as in the production of compound (I-2) of reaction formula 3.
  • Compound (47) can be produced, for example, by an amidation reaction of compound (45) and compound (46).
  • compound (45) and compound (46) are combined with an inert solvent (eg, DMF, acetonitrile, etc.) in the presence of a dehydrating condensing agent (eg, WSC, HATU, etc.) and an additive (eg, HOBt, etc.). Reaction in dichloromethane, THF, etc.).
  • compound (46) may be used after being converted into a reactive derivative of carboxylic acid (for example, acid chloride, acid anhydride, mixed acid anhydride, active ester, active amide, etc.).
  • a base for example, a triethylamine, a pyridine, etc.
  • Compound (48) can be produced, for example, by subjecting compound (47) to a reduction reaction.
  • This reaction is carried out, for example, by reacting compound (47) in the presence of a reducing agent (eg, borane, lithium aluminum hydride) in an inert solvent (eg, toluene, THF, etc.).
  • a reducing agent eg, borane, lithium aluminum hydride
  • an inert solvent eg, toluene, THF, etc.
  • Compound (49) can be produced, for example, by subjecting compound (48) to deprotection.
  • Compound (50) can be produced, for example, by subjecting compound (49) to an acylation reaction. This reaction is performed, for example, in the same manner as in the production of compound (I-2) of reaction formula 3.
  • Compound (5-4) can be produced, for example, by subjecting compound (50) to deprotection.
  • R 11a and R 11b independently represent a hydroxyl group or a substituent, and these may be bonded to each other to form a ring. Each symbol has the same meaning as described above. 26-1 is encompassed by compound (26).)
  • Compound (53) can be produced, for example, by a nucleophilic substitution reaction of compound (51) and compound (52).
  • compound (51) and compound (52) are reacted with an inert solvent (eg, DMF, acetonitrile, dichloromethane, THF, etc.) in the presence of a base (eg, sodium hydride, potassium carbonate, triethylamine, pyridine, etc.).
  • an inert solvent eg, DMF, acetonitrile, dichloromethane, THF, etc.
  • a base eg, sodium hydride, potassium carbonate, triethylamine, pyridine, etc.
  • Compound (54) can be produced, for example, by a boronation reaction of compound (53).
  • a halogen atom is converted into a metal atom with an alkyl metal (eg, butyllithium, isopropylmagnesium bromide, etc.) in compound (53) in an inert solvent (eg, diethyl ether, toluene, THF, etc.).
  • an organic boron compound for example, trimethoxyborane etc.
  • Compound (26-1) can be produced, for example, by subjecting the boron atom of compound (54) to an oxidation reaction.
  • compound (54) is reacted with an oxidizing agent (eg, oxygen, hydrogen peroxide, m-chloroperbenzoic acid, sodium perborate, etc.) in an inert solvent (eg, water, THF, etc.).
  • an oxidizing agent eg, oxygen, hydrogen peroxide, m-chloroperbenzoic acid, sodium perborate, etc.
  • an inert solvent eg, water, THF, etc.
  • a base for example, sodium hydroxide
  • Compound (56) can be produced, for example, by an alkylation reaction or Mitsunobu reaction of compound (55) and compound (17). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (57) can be produced, for example, by a boronation reaction of compound (56). This reaction is performed, for example, in the same manner as in the method for producing compound (54) of reaction formula 12.
  • Compound (22-1) can be produced, for example, by subjecting the boron atom of compound (57) to an oxidation reaction. This reaction is performed, for example, in the same manner as in the method for producing compound (26-1) of reaction formula 12.
  • Compound (60) can be produced, for example, by an alkylation reaction or Mitsunobu reaction between compound (58) and compound (59). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (61) can be produced, for example, by a reduction reaction of compound (60). This reaction is performed, for example, in the same manner as in the method for producing compound (9) of reaction formula 4.
  • Compound (62) can be produced, for example, by deprotection of compound (61).
  • Compound (9-2) can also be produced, for example, by an alkylation reaction of compound (62) and compound (6). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (64) can be produced, for example, by an alkylation reaction or Mitsunobu reaction between compound (63) and compound (17). This reaction is performed, for example, in the same manner as in the production of compound (I-1) of reaction formula 2.
  • Compound (65) can be produced, for example, by a reduction reaction of aromatic ring P 1 of compound (64).
  • compound (64) is reacted with an inert solvent (eg, rhodium-carbon, palladium-carbon, platinum oxide, etc.) and a hydrogen source (eg, hydrogen gas, formic acid, ammonium formate, etc.).
  • an inert solvent eg, rhodium-carbon, palladium-carbon, platinum oxide, etc.
  • a hydrogen source eg, hydrogen gas, formic acid, ammonium formate, etc.
  • the reaction is performed in ethanol, methanol, acetic acid, THF, or the like.
  • hydrogen pressure is usually 1 to 10 atmospheres.
  • Compound (70) can also be produced, for example, by an alkylation reaction of compound (68) and compound (69).
  • compound (68) and compound (69) are reacted in the presence of a base (for example, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, DBU, etc.) in an inert solvent (for example, DMF, acetonitrile, (Ethanol, THF, water, etc.).
  • a phase transfer catalyst for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc. may be used as necessary.
  • Compound (16-1) can be produced, for example, by subjecting compound (70) to deprotection.
  • Compound (73) can be produced, for example, by a coupling reaction of compound (71) and compound (72).
  • compound (71) and compound (72) are present in the presence of a metal catalyst (for example, bistriphenylphosphinedichloropalladium (II) and copper iodide (I)) and a base (for example, triethylamine, pyridine, etc.).
  • a metal catalyst for example, bistriphenylphosphinedichloropalladium (II) and copper iodide (I)
  • a base for example, triethylamine, pyridine, etc.
  • the reaction is usually carried out in an inert solvent (eg, toluene, THF, DMF, etc.) under an inert gas (eg, argon, nitrogen, etc.) atmosphere.
  • an inert solvent eg, toluene, THF, DMF, etc.
  • an inert gas eg, argon
  • Compound (74) can be produced, for example, by a reduction reaction of compound (73). This reaction is performed, for example, in the same manner as in the method for producing compound (1-2) of reaction formula 8.
  • Compound (16-2) can be produced, for example, by subjecting compound (74) to deprotection.
  • the compound (16-2) can be produced by performing the reaction leading from the compound (73) to the compound (16-2), that is, the reduction reaction and the deprotection reaction at the same time or by changing the order.
  • compound (77) can be produced, for example, by an alkylation reaction of compound (75) and compound (76).
  • the alkylation reaction is carried out, for example, by converting the compound (75) and the compound (76) into a base (for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4.0] undeca-7-ene). Etc.) in the presence of an inert solvent (for example, DMF, acetonitrile, THF, toluene, water, etc.).
  • a base for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4.0] undeca-7-ene).
  • Etc. in the presence of an inert solvent (for example, DMF, acetonitrile, THF, toluene, water, etc.).
  • a phase transfer catalyst for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.
  • compound (76) is an alcohol
  • compound (77) can be produced, for example, by Mitsunobu reaction between compound (75) and compound (76).
  • Mitsunobu reaction can be carried out, for example, by converting compound (75) and compound (76) into a hydroxy group activator (eg, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl).
  • a hydroxy group activator eg, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl.
  • an inert solvent for example,
  • Compound (78) can be produced, for example, by a reduction reaction of compound (77).
  • a metal hydride compound for example, diisobutylaluminum hydride
  • a metal hydride complex compound for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride, hydrogen
  • a reducing agent such as bis (2-methoxyethoxy) aluminum chloride
  • an inert solvent for example, ethanol, methanol, THF, etc.
  • Compound (1-3) is produced, for example, using compound (78), for example, in the same manner as in the production of compound (I-1) from compound (4) in Reaction Scheme 2.
  • Compound (1-3) is produced, for example, using compound (79), for example, in the same manner as in the production of compound (I-1) from compound (6) in Reaction Scheme 2.
  • compound (81) can be produced, for example, by an alkylation reaction of compound (80) and compound (3).
  • the alkylation reaction is carried out, for example, by converting the compound (80) and the compound (3) into a base (for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4.0] undeca-7-ene). Etc.) in the presence of an inert solvent (for example, DMF, acetonitrile, THF, toluene, water, etc.).
  • a base for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4.0] undeca-7-ene).
  • Etc. in the presence of an inert solvent (for example, DMF, acetonitrile, THF, toluene, water, etc.).
  • a phase transfer catalyst for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.
  • compound (3) is an alcohol
  • compound (81) can be produced, for example, by Mitsunobu reaction between compound (80) and compound (3).
  • Mitsunobu reaction can be achieved, for example, by converting compound (80) and compound (3) into a hydroxy group activator (eg, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl).
  • a hydroxy group activator eg, cyanomethylene tri-n-butylphosphorane, diisopropyl azodicarboxylate and triphenylphosphine, diethyl azodicarboxylate and triphenyl.
  • an inert solvent for example, toluene, T
  • Compound (83) can be produced, for example, by subjecting compound (82) to an alkoxylation reaction.
  • the compound (82) and an alcohol represented by the chemical formula R 6 —OH can be converted into a base (for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4. 0] undecaker 7-ene) and the like in the presence of an inert solvent (eg, DMF, acetonitrile, THF, toluene, water, etc.).
  • a base for example, potassium carbonate, sodium hydride, sodium hydroxide, DBU (1,8-diazabicyclo [5.4. 0] undecaker 7-ene
  • an inert solvent eg, DMF, acetonitrile, THF, toluene, water, etc.
  • the alcohol represented by the chemical formula R 6 —OH may be used in excess of the compound (82), or a phase transfer catalyst (eg, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.) may be used. Good.
  • a phase transfer catalyst eg, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, etc.
  • Compound (81) can also be produced, for example, by a formylation reaction of compound (83).
  • compound (83) is reacted with an alkyl metal (eg, butyl lithium) or a metal amide (eg, lithium diisopropylamide, lithium) in an inert solvent (eg, diethyl ether, toluene, THF, etc.).
  • an alkyl metal eg, butyl lithium
  • a metal amide eg, lithium diisopropylamide, lithium
  • an inert solvent eg, diethyl ether, toluene, THF, etc.
  • a formylating agent eg, DMF, ethyl formate, etc.
  • Compound (21) can be produced, for example, by subjecting compound (22) to a protection reaction.
  • Compound (84) can be produced, for example, by subjecting compound (21) to deprotection.
  • Compound (5-1) can be produced, for example, by subjecting compound (85) to deprotection.
  • the functional group in the molecule can be converted to the target functional group by combining a chemical reaction known per se.
  • the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, an acylation reaction, a urealation reaction, a hydrolysis reaction, an amination reaction, an esterification reaction, an aryl coupling reaction, and a deprotection reaction.
  • Compound (I) obtained by the above production method can be isolated and purified by a known means such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • the optical isomer can be produced by a method known per se.
  • Compound (I) may be a crystal. Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallization by applying a crystallization method known per se to compound (I). In the present specification, the melting point is measured using, for example, a trace melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point. In general, the melting point may vary depending on measurement equipment, measurement conditions, and the like. The crystal in the present specification may be a crystal having a value different from the melting point described in the present specification as long as it is within a normal error range.
  • the crystals of the present invention are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal properties), and are extremely useful as pharmaceuticals. Useful.
  • MS mass spectrum
  • LC / MS liquid chromatograph mass spectrometer
  • ESI ElectroSpray Ionization
  • APCI Adtomospheric Pressure Chemical Ionization
  • ESI + positive mode
  • ESI- negative mode
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated should be observed as a fragment ion. There is also. Depending on the compound, a peak in which sodium ion (+ Na) is added to the molecular ion peak may be observed as a fragment ion. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion.
  • the solid obtained was dissolved in ethyl acetate (70 mL), 4 M hydrogen chloride / ethyl acetate (100 mL) was added, and the mixture was stirred at room temperature for 1.5 hr. did.
  • the reaction mixture was concentrated under reduced pressure, the residue was dissolved in pyridine (100 mL), acetic anhydride (30 mL) was added, and the mixture was stirred at room temperature for 16 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether.
  • the obtained solid was purified by NH silica gel column chromatography (THF) to obtain the title compound (7.36 g).
  • reaction mixture was concentrated under reduced pressure, the residue was dissolved in pyridine (20 mL), acetic anhydride (0.345 mL) was added, and the mixture was stirred at room temperature for 3 hr.
  • 1 M aqueous sodium hydroxide solution 10 mL
  • the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and saturated brine.
  • the organic layer was separated, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.88 g).
  • the precipitate was filtered off, and the filtrate was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue (645 mg) was dissolved in DMF (4.7 mL), sodium azide (0.462 g) was added at room temperature, and the mixture was stirred at 80 ° C. for 3 hr. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • CHIRALPAK AD trade name
  • Example 5b 1- ⁇ 2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ urea optically active substance
  • Example 6 N-[(1S) -2- (4- ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ phenoxy) -1-methylethyl] acetamide [4- (cyclopropylmethoxy) phenyl] methanol and N-[( Using 1S) -2- (4-hydroxyphenoxy) -1-methylethyl] acetamide, the title compound was obtained in the same manner as in Step E of Example 1 or a method analogous thereto.
  • Example 9 N- ⁇ (1S) -2-[(4- ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ phenyl) sulfinyl] -1-methylethyl ⁇ acetamide N- ⁇ (1S) -2-[(4- Add 3-chloroperoxybenzoic acid (112 mg) to a solution of ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ phenyl) sulfanyl] -1-methylethyl ⁇ acetamide (250 mg) in THF (5 mL) at room temperature. For 15 minutes. The precipitated solid was collected by filtration and washed with ethyl acetate to give the title compound (118 mg).
  • Example 10 N- ⁇ (1S) -2-[(4- ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ phenyl) sulfonyl] -1-methylethyl ⁇ acetamide N- ⁇ (1S) -2-[(4- Add 3-chloroperoxybenzoic acid (280 mg) to a solution of ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ phenyl) sulfanyl] -1-methylethyl ⁇ acetamide (250 mg) in THF (5 mL) at room temperature. For 15 minutes. The reaction mixture was passed through a NH silica gel short column (ethyl acetate), the solvent was distilled off under reduced pressure, and the obtained solid was washed with ethyl acetate to obtain the title compound (223 mg).
  • the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane / ethyl acetate). The solid obtained was dissolved in ethanol (40 mL), 10% palladium-carbon (50% water content, 2.0 g) was added, and the mixture was added under a hydrogen atmosphere at room temperature. For 16 hours. After removing the catalyst by Celite filtration, the obtained filtrate was concentrated under reduced pressure.
  • Example 12 N-[(1S) -3- (4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ phenyl) -1-methylpropyl] acetamide N-[(1S) -3- (4- Using hydroxyphenyl) -1-methylpropyl] acetamide and [4- (cyclopropylmethoxy) -2-fluorophenyl] methanol, the title compound was obtained in the same manner as in Step E of Example 1 or a method analogous thereto. .
  • Example 14 N-[(1S) -3- ⁇ 4-[(4-Ethoxy-2-fluorobenzyl) oxy] phenyl ⁇ -1-methylpropyl] acetamide (4-ethoxy-2-fluorophenyl) methanol (118 mg) Thionyl chloride (0.084 mL) was added to a toluene (1 mL) solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give DMF (1 mL), N-[(1S) -3- (4-hydroxyphenyl) -1-methylpropyl] acetamide (120 mg) and cesium carbonate (120 mg).
  • Methyl 2-fluoro-4-propoxybenzoate Methyl 2-fluoro-4-hydroxybenzoate (2.85 g), 1-iodopropane (3.12 g) and cesium carbonate (8.19 g) in DMF (17 mL) suspension The solution was stirred at 50 ° C. for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.39 g).
  • Example 18 Performed with N- ⁇ 1-[(4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ phenoxy) methyl] propyl ⁇ acetamide tert-butyl [1- (hydroxymethyl) propyl] carbamate
  • the title compound was obtained in the same manner as in Step A of Example 1, Step B of Example 1, Step C of Example 1 and Step E of Example 1 or a method analogous thereto.
  • Example 20 (4- ⁇ [(2S) -2- (acetylamino) propyl] oxy ⁇ phenoxy) [4- (cyclopropylmethoxy) phenyl] acetic acid ethyl (4- ⁇ [(2S) -2- (acetylamino) propyl]
  • 1 M aqueous sodium hydroxide solution 1.2 mL
  • methanol 2 mL
  • the reaction mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (174 mg).
  • Trimethyl borate (0.600 mL) was added to the reaction mixture, and the resulting mixture was stirred at 0 ° C. for 30 minutes.
  • 8 M aqueous sodium hydroxide solution (0.719 mL) and 30% aqueous hydrogen peroxide (2 mL)
  • the reaction mixture was acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was acidified with 0.5 M hydrochloric acid, washed with ethyl acetate, and the aqueous layer was basified with saturated sodium bicarbonate. Ethyl acetate (10 mL) and acetic anhydride (10 mL) were added to this aqueous layer and stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (1.11 g).
  • Example 26 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -3-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [4- (cyclopropylmethoxy ) -3-Fluorophenyl] methanol was used to obtain the title compound by a method similar to or similar to Step A and Step F of Example 2.
  • Example 27 N- ⁇ (1S) -2-[(trans-4- ⁇ [3-chloro-4- (cyclopropylmethoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [3-chloro-4- The title compound was obtained in the same manner as in Step A and Step F of Example 2 or a method analogous thereto using (cyclopropylmethoxy) phenyl] methanol.
  • Example 30 N-[(1S) -2- (3- ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ phenoxy) -1-methylethyl] acetamide Step A of Example 22 with 3- (benzyloxy) phenol The title compound was obtained in the same manner as in Step B of Example 7, Step C of Example 1 and Step E of Example 1, or a method analogous thereto.
  • Example 32 N-[(1S) -2- (4- ⁇ [3- (cyclopropylmethoxy) benzyl] oxy ⁇ phenoxy) -1-methylethyl] acetamide [3- (cyclopropylmethoxy) phenyl] methanol and N-[( 1S) -2- (4-Hydroxyphenoxy) -1-methylethyl] acetamide was used to give the title compound by the same method as in Step E of Example 1 or a method analogous thereto.
  • Example 33 N-[(1S) -3- (4- ⁇ [3- (cyclopropylmethoxy) benzyl] oxy ⁇ phenyl) -1-methylpropyl] acetamide [3- (cyclopropylmethoxy) phenyl] methanol and N-[( 1S) -3- (4-Hydroxyphenyl) -1-methylpropyl] acetamide was used to give the title compound in the same manner as in Step E of Example 1 or a method analogous thereto.
  • Example 40a N-[(1S) -2- ⁇ [trans-4-( ⁇ 2-chloro-4-[(2,2-difluorocyclopropyl) methoxy] benzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl] acetamide Optically active form of
  • Example 41 N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2-fluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl] acetamide N-[(1S) -2-( ⁇ trans-4-[(2-fluoro-4-hydroxybenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide (400 mg) in DMF (5 mL) To the mixture were added potassium carbonate (489 mg) and (2,2-difluorocyclopropyl) methyl methanesulfonate (658 mL), and the mixture was heated and stirred at 60 ° C.
  • Example 42 N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2-fluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl] acetamide
  • the optically active form of N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2-fluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1- Methylethyl] acetamide diastereomer mixture (430 mg) was analyzed by HPLC (column: CHIRALPAK OJ (trade name), 50 mm ID ⁇ 500 mmL, Daicel Chemical Industries, mobile phase: hexane / 2-propanol 70: 30).
  • Example 43 N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2-fluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl] acetamide
  • the optically active form of N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2-fluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1- Methylethyl] acetamide diastereomer mixture (430 mg) was analyzed by HPLC (column: CHIRALPAK OJ (trade name), 50 mm ID ⁇ 500 mmL, Daicel Chemical Industries, mobile phase: hexane / 2-propanol 70: 30).
  • Example 45 N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2,6-difluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl
  • Example 46 N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(2,2-difluorocyclopropyl) methoxy] -2,6-difluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl
  • Example 47 N- ⁇ (1S) -2-[(trans-4- ⁇ [5- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide 2-fluoro-5-hydroxy
  • the title compound was obtained in the same manner as in Step 15 of Example 15, Step B of Example 15, Step D of Example 36 and Step B of Example 7 using benzoic acid and bromomethylcyclopropane.
  • Example 50 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [4- (cyclopropylmethoxy) phenyl] methanol
  • the title compound was obtained in the same manner as in Steps A and F of Example 2.
  • Example 51 N- ⁇ (1S) -2-[(trans-4- ⁇ [6- (cyclopropylmethoxy) -4-fluoropyridin-3-yl] methoxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [6- The title compound was obtained in the same manner as in Steps A and F of Example 2 using (cyclopropylmethoxy) -4-fluoropyridin-3-yl] methanol.
  • Example 52 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -2,6-difluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [4- (cyclo The title compound was obtained in the same manner as in Steps A and F of Example 2 using (propylmethoxy) -2,6-difluorophenyl] methanol.
  • Example 53 N- ⁇ (1S) -2-[(trans-4- ⁇ [6- (cyclopropylmethoxy) -4-methylpyridin-3-yl] methoxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [6- The title compound was obtained in the same manner as in Steps A and F of Example 2 using (cyclopropylmethoxy) -4-methylpyridin-3-yl] methanol.
  • Example 54 Optically active form of methyl ⁇ 2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ carbamate
  • Example 56 N- ⁇ (1S) -2-[(trans-4- ⁇ [2-cyano-4- (cyclopropylmethoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide 2- (bromomethyl) -5
  • the title compound was obtained in the same manner as in Step F of Example 2 using-(cyclopropylmethoxy) benzonitrile.
  • Example 57 N-[(1S) -2-( ⁇ trans-4-[(2-chloro-4-ethoxybenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide 1- (bromomethyl) -2-chloro-4
  • the title compound was obtained in the same manner as in Step F of Example 2 using -ethoxybenzene.
  • Example 58 N- ⁇ (1S) -2-[(trans-4- ⁇ [2-chloro-4- (1-methylethoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [2-chloro-4 The title compound was obtained in the same manner as in Steps A and F of Example 2 using-(1-methylethoxy) phenyl] methanol.
  • Example 59 N- ⁇ (1S) -2-[(trans-4- ⁇ [5- (cyclopropylmethoxy) -3-fluoropyridin-2-yl] methoxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [5- The title compound was obtained in the same manner as in Steps A and F of Example 2 using (cyclopropylmethoxy) -3-fluoropyridin-2-yl] methanol.
  • Example 61 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -2-methylbenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [4- (cyclopropylmethoxy ) -2-Methylphenyl] methanol was used to obtain the title compound in the same manner as in Steps A and F of Example 2.
  • Example 62 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -3- (trifluoromethoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide [4- The title compound was obtained in the same manner as in Steps A and F of Example 2 using (cyclopropylmethoxy) -3- (trifluoromethoxy) phenyl] methanol.
  • Example 64 N-[(1S) -3- (trans-4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) -1-methylpropyl] acetamide [4- (cyclopropylmethoxy) -2 The title compound was obtained in the same manner as in Step D of Example 34 using [-fluorophenyl] methanol.
  • Example 68 N- ⁇ (1S) -2-[(trans-4- ⁇ [2-fluoro-4- (2-methylpropoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide 1-bromo-2- The title compound was obtained in the same manner as in Step D of Example 35 using methylpropane.
  • Example 70 N- ⁇ (1S) -2-[(cis-4- ⁇ [3- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide 2-fluoro-3-hydroxy After performing the same operation as in Step C of Example 34 using benzaldehyde and bromomethylcyclopropane, N- ⁇ (1S) -2-[(cis-4-hydroxycyclohexyl) oxy] -1-methylethyl ⁇ The title compound was obtained in the same manner as in Step D of Example 36 using acetamide.
  • Example 71 N- ⁇ (1S) -2-[(cis-4- ⁇ [5- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide (5- (cyclopropylmethoxy ) -2-Fluorophenyl) methanol and N- ⁇ (1S) -2-[(cis-4-hydroxycyclohexyl) oxy] -1-methylethyl ⁇ acetamide as in step D of Example 36 Gave the title compound.
  • Example 75 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ -4-methylcyclohexyl) oxy] -1-methylethyl ⁇ acetamide N- ⁇ (1S) -2-[(4-Hydroxy-4-methylcyclohexyl) oxy] -1-methylethyl ⁇ acetamide was used to obtain N- ⁇ (1S) -2 obtained by the same method as in Step B of Example 3.
  • Example 76 N- ⁇ (1S) -2-[(cis-4- ⁇ [4- (cyclopropylmethoxy) -2-fluorobenzyl] oxy ⁇ -4-methylcyclohexyl) oxy] -1-methylethyl ⁇ acetamide N- ⁇ (1S) -2-[(4-Hydroxy-4-methylcyclohexyl) oxy] -1-methylethyl ⁇ acetamide was used to obtain N- ⁇ (1S) -2 obtained by the same method as in Step B of Example 3.
  • reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (71.5 mg) as a white solid.
  • Triethylamine (1.90 mL) and methanesulfonyl chloride (0.791 mL) were added to a THF (10 mL) solution of cyclopropylethanol (587 mg) and stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 80 N- ⁇ (1S) -2-[(trans-4- ⁇ [3- (cyclobutylmethoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide (bromomethyl) cyclobutane
  • the title compound was obtained in the same manner as in Step B.
  • Example 82 N- ⁇ (1S) -2-[(trans-4- ⁇ [4- (2,2-difluoropropoxy) -2-fluorobenzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide N- ⁇ ( 1S) -2-[(trans-4- ⁇ [2-fluoro-4- (2-oxopropoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇ acetamide (177 mg), bis (2-methoxy A mixture of ethyl) aminosulfur trifluoride (297 mg) and toluene (20 mL) was stirred at room temperature for 1 hour, followed by 80 ° C.
  • Example 83 N-[(1S) -2- ⁇ [trans-4-( ⁇ 4-[(3,3-difluorocyclobutyl) methoxy] -2-fluorobenzyl ⁇ oxy) cyclohexyl] oxy ⁇ -1-methylethyl] acetamide N-[(1S) -2-( ⁇ trans-4-[(2-fluoro-4-hydroxybenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide and (3,3-difluorocyclobutyl) methyl The title compound was obtained in the same manner as in Step E of Example 7 using methanesulfonate.
  • reaction mixture was passed through silica gel, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • a THF solution 0.5 M, 30.9 mL
  • 2-methylallylmagnesium chloride was added to a THF (40 mL) solution of the obtained residue, and the mixture was stirred at room temperature for 20 minutes.
  • To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 87 N-[(1S) -2-( ⁇ trans-4-[(2-fluoro-4-propoxybenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide N-[(1S) -2-( ⁇ trans-4-[(2-Fluoro-4-hydroxybenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide and 1-iodopropane and the title compound by a method similar to Example 7, step E. Obtained.
  • Example 88 N-[(1S) -2-( ⁇ trans-4-[(4-butoxy-2-fluorobenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide N-[(1S) -2-( ⁇ The title compound was obtained in the same manner as in Step E of Example 7 using trans-4-[(2-fluoro-4-hydroxybenzyl) oxy] cyclohexyl ⁇ oxy) -1-methylethyl] acetamide and 1-iodobutane. It was.
  • Example 90 N- ⁇ (1S) -2-[(trans-4- ⁇ [2-fluoro-4- (2,2,3,3-tetrafluoropropoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methylethyl ⁇
  • the title compound was obtained in the same manner as in Step D of Example 35 using acetamide 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate.
  • Example 91 N- ⁇ (1S) -2-[(trans-4- ⁇ [2-fluoro-4- (2,2,3,3,3-pentafluoropropoxy) benzyl] oxy ⁇ cyclohexyl) oxy] -1-methyl
  • the title compound was obtained in the same manner as in Step D of Example 35 using ethyl ⁇ acetamide 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate.
  • the resulting residue was mixed with THF (10 mL), methanol (10 mL), and 1 M aqueous sodium hydroxide solution (10 mL), and the resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (498 mg) as a colorless oily compound.
  • N- (2- ⁇ [trans-3- (benzyloxy) cyclobutyl] oxy ⁇ -1-methylethyl) acetamide (65.5 mg, mixture with impurities), 20% palladium hydroxide / carbon (50%
  • a mixture of water (65 mg) and ethanol (2 mL) was stirred at room temperature for 4 hours.
  • the catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure.
  • the obtained residue was 1- (bromomethyl) -4- (cyclopropylmethoxy) -2-fluorobenzene (306 mg), tetrabutylammonium hydrogen sulfate (8.02 mg), 50% aqueous sodium hydroxide solution (2 mL), and Mix with toluene (4 mL) and stir the resulting mixture at 100 ° C. for 3 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Tables 1 to 13 show the measured values of MS or NMR spectrum data in addition to the compound names and structural formulas of the example compounds.
  • the measured value of MS usually indicates the measured value in the positive mode (ESI +), and the measured value in the negative mode (ESI-) is indicated with [MH] - . Further, in the positive mode (ESI +), when a fragment peak in which sodium ion (+ Na) was added to the molecular ion peak was observed, [M + Na] + was also written.
  • Test example 1 The ACC2 inhibitory action of the compound of the present invention was evaluated by the following method. (1) Cloning of human ACC2 gene and preparation of recombinant baculovirus The human ACC2 gene was cloned by PCR using Primer 1 and Primer 2 shown below using a human skeletal muscle cDNA library (Clontech) as a template. Primer 1 and Primer 2 were prepared by adding SalI and XbaI restriction enzyme recognition sequences based on the information on the base sequence of the human ACC2 gene (Genbank Accession U89344).
  • Primer 1 5'-AAAAGTCGACCCACCATGGTCTTGCTTCTTTGTCTATCTTG-3 '(SEQ ID NO: 1)
  • Primer 2 5'-TTTTTCTAGATCAGGTAGAGGCCGGGCTGTCCATG-3 '(SEQ ID NO: 2)
  • PCR was performed using Pyrobest DNA polymerase (Takara Bio Inc.). The obtained PCR product was cloned into pT7 Blue vector (Novagen), and after confirming the base sequence, digested with restriction enzymes SalI and XbaI.
  • the obtained DNA fragment was inserted into pFAST-BacHTa (Invitrogen) digested with restriction enzymes SalI and XbaI to prepare an expression plasmid ACC2 / pFAST-BacHTa.
  • pFAST-BacHTa Invitrogen digested with restriction enzymes SalI and XbaI to prepare an expression plasmid ACC2 / pFAST-BacHTa.
  • PCR using Primer 3 (added with a SalI restriction enzyme recognition sequence) and Primer 4 prepared from information on the base sequence of the human ACC2 gene (Genbank Accession U89344) and ACC2 from which the mitochondrial translocation sequence was removed A plasmid for expression was prepared.
  • Primer 3 5'-CCAGGTCGACCCGCCAACGGGACTGGGACACAAGG-3 '(SEQ ID NO: 3)
  • Primer 4 5'-CGCACTCTCAGTTTCCCGGATTCCC-3 '(SEQ ID NO: 4)
  • PCR was performed using Pyrobest-DNA polymerase (Takara Bio Inc.). The obtained PCR product was cloned into pT7 Blue vector (Novagen). After confirming the nucleotide sequence, it was digested with restriction enzymes SalI and AflII.
  • the obtained DNA fragment was inserted into ACC2 / pFAST-BacHTa digested with restriction enzymes SalI and AflII to prepare an expression plasmid ACC2mito7 / pFAST-BacHTa.
  • an expression plasmid ACC2mito7 / pFAST-BacHTa was prepared using the expression plasmids ACC2mito7 / pFAST-BacHTa and BAC-TO-BAC Baculovirus Expression System (Invitrogen), a recombinant baculovirus virus stock BAC-ACC2 (N terminal deletion (hereinafter referred to as Nd)) was prepared.
  • ACC2 (Nd) protein SF-9 cells were cultured in insect cell medium (5% fetal bovine serum (Trace), 50 mg / L Gentamicin (Wako Pure Chemical Industries), 0.1% Pluronic F- Sf-900IISFM medium containing 68 (Invitrogen Corp.) (Invitrogen Corp.)) 10 L, seeded at 1.0 ⁇ 10 6 cells / mL, using a Wave bioreactor (GE Healthcare Corp.), 27 ° C., 20 rpm The shaking culture was performed at a rocking angle of 10 degrees and an oxygen concentration of 30%. Recombinant baculovirus BAC-ACC2 (Nd) was added on the second day of culture and cultured for 3 days.
  • insect cell medium 5% fetal bovine serum (Trace), 50 mg / L Gentamicin (Wako Pure Chemical Industries), 0.1% Pluronic F- Sf-900IISFM medium containing 68 (Invitrogen Corp.) (Invitrogen Corp.)) 10 L,
  • the culture solution was centrifuged at 1000 ⁇ g for 10 minutes to obtain virus-infected cells.
  • the cells were washed with phosphate physiological buffer (Invitrogen) and centrifuged under the same conditions, and the obtained cells were stored frozen at -80 ° C. After thawing the cryopreserved cells in ice, 25 mM HEPES buffer containing 10% Glycerol, 0.3 M NaCl, 1 mM EDTA, 25 mM Sodium ⁇ -Glycerophosphate, and 1 mM Sodium Orthovanadate with Complete Protease Inhibitor (Roche) added ( It was suspended in 900 mL of pH 7.5).
  • phosphate physiological buffer Invitrogen
  • the obtained suspension was homogenized three times using a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 seconds.
  • the obtained cell lysate was clarified by centrifugation at 186,000 ⁇ g for 60 minutes.
  • 5 mL of AF-chelate 650M Ni chelate carrier (Tosoh Corporation) was added and rotated at 4 ° C. for 1 hour.
  • the support was transferred to an open column by centrifugation at 1000 ⁇ g for 5 minutes.
  • ACC2 (Nd) (1.1 mg / ml) obtained in (2) above was used as a buffer for enzyme reaction (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 10 mM Tripottasium Citrate, 2 After dilution to a concentration of 6.4 ⁇ g / ml with mM Dithiothreitol, 0.75 mg / ml Fatty acid free BSA), 10 ⁇ l was added to each well of a 384 well assay plate (Nunc 265196).
  • the reaction was stopped by adding 5 ⁇ l of malachite green solution to each reaction solution thus obtained and stirring.
  • the obtained reaction solution was allowed to stand at room temperature for 20 minutes, and then the absorbance (620 nm) was measured using wallac1420 (Perkin Elmer).
  • the ACC2 inhibition rate (%) was determined according to the following formula. (1 ⁇ (absorbance of test compound added group ⁇ absorbance of control group) ⁇ (absorbance of test compound non-added group ⁇ absorbance of control group)) ⁇ 100
  • IC 50 value the inhibitory activity
  • the compound concentration showing a 50% inhibition rate was calculated from the dose-response curve using XLfit.
  • a compound with an inhibition rate of less than 50% at a compound concentration of 10 ⁇ M was expressed as> 10 ⁇ M.
  • Table 14 and Table 15 show the inhibition rate (%) against ACC2 at 10 ⁇ M of the test compound.
  • Test example 2 The ACC1 inhibitory action of the compound of the present invention was evaluated by the following method. (1) Cloning of human ACC1 gene and preparation of recombinant baculovirus The human ACC1 gene was cloned by PCR using Primer 1 and Primer 2 shown below using a human liver cDNA library (Clontech) as a template. Primer1 and Primer2 were prepared by adding SalI and NotI restriction enzyme recognition sequences based on the information on the base sequence of the human ACC1 gene (Genbank Accession U19822).
  • Primer 1 5'-AAAAGTCGACCCACCATGGATGAACCTTCTCCCTTGGCCC-3 '(SEQ ID NO: 5)
  • Primer 2 5'-AAAAGCGGCCGCCTACGTAGAAGGGGAGTCCATAGTG-3 '(SEQ ID NO: 6)
  • PCR was performed using Pyrobest DNA polymerase (Takara Bio Inc.). The obtained PCR product was cloned into pT7 Blue vector (Novagen), and after confirming the nucleotide sequence, it was digested with restriction enzymes SalI and NotI.
  • the obtained DNA fragment was inserted into pFAST-BacHTc (Invitrogen) digested with restriction enzymes SalI and NotI to prepare an expression plasmid ACC1 / pFAST-BacHTc.
  • pFAST-BacHTc Invitrogen
  • restriction enzymes SalI and NotI restriction enzymes SalI and NotI
  • a recombinant baculovirus virus stock BAC-ACC1 was prepared.
  • the cells were washed with phosphate physiological buffer (Invitrogen) and centrifuged under the same conditions, and the obtained cells were stored frozen at -80 ° C. After thawing the cryopreserved cells in ice, 25 mM HEPES buffer solution (pH 7. 5) Suspended in 100 mL. The obtained suspension was homogenized three times using a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 seconds. The obtained cell lysate was clarified by centrifugation at 185700 ⁇ g for 50 minutes, followed by filtration using a 0.45 ⁇ m filter.
  • phosphate physiological buffer Invitrogen
  • 25 mM HEPES buffer solution pH 7.5
  • the obtained suspension was homogenized three times using a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 seconds.
  • the obtained cell lysate was clarified by centrifugation at 185700 ⁇ g for 50 minutes, followed by filtration using
  • the filtrate was passed through a column packed with 12 mL of Ni-NTA Super Flow Gel (Qiagen) at a flow rate of about 5 mL / min.
  • the column was washed with buffer A (50 mM HEPES (pH 7.5) containing 0.3 M NaCl), further washed with buffer A containing 20 mM Imidazole, and then eluted with buffer A containing 100 mM Imidazole.
  • the eluate was concentrated with Vivapine 20 (Viva Science) having a molecular weight cut off of 30K.
  • the resulting concentrated solution was dialyzed using 358 mL of Sephadex G-25 (Amersham Biosciences) equilibrated with 50 mM HEPES (pH 7.5) containing 10 mM MgCl 2 , 2 mM Dithiothreitol, 10 mM Tripotassium Citrate, 0.3 M NaCl.
  • the dialyzed internal solution was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 30K, and then the concentrated solution was filtered with a 0.22 ⁇ m filter to obtain ACC1.
  • the obtained ACC1 was stored frozen at ⁇ 80 ° C.
  • test compound addition group 5 ⁇ l each of a test compound dissolved in dimethyl sulfoxide (DMSO) diluted with an enzyme reaction buffer was added to each well and incubated at 30 ° C. for 60 minutes.
  • DMSO dimethyl sulfoxide
  • a substrate solution 50 mM KHCO 3 , 200 ⁇ M ATP, 200 ⁇ M Acetyl-CoA
  • the reaction was stopped by adding 5 ⁇ l of malachite green solution to each reaction solution thus obtained and stirring.
  • the obtained reaction solution was allowed to stand at room temperature for 20 minutes, and then the absorbance (620 nm) was measured using wallac1420 (Perkin Elmer).
  • the ACC1 inhibition rate (%) and the inhibitory activity (IC 50 value) were determined.
  • Table 16 shows the ACC2 inhibitory activity and ACC1 inhibitory activity (IC 50 value) of the test compounds.
  • Test example 3 Male F344 / Jcl rats (CLEA Japan, Tokyo) that arrived at 5 weeks old were fed Western diet (D12079B, Research Diets) and acclimatized for more than 3 weeks, and then tested for malonyl-CoA content at 8-10 weeks of age. Used for. In the experiment for measuring the malonyl-CoA content, acclimation was administered 2-5 days before the test compound administration, and the groups were divided so that there was no difference between the administration groups based on the body weight of the previous week.
  • the test compound was prepared in advance as a 0.5% Methyl Cellulose (Wako) suspension at a dose of 5 mL / kg, and PM5: 00 based on the body weight (measured at AM8: 00-11: 00) on the day of test compound administration.
  • the thigh muscle was quickly removed, put into 80-150 mg strips, placed in an Eppendorf tube, and quickly frozen in liquid nitrogen to measure malonyl-CoA content.
  • the tissue was stored at ⁇ 80 ° C. until use.
  • MBP-DBAA di-n-butylammonium acetate aqueous solution
  • the total amount of the extract was centrifuged (13,000 rpm, 2 min), and the supernatant was added to a solid phase extraction cartridge (OASIS HLB 1 cc / 30 mg, WAT05882, Waters) for solid phase extraction.
  • the solution was reduced to 5%, and the solution was fed under the same conditions until the analysis end time (10 minutes).
  • the eluate having an analysis time of 2.0 to 6.0 minutes was introduced into MS / MS.
  • the analysis was performed at a column temperature of 40 ° C. and a sample injection volume of 10 ⁇ L.
  • the mass spectrometer used was API5000 (AB Sciex), turbo ion spray was used as the ionization mode, and ions were detected by selected reaction monitoring (SRM) in the negative ion mode. Ion spray was performed using zero air and the voltage was 4.5 kV. Nitrogen was used for collision-induced decomposition of ions.
  • a precursor ion and a fragment ion were set to malonyl CoA; m / z 852.0 ⁇ m / z 808.0 and [ 13 C 3 ] -malonyl CoA; m / z 855.0 ⁇ m / z 810.0 Da, respectively.
  • the internal area ([ 13 C 3 ] -malonyl-CoA) and the peak area ratio of malonyl-CoA were used.
  • All values are shown as mean ⁇ standard deviation, and Welch test was used for statistical analysis. The results are shown in Table 17.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • the compound of the present invention has an ACC (acetyl-CoA carboxylase) inhibitory action and prevents obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic complications, metabolic syndrome, sarcopenia, cancer, etc. Useful for treatment.
  • ACC acetyl-CoA carboxylase

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Abstract

Cette invention concerne un composé représenté par la formule (I) (dans la formule, chacune des valeurs numériques est telle que décrite dans la description) ou son sel.
PCT/JP2012/052899 2011-02-09 2012-02-08 Composé monocyclique Ceased WO2012108478A1 (fr)

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WO2013061962A1 (fr) 2011-10-24 2013-05-02 武田薬品工業株式会社 Composé bicyclique
WO2013092976A1 (fr) * 2011-12-23 2013-06-27 Boehringer Ingelheim International Gmbh Nouveaux dérivés de la pipéridine, leurs compositions pharmaceutiques et leurs utilisations
US8703758B2 (en) 2010-04-27 2014-04-22 Takeda Pharmaceutical Company Limited Bicyclic compound
US8729102B2 (en) 2010-11-30 2014-05-20 Takeda Pharmaceutical Company Limited Bicyclic compound
WO2015036892A1 (fr) 2013-09-12 2015-03-19 Pfizer Inc. Utilisation d'inhibiteurs de l'acétyl-coa carboxylase pour traiter l'acné vulgaire
WO2015056782A1 (fr) * 2013-10-17 2015-04-23 塩野義製薬株式会社 Nouveau dérivé d'alkylène
WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
JP2016037462A (ja) * 2014-08-07 2016-03-22 長谷川香料株式会社 ソラノンの製造方法およびその合成中間体
WO2016159049A1 (fr) * 2015-03-31 2016-10-06 武田薬品工業株式会社 Composé monocyclique

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WO2010003624A2 (fr) * 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010050445A1 (fr) * 2008-10-27 2010-05-06 武田薬品工業株式会社 Composé bicyclique
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JP2005194191A (ja) * 2001-12-28 2005-07-21 Ajinomoto Co Inc 抗肥満薬、脂肪肝治療薬
US20070167435A1 (en) * 2005-12-21 2007-07-19 Schering Corporation Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
WO2008079610A2 (fr) * 2006-12-21 2008-07-03 Abbott Laboratories Nouveaux inhibiteurs d'acétyl-coa-carboxylase (acc) et utilisation dans le traitement du diabète, de l'obésité et du syndrome métabolique
WO2010003624A2 (fr) * 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010050445A1 (fr) * 2008-10-27 2010-05-06 武田薬品工業株式会社 Composé bicyclique
WO2011067306A1 (fr) * 2009-12-03 2011-06-09 Novartis Ag Dérivés de cyclohexane comme inhibiteurs de l'acétyl-coa carboxylase (acc)

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Publication number Priority date Publication date Assignee Title
US8703758B2 (en) 2010-04-27 2014-04-22 Takeda Pharmaceutical Company Limited Bicyclic compound
US8729102B2 (en) 2010-11-30 2014-05-20 Takeda Pharmaceutical Company Limited Bicyclic compound
CN103998432A (zh) * 2011-10-24 2014-08-20 武田药品工业株式会社 双环化合物
WO2013061962A1 (fr) 2011-10-24 2013-05-02 武田薬品工業株式会社 Composé bicyclique
US9133129B2 (en) 2011-10-24 2015-09-15 Takeda Pharmaceutical Company Limited Bicyclic compound
WO2013092976A1 (fr) * 2011-12-23 2013-06-27 Boehringer Ingelheim International Gmbh Nouveaux dérivés de la pipéridine, leurs compositions pharmaceutiques et leurs utilisations
US8765959B2 (en) 2011-12-23 2014-07-01 Boehringer Ingelheim International Gmbh Piperidine derivatives
WO2015036892A1 (fr) 2013-09-12 2015-03-19 Pfizer Inc. Utilisation d'inhibiteurs de l'acétyl-coa carboxylase pour traiter l'acné vulgaire
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WO2015056782A1 (fr) * 2013-10-17 2015-04-23 塩野義製薬株式会社 Nouveau dérivé d'alkylène
WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
US10011609B2 (en) 2013-11-14 2018-07-03 Cadila Healthcare Limited Heterocyclic compounds
US10246470B2 (en) 2013-11-14 2019-04-02 Cadila Healthcare Limited Heterocyclic compounds
JP2016037462A (ja) * 2014-08-07 2016-03-22 長谷川香料株式会社 ソラノンの製造方法およびその合成中間体
WO2016159049A1 (fr) * 2015-03-31 2016-10-06 武田薬品工業株式会社 Composé monocyclique
US10252997B2 (en) 2015-03-31 2019-04-09 Takeda Pharmaceutical Company Limited Monocyclic compound

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